Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic since 2019, spreading rapidly and posing a significant threat to human health and life. With over 6 billion confirmed cases of the virus, the need for effective therapeutic drugs has become more urgent than ever before. RNA-dependent RNA polymerase (RdRp) is crucial in viral replication and transcription, catalysing viral RNA synthesis and serving as a promising therapeutic target for developing antiviral drugs. In this article, we explore the inhibition of RdRp as a potential treatment for viral diseases, analysing the structural information of RdRp in virus proliferation and summarizing the reported inhibitors’ pharmacophore features and structure–activity relationship profiles. We hope that the information provided by this review will aid in structure-based drug design and aid in the global fight against SARS-CoV-2 infection.

Graphical Abstract

Full text

Vol.:(0123456789)
Topics in Current Chemistry (2023) 381:22
https://doi.org/10.1007/s41061-023-00432-x
1 3
REVIEW
Structure‑Based Drug Design ofRdRp Inhibitors
againstSARS‑CoV‑2
KiranShehzadi1· AfsheenSaba1· MingjiaYu1· JianhuaLiang1,2
Received: 3 March 2023 / Accepted: 15 May 2023
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a
worldwide pandemic since 2019, spreading rapidly and posing a significant threat to
human health and life. With over 6 billion confirmed cases of the virus, the need for
effective therapeutic drugs has become more urgent than ever before. RNA-depend-
ent RNA polymerase (RdRp) is crucial in viral replication and transcription, catalys-
ing viral RNA synthesis and serving as a promising therapeutic target for develop-
ing antiviral drugs. In this article, we explore the inhibition of RdRp as a potential
treatment for viral diseases, analysing the structural information of RdRp in virus
proliferation and summarizing the reported inhibitors’ pharmacophore features and
structure–activity relationship profiles. We hope that the information provided by
this review will aid in structure-based drug design and aid in the global fight against
SARS-CoV-2 infection.
* Mingjia Yu
6120210204@bit.edu.cn
* Jianhua Liang
ljhbit@bit.edu.cn
1 Key Laboratory ofMedical Molecule Science andPharmaceutical Engineering, Ministry
ofIndustry andInformation Technology, School ofChemistry andChemical Engineering,
Beijing Institute ofTechnology, Beijing10081, China
2 Yangtze Delta Region Academy ofBeijing Institute ofTechnology, Jiaxing314019, China

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 2 of 53
Graphical Abstract
Highlights
• Exploring the potential clinical targets for attenuating coronavirus disease 2019
(COVID-19) by structure-based drug designing of RdRp inhibitors.
• RdRp catalytic site and druggable cavities predictions of SARS-CoV-2.
• Pharmacophoric features and structure–activity relationship analysis of different
repurposed therapeutic drugs for COVID-19 against RdRp of SARS-CoV-2.
• Current treatments are logistically challenging, increasing the need for safe and
effective oral therapies.
• Ongoing global efforts to prevent the spread of COVID-19 disease and the cur-
rent status of SARS-CoV-2.
Keywords RdRp· SARS-CoV-2· RdRp inhibitors· COVID-19· Therapeutic target
Abbreviations
EUA Emergency Use Authorization
FDA Food and Drug Administration
ACE2 Angiotensin-converting enzyme 2
NHC N4-hydroxycytidine
RSV Respiratory syncytial virus

1 3
Topics in Current Chemistry (2023) 381:22 Page 3 of 53 22
TNF-α Tumour necrosis factor α
ExoN Exoribonuclease
CTP Cytidine triphosphate
HBD Hydrogen-bond donors
HBA Hydrogen-bond acceptors
NiRAN Nidovirus RdRp-associated nucleotidyl transferase
1 Introduction
Coronaviruses (CoVs) are enveloped positive-sense RNA viruses that can cause res-
piratory infections ranging from mild to severe in humans and various animals. In
December 2019, a few cases of atypical pneumonia, later identified as coronavirus
disease 2019 (COVID-19), were first reported in Wuhan, caused by the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2). It is believed that the virus ini-
tially jumped from an infected animal to humans during the first week [1, 2]. Upon
further examination, the etiological agent was identified as an RNA virus with high
genetic homology to both the severe acute respiratory (SARS-CoV) and Middle East
respiratory syndrome (MERS-CoV) viruses [3, 4] (Fig.1).
The ongoing COVID-19 pandemic has issued a grave public health warning,
placing millions of people at risk in multiple countries [5]. As of February 19,
2023, the WHO has reported more than 756,581,850 confirmed cases and 6,844,267
deaths [6]. Despite this, there is currently no explicit medication for COVID-19, and
the selection of therapeutic drugs is primarily based on experiences treating SARS
Fig. 1 Confirmed cases of COVID-19 from January 2020 to February 2023 globally reported to WHO

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 4 of 53
or other influenza viruses. As such, there is an urgent need to develop safe and effec-
tive antiviral medications.
It is worth noting that current medications are explicitly designed for a virus’s
genome, and the physical structure of SARS-CoV-2 may change over time, poten-
tially limiting their invivo efficacy. However, some non-structural or accessory pro-
teins may serve as promising molecular targets for developing therapeutic drugs.
Rather than directly targeting viral replication, some therapeutic strategies can mod-
ify host immune responses to combat the virus or inhibit the inflammatory response
generated during the viral invasion, ultimately reducing the physiological response
to sickness. The replication of the SARS-CoV-2 genome and its gene transcription
is primarily controlled by the viral RdRp, which has been identified as a promising
target for designing novel antiviral strategies. Remdesivir, a nucleoside analog, has
shown antiviral activity in cell culture and animal models against the RdRp of multi-
ple coronaviruses [7, 8], showing antiviral activity in cell culture and animal models
[9]. It is covalently incorporated into the primer strand at the first replicated base
pair when a partial double-stranded RNA template is inserted into the central chan-
nel of the RdRp and can terminate its chain elongation [10]. Other potential medica-
tions with evident anti-SARS-CoV-2 activity in either cellular studies or clinical tri-
als include EIDD-2801, Sofosbuvir, Galidesivir, AT-527, IDX-184, Favipiravir, and
Ribavirin [11].
2 Structural Organization oftheSARS‑CoV‑2 Genome
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; betacoronavirus),
a member of the Coronaviridae family, has a genome of 30kb of single-stranded
positive-sense RNA [12, 13], and its pharmacological treatments target both the
genome and structure of the virus (Fig. 2). Upon invading the host cell, the viral
genome, comprising 14 open reading frames (ORFs), is liberated into the cytoplasm
for replication and transcription. ORFs 1a and 1b encode two replicase polyproteins,
PP1a and PP1ab, further subdivided into non-structural proteins [14].
The SARS-CoV-2 virus and its various strains, including the AY.4.2, Delta and
Omicron variants, have caused significant disruptions worldwide. Mutations on the
spike (S)-gene, which codes for the spike (S) protein, appear to increase transmis-
sibility by binding the S protein to the angiotensin-converting enzyme 2 (ACE2)
receptor [15–17]. Unfortunately, treatment options for SARS-CoV-2 are currently
limited and cannot keep up with the virus’s mutation rate. However, drug design
has identified seven primary targets during the search, including the membrane
protein, envelope protein, nucleocapsid protein, spike protein, protease, helicase,
hemagglutinin esterase and non-structural proteins 16NSPs [18–20]. Of these
targets, RdRp, also known as nsp12, is a critical protease in the virus’s life cycle
with conserved catalytic sites [21]. RdRp forms a replicase complex with other
non-structural proteins, such as nsp7 and nsp8, to facilitate viral RNA genome
replication and transcription [22]. Notably, the RdRp of SARS-CoV-2 shares 96%
sequence similarity with SARS-CoV, indicating the conserved nature of RdRp in
coronaviruses [23, 24].

1 3
Topics in Current Chemistry (2023) 381:22 Page 5 of 53 22
3 Currently Available Therapeutics andTreatment Options
forSARS‑CoV‑2
Current SARS-CoV-2 outbreaks have prompted investment in ongoing studies to
exploit various viral target proteins for therapy through five typical mechanisms
as follows, but strategies aimed at blocking the viral proteins, as in drug and
vaccine development, have primarily failed [25]. It has been shown that SARS-
CoV-2 undergoes rapid recombination to generate new strains of altered viru-
lence to escape the host antiviral defensive system, which lead to severe cytokine
storms.
1. Enhance a pharmacological immune response (enhance immune function).
2. Destroy the virus, and act on the pathogen itself.
3. Restrict virus entry in the cell (block host cell-binding proteins or virus-binding
proteins).
4. Impede virus replication.
5. Treat symptoms.
The first choice is considered the best for the patient since it is potentially long-
lasting and "friendly," and may also have preventive properties against subsequent
Fig. 2 The SARS-CoV-2 genome structural organization: it encodes two large ORF1a and ORF1b genes,
which encode non-structural proteins that form a replication–transcription complex. The non-structural
protein 3 (nsp3) encodes for papain-like protease (PLP), and non-structural protein 5 (nsp5) encodes for
3C-like (3CL) protease

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 6 of 53
viral attacks. Antiviral medications such as ritonavir, lopinavir, oseltamivir, riba-
virin and ganciclovir were tested in several investigations to decrease infection
rate and the risk of respiratory problems [26–28]. In general, every enzyme and
protein involved in the replication of the SARS-CoV-2 virus and the regulation
of host cellular machinery is a promising druggable target in the search for treat-
ment options [29]. In this perspective, we summarized the primary host-based
and virus-based targets from a structural point of view and information about
reported therapeutic drugs with efficacy against various SARS-CoV-2 target pro-
teins (Fig. 3). However, randomized controlled studies are needed to establish
the effectiveness of these antiviral medicines against SARS-CoV-2. Therefore, in
review, we had the more recent information available from the literatures on bioc-
idal agents, immunomodulatory drugs of SARS-CoV-2 and the clinical charac-
teristics of SARS-CoV-2. We concluded with a possible therapeutic plan against
SARS-CoV-2.
Fig. 3 Currently available drugs along with their targets in viral life cycle or virus–host interactions

1 3
Topics in Current Chemistry (2023) 381:22 Page 7 of 53 22
4 The Active Cavities ofRNA‑Dependent RNA Polymerase
inCoronavirus
RdRp is a crucial therapeutic target since it is essential for RNA genome replica-
tion, and the host does not have a functional protein that can perform the same
function. RdRp is considered a promising target in the development and discov-
ery of drugs because of its lack of an analogue in mammalian cells, and its block-
age is not anticipated to have target-related adverse effects. The 3-D crystal struc-
ture of RdRp of SARS-CoV-2 (PDB ID: 7BTF) was obtained from the protein
database with a resolution of 2.9Å [30, 31]. The catalytic sites of RdRp were
predicted using the CASTp server [32] containing four potential drug-binding
cavities (Fig.4). The CASTp web server provides a complete and detailed analy-
sis of surface pockets and protein cavities, essential in judging docking models’
reliability.
A deep and wide groove domain in the core structure of SARS-CoV-2 RdRp
depicts a cupped right hand interlinked by “thumb”, “finger” and “palm” subdo-
mains [33]. The thumb subdomain (residues 819–920) forms a tight circle with
the finger subdomain (residues 397–581 and 62–679) in the nsp12 [34, 35]. The
palm domain, the most conserved domain, contains five of the seven conventional
RdRp catalytic motifs (A–E), whereas the finger domains include the remaining
two (F and G). The RdRp core, which is structurally conserved, and associated
motifs are crucial for viral RdRp catalytic function and could therefore be tar-
geted for therapeutic intervention [36]. The nsp12 (RdRp) is a multi-subunit with
a molecular weight of 106kDa, much larger than other (+) RNA viruses. The
nsp12, nsp7 and nsp8 form a 160kDa replicase complex responsible for the rep-
lication and transcription of the viral RNA genome [37]. Since the RdRp enzyme
Fig. 4 Potential drug-binding cavities of SARS-CoV-2 RdRp are detected by the CASTp server

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 8 of 53
plays a role in replicating the new coronavirus by synthesizing RNA, RdRp has
become an attractive therapeutic target for drug research.
5 The Potential Antiviral Drugs Inhibit Viral Replication byTargeting
RdRp
This review provides an overview of the potential use of existing antiviral drugs as
enzyme inhibitors to repurpose them as effective candidates for inhibiting SARS-
CoV-2 polymerase. Notably, coronavirus RdRp screening methods are more
complex than those for other viral target proteins, such as proteases [62]. Despite
increasing interest in current knowledge, only a few studies have reported on RdRp
screening for coronaviruses. This study describes the docking analysis and crystal
structures of reported RdRp inhibitors binding with RdRp to elaborate on the struc-
ture–activity relationship of the existing drug. Several antiviral compounds have
been screened to determine how well-repurposed nucleotide analogues interact with
the SARS-CoV-2 RdRp active sites. Invitro research and in silico analysis indicated
that some broad-spectrum antiviral medications could potentially be therapeutic
platforms against SARS-CoV-2. Depending on their structure and binding affinity,
nucleotide analogues mimic the natural substrates of the SARS-CoV-2 RdRp and
cause either rapid or gradual chain termination [66, 67]. Moreover, several nucleo-
tide analogues are prodrugs that must undergo phosphorylation inside the cell to
have an antiviral effect. In various circumstances, numerous host enzymes carry out
intracellular phosphorylation, converting the prodrug into the bioactive triphosphate
forms of these drugs [68, 69].
5.1 Favipiravir
Favipiravir (1, Table1) is an antiviral agent serving as an inhibitor for RdRp in
intracellular phosphoribosylation active form, i.e., favipiravir ribofuranosyl-5′-
triphosphate (favipiravir-RTP) (Fig. 5). The 6-fluoro-3-hydroxypyrazine-2-carbox-
amide [favipiravir (FPV)] is a purine nucleotide analogue produced by Toyama
Chemicals in Japan to treat influenza and viral infections of the nose and throat [70].
FPV has been shown to have antiviral properties in vitro and in vivo against the
influenza viruses (A, B and C) and Lassa, Ebola and other viruses. Although FPV
has not yet been approved by the US Food and Drug Administration (FDA), it has
recently been examined and found to be a promising therapeutic approach for coro-
navirus disease 2019 (COVID-19) [40]. The investigation of FPV as a therapeutic
for COVID-19 revealed that, although it did not significantly decrease RNA pro-
duction invitro, it may still be effectively integrated into RNA products to reduce
the precision of RNA synthesis. Like other common nucleotide triphosphate (NTP)
substrates, FPV effectively enters RNA products. These findings imply that this drug
may have broad-spectrum antiviral efficiency by similar mechanisms against a panel
of several RNA viruses. In cell-based experiments, administration of FPV was dem-
onstrated to cause mutations in the progeny virion of SARS-CoV-2, indicating that

1 3
Topics in Current Chemistry (2023) 381:22 Page 9 of 53 22
Table 1 The inhibitors of RNA-dependent RNA polymerase reported
RdRp inhibitors Clinical phase Approved therapeutic applications Mechanism of action References
N
H
N
F
O
NH
2
O
Favipiravir, 1
Random SARS-CoV-2
trials and approved
in 2014 for clinical
use
Influenza viruses A, B and C;
Ebola; yellow fever; chikungu-
nya; and norovirus
Restricts the inclusion of nucleo-
tidesfor replication of viral genome
by binding to the viral RdRp’s
catalytic site
[38–41]
N
N
NO
NH
2
O
HO
HO
HO
Ribavirin, 2
Clinically accepted in
1985
Hepatitis C virus (HCV), viral
haemorrhagic fevers and respira-
tory syncytial virus (RSV)
Suppresses mRNA encapsulation
and inhibits viral RNA polymerase
replication
[42]
O
N
FOH
N
O
H
2
N
OH
ALS8112, 3
Cl
4'
2' 3'
5'
Phase I/II trial for
RSV infection
RSV A and B subtypes, and Para -
myxoviridae and Rhabdoviridae
families
Inhibits the activity of RdRp by
targeting the L protein of RSV
[43]

