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Infectious Disorders - Drug Targets, 2020, 20, 1-0 1
1871-5265/20 $65.00+.00 © 2020 Bentham Science Publishers
REVIEW ARTICLE
Pharmacological Strategies for COVID-19 - A Review of the Most Promis-
ing Repurposed Antiviral Drugs
Deepti Chopra1, Jaspreet K Sidhu1, Bharti Bhandari2,*, Anurag Srivastava3 and Rakesh Gupta4
1Department of Pharmacology, Government Institute of Medical Sciences, Greater Noida, Uttar Pradesh, India-
201310; 2Department of Physiology, Government Institute of Medical Sciences, Greater Noida, Uttar Pradesh, India-
201310; 3Department of Community Medicine, Government Institute of Medical Sciences, Greater Noida, Uttar
Pradesh, India- 201310; 4Department of Pediatrics Government Institute of Medical Sciences, Greater Noida, Uttar
Pradesh, India- 201310
ARTICLE HISTORY
Received: May 13, 2020
Revised: October 08, 2020
Accepted: October 22, 2020
DOI:
10.2174/1871526520666201218151841
Abstract: A novel coronavirus, SARS- CoV-2 (2019-nCoV), emerged in December 2019 as an im-
mediate global challenge. Comprehensive efforts at the present time are focused simultaneously on
containing the spread of this virus and extenuating the ill effects. There is an immediate need for
drugs that can help before a vaccine can be developed. Researchers are endeavoring to find antivi-
ral therapies specific to the virus. As the condition is an emerging, rapidly evolving situation and
development of new drugs is a long process, and is unfeasible to face the immediate global chal-
lenge. Strategy to reposition the previously used drugs can prove to be effective to combat this diffi-
cult to treat pandemic.
Several drugs such as Hydroxychloroquine, Umifenovir, Remdesivir, Lopinavir/Ritonavir, interfer-
on, Darunavir, Favipiravir, Nitazoxanide, etc. are currently undergoing clinical studies to test the
safety and efficacy of the drug against this pandemic. The present review gives a snapshot look at
the current clinical experience with repurposed antiviral drugs.
Keywords: COVID-19, 2019-nCoV, SARS- CoV-2, novel coronavirus, repurposed drugs, antiviral therapies.
1. INTRODUCTION
Multiple cases of novel coronavirus pneumonia were
identified in Wuhan, Hubei, China in December 2019 [1].
The etiological agent for this was called the 2019 novel coro-
navirus (2019-nCoV) or the severe acute respiratory syn-
drome coronavirus 2 (SARS- CoV-2). The disease caused
by SARS- CoV-2 infection is known as the Coronavirus Dis-
ease 2019 (COVID-19) [2], the symptoms of which range
from mild, self-limiting respiratory tract illness to fatal pneu-
monia, multiorgan failure, and death [3-6]. Similar to SARS
(disease that emerged in China in 2002), the Wuhan pneumo-
nia was linked to a market selling myriad species of live ani-
mals [7]. On 11 March 2020, the World Health Organization
(WHO) declared that COVID-19 is a pandemic [8].
The novel coronavirus belongs to the β-type coron-
avirus. SARS- CoV-2 is the seventh reported human infect-
ing virus belonging to the family of Coronaviridae. Coron-
aviruses are single stranded, enveloped RNA virus [9]. The
virus has protrusions that mimic a crown under the electron
microscope, hence the name coronavirus. The other coron-
aviruses include HKU1, NL63, 229E and OC43 which are re-
sponsible for causing mild respiratory disease in humans [1,
10].
*Address correspondence to this author at the Department of Physiology,
Government Institute of Medical Sciences, Greater Noida, Uttar Pradesh,
India- 201310; Tel: 08003996865; E-mail: drbhartibhandari@yahoo.co.in
Apart from the SARS- CoV-2, two other coronaviruses
have triggered major respiratory distress syndrome epi-
demics in the 21st century, a) the 2003 severe acute respirato-
ry coronavirus syndrome (SARS- CoV), b) the 2012 Middle
East respiratory coronavirus syndrome (MERS-CoV) [11,
12]. The novel coronavirus (SARS- CoV-2) has shown ge-
netic similarities with SARS- CoV and MERS-CoV [1].