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 10 of 53
Table 1 (continued)
RdRp inhibitors Clinical phase Approved therapeutic applications Mechanism of action References
O
N
FO
N
H
2
N
O
ALS-8176,4
Cl
O
O
O
Discontinued – infec-
tion, RSV – 2019
phase II – infection,
RSV – 2014
RSV Suppresses the RNA polymerase
activity in non-human primates of
the RSV L–P protein complex by
RNA chain termination
[44, 45]
O
N
OH
N
O
H
2
N
OH
N
3
4'-Azido-2'-deoxy-2'-
C-methylcytidine,5
Biological testing HCV and HIV(human immunode-
ficiency virus)
Inhibits HCV NS5B RdRp [46]
O
N
HO OH
N
O
H
2
N
OH
NM 107, 6
Phase II clinical trial
of hepatitis C
Dengue virus, norovirus and HCV This metabolite is phosphorylated
into its 5-triphosphate molecule,
which inhibits viral RdRp NS5B
activity, and replication of the virus
is impeded
[47]

1 3
Topics in Current Chemistry (2023) 381:22 Page 11 of 53 22
Table 1 (continued)
RdRp inhibitors Clinical phase Approved therapeutic applications Mechanism of action References
O
N
HO O
N
O
H2N
OH
O
NH2
Valopicitabine, 7
3'
2'
4'
Phase II testing of
HCV
HCV, dengue-2 virus, yellow fever
virus and West Nile virus
Nucleotide/nucleoside derivative
inhibited the RNA strand elonga-
tion by blocking the HCV RdRp
enzymatic activity
[48, 49]
O
N
HO OH
N
O
H
N
HO
OH
NHC, EIDD-1931, 8
Biological testing
phase
SARS-CoV-2,Middle East res-
piratory syndrome coronavirus
(MERS-CoV), mouse hepatitis
virus and Venezuelan equine
encephalitis virus
Significantly changes the encapsida-
tion, multiplication and transla-
tion-dependent viral replication
mechanisms
[50, 51]

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 12 of 53
Table 1 (continued)
RdRp inhibitors Clinical phase Approved therapeutic applications Mechanism of action References
O
N
HO OH
HN
O
N
HO
O
O
Molnupiravi (EIDD-2801), 9
Phase II/III clinical
trial of COVID-19
Efficacy against various coronavi-
ruses and influenza viruses
Molnupiravir is immediately broken
down into EIDD-1931 and becomes
the 5′-triphosphate. EIDD-1931
is an RdRp inhibitor and, after
integrating into the developing
RNA chain, results in a devastating
replication error
[52–55]
H
N
HO OH
HO
H
N
N
N
NH
2
Galidesivir, 10
Phase I clinical trial of
COVID-19 in 2020;
phase I testing of
viral haemorrhagic
fever in 2019
Ebola, SARS-CoV-2, haemor-
rhagic fever virus, Marburg, yel-
low fever, Zika and Rift Valley
fever viruses
Phosphorylated by cellular kinases
to a triphosphate and targeting
virus RdRp and terminate viral
replication
[56]

1 3
Topics in Current Chemistry (2023) 381:22 Page 13 of 53 22
Table 1 (continued)
RdRp inhibitors Clinical phase Approved therapeutic applications Mechanism of action References
O
PN
NN
NH
2
N
OH
HO
O
HN
O
O O
Remdesivir,11
Approved by the FDA
for SARS-CoV-2 in
case of emergency
use in 2020
SARS-CoV-2, MERS-CoV, SARS-
CoV-1, Ebola and Marburg
viruses
Competes for integration by viral
RdRp with adenosine triphosphate
(ATP) and nucleotides
[57–59]

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 14 of 53
Table 1 (continued)
RdRp inhibitors Clinical phase Approved therapeutic applications Mechanism of action References
O
N
OH
F
O
P
O
HN
O
O
N
N
N
NH
NH
2
.0.5 H
2
SO
4
AT-527,12
Phase II trials of
COVID-19 and
hepatitis C
HCV and SARS-CoV-2 Inhibited replication of SARS-CoV-2
by targeting RdRp; efficacy is 90%
in HCoV-OC43, HCoV-229E and
Huh-7 cells
[60, 61]
O
N
OH
OH
O
P
O
O
P
N
N
NH
O
NH
2
OOH
OH
O
P
O
IDX-184, 13
OH
OH
Discontinued – hepati-
tis C in 2013
Phase II trial of hepati-
tis C in 2009
HCV, MERS, SARS and Zika
virus
Inhibits the viral replication process
by binding to the active site of
RdRp and contends with endog-
enous nucleotide guanosine triphos-
phate (GTP) for NS5B polymerase
active site
[62, 63]

1 3
Topics in Current Chemistry (2023) 381:22 Page 15 of 53 22
Table 1 (continued)
RdRp inhibitors Clinical phase Approved therapeutic applications Mechanism of action References
O
N
FOH
HN
O
O
O
4'
2' 3'
5'
PH
N
O
OO
O
Sofosbuvir (PSI-7977), 14
Nine phase II/III rand-
omized clinical trials
of COVID-19
Chronic HCV, HAV, ZIKV(Zika
virus) infection and yellow fever
Selectively inhibits viral replication
after attaching to viral RdRp
[64, 65]

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 16 of 53
this drug can evade the coronaviruses’ proofreading mechanism to exhibit antiviral
activity through many rounds of RNA synthesis [71].
The reported docking analysis of FPV demonstrated significant binding interac-
tions with crucial amino acid residues of the target receptors [72]. The literature
revealed that FPV prodrug showed less critical interaction with the predicted active
site of target receptor RdRp (PDB ID: 7BV2) of SARS-CoV-2 (−5.336kcal/mol)
than its active triphosphate metabolite (− 8.951 kcal/mol). Interestingly, docked
results showed that FPV prodrug does not form the salt bridge of Mg2+ with the
first ribofuranose-linked phosphate group. Reported structure–activity relation-
ship (SAR) analysis of FPV revealed that, for RdRp inhibition, it must involved salt
bridge formation of the first ribofuranose-linked phosphate group with the Mg2+ and
also show interaction with crucial amino acid residues HIS439, LYS545, ILE548,
SER549, ARG553, ARG555, VAL557, LYS621, CYS622, SER682, ASN691, and
ASP760. Furthermore, hydrogen bond formation with uracil (U20) in the is crucial
for inhibiting viral replication (Fig.6) [73, 74].
Naydenova et al. create a cryo-electron microscopy (EM) crystal structure of
antiviral drug FPV with SARS-CoV-2 RdRp (PDB ID: 7AAP at a resolution of
2.50Å). The active triphosphate metabolite of FPV-RTP was used by Naydenova
etal. to analyse the structure of RdRp of SARS-CoV-2 co-crystallized with FPV
using cryo-EM techniques [75]. The cryo-EM structure shows that FPV-RTP
terminates chain extension by pairing with the template strand to + 1 nucleotide
Fig. 5 Bioconversion of the FPV inactive form to active triphosphate (RTP) form

1 3
Topics in Current Chemistry (2023) 381:22 Page 17 of 53 22
through noncovalent contacts. FPV-RTP also interacts with ASN691, uracil
(U20), LYS545, cytosine (C10) and SER814 through conventional hydrogen
bonds (Fig.7).
FPV showed protective effects against various RNA viral infections in ani-
mal models, although it had a low invitro selectivity against SARS-CoV-2 [half
maximal effective concentration (EC50) 61.88µM], indicating that further invivo
research on this medication against SARS-CoV-2 may be beneficial. Clinical
trial data from phases I, II and III showed that FPV had good overall efficacy.
It causes chain termination and viral mutagenesis by inhibiting the error-prone
viral RdRp [76]. Most patients infected with SARS-CoV-2 (80–85%) have mild
to severe sickness and continue to disseminate the virus. FPV used to treat mild
to moderate cases can potentially lessen the impact of the continuing epidemic.
FPV’s most important side effect was teratogenicity, followed by abnormal liver
enzymes, mental symptoms, intestinal symptoms and elevation in serum uric acid
in a randomized test of FPV in 241 patients with SARS-CoV-2 [77].
Fig. 6 Favipiravir’s structure–activity relationship profile as a potent inhibitor of RdRp

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 18 of 53
5.2 Ribavirin
Ribavirin (2, Table1) is a guanosine (purine) analogue that can inhibit viral RNA
synthesis. It was first registered in the 1980s and clinically used with interferon
for hepatitis B and C. It is also used for viral diseases such as haemorrhagic fever
and respiratory syncytial viral pneumonia [78, 79]. The adenosine kinase cataly-
ses the phosphorylation of ribavirin to produce ribavirin monophosphate (RMP),
and then nucleoside mono- and di-phosphate kinases catalyse RMP into ribavirin
triphosphate (RTP) [80]. Unal etal. reported that the docking analysis of riba-
virin against RdRp (PDB ID: 6M71) formed four conventional hydrogen bonds
with TRP617, ASP761, SER814 and HIS810 with a binding energy of −6.2kcal/
mol (Fig.8) [81]. The docking analysis of RMP predicts that it forms a hydrogen
bond with crucial amino acid residues ASP544, ASN612, THR601 and ARG476
of RdRp of SARS-CoV-2. Unexpectedly, RMP does not bind the complementary
strand nucleotide as effectively and tends to act through a distinct mechanism
than other known medications [82, 83]. Elfiky investigated that ribavirin strongly
inhibits RdRp (PDB ID: 6NUR) activity with binding affinity −7.8kcal/mol by
interacting with TRP508, TYR510, LYS512, CYS513, ASP514, ASN582 and
ASP651 residues of the receptor [84]. Another study showed the binding analy-
sis of RTP with RdRp (PDB ID: 7BV2) of SARS-CoV-2. The analysts predict
Fig. 7 Crystal structure of RNA bound with RdRp in complex with FPV (PDB ID: 7AAP).The close-up
view of FPV-RTP covalently bound with the catalytic site of RdRp primer (using PyMol software) and
two-dimensional interaction analysis using BIOVIA Discovery Studio Visualizer v4.5

1 3
Topics in Current Chemistry (2023) 381:22 Page 19 of 53 22
that RTP is a more potent inhibitor than its prodrug, with a binding affinity of
−9.280kcal/mol (Fig.8) [73].
Triphosphate moiety is essential for its inhibitory activity, as it involves a
nucleotide analogue, RTP, which may hinder the activity of RdRp in three dif-
ferent ways: (1) by competing with the enzyme’s natural substrate without itself
serving as a substrate, (2) by acting as an alternative substrate for the polymerase
and resulting chain termination or (3) by acting as an alternative substrate for the
polymerase without doing chain termination. If RTP just interacted with RNA
polymerase as in the previous two situations, viral replication would be instantly
inhibited, leading to the breakup of the viral RNA chain [85]. Li etal. create
the cryo-EM structure of the drug with PDB ID: 7DFH at a resolution of 2.97Å
[30]. The cryo-EM structure shows that ribavirin-RTP terminates chain extension
by pairing with RNA template strand to +1 nucleotide through covalent inter-
action with guanine (G20) and interacting with two metal ions (Mg2+1005 and
Mg2+1004) through attractive charges (Fig.9).
Ribavirin was tested against SARS-CoV in 2003 and then used therapeuti-
cally in conjunction with interferon and corticosteroids; nevertheless, the results
of the antiviral effect were inadequate [86]. Commercially, ribavirin is marketed
Fig. 8 Structure–activity relationship studies of ribavirin as a RdRp inhibitor

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 20 of 53
as an oral solution, an oral dosage form capsule and an inhalation formulation.
Ribavirin has not been tested in the inhaled dosage when used in the treatment
against SARS-CoV, MERS-CoV and SARS-CoV-2. Moreover, the injectable dose
is not marketed in the USA [87, 88]. Additionally, in two minor investigations for
SARS, oral ribavirin was administered at a 4.0g dosage followed by 1.2g for 8h.
Information on the treatment of COVID-19 is currently restricted to studies that
employ a combined therapy that includes 400mg taken twice daily for 14days
[89]. The longer half-life of ribavirin is about 40days. Increasing doses might
make the better condition more quickly achievable. The most frequent side effects
of ribavirin treatment for SARS are hypocalcemia and haemolytic anaemia. The
probability of adverse side effects is more significant in patients with poor renal
function and older age [90, 91].
Furthermore, patients suffering from prior cardiovascular problems should also be
considered because haemoglobin lowering raises the risk of exacerbations [92, 93].
Since the metabolism and excretion of ribavirin do not depend on the CYPP450 metab-
olism pathway, it does not interact with other medications. However, owing to the
increasing side effects and toxicity caused by ribavirin, some other treatments should
be used with caution [94].
Fig. 9 Crystal structure of RNA bound with RdRp in complex with ribavirin (PDB ID: 7DFH). The
close-up view of ribavirin covalently bound with the catalytic site of RdRp primer (using PyMol soft-
ware) and its two-dimensional interaction analysis by using BIOVIA Discovery Studio Visualizer v4.5

1 3
Topics in Current Chemistry (2023) 381:22 Page 21 of 53 22
5.3 4′‑Cytosine Nucleoside Analogues
A series of 4′-cytosine nucleoside analogues investigated based on their pharmaco-
logical and pharmacokinetic characteristics by Janssen, including 4′-chloromethyl-2′-
deoxy-2′-fluorocytidine (ALS8112, 3, Table 1); 3′,5′-di-O-isobutyryl (ALS-8176, 4,
Table1); and 4′-azido-2′-deoxy-2′-C-methylcytidine (5, Table1), was shown to have
the most promising inhibiting activity against RSV polymerase and NS5B polymerase,
respectively [43–45].
ALS-8112 specifically inhibited rhabdoviruses and paramyxoviruses, and ALS-8176
suppressed RSV multiplication in non-human primates, while ALS-8112 also inhibited
all RSV strains invitro. The active 5′-triphosphate metabolite of ALS-8112 formed
inside the cell and inhibited the viral RNA polymerase. The literature showed that anti-
RSV of 4′-cytosine nucleoside analogues impede the replication of SARS-CoV-2 up
to 20 micromolar concentrations in Vero cells [95]. The docking analysis of 4′-cyto-
sine nucleoside analogues against RdRp (PDB ID: 7AAP) of SARS-CoV-2 showed
that ALS8112 has less inhibitory potential with a binding affinity of −6.11 kcal/
mol (Fig. 10) [96] than its active metabolite ALS8176. The in silico screening of
ALS8176 against RdRp (PDB ID: 6M71) of SARS-CoV-2 exhibits a binding affin-
ity of −6.9kcal/mol (Fig.10) [97]. Another study investigated the structure–activity
relationship of lumicitabine (ALS8176), an oral version of the parent drug ALS8112.
In ALS8176, the 3′ and 5′ ester groups are essential for inhibitory activity, forming
a hydrogen bond with ASP711 and exhibiting hydrophobic interaction with THR710.
The 4-chloromethyl moiety of ALS8176 is a crucial substituent for polymerase speci-
ficity and is efficiently recognized by RdRp resulting in chain termination. The docking
analysis showed that 4-chloromethyl moiety is involved in attractive charge interaction
with LYS47 of receptor protein. The literature study showed that the incorporation of
the ALS8176 into the extended RNA primer caused immediate chain termination due
to the inability to incorporate subsequent nucleotide into the growing chain [98].
ALS-8112 chose the RNA polymerase-encoding domain of the L gene of RSV for
mutations associated with resistance. In biochemical experiments, the recombinant
RSV polymerase complex detected the 5′-triphosphate metabolite with high specificity,
terminating the process of RNA production. While structurally comparable compounds
showed dual RSV/HCV suppression, 5′-triphosphate derivatives did not affect host
or viral polymerases, including those from unrelated viruses like hepatitis C. A com-
parative analysis of RdRp inhibitors by Dweipayan showed that the binding affinity of
4′-azido-2′-deoxy-2′-C-methylcytidine is −4.88kcal/mol (Fig.10) [96]. The substantial
decrease in binding affinity is due to substituting the azido group instead of halide. The
potent nucleoside inhibitor effectively inhibits the NS5B polymerase, i.e., 4′-azido-2′-
deoxy-2′-C-methylcytidine, which has a 1.2mM EC50 value and a high to moderate
invivo efficacy in rats [99].
5.4 2′‑C‑Methylcytidine (NM 107) andDerivative (Valopicitabine)
The 2′-C-methylcytidine (NM 107, 6, Table 1) is a potent inhibitor of the HCV
RNA-dependent RNA polymerase [100]. Several other RNA viruses have been