The spike protein present on the SARS- CoV-2 binds to
the angiotensin-converting enzyme 2 (ACE2) receptor (host
cell receptor), followed by membrane fusion and endocyto-
sis. A cellular serine protease, Transmembrane Serine Pro-
tease 2 (TMPRSS2) helps the virus to enter the target cells
[13]. Other nonstructural proteins such as 3-chymotrypsin-
like protease also play a crucial role in processing the viral
RNA [14-16].
As the global pandemic of COVID-19 is spreading, stren-
uous efforts are being undertaken worldwide to develop
promising therapies. Up till now, there have been no drugs
or vaccines on the horizon, which is potentially active
against SARS- CoV-2, with proven effectiveness. Novel
treatments and/or vaccines will take time to develop. Howev-
er, based on previous experiences with interventions in infec-
tions caused by other viruses, there has been growing inter-
est in using existing medications for the treatment of 2019-n-
CoV. Most of these medicines for SARS- CoV-2 are being
considered based on the findings of in vitro studies and ani-
mal studies with similar viruses (like SARS- CoV, MERS-
CoV). However, some drugs that have shown positive find-
2 Infectious Disorders - Drug Targets, 2020, Vol. 20, No. 0 Chopra et al.
ings in other non-similar viruses (like HIV) are also being
considered as a potential therapeutic candidate for SARS-
CoV-2 infection [15, 17-19].
Research hitherto has identified more than 30 agents
(Western medicines, natural products, and traditional Chi-
nese medicines) that may have potential efficacy against
COVID-19 [17]. In the present review, we have discussed
the experiences of some of the most promising repurposed
antiviral drugs for SARS- CoV-2 infection, with particular
focus on the clinical trials that are underway.
2. METHODS
Relevant original research articles, case reports, case se-
ries, and review English-language articles available till June
2020 were included. The articles were retrieved from
PubMed and Google scholar. The data for the ongoing trials
was retrieved from the ClinicalTrials.gov site.
Keywords included COVID-19, 2019-nCoV, coron-
avirus, SARS- CoV-2, SARS, MERS alone and also in com-
bination with pharmacological treatment, potential interven-
tions, drug targets, antiviral therapies.
2.1. Promising Repositioned Drugs for the Novel Coron-
avirus Infections
Drugs such as Lopinavir/Ritonavir, ribavirin, umifen-
ovir, remdesivir, darunavir, favipiravir, hydroxychloroquine,
nitazoxanide, interferon, nafamostat, camostat mesylate, tei-
coplanin have been used based on the experience with
SARS and MERS or other viruses.
2.1.1. Umifenovir (Arbidol)
It is an antiviral drug approved in China and Russia for
treating influenza, SARS, and Lassa infections [20]. Studies
have shown Umefenovir (Arbidol) to be beneficial in
COVID-19 patients. Deng et al. (2020) studied two groups
of patients; one group was offered treatment with oral LPV/r
alone as monotherapy and another group was offered Arbi-
dol and Lopinavir/Ritonavir (LPV/r) combination therapy. A
favorable clinical response with Arbidol and LPV/r combina-
tion was observed [21].
In another study by Zhu et al. (2020), Lopinavir/Riton-
avir group was compared to Arbidol group. On day 14 of
treatment, viral load in Umifenovir (Arbidol) group was sig-
nificantly low as compared to Lopinavir/Ritonavir group.
The study concluded that Arbidol monotherapy may be supe-
rior to Lopinavir/Ritonavir in treating COVID-19 [22].
2.1.2. Favipiravir
It is a purine nucleic acid analog and a potent RNA-de-
pendent RNA polymerase (RdRp) inhibitor approved in Ja-
pan for use in influenza [15]. In addition to its anti-influenza
virus activity, favipiravir has been shown to be effective in
inhibiting the replication of other RNA viruses (such as fla-
vivirus, alphavirus, bunyavirus, arenaviruses) [23]. Favipi-
ravir is converted into an active form in cells and is recog-
nized as a substrate by viral RNA polymerase, thus inhibit-
ing RNA polymerase activity [24]. It is therefore expected,
favipiravir may have potential antiviral action on SARS-
CoV-2, which is an RNA virus.