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 22 of 53
inhibited by it, including pestivirus bovine virus, HCV and flaviviruses, notably
West Nile virus, yellow fever virus and dengue-2 virus. The SAR studies show that
2′-C-methylcytidine effectively prevents hepatitis E virus (HEV) replication, making
it a promising option for anti-HEV medication development [101, 102]. The research
on pyrimidine nucleotide inhibitors as prospective antiviral medications showed that
certain nucleotide substituents at the nucleoside’s C2′ and C4′ positions demonstrate
blatant therapeutic potential [103, 104]. As virus RNA strands develop, the insertion
of 2′-C-modified monophosphates onto their 3′ terminus of the RNA strand encour-
ages the termination of RNA strands’ elongation due to steric restriction between the
synthetic 2′-C-group of unnatural and entering natural nucleotide inhibitor [105].
In 2020, several antiviral drugs and 2′-C-methylcytidine under clinical trials for
Fig. 10 SAR profile of 4′-cytosine nucleoside derivatives as anti-RdRp compounds

1 3
Topics in Current Chemistry (2023) 381:22 Page 23 of 53 22
other viral RdRp were computationally investigated against RdRp of SARS-CoV-2
by Elfiky. He used eight different conformations of RdRp (PDB: 7BTF) of SARS-
CoV-2 as targets for small antiviral drug molecules. The docking analysis showed
that 2′-C-methylcytidine (NM 107) is a potent inhibitor of RdRp of SARS-CoV-2
with a binding affinity of −7.31kcal/mol [106]. Moreover, the comparative dock-
ing analysis of RdRp inhibitors of SARS-CoV-2 showed that 2′-C-methylcytidine
phosphorylated to form 2′-C-methylcytidine triphosphate. The 2′-C-methylcytidine
triphosphate prevents the virus’s RNA chain elongation and inhibits the RdRp (PDB
ID: 7AAP) activity with a binding affinity of −7.19kcal/mol. Another study showed
that 2′-C-methylcytidine inhibits the activity of RdRp (PDB ID: 7BV2) by forming
a hydrogen bond with THR556, ASP760, ASP623 and TYR619 of the predicted tar-
get site of the receptor (Fig.11) [107].
Moreover, the structure–activity relationship analysis of valopicitabine, the
3′-O-
l
-valinyl ester of NM-107, inhibits the activity of RdRp (PDB ID: 7BV2) by
forming a hydrogen bond with ARG553, THR556, TYR619 and ASP623 residues.
It also shows hydrophobic interaction with LYS714 [107]. According to pharma-
cokinetic investigations, this novel therapeutic agent has 2′-C-methylcytidine and
low oral bioavailability. The 3′-O-
l
-valinyl ester derivative valopicitabine was cre-
ated to get over this restriction. Valopicitabine (7, Table1), the 3′-O-valinyl ester
of NM-107, was designed to generate a substance with higher absorption and
Fig. 11 SAR analysis of 2′-C-methylcytidine and its derivative as potent RdRp inhibitor

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 24 of 53
bioavailability than its parent molecule. Valopicitabine is an acid-stable prodrug
with outstanding physicochemical and toxicokinetic properties [108, 109]. Recently
a phase III clinical trial for the prodrug valopicitabine (NM283) has been started. It
has an EC50 value of 0.67µM, which might prevent the viral chain elongation and
inhibit the function of viral RdRp [110]. Valopicitabine is a more potent inhibitor of
RdRp with improved physicochemical and pharmacokinetic profile compared with
its parent compound, 2′-C-methylcytidine. The toxicokinetic analysis has shown that
valopicitabine (NM283) is an acid-stable prodrug of NM107 with excellent toxi-
cokinetic profiles [111].
5.5 NHC (EIDD‑1931) andMolnupiravir (EIDD‑2801)
The cytidine deaminase can convert cytidine analogues into cytidine and uridine
triphosphates. NHC, EIDD-1931 (8, Table 1) is a β-D-N4-hydroxycytidine orally
active ribonucleoside derivative with vast therapeutic potential against a variety
of RNA viruses, notably MERS-CoV (EC50 0.56 mM) and SARS-CoV-2 (IC50
0.30mM). NHC functions as a weak substitute substrate for cytidine triphosphate
(CTP) to significantly influence viral replication processes such as translation, repli-
cation and encapsulation that depend on these structures [112].
EIDD-1931 is a ribonucleoside analogue that induces RNA viral mutations and
has recently been proposed as a COVID-19 treatment option. As the little cyto-
toxic effect of this drug was seen, NHC displayed a positive effectiveness and
safety profile [113, 114]. NHC is a potential candidate in phase II clinical studies
to treat symptomatic adolescent outpatients and freshly hospitalized patients with
COVID-19. Additionally, preclinical research is being done to assess its potential
as a therapy for MERS-CoV infection. Furthermore, EIDD-2801 improved respira-
tory performance and decreased viral intensity in mice infected with MERS-CoV
and SARS-CoV [115]. Considering its physicochemical profile, oral or parenteral
option, and veridical, this active ingredient may treat COVID-19 [116, 117].
Molnupiravir, β-D-N4-deoxycytidine, rapidly cleaves to EIDD-1931 in plasma
and is then distributed to various organs, where it is converted to 5′-triphosphate
(Fig.12). The virally encoded RdRp uses EIDD-1931 5′-triphosphate as a substrate,
and when it integrates into the growing RNA chain, it results in a catastrophic rep-
lication error [118, 119]. In the plasma. the host’s esterase rapidly breaks down
molnupiravir into EIDD-19311, which is afterwards changed into molnupiravir
triphosphate by the host’s kinase once it enters the intracellular space. Molnupiravir
triphosphate serves as an active antiviral compound and strongly inhibits RdRp.
Fig. 12 Molnupiravir metabolic process

1 3
Topics in Current Chemistry (2023) 381:22 Page 25 of 53 22
The 5′-isopropyl ester of NHC, molnupiravir (9, Table1), has a wide range of anti-
influenza and anti-multiple coronavirus properties. The docking analysis showed
that EIDD-1931 formed hydrogen bonds with ASN781 and LYS545, whereas the
5′-isopropyl ester derivative (EIDD-2801) of EIDD-1931 showed strong RdRp
(PDB ID: 7BV2) inhibitory activity by forming an H-bond with LYS545, SER759
and uracil (U10) with the binding energy of −6.49kcal/mol [115, 120]. The struc-
ture–activity relationship of molnupiravir triphosphate exhibits strong interaction
with RdRp (PDB ID: 7BV2) of SARS-CoV-2 by forming conventional hydrogen
bonds with ARG555, U10 and U20. It shows a binding affinity of −8.39kcal/mol by
forming an attractive charge interaction with ARG555, unfavourable attraction with
Mg2+1004, hydrophobic interaction with Mg2+1005 and pi–pi stacked interaction
with uracil (U20). Moreover, molnupiravir triphosphate also interacts with RdRp
of the Delta AY.4 subvariant of SARS-CoV-2 through various types of interaction
with crucial amino acid residues (CYS622, TYR622, LYS62, TRP617, ASP761 and
U20) with a binding energy of −10.28kcal/mol [121] (Fig.13).
Fig. 13 Structure–activity relationship of NHC derivatives as anti-RdRp agents

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 26 of 53
Molnupiravir was investigated for mutagenicity in two rodent models invivo.
Based on available genotoxicity evidence and a 72-h treatment period, the FDA sug-
gested that molnupiravir had a low risk of cytotoxicity. Furthermore, treatment with
molnupiravir entirely prevented virus transmission to untreated rodents, indicat-
ing that early treatment molnupiravir may be able to stop secondary SARS-CoV-2
spread [122, 123].
5.6 Galidesivir
Galidesivir (10, Table 1) is a wide-ranging antiviral drug that has the potential
to cure COVID-19 and is well tolerated and effective in phase I investigations in
healthy volunteers. Galidesivir is an adenosine nucleoside precursor that prevents
viral RNA polymerase. Galidesivir phosphorylated into a triphosphate can resemble
the intracellular kinases ATP to treat HCV [124, 125]. The drug’s monophosphate
nucleotide is incorporated by viral RNA polymerases into the developing RNA
sequence, leading to faster chain termination and inhibiting the function of viral
RdRp. It is undergoing a phase II human trial for treating coronavirus in Brazil and
other countries [126, 127].
Galidesivir has shown broad-spectrum action invitro with EC50 ranging from 3
to 68μM against approximately 20 RNA viruses in nine distinct categories, includ-
ing flaviviruses, paramyxoviruses, bunyaviruses, arenaviruses and coronaviruses
[15, 128]. The docking studies suggest that, compared with ATP (adenosine triphos-
phate), the active metabolite galidesivir triphosphate demonstrated a greater affinity
for SARS-CoV-2 RdRp. The metal ions in the nsp12 structure also consist of two
pieces of Zn2+ and Mg2+. ATP forms a salt bridge with Mg2+ to bind with it and
activate RNA polymerase [129]. The prodrug galidesivir, according to molecular
docking results, creates a salt bridge with Mg2+. It has been found that the inter-
action of Mg2+ with RdRp inhibitors is essential to connect with the RNA strand.
The predicted binding energy for galidesivir is −6.187kcal/mol, while galidesivir
triphosphate showed a binding affinity of −8.994kcal/mol. Another study showed
the inhibitory potential of galidesivir against SARS-CoV-2 RdRp (PDB ID: 6M71)
with interaction affinity of −6.81kcal/mol [130] by forming hydrogen bonds with
ASP36, ASP221 and THR206, and various other interactions with crucial amino
acids residue of target binding sites (Fig.14). Moreover, the structure–activity anal-
ysis showed that galidesivir triphosphate exhibits more inhibitor activity against
RdRp (PDB ID: 7BV2) by forming an attractive charge interaction with Mg2+1005,
U20 and ARG553. It also forms a hydrogen bond with ARG555 (Fig.14) [73]. More
clinical and invitro research on galidesivir is needed [131].
5.7 Remdesivir
Remdesivir (11, Table1) is a promising small-molecule antiviral medication that
has proved effective for RNA viruses from various groups, such as Coronaviridae
(MERS-CoV, SARS-CoV and others). Remdesivir, a wide-ranging antiviral drug
initially developed to combat Ebola, was produced by Gilead Sciences. It can

1 3
Topics in Current Chemistry (2023) 381:22 Page 27 of 53 22
suppress viral replication by inhibiting the virus’s ability to proliferate by stop-
ping RNA transcription prematurely [132]. However, clinical studies of remdesi-
vir showed that it could significantly reduce SARS-CoV-2 infection in Vero cells
during an invitro trial [133]. Early injection of remdesivir reduced the pulmonary
infiltrates in a rhesus macaque model of COVID-19. The replication of SARS-
CoV-2 in human nasal and bronchial airway epithelial cells was also reported to
be significantly inhibited by remdesivir [134]. These results encouraged its usage
in SARS-CoV-2 infection in the absence of other therapeutic therapies [135].
Remdesivir is an adenosine analogue prodrug that effectively inhibits viral RNA
polymerases when intracellularly metabolized to an ATP analogue [136]. We can
see from the drug’s clinical trials that the drug’s effect on the target RdRp is rela-
tively stable [137].
The structure–activity analysis showed that remdesivir is a prodrug trans-
formed inside cells into triphosphate (RTP, active form) (Fig.15). Gilead Sci-
ences created monophosphorylated remdesivir to have greater cellular absorption
invivo. Exoribonuclease (ExoN) proofreading efficiency is interfered with, and
RdRp polymerization activity is inhibited by the GS-5734 1′-CN group, which is
crucial in the termination of RNA replication [138].
Fig. 14 SAR studies of galidesivir and galidesivir triphosphate as RdRp inhibitor

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 28 of 53
The docking analysis revealed that nucleotide analogues block the RdRp activ-
ity in viruses by working with the chain termination mechanism. Remdesivir forms
a hydrogen bond with ASP761 residue of RdRp (PDB ID: 7BTF) via its −NH2
group on the triazine ring, resulting in a binding affinity of −7.9kcal/mol. Moreo-
ver, through polar interactions, remdesivir interacts with receptor residues TYR619,
LYS621, CYS622, ARG624 and ARG553 [139].
Since viral proteases are essential for viral replication, many research groups con-
centrate on developing inhibitors of these enzymes. The FDA approved remdesivir,
an RdRp inhibitor, as the first and sole medication to treat COVID-19 in 2020. The
SARS-CoV-2 RdRp complex with the antiviral medication remdesivir has a cryo-
EM crystal structure (PDB ID: 7BV2). The co-crystallized structures of remdesivir
help us understand the viral RNA replication mechanism [140].
Moreover, the active metabolite (RdRp-RTP) was used by Xu etal. to create the
cryo-EM structure of the drug with PDB ID: 7BV2 at a resolution of 2.5Å. Accord-
ing to the crystal structure, Remdesivir monophosphate (RMP) attaches at the centre
of the active site, and pyrophosphate is at the access point of the nucleotide entry
channel to the enzyme active site. It impedes the entrance of nucleotide triphosphate
to the active site. RMP also interacts with the LYS545 and ARG555 residues in the
binding site. ASP623, SER682 and ASN691 are three residues with strong hydrogen
bonds in the active site. ASN691 also interacts with a 2′-OH group of the sugar moi-
ety [141]. A noteworthy feature is that the implicit and allosteric binding sites offer
a flexible design framework to develop high-potency antagonists of RdRp of SARS-
CoV-2 with kinetic selectivity [10] (Fig.16).
The findings of the ongoing clinical studies in the USA and China will be essen-
tial to determine whether remdesivir is a feasible COVID-19 therapeutic option. In
Fig. 15 Bioconversion of remdesivir (inactive form) to active triphosphate (RTP) form

1 3
Topics in Current Chemistry (2023) 381:22 Page 29 of 53 22
addition, the FDA in the USA has approved one clinical test. On 19 January 2020,
a 35-year-old Washington resident received remdesivir and did not have to worry
about COVID-19. However, further investigation is required into the drug’s thera-
peutic potential in infected patients. If the trial treatment works, it will be vital to
ensure that the medication is commercially available and can meet the challenges of
the current epidemic and future outbreaks [142, 143].
We discovered that the medicine could only significantly reduce hospital stay
length while not influencing fatality rates. The drug is still being tested, and research-
ers are using the test results to study mortality reduction. Second, remdesivir therapy
Fig. 16 Cryo-EM co-crystal structure of RNA bound with RdRp in complex with remdesivir (PDB
ID: 7BV2). The close-up view of RMP covalently bound with the catalytic site of RdRp primer (using
PyMol software) and two-dimensional interaction analysis using BIOVIA Discovery Studio Visualizer
v4.5

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 30 of 53
was found to cause 66% of adverse responses in clinical trials [144]. As a result,
we may conclude that, while this medicine is a novel concept with a well-chosen
research direction, it still has several flaws that need to be addressed [145]. Remde-
sivir inhibits the function of the virus RdRp and prevents the virus ExoN from per-
forming proofreading, inhibiting replication of the virus [146]. Even in non-human
primates with diverse viral diseases, such as the rodent SARS-CoV model and the
rhesus monkey Ebola virus model, the in-vivo and in-vitro experiments have pro-
duced positive results by decreasing viral levels [147, 148].
Initial studies from invitro test investigations suggested remdesivir’s therapeutic
potential for treating human infections carried by novel emerging SARS-CoV-2, for
which multiple research organizations launched numerous scientific trials [149].
These investigations have provided a new option for study into designing and
altering remdesivir to efficiently generate a large variety of therapeutically active
molecules to combat infectious diseases. Nucleotides are biologically active com-
pounds, essential in almost every biochemical function, such as intestinal develop-
ment, cellular immune system functioning and nutritional digestion. They interact
with RNA through base chemisorption, stacking, hydrogen bonds, van der Waal
interactions and binding to the phosphate backbone of RNA [150]. The choice of
artificial synthetic nucleotide compounds is regarded as novel chemicals concerning
antiviral activities. The peptide nucleic acid (PNA) lead molecule has strong spe-
cific sequence identification ability and hybridization stability and is not degraded
by protease and nuclease [151].
In recent research, Bichismita Sahu and coworkers developed scaffolds formed
from PNA and systematically performed in-silico analysis [152]. The designed com-
pounds have good RdRp-binding affinity. They examined the impact of oligonucleo-
tides on the binding effect of the derivatives using different PNA backbones, includ-
ing 2-pyrrolidinyl amide, 2-aminoethyl prolyl and γ-PNA. The noticeable reduction
of binding affinity caused by unaltered PNA’s backbone compared with the cyclic
substituent can be mitigated by adding steric hindrance. As a result, investigators
used the backbone of γ-PNA instead of the original aeg-PNA. Generally, these alter-
ations give PNA oligomers steric strain, which causes the structure to pre-organize.
The research data showed one of the 2-pyrrolidinyl amide and γ-PNA derivatives
(Compounds A and B, as shown in Fig.17) demonstrated better binding capacity
than remdesivir. The PNA scaffold with a 2-pyrrolidinyl amide backbone with cyclic
moiety showed inhibitory activity (−7.9kcal/mol) against RdRp (PDB ID: 7BTF)
by forming a hydrogen bond with TYR38 and ASP40 and also showed strong ionic
interaction with ASP221 (Fig.17A). However, the inhibitory activity of the PNA
scaffold with an open chain backbone is −7.8kcal/mol (Fig.17B) [152].
5.8 AT‑527
AT-527 (12, Table 1) is a guanosine nucleoside dual prodrug orally administered
to patients. It has shown potent efficacy invitro against clinical strains of HCV and
efficacy invivo with the 1-week monotherapy treatment of patients infected with
HCV by explicitly inhibiting the viral RdRp [60, 153]. Moreover, AT-527 was

1 3
Topics in Current Chemistry (2023) 381:22 Page 31 of 53 22
Fig. 17 Chemical structures of 2-pyrrolidinyl amide (A) and γ-PNA derivatives (B)
Fig. 18 Chemical structures of AT-527 and its active derivatives

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 32 of 53
recently reported to be effective and well tolerated at regular dosages of 550mg for
3months and showed a high rate of effectiveness in phase II clinical investigations
with HCV-infected patients [154]. The free basic form of AT-527, AT-511 (Fig.18),
was investigated invitro against SARS-CoV-2, and the results of this investigation
demonstrate its solid antiviral efficacy. Following oral administration, the bioac-
tive metabolite’s expected concentration in lung tissue increases the prospect that
AT-527 could be a successful COVID-19 therapeutic option.
The host cell must first undergo metabolism to produce a biologically active
derivative AT-9010 (Fig.18) of AT-527. More than 40 HCV-infected individuals
have received oral treatment with AT-527 in combination with daclatasvir, proving
human safety and acceptability [155, 156]. The outstanding pharmacokinetics in
combination with a dosage of 550mg twice a day should result in lung exposures
to the active metabolite that are notably higher than the medication’s invitro EC90
against SARS-CoV-2 multiplication and could, therefore, result in successful anti-
viral therapy. A phase II clinical investigation is now being conducted to investigate
the efficacy of AT-527 for SARS-CoV-2-infected patients [157].
The cellular enzymes metabolize AT-527, a prodrug of a guanosine nucleotide
analogue, into the active triphosphate form (AT-9010) by masking both the base and
phosphate group. Further, it inhibits the replication of SARS-CoV-2 by targeting the
RdRp and the NiRAN (Nidovirus RdRp-associated nucleotidyltransferase) [158].
The docking analysis of AT-527 against RdRp (PDB ID: 7BV2) shows that ribose
moiety forms hydrogen bonds with SER814 residue and that the 5′-phosphate inter-
acted with CYS813. The 2′-fluoro group of the ribose ring shows interaction with
THR206 (see Fig.19) [159].
Shannon and co-workers proposed the dual mechanism of action of AT-527 and
predicted the cryo-electron microscopic crystal structure of SARS-CoV-2 RdRp in
complex with the active form of AT-527 (PDB ID: 7ED5) with the resolution of
2.98Å [60, 119, 160]. The crystal structure showed that the active form AT-9010
had been incorporated into the RdRp active site at the 3′ end of the RNA product
strand. To facilitate the incorporation of AT-9010 into the RNA product strand, the
visible 5′ end of the RNA templates comprises four consecutive cytidine bases. At
Fig. 19 SAR profile of AT-527 against SARS-CoV-RdRp

1 3
Topics in Current Chemistry (2023) 381:22 Page 33 of 53 22
the +1 position of the RNA product, AT-9010 is incorporated and paired with cyto-
sine (C27) on the template strand (Fig.20). The RdRp–RNA complex appears to be
in a post-translocation state, with the second AT-9010 occupying the −1 site and
ready to incorporate, preventing other NTPs from being entered. The C27 of the
template RNA strand is canonically base-paired with the guanine nucleobase of the
incorporated AT-9010. Second, the AT-9010 ribose’s hydrophobic 2′-methyl group
increases the inhibitory action by forming a hydrophobic barrier that hinders the
incoming NTP’s ribose from being positioned correctly. As a result, the addition
of AT-9010 stops the extension of the RNA strand, and the subsequent disruption
of the complex’s catalytic site by AT-9010 renders it resistant to ExoN removal.
AT-9010 functions as a chain terminator since it precludes further elongation of the
product strand. AT-9010 also interacts with crucial amino acid residues of RdRp
(LYS545, SER682, C26, ASN691 and CYS622) through conventional hydrogen
bonds (Fig.20) [161].
5.9 2‑Methylguanosine Glucose‑1‑Phosphate (IDX‑184)
A prodrug of 2-methylguanosine glucose-1-phosphate named IDX-184 (13, Table1)
targets the viral protein. The native nucleotide guanosine-5′-triphosphate (GTP)
competes with it for the virus polymerase catalytic site, preventing polymerization
[70, 162].
Fig. 20 Co-crystal structure of RNA bound with RdRp in complex with AT-527 (PDB ID: 7ED5). The
close-up view of AT-527 at the catalytic site of RdRp (using PyMol software) and two-dimensional inter-
action analysis using BIOVIA Discovery Studio Visualizer v4.5

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 34 of 53
The 2-C-methylguanosine triphosphate is the active form of this drug. It
inhibits HCV invitro with potency and selectivity. Additionally, it is very well
tolerated due to the active structure formed inside the hepatocytes. The toxic-
ity of IDX-184 was decreased due to the active drug’s lower systemic concen-
tration. While in clinical studies to treat HCV, MERS, SARS and Zika virus
RdRps, IDX-184 performed better than other medications [163–165]. Addition-
ally, four novel IDX-184 derivatives (2-hydroxyphenyl-oxidanyl, 13a), (3,5-dihy-
droxy phenyl-oxidanyl, 13b), (3-hydroxyphenyl-oxidanyl, compound 13c) and
(3-sulfanylphenyl-oxidanyl, 13d, Fig. 21) exhibit promising results in attaching
to the SARS-CoV-2 RdRp compared with parent IDX-184 [166]. Currently, drugs
that specifically bind and inhibit SARS-CoV-2 proteins are urgently needed.
The treatment of COVID-19 may be achieved efficiently by the treatment with
novel derivatives 13b and 13c of IDX-184 with the improved binding affinity to
the SARS-CoV-2 RdRp. Therefore, following validation of the binding assays,
invitro investigations and invivo studies, these two derivatives of IDX-184 may
be employed to target SARS-CoV-2 RdRp successfully [167, 168].
Docking studies demonstrated the in-depth binding of IDX-184 to the SARS-
CoV-2 RdRp (PDB ID: 6NUR). Researchers proposed that continued refinement
of this chemical would lead to a more potent molecule useful against SARS-
CoV-2 [169]. A guanosine derivative IDX-184 (−9.0 kcal/mol) competes with
GTP (−8.7kcal/mol) for binding. IDX-184 binding is a bit better than GTP. More
investigation of the complexes is necessary to fully understand how the dock-
ing complexes bind to the SARS-CoV-2 RdRp. The computational analysis of
IDX-184 showed that 10 H-bonds were formed with receptor’s residues ARG444,
LYS512 (2), ASP651, ASP652, ALA653 (3), TRP691 and GLU702. On the
other hand, just one salt bridge was created with ASP514, while two metal con-
tacts were created between IDX-184 and the RdRp’s active site residue ASP652
(Fig.22) [84].
Fig. 21 Chemical structure of IDX-184 and its derivatives

1 3
Topics in Current Chemistry (2023) 381:22 Page 35 of 53 22
5.10 2′‑Deoxy‑2′‑Fluoro‑β‑C‑Methyluridine‑5′‑Monophosphate
The research shows that uracil analogue RdRp inhibitors are the best antiviral drugs
with direct action [170]. The uracil derivative PSI-7672 (Fig.23) can significantly
Fig. 22 Chemical structure of IDX-184 with SAR analysis as RdRp inhibitor
Fig. 23 Chemical structures of uracil derivative 2′-deoxy-2′-fluoro-β-C-methyluridine-5′-monophosphate

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 36 of 53
inhibit HCV replication. The −CH3 and −F moiety at the C-2′ position maintain the
drug’s potency and safety [171]. The negatively charged nature of substances con-
taining phosphoric acid groups prevents the body from readily absorbing these sub-
stances [172]. The first prodrug, PSI-7672, was created when the prodrug concept
was eventually adopted. The structure–activity relationship analysis showed that the
D-alanine derivative of 2′-deoxy-2′-a-fluoro-β-C-methyluridine-5′-monophosphate
is inactive, and only the natural
l
-amino acid can be active. The amino acid’s iso-
meric form is essential. At the R1 position of 2′-deoxy-2′-fluoro-β-C-methyluridine-
5′-monophosphate (Fig.23), a –CH3 and CH3–CH2-group can be substituted, which
increases the drug’s efficacy. However, replacing a larger alkyl group at the R1 posi-
tion results in a noticeable loss of molecule activity. The methyl group has the high-
est potency compared with other alkyl groups. The substitution at the R2 position
offers the necessary micromolar inhibitory activity. The inhibitory potential of the
drug molecule (2′-deoxy-2′-fluoro-β-C-methyluridine-5′-monophosphate) increases
in the short alkyl and branched alkyl groups if the amino acid is alanine and the R3
position is phenyl substituted. However, 2-butyl, n-butyl and n-pentyl esters were
cytotoxic.
Halogenated alkyl functional group and phenyl moiety at the R2 position does
not sufficiently increase the potency of the drug molecule. According to the phos-
phoramidate ester group analysis at the R3 position, a phenyl-substituted deriva-
tive showed good potency and was not harmful. Finally, it was found that PSI-7851
(Fig.23) has a favourable pharmacokinetic profile and is an excellent direct-acting
antiviral (DAA) for suppressing HCV. PSI-7851 is a combination of two racemic,
S-isomer PSI-7976 and R-isomer PSI-7977 (Fig.23) [173]. Sofosbuvir (PSI-7977)
(14, Table 1) has been considered a possible helpful medication for preventing
SARS-CoV-2 infection [174]. For treating COVID-19 patients, the administration
of PSI-7977 and routine medical care led to higher 2-week recovery efficiency and
decreased hospital stays. Moreover, Pinar Mesci etal. revealed that PSI-7977 might
treat cognitive problems caused by SARS-CoV-2 [175–177]. Sofosbuvir (PSI-7977)
treated HCV safely and effectively without interferon. This drug was also effective
against the hepatitis A virus, zika virus (ZIKV) infection and yellow fever. Sofosbu-
vir drug’s high invitro activity (14,110nM) and lack of apparent toxicity encourage
future invivo research. Because the RdRp replication process of HCV and SARS-
CoV-2 are similar, it was hypothesized that the replication of SARS-CoV-2 was
probably suppressed by PSI-7977 (sofosbuvir) [178]. In silico, sofosbuvir can create
two hydrophobic interactions with TYR510 and ASP651 and seven hydrogen bonds
with TRP508 (3), LYS512 (2), ALA653 and TRP691 of the SARS-CoV-2 RdRp
(PDB ID: 6NUR) with a binding energy of −7.5kcal/mol [179] (Fig.24).
Furthermore, Chien and co-workers investigate that SARS-CoV-2 RdRp is irre-
versibly blocked by sofosbuvir triphosphate, preventing polymerase-mediated RNA
extension. Sofosbuvir activity was not verified in a human cell-line model, despite
modelling and docking studies showing a potential role for the drug in inhibiting
SARS-CoV-2 RdRp activity [180]. However, nine randomized clinical studies were
undertaken on 66 persons with mild to severe COVID-19 to examine the effective-
ness of sofosbuvir in combination with other medications [181]. Clinical recov-
ery within 14days of treatment was the main consequence. The data from cellular