Favipiravir has shown to effectively inhibit the SARS-
CoV-2 infection in Vero E6 cells [25]. It is indicated that
favipiravir has more potent antiviral action than that of Lopi-
navir/Ritonavir. In the clinical study conducted in Shenzhen,
China, the effects of Favipiravir and Lopinavir/Ritonavir
were compared. It was observed that Favipiravir 1,600 mg
orally twice on Day 1 followed by Favipiravir 600 mg twice
daily with interferon-alpha (IFN-alpha) aerosol inhalation
(days 2-14), led to faster viral clearance than the Lopi-
navir/Ritonavir plus IFN-alpha aerosol inhalation group (14
days). There was also significant improvement in chest imag-
ing. The number of adverse events in the Favipiravir arm of
the study was also significantly fewer than that in the con-
trol arm [26].
In a study done by Chen et al., Favipiravir was found to
be more effective for patients of COVID-19 without any co-
morbidities (diabetes, hypertension). The 7 days clinical re-
covery rate was higher in Favipiravir group as compared to
the Arbidol group [27].
2.1.3. Remdesivir (RDV)
It is an adenosine analogue antiviral, currently in clinical
development for treatment of Ebola virus disease [15, 28]
Remdesivir is a prodrug that requires metabolism by the
host cell to form the pharmacologically active triphosphate,
which inhibits viral RNA polymerase and evades proofread-
ing by viral exonuclease and inhibits virus replication. It in-
corporates into nascent viral RNA and results in premature
chain termination [15, 29].
Remdesivir has been recognized as a promising broad
spectrum antiviral drug effective against a wide range of
RNA viruses (including SARS/MERS-CoV) infection in hu-
man airway epithelial cells [30].
RDV and IFN-beta were found to possess superior in
vitro antiviral activity against MERS-CoV as compared with
Lopinavir (LPV) and Ritonavir (RTV). Prophylactic and
therapeutic Remedesivir diminishes MERS-CoV replication
and improve pulmonary function and reduce lung viral loads
and severe lung pathology in MERS-CoV mouse model
[31].
In another study, the efficacy of prophylactic and thera-
peutic Remdesivir treatment in nonhuman primate (rhesus
macaque) model of MERS-CoV infection was studied. The
results showed that prophylactic Remdesivir treatment (24
hours prior to inoculation) completely prevented MERS-
CoV induced clinical disease by inhibiting MERS-CoV repli-
cation. Similarly, therapeutic Remdesivir, if given 12 hours
postinoculation, also provided benefit [32]. Wang et al.
found that Remdesivir potently blocks SARS- CoV-2 infec-
tion at low micromolar concentrations and has a high selec-
tivity index. The authors demonstrated that Remdesivir func-
tions at post virus entry stage [25].
Holshue et al. reported a case of a 2019-nCoV infection
in the United States, who was successfully treated with intra-
Pharmacological Strategies for COVID-19 Infectious Disorders - Drug Targets, 2020, Vol. 20, No. 0 3
venous Remdesivir, no adverse effects were observed in as-
sociation with the infusion [33].
2.1.4. Lopinavir/ Ritonavir (LPVr)
This is an approved oral combination drug for treating
HIV.
LPV is a protease inhibitor, which is combined with Rito-
navir (RTV) to increase the LPV half-life, may inhibit the ac-
tion of 3-chymotrypsin-like protease (3CLpro), thereby dis-
rupting the process of viral replication and release from host
cells [34, 35].
Preliminary evidence of the effectiveness of Lopi-
navir/Ritonavir against other coronaviruses is present.
LPV/RTV was shown to be effective against SARS- CoV in
patients and in tissue culture.
Kim et al. had also reported a successful case of MERS-
CoV disease treated with triple combination therapy
LPV/RTV, Ribavirin, and IFN-alpha 2a in South Korea
[36]. Chu et al. found that Lopinavir/ Ritonavir has an-
ti-SARS- CoV activity in vitro and in clinical studies. The
authors concluded that the use of LPV/RTV with Ribavirin
in the treatment of SARS was associated with less adverse
clinical outcomes (ARDS or death) [34].
Currently, there is no strong evidence of efficacy of Lopi-
navir/Ritonavir in the treatment of COVID-19 [15]. There
are no reported in vitro studies of this combination against
the SARS- CoV-2 virus [37]. Few clinical studies have pro-
vided some clues for treatment of 2019-nCoV pneumonia
[37, 38]. Wang et al. reported the characteristics of four pa-
tients of COVID-19 who were given antiviral treatment, in-
cluding Lopinavir/Ritonavir, Arbidol, and a traditional Chi-
nese medicine along with supportive care. They found that
after treatment, three patients showed significant improve-
ment in symptoms [38].