1 3
Topics in Current Chemistry (2023) 381:22 Page 37 of 53 22
models and invivo research will help elucidate this drug’s potential against SARS-
CoV-2, given its excellent safety profile and oral accessibility [182].
6 Pharmacophore Modelling ofRdRp Inhibitors
A pattern of functional groups determines the bioactivity of a molecule called a
pharmacophore. By defining the molecular functional characteristics required for
a molecule to bind to a specific receptor and then directing the virtual screening
of vast datasets of compounds for selecting the most suitable candidates, pharma-
cophore approaches represent one of the most intriguing tools ever created [183].
Pharmacophoric modelling is based on the idea that identical chemical function-
alities and a common spatial arrangement cause biological activity on the same
target. The pharmacophoric model depicts the chemical properties of a molecule
that can interact with its ligand as geometric elements such as spheres, planes and
vectors. Hydrophobic regions (H), hydrogen-bond acceptors (HBAs), hydrogen-
bond donors (HBDs), negatively and positively ionizable groups, aromatic groups
and metal coordinating sites are the most significant pharmacophoric feature types
[184]. To reveal the shape and size of the binding pocket, further size limitations in
the form of exclusion volumes in forbidden areas can be included [185, 186]. The
RdRp–Remdesivir complex model’s pharmacophore structure was created in recent
research [187]. Below are the pharmacophore properties and their x, y and z coordi-
nates and radius in Table2.
These pharmacophore properties, including one hydrogen-bond donor, six hydro-
gen-bond acceptors and two aromatic rings, are present in the remdesivir when cou-
pled with SARS-CoV-2 RdRp. Remdesivir interacts with the active site of the RdRp
receptor enzyme by hydrogen with GLN773 (3.33 Å) and by cation-pi bonding with
LYS47 (3.40Å) [188, 189]. The pharmacophoric map of RdRp inhibitors revealed
that hydrophobic groups, which can take the form of aromatic rings or other struc-
tures, are crucial to the compounds’ ability to bind to the active site of the receptor
Fig. 24 Structure–activity relationship of 2′-deoxy-2′-fluoro-β-C-methyluridine-5′-monophosphate

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 38 of 53
Table 2 In vitro and invivo studies of remdesivir as an anti-RdRp agent
+++: Highest inhibitory effect
Drug In vitro studies In vivo studies
MERS-CoV SARS-CoV SARS-CoV-2 EC50 (μM) SARS-CoV-2 MERS-CoV SARS-CoV SARS-CoV-2
Remdesivir/GS-5734 +++ +++ +++ 1.76 +++ +++ +++

1 3
Topics in Current Chemistry (2023) 381:22 Page 39 of 53 22
protein [190]. Furthermore, the presence of HBA and HBD groups improves the
interaction between inhibitors and the receptor’s active site. Unexpectedly, HBA/
HBD groups, like RdRp inhibitors, can enhance their interactions and should be
considered vital components in the enzyme inhibition process [10, 191] (Table3).
7 The Current Status ofSARS‑CoV‑2
The mutation rate of SARS-CoV-2 is exceptionally high since it is a positive-sense
single-stranded RNA-encapsulated virus. There are almost 100 mutant strains in
existence right now. However, the spike protein mutation accounts for many of these
mutant strains [192]. Furthermore, mutations do not happen linearly; many muta-
tions frequently occur simultaneously [193]. It will present a more significant chal-
lenge to the vaccine at this time or will evade the vaccine’s immunological protec-
tion. The Alpha, Delta and newly discovered Omicron viruses are among the most
well known [194]. Although vaccine research and development has always been a
priority for various countries, SARS-CoV-2 is easy to transcribe during replication.
It frequently results in some surface proteins or vaccines targeting regions that seem
changeable, and they cannot keep up with the virus mutation rate. Therefore, SARS-
CoV-2 cannot be regulated effectively or consistently.
Unfortunately, few anti-virus vaccinations or medicines have been licensed to
treat illnesses caused by SARS-CoV-2. Clinical management includes infection
control, prevention and supportive care, including mechanical ventilation and sup-
plemental oxygen when required. Although many nations are working on a SARS-
CoV-2 vaccine, it is almost certain that none of the vaccines will be prepared by the
end of the year. Currently, four types of vaccines are undergoing clinical trials: pro-
tein subunit, whole virus, nucleic acid (RNA and DNA) and viral vector [195]. Each
of these vaccinations protects humans by inducing immunity [29].
Furthermore, certain vaccinations are dangerous and cannot be used. Thus, more
dangers during testing make vaccine development a complicated path. Vaccine
research is essential from this point of view, but finding one or two relatively stable
targets to produce a drug that can work for a long time without fear of SARS-CoV-2
mutation is even more critical in the long run [196, 197].
Table 3 Pharmacophoric features, radius, and x-, y- and z-coordinates of the RdRp–remdesivir complex
[189]
Pharmacophore X-coordinate Y-coordinate Z-coordinate Radius (Å)
Aromatic 89.8 93.7 106.3 1.1
Aromatic 90.83 92.17 105.29 1.1
HBD 89.65 92.18 108.62 0.5
HBA1 89.86 94.51 105.12 0.5
HBA2 89.2 94.17 107.45 0.5
HBA3 92.24 95.34 102.13 0.5
HBA4 92.6 88.02 103.36 0.5

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 40 of 53
As a result, there has been increased demand to develop another medicine that
can effectively combat the infection. The focus of this effort has primarily been on
repurposing existing medications. According to WHO officials, many drugs have
successfully treated COVID-19.
8 Discussion
Initially established as a respiratory tract pathogen, subsequent studies have dem-
onstrated that this viral infection can impact other organs and systems. The RdRp
protein, crucial for RNA viruses, has been identified as a promising target for cre-
ating antiviral treatments. Repurposing existing RdRp inhibitors for SARS-CoV-2
is still a viable option to explore the correlation between the drug-binding sites of
SARS-CoV, SARS-CoV-2 and MERS-CoV RdRps. Remdesivir, with its complex
structure that inhibits RdRp, has provided insight into the mechanisms of viral RNA
replication and a rationale for designing drugs to combat novel viral infections. It
was discovered that remdesivir is covalently inserted into the primer strand, leading
to chain elongation termination. The current list of potential medications includes
EIDD-2801, sofosbuvir, galidesivir, remdesivir, AT-527, IDX-184, favipiravir and
ribavirin, all of which have demonstrated anti-SARS-CoV-2 activity in cellular stud-
ies or clinical trials. These nucleoside analogues, such as remdesivir, can concen-
trate within the inner cavity of viral RdRps and block it via RNA chain termination.
This approach involves converting the parent compound to the triphosphate-acti-
vated state. EIDD-2801, galidesivir, remdesivir, favipiravir and ribavirin maintain
the entire ribose group and build a strong hydrogen-bond network resembling natu-
ral substrates. We assessed the pros and cons of nucleoside inhibitors (NIs) to evalu-
ate potential medications better. The biochemical properties of NIs target the active
site of viral RdRps. Most NI antiviral activity is broad-spectrum. Several effective
anti-HCV NIs suggest that the active binding sites of these inhibitors are relatively
conserved [198, 199]. The challenge in developing nucleoside inhibitors is the high
cellular natural NTP concentration level. Triphosphorylated NIs require higher
doses to achieve their antiviral effect due to competition with high levels of cellular
NTP, increasing the risk of drug toxicity.
Cryo-electron microscopy frameworks of RdRp have elucidated the inhibi-
tory mechanism of remdesivir. RdRp inhibitors are typically modified nucleosides
with structurally modified nucleobase and ribose groups, which can be recognized
by RdRp and function as their substrates after undergoing tri-phosphorylation by
kinases. Subsequently, they can be integrated into a growing viral RNA strand.
Hence, the chemical modifications in the structure of nucleoside inhibitors of RdRp
impede the incorporation of a new nucleotide in the ever-increasing chain of viral
RNA, efficiently causing RNA chain termination [200] (Fig.25).
After entering the body, remdesivir undergoes metabolism, hydrolysis,and phos-
phorylation to form its active form, remdesivir monophosphate (RDV-MP) [201,
202].
RDV-MP then boosts the active triphosphate metabolite and interacts with the
basic amino acid residues LYS545 and ARG555 of RdRp. Magnesium ions and

1 3
Topics in Current Chemistry (2023) 381:22 Page 41 of 53 22
pyrophosphate create two ionic bond contacts close to RDV-MP, which are absent in
all other configurations of the SARS-CoV-2 RdRp complex with RNA. The triphos-
phate occupying the nucleotide input site may prevent nucleotide triphosphates
(NTP) from entering the active site, providing a possible mechanism for remdesi-
vir’s inhibitory effect [203, 204]. Other nucleotides, including favipiravir, ribavirin,
IDX-184, galidesivir, EIDD-2801 and molnupiravir, effectively hinder SARS-CoV-2
replication by targeting RdRp [205] (Fig.26).
Moreover, structural modifications enabling covalent integration of phosphate
at the growing terminus are more favourable, and the development of derivatives
of pyrophosphate bonded with additional functional groups, such as fluorine, can
enhance their hydrogen bond acceptance and improve interactions with RdRp [206,
207]. Virtual screening analysis has demonstrated that newly designed medicines
containing phenyl pyrazole or tetrazole functionalities increase the likelihood of
inhibiting RdRp [208]. Aryl di-keto acids have been proven to be highly effec-
tive and temporary inhibitors of HCV’s RdRp. They act as product-like mimics,
binding the two Mg2+ ions (divalent cations) at the active site of HCV, similar to
Fig. 25 General mechanism of action of nucleoside-based RdRp inhibitors
Fig. 26 Mechanism of action of remdesivir as an anti-RdRp agent

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 42 of 53
pyrophosphate mimetic inhibitors. The investigation showed that bioisosteres tetra-
zoles or triazoles, such as ribavirin, could replace the free carboxylic acid moiety
of aryl di-keto acids since the free acidic functional group causes biological and
chemical instability and low membrane permeability of drug molecules [209, 210]
(Fig.27).
The discussion in this review indicates that targeting RdRp could be the most
effective therapeutic strategy for combating COVID-19 infection since it is the pri-
mary receptor for viral replication. Small-molecule inhibitors are considered the best
option during development due to their research progress, safety and efficacy, com-
pared with alternative treatments like oligonucleotide, monoclonal antibody-based,
peptide and plasma therapies. However, there is a need to discover target-specific
lead compounds, and expert investigation on SARS-CoV-2 infections is ongoing. To
develop novel medications, it is crucial to understand the pharmacophore character-
istics that are essential for all substances.
9 Conclusion andFuture Aspects
SARS-CoV-2 has rapidly spread to nearly 199 countries worldwide, with no specific
treatment available to combat this wild-type virus. Developing drugs for COVID-19
is a complex yet necessary process due to the virus’s genetic alterations and medi-
cation resistance, which pose challenges in treatment strategies. One of the major
problems in drug design is to enhance the drug’s potency against genetic variants,
for which adding a suitable pharmacophore to a newly designed molecule is pre-
ferred. Although pharmacophore modelling and docking studies have successfully
recognized remdesivir as an effective inhibitor of the RdRp enzyme, clinical trials
are necessary to confirm these findings. Apart from remdesivir, several nucleotides
like ribavirin, EIDD-2801, favipiravir and galidesivir have shown efficacy in block-
ing SARS-CoV-2 replication. Additionally, some FDA-approved small molecules
for clinical use have demonstrated effectiveness against SARS-CoV-2. This review
summarizes existing antiviral drugs and their structure–activity relationship, and
comparing or incorporating their characteristics is crucial to optimize or to design
more effective drugs in the future.
Acknowledgements This work was supported by grants from the National Natural Science Foundation
of China (32201053) and the Beijing Institute of Technology Research Fund Program for Young Scholars
(3100012222222). The image of the graphical abstract was created with tools obtained from BioRender.
com.
Fig. 27 Replacement of free carboxylic acid with triazole

1 3
Topics in Current Chemistry (2023) 381:22 Page 43 of 53 22
Data availability statement The data supporting this work is available in this paper, and all other details
are present in the supporting information. Furthermore, the data supporting this study are available from
the corresponding author upon reasonable request.
Declarations
Conflict of Interest The authors declare no conflict of interest, financial or otherwise.
Consent for Publication Not applicable.
References
1. Park SE (2020) Epidemiology, virology, and clinical features of severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2; coronavirus disease-19). Pediatr Infect Vaccine 27(1):1–10
2. Ilyas M, Muhammad S, Iqbal J, Amin S, Al-Sehemi AG, Algarni H, Alarfaji SS, Alshahrani MY,
Ayub K (2022) Insighting isatin derivatives as potential antiviral agents against NSP3 of COVID-
19. Chem Pap 76(10):6271–6285
3. Wu W, Wang A, Liu M (2020) Clinical features of patients infected with 2019 novel coronavirus in
Wuhan, China. Lancet 395(10223):497–506
4. Dyall J, Gross R, Kindrachuk J, Johnson RF, Olinger GG Jr, Hensley LE, Frieman MB, Jahrling
PB (2017) Middle East respiratory syndrome and severe acute respiratory syndrome: current thera-
peutic options and potential targets for novel therapies. Drugs 77(18):1935–1966
5. Deng S-Q, Peng H-J (2020) Characteristics of and public health responses to the coronavirus dis-
ease 2019 outbreak in China. J Clin Med 9(2):575
6. Allan M, Lièvre M, Laurenson-Schaefer H, de Barros S, Jinnai Y, Andrews S, Stricker T, Formigo
JP, Schultz C, Perrocheau A (2022) The World Health Organization COVID-19 surveillance data-
base. Int J Equity Health 21(Suppl 3):167
7. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY,
Jordan R (2018) Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by
the viral polymerase and the proofreading exoribonuclease. MBio 9(2):e00221-18
8. Harrison AG, Lin T, Wang P (2020) Mechanisms of SARS-CoV-2 transmission and pathogenesis.
Trends Immunol 41(12):1100–1115
9. Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Götte M (2020) The antiviral compound remde-
sivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome
coronavirus. J Biol Chem 295(15):4773–4779
10. Yin W, Mao C, Luan X, Shen D-D, Shen Q, Su H, Wang X, Zhou F, Zhao W, Gao M (2020) Struc-
tural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesi-
vir. Science 368(6498):1499–1504
11. Parvez MSA, Karim MA, Hasan M, Jaman J, Karim Z, Tahsin T, Hasan MN, Hosen MJ (2020)
Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2
using comprehensive drug repurposing and molecular docking approach. Int J Biol Macromol
163:1787–1797
12. Jordheim LP, Durantel D, Zoulim F, Dumontet C (2013) Advances in the development of nucleo-
side and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov 12(6):447–464
13. Schuler J, Falls Z, Mangione W, Hudson ML, Bruggemann L, Samudrala R (2022) Evaluating the
performance of drug-repurposing technologies. Drug Discov Today 27(1):49–64
14. Zhang J, Xiao T, Cai Y, Chen B (2021) Structure of SARS-CoV-2 spike protein. Curr Opin Virol
50:173–182
15. Li G, De Clercq E (2020) Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat
Rev Drug Discov 19(3):149–150
16. Aronskyy I, Masoudi-Sobhanzadeh Y, Cappuccio A, Zaslavsky E (2021) Advances in the compu-
tational landscape for repurposed drugs against COVID-19. Drug Discov Today 26(12):2800–2815
17. Muhammad S, Amin S, Iqbal J, Al-Sehemi AG, Alarfaji SS, Ilyas M, Atif M, Ullah S (2022)
Insighting the therapeutic potential of fifty (50) shogaol derivatives against mpro of SARS-CoV-2.
J Comput Biophys Chem 21(05):555–568