Evidence from literature shows the recovery of patients
treated with Lopinavir/Ritonavir in combination with the an-
ti-flu drug Oseltamivir [39]. Cao and colleagues' study con-
cluded that in hospitalized adult patients with severe
Covid-19, no additional benefit was observed with Lopi-
navir/Ritonavir treatment (400 mg and 100 mg, respective-
ly) twice a day for 14 days than the standard care [40].
2.1.5. Darunavir
Evidence from in vitro studies demonstrated activity of
darunavir (second-generation of HIV-1 protease inhibitor)
against SARS- CoV-2, but no clinical studies are available
[15].
2.1.6. Chloroquine and Hydroxychloroquine
Chloroquine and Hydroxychloroquine (antimalarial
drugs) have been used for the treatment of several chronic in-
flammatory diseases such as systemic lupus erythematosus
and rheumatoid arthritis. Hydroxychloroquine, has a better
clinical safety profile and fewer drug–drug interactions as
compared to chloroquine and has fewer adverse effects on
patients. Hydroxychloroquine (HCQ) is commonly pre-
scribed for various dermatological indications such as derma-
tomyositis, sarcoidosis, polymorphous light eruptions, chron-
ic actinic dermatitis, lichen planus [41].
Evidence from studies have shown that 4-aminoquino-
lines (Chloroquine and HCQ) are active in vitro against a
range of viruses [42]. In vitro studies report antiviral activity
of chloroquine and HCQ against SARS- CoV-2. Manli
Wang et al. reported that Chloroquine potently blocked
2019-nCoV infection in Vero E6 cells at low-micromolar
concentration and showed high selectivity index [25].
2.1.7. Mechanism of Action
Chloroquine and Hydroxychloroquine are weak bases
and increase endosomal pH, they inactivate enzymes that
viruses require for replication and interferes with glycosyla-
tion of angiotensin converting enzyme-2, (the receptor that
SARS- CoV-2 uses to enter cells). Thereby, possess the po-
tential to block viral infection [15, 43].
These agents also have immunomodulatory effects, can
block the production of interleukin-6 and other pro-inflam-
matory cytokines, which are key mediators of acute respira-
tory distress syndrome (ARDS). The drugs inhibit autopha-
gy and lysosomal activity in host cells [44, 45].
Although empirical evidence for the effectiveness of
Chloroquine and Hydroxychloroquine in COVID-19 is cur-
rently very limited. Nevertheless, the results of chloroquine
and hydroxychloroquine trials against COVID-19, are found
to be more promising than previous trials in other viral dis-
eases.
Results of the first clinical results were reported in the
news from China. Study done with 100 patients with mild to
severe COVID-19 pneumonia, reported that chloroquine
twice daily is superior to the control group in reducing symp-
tom duration, radiological improvement and promoting virus
negative seroconversion [15, 46]. The study by Gautret, P et
al. (2020) found that use of HCQ alone and in combination
with azithromycin in COVID-19 patients was highly and sig-
nificantly effective in clearing viral nasopharyngeal carriage
in only three to six day. However, the combination therapy
with azithromycin and HCQ resulted in superior viral clear-
ance [47]. Another study from China by Chen et al., evaluat-
ed the efficacy and safety of HCQ in 30 COVID-19 patients.
The treatment group received HCQ 400 mg per day for 5
days plus conventional treatment, while those in the control
group were given conventional treatment only. The authors
found a comparable duration of virological clearance and
body temperature normalization [48].
2.1.8. Nitazoxanide
Nitazoxanide is an antiprotozoal agent with broad antivi-
ral activity and a relatively favorable safety profile. Nitazox-
anide has demonstrated in vitro antiviral activity against
MERS and SARS- CoV-2 at a low-micromolar concentra-
tion [25, 49].
4 Infectious Disorders - Drug Targets, 2020, Vol. 20, No. 0 Chopra et al.
Table 1. The table below shows the details of the trials with respect to the drugs used.