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 44 of 53
18. McBride R, Van Zyl M, Fielding BC (2014) The coronavirus nucleocapsid is a multifunctional
protein. Viruses 6(8):2991–3018
19. Hilgenfeld R (2014) From SARS to MERS: crystallographic studies on coronaviral proteases ena-
ble antiviral drug design. FEBS J 281(18):4085–4096
20. Li F (2016) Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol
3:237–261
21. Morse JS, Lalonde T, Xu S, Liu WR (2020) Learning from the past: possible urgent prevention
and treatment options for severe acute respiratory infections caused by 2019-nCoV. Chembio-
chem 21(5):730–738
22. Hillen HS (2021) Structure and function of SARS-CoV-2 polymerase. Curr Opin Virol
48:82–90
23. Te Velthuis AJ, Van Den Worm SH, Snijder EJ (2012) The SARS-coronavirus nsp7+ nsp8 com-
plex is a unique multimeric RNA polymerase capable of both de novo initiation and primer
extension. Nucleic Acids Res 40(4):1737–1747
24. Muhammad S, Qaisar M, Iqbal J, Khera RA, Al-Sehemi AG, Alarfaji SS, Adnan M (2022)
Exploring the inhibitory potential of novel bioactive compounds from mangrove actinomycetes
against nsp10 the major activator of SARS-CoV-2 replication. Chem Pap 76(5):3051–3064
25. Kaushik D, Bhandari R, Kuhad A (2021) TLR4 as a therapeutic target for respiratory and neu-
rological complications of SARS-CoV-2. Expert Opin Ther Targets 25(6):491–508
26. Li X, Yang Y, Liu L, Yang X, Zhao X, Li Y, Ge Y, Shi Y, Lv P, Zhang J (2020) Effect of combi-
nation antiviral therapy on hematological profiles in 151 adults hospitalized with severe corona-
virus disease 2019. Pharmacol Res 160:105036
27. Tompa DR, Immanuel A, Srikanth S, Kadhirvel S (2021) Trends and strategies to combat viral
infections: a review on FDA approved antiviral drugs. Int J Biol Macromol 172:524–541
28. Singhal T (2020) A review of coronavirus disease-2019 (COVID-19). Indian J Pediatr
87(4):281–286
29. Bobrowski T, Melo-Filho CC, Korn D, Alves VM, Popov KI, Auerbach S, Schmitt C, Moorman
NJ, Muratov EN, Tropsha A (2020) Learning from history: do not flatten the curve of antiviral
research! Drug Discov Today 25(9):1604–1613
30. Bank PD (2021) RCSB protein data bank: integrated searching and efficient access to macromo-
lecular structure data from the PDB archive. Found Crystallogr 77:a253
31. Kouranov A, Xie L, de la Cruz J, Chen L, Westbrook J, Bourne PE, Berman HM (2006)
The RCSB PDB information portal for structural genomics. Nucleic Acids Res 34(Suppl
1):D302–D305
32. Tian W, Chen C, Liang J (2018) CASTp 30: computed atlas of surface topography of proteins and
beyond. Biophys J 114(3):50a
33. Chan JF-W, Kok K-H, Zhu Z, Chu H, To KK-W, Yuan S, Yuen K-Y (2020) Genomic characteriza-
tion of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneu-
monia after visiting Wuhan. Emerg Microbes Infect 9(1):221–236
34. Grellet E, Goulet A, Imbert I (2022) Replication of the coronavirus genome: a paradox among
positive-strand RNA viruses. J Biol Chem 298:101923
35. Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, Wang T, Sun Q, Ming Z, Zhang L (2020) Structure
of the RNA-dependent RNA polymerase from COVID-19 virus. Science 368(6492):779–782
36. Shu B, Gong P (2016) Structural basis of viral RNA-dependent RNA polymerase catalysis and
translocation. Proc Natl Acad Sci 113(28):E4005–E4014
37. Kirchdoerfer RN, Ward AB (2019) Structure of the SARS-CoV nsp12 polymerase bound to nsp7
and nsp8 co-factors. Nat Commun 10(1):2342
38. Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, Nomura N, Egawa H,
Shiraki K (2005) Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chem-
other 49(3):981–986
39. Furuta Y, Komeno T, Nakamura T (2017) Favipiravir (T-705), a broad spectrum inhibitor of viral
RNA polymerase. Proc Jpn Acad Ser B 93(7):449–463
40. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL (2013) Favipiravir (T-705), a
novel viral RNA polymerase inhibitor. Antivir Res 100(2):446–454
41. Abdelnabi R, de Morais ATS, Leyssen P, Imbert I, Beaucourt S, Blanc H, Froeyen M, Vignuzzi M,
Canard B, Neyts J (2017) Understanding the mechanism of the broad-spectrum antiviral activity of
favipiravir (T-705): key role of the F1 motif of the viral polymerase. J Virol 91(12):e00487-17

1 3
Topics in Current Chemistry (2023) 381:22 Page 45 of 53 22
42. Graci JD, Cameron CE (2006) Mechanisms of action of ribavirin against distinct viruses. Rev Med
Virol 16(1):37–48
43. Deval J, Fung A, Stevens SK, Jordan PC, Gromova T, Taylor JS, Hong J, Meng J, Wang G, Dyat-
kina N (2016) Biochemical effect of resistance mutations against synergistic inhibitors of RSV
RNA polymerase. PLoSOne 11(5):e0154097
44. Deval J, Hong J, Wang G, Taylor J, Smith LK, Fung A, Stevens SK, Liu H, Jin Z, Dyatkina N
(2015) Molecular basis for the selective inhibition of respiratory syncytial virus RNA polymerase
by 2′-fluoro-4′-chloromethyl-cytidine triphosphate. PLoS Pathog 11(6):e1004995
45. Wang G, Deval J, Hong J, Dyatkina N, Prhavc M, Taylor J, Fung A, Jin Z, Stevens SK, Serebryany
V (2015) Discovery of 4′-chloromethyl-2′-deoxy-3′, 5′-di-O-isobutyryl-2′-fluorocytidine (ALS-
8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus
infection. J Med Chem 58(4):1862–1878
46. Nilsson M, Kalayanov G, Winqvist A, Pinho P, Sund C, Zhou X-X, Wähling H, Belfrage A-K,
Pelcman M, Agback T (2012) Discovery of 4′-azido-2′-deoxy-2′-C-methyl cytidine and prodrugs
thereof: a potent inhibitor of hepatitis C virus replication. Bioorg Med Chem Lett 22(9):3265–3268
47. Rondla R, Coats SJ, McBrayer TR, Grier J, Johns M, Tharnish PM, Whitaker T, Zhou L, Schinazi
RF (2009) Anti-hepatitis C virus activity of novel β-d-2′-C-methyl-4′-azido pyrimidine nucleoside
phosphoramidate prodrugs. Antivir Chem Chemother 20(2):99–106
48. Deutsch M, Hadziyannis S (2008) Old and emerging therapies in chronic hepatitis C: an update. J
Viral Hepat 15(1):2–11
49. Gerber L, Welzel TM, Zeuzem S (2013) New therapeutic strategies in HCV: polymerase inhibitors.
Liver Int 33:85–92
50. Andreou A, Trantza S, Filippou D, Sipsas N, Tsiodras S (2020) COVID-19: the potential role of
copper and N-acetylcysteine (NAC) in a combination of candidate antiviral treatments against
SARS-CoV-2. InVivo 34(3 suppl):1567–1588
51. Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NC, Morin MJ, Szewczyk LJ,
Painter GR (2021) Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel
broad-spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrob Agents Chem-
other 65(5):e02428-20
52. Cox RM, Wolf JD, Plemper RK (2021) Therapeutically administered ribonucleoside analogue
MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat Microbiol 6(1):11–18
53. Celik I, Tallei TE (2022) A computational comparative analysis of the binding mechanism of mol-
nupiravir’s active metabolite to RNA-dependent RNA polymerase of wild-type and Delta subvari-
ant AY 4 of SARS-CoV-2. J Cell Biochem 123(4):807–818
54. Painter GR, Bowen RA, Bluemling GR, DeBergh J, Edpuganti V, Gruddanti PR, Guthrie DB,
Hager M, Kuiper DL, Lockwood MA (2019) The prophylactic and therapeutic activity of a broadly
active ribonucleoside analog in a murine model of intranasal Venezuelan equine encephalitis virus
infection. Antivir Res 171:104597
55. Agostini ML, Pruijssers AJ, Chappell JD, Gribble J, Lu X, Andres EL, Bluemling GR, Lockwood
MA, Sheahan TP, Sims AC (2019) Small-molecule antiviral β-
D
-N 4-hydroxycytidine inhibits a
proofreading-intact coronavirus with a high genetic barrier to resistance. J Virol 93(24):e01348-19
56. Julander JG, Demarest JF, Taylor R, Gowen BB, Walling DM, Mathis A, Babu Y (2021) An update
on the progress of galidesivir (BCX4430), a broad-spectrum antiviral. Antivir Res 195:105180
57. Aschenbrenner DS (2021) Remdesivir approved to treat COVID-19 amid controversy. Am J Nurs
121(1):22–24
58. Young B, Tan TT, Leo YS (2021) The place for remdesivir in COVID-19 treatment. Lancet Infect
Dis 21(1):20–21
59. Hendaus MA (2021) Remdesivir in the treatment of coronavirus disease 2019 (COVID-19): a sim-
plified summary. J Biomol Struct Dyn 39(10):3787–3792
60. Shannon A, Fattorini V, Sama B, Selisko B, Feracci M, Falcou C, Gauffre P, El Kazzi P, Delpal A,
Decroly E (2022) A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase. Nat
Commun 13(1):621
61. Good SS, Westover J, Jung KH, La Colla P, Collu G, Moussa A, Canard B, Sommadossi J-P
(2020) AT-527 is a potent invitro replication inhibitor of SARS-CoV-2, the virus responsible for
the COVID-19 pandemic. Biorxiv 2020:242834
62. Elfiky AA, Elshemey WM, Gawad WA (2015) 2′-Methylguanosine prodrug (IDX-184), phos-
phoramidate prodrug (sofosbuvir), diisobutyryl prodrug (R7128) are better than their parent

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 46 of 53
nucleotides and ribavirin in hepatitis C virus inhibition: a molecular modeling study. J Comput
Theor Nanosci 12(3):376–386
63. Elfiky AA (2016) Zika viral polymerase inhibition using anti-HCV drugs both in market and under
clinical trials. J Med Virol 88(12):2044–2051
64. Sadeghi A, Ali Asgari A, Norouzi A, Kheiri Z, Anushirvani A, Montazeri M, Hosamirudsai
H, Afhami S, Akbarpour E, Aliannejad R (2020) Sofosbuvir and daclatasvir compared with
standard of care in the treatment of patients admitted to hospital with moderate or severe
coronavirus infection (COVID-19): a randomized controlled trial. J Antimicrob Chemother
75(11):3379–3385
65. Vicenti I, Zazzi M, Saladini F (2021) SARS-CoV-2 RNA-dependent RNA polymerase as a ther-
apeutic target for COVID-19. Expert Opin Ther Patents 31(4):325–337
66. Shannon A, Canard B (2023) Kill or corrupt: mechanisms of action and drug-resistance of
nucleotide analogues against SARS-CoV-2. Antivir Res 210:105501
67. Moeller NH, Shi K, Demir Ö, Belica C, Banerjee S, Yin L, Durfee C, Amaro RE, Aihara H
(2022) Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN. Proc Natl
Acad Sci 119(9):e2106379119
68. Jia X, Schols D, Meier C (2020) Lipophilic triphosphate prodrugs of various nucleoside ana-
logues. J Med Chem 63(13):6991–7007
69. Mackman RL (2022) Phosphoramidate prodrugs continue to deliver, the journey of remdesivir
(GS-5734) from RSV to SARS-CoV-2. ACS Med Chem Lett 13(3):338–347
70. Elfiky AA (2020) Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci
248:117477
71. Wang Z, Yang L, Zhao X-E (2021) Co-crystallization and structure determination: an effective
direction for anti-SARS-CoV-2 drug discovery. Comput Struct Biotechnol J 19:4684–4701
72. Zhang W-F, Stephen P, Theriault J-F, Wang R, Lin S-X (2020) Novel coronavirus polymer-
ase and nucleotidyl-transferase structures: potential to target new outbreaks. J Phys Chem Lett
11(11):4430–4435
73. Celik I, Erol M, Duzgun Z (2021) In silico evaluation of potential inhibitory activity of remde-
sivir, favipiravir, ribavirin and galidesivir active forms on SARS-CoV-2 RNA polymerase. Mol
Divers 26:279–292
74. Du YX, Chen XP (2020) Favipiravir: pharmacokinetics and concerns about clinical trials for
2019-nCoV infection. Clin Pharmacol Ther 108(2):242–247
75. Naydenova K, Muir KW, Wu L-F, Zhang Z, Coscia F, Peet MJ, Castro-Hartmann P, Qian P,
Sader K, Dent K (2021) Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the
presence of favipiravir-RTP. Proc Natl Acad Sci 118(7):e2021946118
76. Pilkington V, Pepperrell T, Hill A (2020) A review of the safety of favipiravir – a potential
treatment in the COVID-19 pandemic? J Virus Erad 6(2):45–51
77. Chen C, Huang J, Yin P, Zhang Y, Cheng Z, Wu J, Chen S, Zhang Y, Chen B, Lu M (2020)
Favipiravir versus arbidol for COVID-19: a randomized clinical trial. MedRxiv 2020:20037432
78. Blattman N (2015) Management of hepatitis C in patients with HIV care for patients with HIV-
HCV co-infection is evolving as new medications are introduced that will provide simpler, more
accessible treatment regimens. Fed Pract 32(Suppl 2):15S
79. Arabi YM, Shalhoub S, Mandourah Y, Al-Hameed F, Al-Omari A, Al Qasim E, Jose J,
Alraddadi B, Almotairi A, Al Khatib K (2020) Ribavirin and interferon therapy for critically ill
patients with Middle East respiratory syndrome: a multicenter observational study. Clin Infect
Dis 70(9):1837–1844
80. Parker WB (2005) Metabolism and antiviral activity of ribavirin. Virus Res 107(2):165–171
81. Unal MA, Bitirim CV, Summak GY, Bereketoglu S, CevherZeytin I, Besbinar O, Gurcan C,
Aydos D, Goksoy E, Kocakaya E (2021) Ribavirin shows antiviral activity against SARS-CoV-2
and downregulates the activity of TMPRSS2 and the expression of ACE2 invitro. Can J Physiol
Pharmacol 99(5):449–460
82. Bylehn F, Menendez CA, Perez-Lemus GR, Alvarado W, De Pablo JJ (2021) Modeling the
binding mechanism of remdesivir, favilavir, and ribavirin to SARS-CoV-2 RNA-dependent
RNA polymerase. ACS Cent Sci 7(1):164–174
83. Uddin R, Jalal K, Khan K (2022) Re-purposing of hepatitis C virus FDA approved direct acting
antivirals as potential SARS-CoV-2 protease inhibitors. J Mol Struct 1250:131920

1 3
Topics in Current Chemistry (2023) 381:22 Page 47 of 53 22
84. Elfiky AA (2020) Ribavirin, remdesivir, sofosbuvir, galidesivir, and tenofovir against SARS-
CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study. Life Sci
253:117592
85. Crotty S, Andino R (2002) Implications of high RNA virus mutation rates: lethal mutagenesis and
the antiviral drug ribavirin. Microbes Infect 4(13):1301–1307
86. Leong HN, Ang B, Earnest A, Teoh C, Xu W, Leo YS (2004) Investigational use of ribavirin
in the treatment of severe acute respiratory syndrome, Singapore, 2003. Trop Med Int Health
9(8):923–927
87. Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, Walmsley SL, Maz-
zulli T, Avendano M, Derkach P (2003) Clinical features and short-term outcomes of 144 patients
with SARS in the greater Toronto area. JAMA 289(21):2801–2809
88. Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, Ahuja A, Yung MY, Leung C, To K
(2003) A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med
348(20):1986–1994
89. Tan EL, Ooi EE, Lin C-Y, Tan HC, Ling AE, Lim B, Stanton LW (2004) Inhibition of SARS coro-
navirus infection invitro with clinically approved antiviral drugs. Emerg Infect Dis 10(4):581
90. Muller MP, Dresser L, Raboud J, McGeer A, Rea E, Richardson SE, Mazzulli T, Loeb M, Louie M
(2007) Adverse events associated with high-dose ribavirin: evidence from the Toronto outbreak of
severe acute respiratory syndrome. Pharmacotherapy 27(4):494–503
91. Barlow A, Landolf KM, Barlow B, Yeung SYA, Heavner JJ, Claassen CW, Heavner MS (2020)
Review of emerging pharmacotherapy for the treatment of coronavirus disease 2019. Pharmaco-
therapy 40(5):416–437
92. Chang C-H, Chen K, Lai M-Y, Chan K (2002) Meta-analysis: ribavirin-induced haemolytic anae-
mia in patients with chronic hepatitis C. Aliment Pharmacol Ther 16(9):1623–1632
93. Knowles SR, Phillips EJ, Dresser L, Matukas L (2003) Common adverse events associated with the
use of ribavirin for severe acute respiratory syndrome in Canada. Clin Infect Dis 37(8):1139–1142
94. Kaur K, Gandhi MA, Slish J (2015) Drug-drug interactions among hepatitis C virus (HCV) and
human immunodeficiency virus (HIV) medications. Infect Dis Ther 4:159–172
95. Zandi K, Amblard F, Musall K, Downs-Bowen J, Kleinbard R, Oo A, Cao D, Liang B, Russell OO,
McBrayer T (2020) Repurposing nucleoside analogs for human coronaviruses. Antimicrob Agents
Chemother 65(1):e01652-20
96. Goswami D (2021) Comparative assessment of RNA-dependent RNA polymerase (RdRp) inhibi-
tors under clinical trials to control SARS-CoV2 using rigorous computational workflow. RSC Adv
11(46):29015–29028
97. Mandal M, Chowdhury SK, Khan AA, Baildya N, Dutta T, Misra D, Ghosh NN (2021) Inhibi-
tory efficacy of RNA virus drugs against SARS-CoV-2 proteins: an extensive study. J Mol Struct
1234:130152
98. Chang J (2022) 4′-Modified nucleosides for antiviral drug discovery: achievements and perspec-
tives. Acc Chem Res 55(4):565–578
99. Clark JL, Hollecker L, Mason JC, Stuyver LJ, Tharnish PM, Lostia S, McBrayer TR, Schinazi RF,
Watanabe KA, Otto MJ (2005) Design, synthesis, and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-
methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 48(17):5504–5508
100. Fung A, Jin Z, Dyatkina N, Wang G, Beigelman L, Deval J (2014) Efficiency of incorporation
and chain termination determines the inhibition potency of 2′-modified nucleotide analogs against
hepatitis C virus polymerase. Antimicrob Agents Chemother 58(7):3636–3645
101. Deore R, Chern JW (2010) NS5B RNA dependent RNA polymerase inhibitors: the promising
approach to treat hepatitis C virus infections. Curr Med Chem 17(32):3806–3826
102. Nishiyama T, Kobayashi T, Jirintai S, Nagashima S, Primadharsini PP, Nishizawa T, Okamoto
H (2019) Antiviral candidates against the hepatitis E virus (HEV) and their combinations inhibit
HEV growth in invitro. Antivir Res 170:104570
103. Qu C, Xu L, Yin Y, Peppelenbosch MP, Pan Q, Wang W (2017) Nucleoside analogue 2′-C-methyl-
cytidine inhibits hepatitis E virus replication but antagonizes ribavirin. Adv Virol 162:2989–2996
104. Lee J-C, Tseng C-K, Wu Y-H, Kaushik-Basu N, Lin C-K, Chen W-C, Wu H-N (2015) Characteri-
zation of the activity of 2′-C-methylcytidine against dengue virus replication. Antivir Res 116:1–9
105. Rocha-Pereira J, Jochmans D, Dallmeier K, Leyssen P, Cunha R, Costa I, Nascimento M, Neyts
J (2012) Inhibition of norovirus replication by the nucleoside analogue 2′-C-methylcytidine. Bio-
chem Biophys Res Commun 427(4):796–800

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 48 of 53
106. Elfiky AA (2021) SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico
perspective. J Biomol Struct Dyn 39(9):3204–3212
107. Jena N (2020) Identification of potent drugs and antiviral agents for the treatment of the SARS-
CoV-2 infection. J Biol Med Chem
108. Pierra C, Amador A, Benzaria S, Cretton-Scott E, d’Amours M, Mao J, Mathieu S, Moussa
A, Bridges EG, Standring DN (2006) Synthesis and pharmacokinetics of valopicitabine
(NM283), an efficient prodrug of the potent anti-HCV agent 2′-C-methylcytidine. J Med Chem
49(22):6614–6620
109. Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK, Lee B, Heckerman D, Carlson
J, Reyor LL (2008) Naturally occurring dominant resistance mutations to hepatitis C virus protease
and polymerase inhibitors in treatment-naive patients. Hepatology 48(6):1769–1778
110. Kumar R, Mishra S, Maurya SK (2021) Recent advances in the discovery of potent RNA-depend-
ent RNA-polymerase (RdRp) inhibitors targeting viruses. RSC Med Chem 12(3):306–320
111. Tian L, Qiang T, Liang C, Ren X, Jia M, Zhang J, Li J, Wan M, YuWen X, Li H (2021) RNA-
dependent RNA polymerase (RdRp) inhibitors: the current landscape and repurposing for the
COVID-19 pandemic. Eur J Med Chem 213:113201
112. Gordon CJ, Tchesnokov EP, Schinazi RF, Götte M (2021) Molnupiravir promotes SARS-CoV-2
mutagenesis via the RNA template. J Biol Chem 297(1):100770
113. Wang M, Wu C, Liu N, Zhang F, Dong H, Wang S, Chen M, Jiang X, Gu L (2021) SARS-CoV-2
RdRp is a versatile enzyme with proofreading activity and ability to incorporate NHC into RNA by
using diphosphate form molnupiravir as a substrate. BioRxiv 2021:468737
114. Urakova N, Kuznetsova V, Crossman DK, Sokratian A, Guthrie DB, Kolykhalov AA, Lock-
wood MA, Natchus MG, Crowley MR, Painter GR (2018) β-D-N 4-hydroxycytidine is a potent
anti-alphavirus compound that induces a high level of mutations in the viral genome. J Virol
92(3):e01965-17
115. Hashemian SMR, Pourhanifeh MH, Hamblin MR, Shahrzad MK, Mirzaei H (2022) RdRp inhibi-
tors and COVID-19: is molnupiravir a good option? Biomed Pharmacother 146:112517
116. Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, Leist SR, Schäfer A,
Dinnon KH III, Stevens LJ (2020) An orally bioavailable broad-spectrum antiviral inhibits SARS-
CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med
12(541):eabb5883
117. Mestres J (2020) The target landscape of N4-hydroxycytidine based on its chemical neighborhood.
BioRxiv 2020:016485
118. Imran M, Kumar Arora M, Asdaq SMB, Khan SA, Alaqel SI, Alshammari MK, Alshehri MM,
Alshrari AS, Mateq Ali A, Al-Shammeri AM (2021) Discovery, development, and patent trends on
molnupiravir: a prospective oral treatment for COVID-19. Molecules 26(19):5795
119. Stevaert A, Groaz E, Naesens L (2022) Nucleoside analogs for management of respiratory virus
infections: mechanism of action and clinical efficacy. Curr Opin Virol 57:101279
120. Zarenezhad E, Marzi M (2022) Review on molnupiravir as a promising oral drug for the treatment
of COVID-19. Med Chem Res 31:232–243
121. Gangadharan S, Ambrose JM, Rajajagadeesan A, Kullappan M, Patil S, Gandhamaneni SH, Vee-
raraghavan VP, Nakkella AK, Agarwal A, Jayaraman S (2022) Repurposing of potential antiviral
drugs against RNA-dependent RNA polymerase of SARS-CoV-2 by computational approach. J
Infect Public Health 15(11):1180–1191
122. Kabinger F, Stiller C, Schmitzová J, Dienemann C, Kokic G, Hillen HS, Höbartner C, Cramer
P (2021) Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol
28(9):740–746
123. Fischer WA, Eron JJ Jr, Holman W, Cohen MS, Fang L, Szewczyk LJ, Sheahan TP, Baric R, Mol-
lan KR, Wolfe CR (2021) A phase 2a clinical trial of molnupiravir in patients with COVID-19
shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl
Med 14(628):eabl7430
124. Ju J, Kumar S, Li X, Jockusch S, Russo JJ (2020) Nucleotide analogues as inhibitors of viral poly-
merases. BioRxiv 2020:927574
125. Abuo-Rahma GE-DA, Mohamed MF, Ibrahim TS, Shoman ME, Samir E, Abd El-Baky RM (2020)
Potential repurposed SARS-CoV-2 (COVID-19) infection drugs. RSC Adv 10(45):26895–26916
126. Jena N (2020) Role of different tautomers in the base-pairing abilities of some of the vital antiviral
drugs used against COVID-19. Phys Chem Chem Phys 22(48):28115–28122

1 3
Topics in Current Chemistry (2023) 381:22 Page 49 of 53 22
127. Taylor R, Bowen R, Demarest JF, DeSpirito M, Hartwig A, Bielefeldt-Ohmann H, Walling DM,
Mathis A, Babu YS (2021) Activity of galidesivir in a hamster model of SARS-CoV-2. Viruses
14(1):8
128. Gandeepan P, Ackermann L (2018) Transient directing groups for transformative C–H activation
by synergistic metal catalysis. Chem 4(2):199–222
129. Romano M, Ruggiero A, Squeglia F, Maga G, Berisio R (2020) A structural view of SARS-CoV-2
RNA replication machinery: RNA synthesis, proofreading and final capping. Cells 9(5):1267
130. Hasan MK, Kamruzzaman M, Manjur OHB, Mahmud A, Hussain N, Mondal MSA, Hosen
MI, Bello M, Rahman A (2021) Structural analogues of existing anti-viral drugs inhibit SARS-
CoV-2 RNA dependent RNA polymerase: a computational hierarchical investigation. Heliyon
7(3):e06435
131. Ataei M, Hosseinjani H (2020) Molecular mechanisms of galidesivir as a potential antiviral treat-
ment for COVID-19. J Pharm Care 2020:150–151
132. Uzunova K, Filipova E, Pavlova V, Vekov T (2020) Insights into antiviral mechanisms of rem-
desivir, lopinavir/ritonavir and chloroquine/hydroxychloroquine affecting the new SARS-CoV-2.
Biomed Pharmacother 131:110668
133. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G (2020) Rem-
desivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV)
invitro. Cell Res 30(3):269–271
134. Pizzorno A, Padey B, Julien T, Trouillet-Assant S, Traversier A, Errazuriz-Cerda E, Fouret J,
Dubois J, Gaymard A, Lescure F-X (2020) Characterization and treatment of SARS-CoV-2 in
nasal and bronchial human airway epithelia. Cell Rep Med 1(4):100059
135. Sun G-Q, Wang S-F, Li M-T, Li L, Zhang J, Zhang W, Jin Z, Feng G-L (2020) Transmission
dynamics of COVID-19 in Wuhan, China: effects of lockdown and medical resources. Nonlinear
Dyn 101:1981–1993
136. Singh AK, Singh A, Singh R, Misra A (2020) Remdesivir in COVID-19: a critical review of phar-
macology, pre-clinical and clinical studies. Diabetes Metab Syndr 14(4):641–648
137. Amirian ES, Levy JK (2020) Current knowledge about the antivirals remdesivir (GS-5734) and
GS-441524 as therapeutic options for coronaviruses. One Health 9:100128
138. Li Y, Zhang D, Gao X, Wang X, Zhang L (2022) 2′-and 3′-ribose modifications of nucleotide ana-
logues establish the structural basis to inhibit the viral replication of SARS-CoV-2. J Phys Chem
Lett 13(18):4111–4118
139. Wakchaure PD, Ghosh S, Ganguly B (2020) Revealing the inhibition mechanism of RNA-depend-
ent RNA polymerase (RdRp) of SARS-CoV-2 by remdesivir and nucleotide analogues: a molecu-
lar dynamics simulation study. J Phys Chem B 124(47):10641–10652
140. Ionescu MI (2020) An overview of the crystallized structures of the SARS-CoV-2. Protein J
39(6):600–618
141. Padhi AK, Shukla R, Saudagar P, Tripathi T (2021) High-throughput rational design of the rem-
desivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance. Iscience
24(1):101992
142. Moirangthem DS, Surbala L (2021) Remdesivir (GS-5734) in COVID-19 therapy: the fourth
chance. Curr Drug Targets 22(12):1346–1356
143. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, Ericson K, Wilk-
erson S, Tural A (2020) First case of 2019 novel coronavirus in the United States. N Engl J Med
382:929–936
144. Sanchez-Codez MI, Rodriguez-Gonzalez M, Gutierrez-Rosa I (2021) Severe sinus bradycar-
dia associated with remdesivir in a child with severe SARS-CoV-2 infection. Eur J Pediatr
180(5):1627–1627
145. Saqrane S, El Mhammedi M, Lahrich S, Laghrib F, El Bouabi Y, Farahi A, Bakasse M (2021)
Recent knowledge in favor of remdesivir (GS-5734) as a therapeutic option for the COVID-19
infections. J Infect Public Health 14(5):655–660
146. Ko W-C, Rolain J-M, Lee N-Y, Chen P-L, Huang C-T, Lee P-I, Hsueh P-R (2020) Arguments in
favour of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents 55:105933
147. Belhadi D, Peiffer-Smadja N, Lescure F-X, Yazdanpanah Y, Mentré F, Laouénan C (2020) A
brief review of antiviral drugs evaluated in registered clinical trials for COVID-19. MedRxiv
2020:20038190