SN Drug Total Trials Early Phase
1Phase 1 Phase 2 Phase 3 Phase 4 Trials Completed Trials Terminated/withdrawn/suspended
1. Hydroxychloroquine 257 5 10 84 113 21 33 34
2. Chloroquine 90 1 3 29 36 11 10 6
3. Ribavirin 13 1 3 5 3 Nil 3 Nil
4. Lopinavir 86 Nil 4 35 30 5 10 3
5. Umifenovir 10 Nil 1 Nil 2 3 1 Nil
6. Favipiravir 37 Nil 4 14 15 1 7 1
7. Remdesivir 59 1 7 22 23 Nil 7 3
8. Darunavir 10 Nil Nil 3 2 1 Nil Nil
9. Oseltamivir 20 Nil 2 2 2 11 1 1
10. Corticosteroids 71 Nil 3 17 14 8 9 3
11. Interferon 98 2 8 43 22 7 9 1
12. Sarilumab 16 1 1 10 5 1 4 1
13. Tocilizumab 70 1 4 31 20 2 8 5
14. Leronlimab 2 Nil Nil 2 Nil Nil Nil Nil
15. Lenzilumab 2 Nil Nil Nil 2 Nil Nil Nil
16. Teicoplanin 2 Nil Nil 2 Nil Nil 1 Nil
17. Nafamostat 4 Nil Nil 3 4 Nil Nil Nil
18. Nitazoxanide 23 Nil Nil 14 11 3 1 Nil
Table 2. Showing details of the trials for the most promising antiviral drugs used for COVID-19.
SN Drug Study Title Interventions Participants Phase Location Primary Out-
come Measure
Trial Identi-
fier Status
1. Favipiravir
Favipiravir combined
with Tocilizumab in the
treatment of Coronavirus
disease in 2019
Favipiravir combined
with Tocilizumab,
Favipiravir,
Tocilizumab.
150 Not appli-
cable China Clinical cure
rate NCT04310228 Recruiting
2. Favipiravir
Coronavirus disease
2019 patients whose nu-
cleic acids changed from
negative to positive
Favipiravir 210 Not appli-
cable China
Viral nucleic
acid test nega-
tive conversion
rate
NCT04333589 Recruiting
3. Favipiravir
Efficacy and safety of
Favipiravir in manage-
ment of Covid-19
Favipiravir
Standard care therapy 100 Phase 3 Egypt
Viral clearance
Clinical improve-
ment
NCT04349241 Completed
4. Favipiravir
Treatments to decrease
the risk of hospitalization
or death in elderly outpa-
tients with symptomatic
SARS- CoV-2 infection
Dietary supplement
Hydroxychloroquine,
Imatinib,
Favipiravir,
Telmisartan
1057 Phase 3 France
-Proportion of
participants with
an occurrence of
hospitalization
Death
NCT04356495 Not yet re-
cruiting
5. Umifenovir
Clinical study of Arbidol
hydrochloride tablets in
the treatment of pneumo-
nia caused by Novel coro-
navirus
Arbidol
Basic treatment 380 Phase 4
Virus negative
conversion rate
in the first week
NCT04260594 Not yet re-
cruiting
6. Umifenovir
The clinical study of car-
rimycin on treatment pa-
tients with COVID-19
Carrimycin
Lopinavir/Ritonavir or
Arbidol or chloroquine
phosphate
or
Basic treatment
520 Phase 4 China
Fever to normal
time
Pulmonary in-
flammtion reso-
lution time
Negative conver-
sion
NCT04286503 Not yet re-
cruiting
7. Umifenovir Umifenovir in hospital-
ized COVID-19 patients
Umifenovir
Interferon-β1a
Lopinavir/Ritonavir
Single dose hydrox-
ychloroquine
Standards of care
40 Phase 4 Iran Time to clinical
improvement NCT04350684
Enrolling
by invita-
tion
Pharmacological Strategies for COVID-19 Infectious Disorders - Drug Targets, 2020, Vol. 20, No. 0 5
SN Drug Study Title Interventions Participants Phase Location Primary Out-
come Measure
Trial Identi-
fier Status
8. Umifenovir
Efficacy of natural honey
treatment in patients with
novel coronavirus
Natural honey
Standard of care and
Lopinavir/Ritonavir or
Arbidol or chloroquine
phosphate or hydrox-
yxhloroquine or osel-
tamivir with or without
azithromycin
1000 Phase 3 Egypt
Rate of recovery
from positive to
negative swabs
-Fever to normal
temperature in
days
Resolution of
lung inflamma-
tion in CT or X
ray
NCT04323345 Recruiting
9. Umifenovir
Evaluating the efficacy
and safety of bromhexine
hydrochloride tablets
combined with standard
treatment/ standard treat-
ment in patients with sus-
pected and mild novel
coronavirus pneumonia
Bromhexine hydrochlo-
ride tablets
Arbidol hydrochloride
granules
Recombinant human in-
terferon α2b spray
60 Not appli-
cable China
Time to clinical
recovery after
treatment
Rate of aggrava-
tion
NCT04273763 Active, not
recruiting
10. Umifenovir
Evaluating and compar-
ing the safety and effi-
ciency of ASC09/Riton-
avir and Lopinavir/Riton-
avir for novel coron-
avirus infection
ASC09/Ritonavir
Lopinavir/Ritonavir 160 Not appli-
cable
Incidence of
composite ad-
verse outcome
NCT04261907 Not yet re-
cruiting
11. Remdesivir
Study to evaluate the
safety and antiviral activi-
ty of remdesivir in partici-
pant with severe coron-
avirus disease
Remdesivir
Standard of care 6000 Phase 3 United
states
Odds of ratio for
improvement on
a 7 point ordinal
scale on day 14
NCT04292899 Completed
12. Remdesivir
Study to evaluate the
safety and antiviral activi-
ty of remdesivir in partici-
pant with moderate coron-
avirus disease compared
to standard of care treat-
ment
Remdesivir
Standard of care 1600 Phase 3 United
states
Odds of ratio for
improvement on
a 7 point ordinal
scale on day 11
NCT04292730 Completed
13. Remdesivir Adaptive COVID-19 trat-
ment trial
Remdesivir
Placebo 572 Phase 3 United
States
Time to recov-
ery NCT04280705 Completed
14. Remdesivir
Trial of treatments for
COVID-19 in hospital-
ized adults
Remdesivir
Loinavir/Ritonavir
Interferon beta-1A
Hydroxychlororquine
Standard of care
3100 Phas e 3 France
Percentage of
subjects report-
ing each severi-
ty rating on a 7-
point ordinal
scale
NCT04315948 Recruiting
15. Remdesivir
The efficacy of different
anti-viral drugs in
COVID 19 infected pa-
tients
Hydroxychloroquine
Remdesivir
Standard of care
700 Phase 3 Norway In hospital mor-
tality NCT04321616 Recruiting
16. Remdesivir
Long-term use of drugs
that could prevent the
risk of serious coiv-19 in-
fections or make it worse
Synthetic anti-malarial
drugs 6000000 France
Identification of
serious covid-19
infections
NCT04356417 Not yet re-
cruiting
17. Hydroxychloroquine
Efficacy and safety of hy-
droxychloroquine for
treatment of covid-19
Hydroxychloroquine 30 Phase 3 China
Virological clear-
ance rate of
throat swabs,
sputum, or low-
er respiratory
tract secreations
at day3,5 & 7
mortality rate of
subjects at
weeks 2
NCT04261517 Completed
18. Hydroxychloroquine
An investgation into ben-
eficial effects of interfer-
on beta 1a, compared to
interferon beta 1b and
base therapeutic regi-
ment in moderate to se-
vere Covid-19: A ran-
domized clinical trial
Hydroxychloroquine
Lopinavir/Ritonavir
Interferon beta 1a
60 Phase 4 Iran Time to clinical
improvement NCT04343768 Completed
6 Infectious Disorders - Drug Targets, 2020, Vol. 20, No. 0 Chopra et al.
SN Drug Study Title Interventions Participants Phase Location Primary Out-
come Measure
Trial Identi-
fier Status
19 Hydroxychloroquine
A Multi-center, Ran-
domized, Double-blind-
ed, Placebo-controlled
Study to Evaluate the
Safety and Efficacy of
Hydroxychloroquine
Monotherapy and in
Combination With
Azithromycin in Patients
With Moderate and Se-
vere COVID-19 Disease
Hydroxychloroquine
with/without
azithromycin/Placebo
20 Not appli-
cable
United
States
Percentage of
participants who
achieve clinical
response
NCT04358081 Completed
2.1.9. Interferons
These are broad-spectrum antivirals mainly used in the
management of hepatitis B and C [50, 51]. Interferon (IFN)
has demonstrated higher antiviral activity in in vitro studies
in SARS- CoV. IFN-β was found to be the most potent in in-
hibiting in vitro viral replication as compared to IFN-α and
IFN-γ [52]. In a study by Cinatl et al. (2003), it was conclud-
ed that Interferon β could be useful alone or in combination
with other antiviral drugs for the treatment of SARS [53].