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 50 of 53
148. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister
R, Hui HC (2016) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhe-
sus monkeys. Nature 531(7594):381–385
149. Anastasiou IA, Eleftheriadou I, Tentolouris A, Tsilingiris D, Tentolouris N (2020) Invitro data of
current therapies for SARS-CoV-2. Curr Med Chem 27(27):4542–4548
150. Qiao Y, Wotring JW, Zhang CJ, Jiang X, Xiao L, Watt A, Gattis D, Scandalis E, Freier S, Zheng
Y (2023) Antisense oligonucleotides to therapeutically target SARS-CoV-2 infection. PLoSOne
18(2):e0281281
151. Su X, Ma W, Feng D, Cheng B, Wang Q, Guo Z, Zhou D, Tang X (2021) Efficient inhibition of
SARS-CoV-2 using chimeric antisense oligonucleotides through RNase L activation. Angew Chem
133(40):21830–21835
152. Sahu B, Behera SK, Das R, Dalvi T, Chowdhury A, Dewangan B, Kalia K, Shard A (2022) Design
and in-silico screening of peptide nucleic acid (PNA) inspired novel pronucleotide scaffolds target-
ing COVID-19. Curr Comput Aided Drug Des 18(1):26–40
153. Good SS, Westover J, Jung KH, Zhou X-J, Moussa A, La Colla P, Collu G, Canard B, Somma-
dossi J-P (2021) AT-527, a double prodrug of a guanosine nucleotide analog, is a potent inhibitor
of SARS-CoV-2 invitro and a promising oral antiviral for treatment of COVID-19. Antimicrob
Agents Chemother 65(4):e02479-20
154. Basu D, Chavda VP, Mehta AA (2022) Therapeutics for COVID-19 and post COVID-19 complica-
tions: an update. Curr Res Pharmacol Drug Discov 2022:100086
155. Mungur O, Berliba E, Bourgeois S, Cardona M, Jucov A, Good S, Moussa A, Pietropaolo K, Zhou
X-J, Brown N (2020) A combination of AT-527, a pan-genotypic guanosine nucleotide prodrug,
and daclatasvir was well-tolerated and effective in HCV-infected subjects. J Hepatol 73:S357
156. Berliba E, Bogus M, Vanhoutte F, Berghmans P-J, Good SS, Moussa A, Pietropaolo K, Murphy
RL, Zhou X-J, Sommadossi J-P (2019) Safety, pharmacokinetics, and antiviral activity of AT-527,
a novel purine nucleotide prodrug, in hepatitis C virus-infected subjects with or without cirrhosis.
Antimicrob Agents Chemother 63(12):e01201-19
157. Good SS, Moussa A, Zhou X-J, Pietropaolo K, Sommadossi J-P (2020) Preclinical evaluation of
AT-527, a novel guanosine nucleotide prodrug with potent, pan-genotypic activity against hepatitis
C virus. PLoSOne 15(1):e0227104
158. Wang X, Sacramento CQ, Jockusch S, Chaves OA, Tao C, Fintelman-Rodrigues N, Chien M,
Temerozo JR, Li X, Kumar S (2021) Combination of antiviral drugs to inhibit SARS-CoV-2 poly-
merase and exonuclease as potential COVID-19 therapeutics. bioRxiv
159. Eltayb WA, Abdalla M, Rabie AM (2023) Novel investigational anti-SARS-CoV-2 agent Ensitrel-
vir “S-217622”: a very promising potential universal broad-spectrum antiviral at the therapeutic
frontline of coronavirus species. ACS Omega 8(6):5234–5246
160. Canard B, Shannon A, Fattorini V, Sama B, Selisko B, Feracci M, Falcou C, Gauffre P, El-Kazzi P,
Decroly E (2021) A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase
161. Shannon A, Fattorini V, Sama B, Selisko B, Feracci M, Falcou C, Gauffre P, Kazzi PE, Decroly E,
Rabah N (2021) Protein-primed RNA synthesis in SARS-CoVs and structural basis for inhibition
by AT-527. bioRxiv 2021:436564
162. Mayhoub AS (2012) Hepatitis C RNA-dependent RNA polymerase inhibitors: a review of struc-
ture–activity and resistance relationships; different scaffolds and mutations. Bioorg Med Chem
20(10):3150–3161
163. Elfiky AA, Elshemey WM (2016) IDX-184 is a superior HCV direct-acting antiviral drug: a QSAR
study. Med Chem Res 25:1005–1008
164. Elfiky AA (2017) Zika virus: novel guanosine derivatives revealed strong binding and possible
inhibition of the polymerase. Future Virol 12(12):721–728
165. Elfiky AA, Ismail AM (2018) Molecular docking revealed the binding of nucleotide/side inhibitors
to Zika viral polymerase solved structures. SAR QSAR Environ Res 29(5):409–418
166. Noor R (2021) Antiviral drugs against severe acute respiratory syndrome coronavirus 2 infection
triggering the coronavirus disease-19 pandemic. Tzu-Chi Med J 33(1):7
167. Elfiky AA, Ismail AM (2017) Molecular modeling and docking revealed superiority of IDX-184 as
HCV polymerase inhibitor. Future Virol 12(7):339–347
168. Zhou X-J, Pietropaolo K, Chen J, Khan S, Sullivan-Bólyai J, Mayers D (2011) Safety and phar-
macokinetics of IDX184, a liver-targeted nucleotide polymerase inhibitor of hepatitis C virus, in
healthy subjects. Antimicrob Agents Chemother 55(1):76–81

1 3
Topics in Current Chemistry (2023) 381:22 Page 51 of 53 22
169. Elfiky AA (2022) Dual targeting of RdRps of SARS-CoV-2 and the mucormycosis-causing fun-
gus: an in silico perspective. Future Microbiol 17(10):755–762
170. Murakami E, Niu C, Bao H, MicolochickSteuer HM, Whitaker T, Nachman T, Sofia MA,
Wang P, Otto MJ, Furman PA (2008) The mechanism of action of β-d-2′-deoxy-2′-fluoro-2′-C-
methylcytidine involves a second metabolic pathway leading to β-d-2′-deoxy-2′-fluoro-2′-C-
methyluridine 5′-triphosphate, a potent inhibitor of the hepatitis C virus RNA-dependent RNA
polymerase. Antimicrob Agents Chemother 52(2):458–464
171. Zhang C (2022) Fluorine in medicinal chemistry: in perspective to COVID-19. ACS Omega
7(22):18206–18212
172. Ma H, Jiang W-R, Robledo N, Leveque V, Ali S, Lara-Jaime T, Masjedizadeh M, Smith DB, Cam-
mack N, Klumpp K (2007) Characterization of the metabolic activation of hepatitis C virus nucleo-
side inhibitor β-
D
-2′-deoxy-2′-fluoro-2′-C-methylcytidine (PSI-6130) and identification of a novel
active 5′-triphosphate species. J Biol Chem 282(41):29812–29820
173. Sofia MJ, Furman PA (2019) The discovery of sofosbuvir: a liver-targeted nucleotide prodrug for
the treatment and cure of HCV. HCV I:141–169
174. Sayad B, Sobhani M, Khodarahmi R (2020) Sofosbuvir as repurposed antiviral drug against
COVID-19: why were we convinced to evaluate the drug in a registered/approved clinical trial?
Arch Med Res 51(6):577–581
175. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HMM, Bao D, Chang W, Espiritu C, Bansal S,
Lam AM (2010) Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol
Chem 285(45):34337–34347
176. Kirby BJ, Symonds WT, Kearney BP, Mathias AA (2015) Pharmacokinetic, pharmacodynamic,
and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir. Clin
Pharmacokinet 54:677–690
177. Gentile I, Maraolo AE, Buonomo AR, Zappulo E, Borgia G (2015) The discovery of sofosbuvir: a
revolution for therapy of chronic hepatitis C. Expert Opin Drug Discov 10(12):1363–1377
178. Bhatia R, Narang RK, Rawal RK (2020) Repurposing of RdRp inhibitors against SARS-CoV-2
through molecular docking tools. Coronaviruses 1(1):108–116
179. Wang Y, Anirudhan V, Du R, Cui Q, Rong L (2021) RNA-dependent RNA polymerase of SARS-
CoV-2 as a therapeutic target. J Med Virol 93(1):300–310
180. Chien M, Anderson TK, Jockusch S, Tao C, Li X, Kumar S, Russo JJ, Kirchdoerfer RN, Ju J (2020)
Nucleotide analogues as inhibitors of SARS-CoV-2 polymerase, a key drug target for COVID-19. J
Proteome Res 19(11):4690–4697
181. Nourian A, Khalili H, Ahmadinejad Z, Kouchak HE, Jafari S, Manshadi SAD, Rasolinejad M,
Kebriaeezadeh A (2020) Efficacy and safety of sofosbuvir/ledipasvir in treatment of patients with
COVID-19; a randomized clinical trial. Acta Bio Medica Atenei Parmensis 91(4)
182. Jockusch S, Tao C, Li X, Chien M, Kumar S, Morozova I, Kalachikov S, Russo JJ, Ju J (2020)
Sofosbuvir terminated RNA is more resistant to SARS-CoV-2 proofreader than RNA terminated
by remdesivir. Sci Rep 10(1):16577
183. Choudhury C, Narahari Sastry G (2019) Pharmacophore modelling and screening: concepts, recent
developments and applications in rational drug design. In Structural bioinformatics: applications in
preclinical drug discovery process, pp 25–53
184. Mosayebnia M, HajiaghaBozorgi A, Rezaeianpour M, Kobarfard F (2022) In silico prediction of
SARS-CoV-2 main protease and polymerase inhibitors: 3D-pharmacophore modelling. J Biomol
Struct Dyn 40(14):6569–6586
185. Giordano D, Biancaniello C, Argenio MA, Facchiano A (2022) Drug design by pharmacophore
and virtual screening approach. Pharmaceuticals 15(5):646
186. Schaller D, Šribar D, Noonan T, Deng L, Nguyen TN, Pach S, Machalz D, Bermudez M, Wolber
G (2020) Next generation 3D pharmacophore modeling. Wiley Interdiscip Rev Comput Mol Sci
10(4):e1468
187. Aouidate A, Ghaleb A, Chtita S, Aarjane M, Ousaa A, Maghat H, Sbai A, Choukrad MB,
Bouachrine M, Lakhlifi T (2021) Identification of a novel dual-target scaffold for 3CLpro and
RdRp proteins of SARS-CoV-2 using 3D-similarity search, molecular docking, molecular dynam-
ics and ADMET evaluation. J Biomol Struct Dyn 39(12):4522–4535
188. Singh S, Banavath HN, Godara P, Naik B, Srivastava V, Prusty D (2022) Identification of antiviral
peptide inhibitors for receptor binding domain of SARS-CoV-2 omicron and its sub-variants: an in-
silico approach. 3 Biotech 12(9):198

Topics in Current Chemistry (2023) 381:22
1 3
22 Page 52 of 53
189. Pundir H, Joshi T, Pant M, Bhat S, Pandey J, Chandra S, Tamta S (2022) Identification of SARS-
CoV-2 RNA dependent RNA polymerase inhibitors using pharmacophore modelling, molecular
docking and molecular dynamics simulation approaches. J Biomol Struct Dyn 40(24):13366–13377
190. Aziz S, Waqas M, Mohanta TK, Halim SA, Iqbal A, Ali A, Khalid A, Abdalla AN, Khan A, Al-
Harrasi A (2023) Identifying non-nucleoside inhibitors of RNA-dependent RNA-polymerase of
SARS-CoV-2 through per-residue energy decomposition-based pharmacophore modeling, molecu-
lar docking, and molecular dynamics simulation. J Infect Public Health 16(4):501–519
191. Brunt D, Lakernick PM, Wu C (2022) Discovering new potential inhibitors to SARS-CoV-2
RNA dependent RNA polymerase (RdRp) using high throughput virtual screening and molecular
dynamics simulations. Sci Rep 12(1):19986
192. Qaisar M, Muhammad S, Iqbal J, Khera RA, Al-Sehemi AG, Alarfaji SS, Khalid M, Hussain F
(2022) Identification of marine fungi-based antiviral agents as potential inhibitors of SARS-
CoV-2 by molecular docking, ADMET and molecular dynamic study. J Comput Biophys Chem
21(02):139–153
193. Velavan TP, Meyer CG (2020) The COVID-19 epidemic. Trop Med Int Health 25(3):278
194. Lauring AS, Tenforde MW, Chappell JD, Gaglani M, Ginde AA, McNeal T, Ghamande S, Douin
DJ, Talbot HK, Casey JD (2022) Clinical severity of, and effectiveness of mRNA vaccines against,
COVID-19 from Omicron, Delta, and Alpha SARS-CoV-2 variants in the United States: prospec-
tive observational study. BMJ 376
195. Ndwandwe D, Wiysonge CS (2021) COVID-19 vaccines. Curr Opin Immunol 71:111–116
196. Ng WH, Liu X, Mahalingam S (2020) Development of vaccines for SARS-CoV-2. F1000Research
9
197. Kremer EJ (2020) Pros and cons of adenovirus-based SARS-CoV-2 vaccines. Elsevier, Amster-
dam, pp 2303–2304
198. Wang G, Dyatkina N, Prhavc M, Williams C, Serebryany V, Hu Y, Huang Y, Wan J, Wu X, Deval
J (2019) Synthesis and anti-HCV activities of 4′-fluoro-2′-substituted uridine triphosphates and
nucleotide prodrugs: discovery of 4′-fluoro-2′-C-methyluridine 5′-phosphoramidate prodrug (AL-
335) for the treatment of hepatitis C infection. J Med Chem 62(9):4555–4570
199. Wang G, Dyatkina N, Prhavc M, Williams C, Serebryany V, Hu Y, Huang Y, Wu X, Chen T,
Huang W (2020) Synthesis and anti-HCV activity of sugar-modified guanosine analogues: discov-
ery of AL-611 as an HCV NS5B polymerase inhibitor for the treatment of chronic hepatitis C. J
Med Chem 63(18):10380–10395
200. Tchesnokov EP, Feng JY, Porter DP, Götte M (2019) Mechanism of inhibition of Ebola virus
RNA-dependent RNA polymerase by remdesivir. Viruses 11(4):326
201. Zhang L, Zhou R (2020) Structural basis of the potential binding mechanism of remdesivir to
SARS-CoV-2 RNA-dependent RNA polymerase. J Phys Chem B 124(32):6955–6962
202. Qudsiani KS, Rahmasari R (2021) Polyamidoamine-remdesivir conjugate: physical stability and
cellular uptake enhancement. Biomed Pharmacol J 14(4):2073–2084
203. Ning S, Yu B, Wang Y, Wang F (2021) SARS-CoV-2: origin, evolution, and targeting inhibition.
Front Cell Infect Microbiol 11:676451
204. Serpi M, Pertusati F (2021) An overview of ProTide technology and its implications to drug dis-
covery. Expert Opin Drug Discov 16(10):1149–1161
205. Menéndez JC (2022) Approaches to the potential therapy of COVID-19: a general overview from
the medicinal chemistry perspective. Molecules 27(3):658
206. Hassanipour S, Arab-Zozani M, Amani B, Heidarzad F, Fathalipour M, Martinez-de-Hoyo R
(2021) The efficacy and safety of favipiravir in treatment of COVID-19: a systematic review and
meta-analysis of clinical trials. Sci Rep 11(1):11022
207. Malone B, Campbell EA (2021) Molnupiravir: coding for catastrophe. Nat Struct Mol Biol
28(9):706–708
208. Mishra A, Rathore AS (2022) Pharmacophore screening to identify natural origin compounds to
target RNA-dependent RNA polymerase (RdRp) of SARS-CoV2. Mol Divers 2022:1–17
209. Gao C, Chang L, Xu Z, Yan X-F, Ding C, Zhao F, Wu X, Feng L-S (2019) Recent advances of
tetrazole derivatives as potential anti-tubercular and anti-malarial agents. Eur J Med Chem
163:404–412
210. Pokhodylo N, Finiuk N, Klyuchivska O, Stoika R, Matiychuk V, Obushak M (2023) Bioisosteric
replacement of 1H–1, 2, 3-triazole with 1H-tetrazole ring enhances anti-leukemic activity of
(5-benzylthiazol-2-yl) benzamides. Eur J Med Chem 250:115126

1 3
Topics in Current Chemistry (2023) 381:22 Page 53 of 53 22
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps
and institutional affiliations.
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under
a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted
manuscript version of this article is solely governed by the terms of such publishing agreement and
applicable law.