Chan JF et al. (2015) found that Lopinavir/Ritonavir-treated
and interferon-β1b-treated marmosets had a better outcome
of MERS-CoV Infection as compared to the untreated ani-
mals [54]. Evidence from literature have demonstrated the
benefits of using interferons in combination with high dose
corticosteroids or Lopinavir/Ritonavir in SARS- CoV pa-
tients [55].
2.1.10. Nafamostat
It is a Serine protease inhibitor that has shown to inhibit
Middle East respiratory syndrome coronavirus entry into hu-
man epithelial cells. Recently Nafamostat has also shown to
inhibit the entry of SARS- CoV-2 into the human epithelial
cells. Proposed mechanisms for its therapeutic action in-
clude directly blocking the virus entry in host epithelial cells
and inhibition of intravascular coagulopathy [56, 57]. Doi et
al. (2020), in a case series, have documented the benefits of
Nafamostat mesylate and Favipiravir combination therapy in
COVID-19 patients [58]. Camostat mesylate, inhibitor of
TMPRSS2, has shown to significantly reduce lung cell line
infection with SARS- CoV-2 and could be considered for
COVID-19 treatment [59].
2.1.11. Teicoplanin
It is a glycopeptide antibiotic that has shown efficacy
against various viruses such as Ebola virus, influenza virus,
flavivirus, hepatitis C virus and human immunodeficiency
virus (HIV) including MERS-CoV and SARS- CoV [60].
Proposed mechanism is blocking viral entry in the cell by in-
hibiting cleavage of the viral spike protein by cathepsin L.
This has also been shown for SARS- CoV-2 [60, 61].
3. CURRENT STATUS IN INDIA
Use of HCQ is now permitted by the US Food and Drug
Administration and by the Ministry of Health & Family Wel-
fare (MOHFW), Government of India also. MOHFW, rec-
ommends the use of Hydroxychloroquine (400mg twice dai-
ly for 1 day followed by 200mg twice daily for 4 days) in
combination with Azithromycin (500 mg once daily for 5
days) as off label indication in patients with severe disease
and requiring ICU management. MOHFW also recommends
prophylaxis with Hydroxychloroquine 400mg twice a day
on Day 1, followed by 400mg once weekly for the next 7
weeks for asymptomatic healthcare workers involved in the
care of suspected or confirmed COVID-19 patients. For pro-
phylaxis of the asymptomatic household contacts of con-
firmed cases, Hydroxychloroquine 400mg twice a day on
Day 1, followed by 400mg once weekly for the next 3
weeks. As no drug is guaranteed to be totally safe, physi-
cians and patients should be aware, and drugs should be ad-
ministered under close medical supervision, with monitoring
for adverse effects [62].
3.1. Glance of the Ongoing Clinical Trials
We searched clinicaltrials.gov for trials registered for ma-
nagement of Covid-19 using search terms- COVID-19, coro-
navirus and drugs. The search as of 23rd April 2020 re-
vealed that a total of 309 trials have been registered so far. A
further search was carried to know the number of trials regis-
tered with specific drugs, which is depicted in Table 1.
Table 2 depicts the details of ongoing trials on some of the
most promising repurposed antiviral drugs used for the treat-
ment of COVID-19 and the trials on hydroxychloroquine
which have been completed [63].
The primary focus of COVID-19 treatment was on the
antiviral activity of various drugs. However, changing trends
in the pathogenesis and presentation of the disease have
brought into focus the role of anti-coagulants. As the current
review primarily focuses on repurposed anti-viral drugs, we
have not discussed the role of other therapeutic options in-
cluding anti-coagulants, steroids or convalescent plasma.
RNA viruses like the SARS- CoV-2 undergo rapid muta-
tion, this finding is corroborating with the presence of vary-
ing strains of this virus throughout the world. The varying
mutation could lead to resistance of the existing therapeutic
drugs and this fact cannot be left unattended. Hence continu-
ous process of newer drug designing and discovery for
SARS- CoV-2 is the need of the hour. Newer methods of
drug designing and prediction of drug targets like bioinfor-
matics, cheminformatics, structure-based drug design, net-
work based methodology would be helpful for expedited
drug development [64].
Pharmacological Strategies for COVID-19 Infectious Disorders - Drug Targets, 2020, Vol. 20, No. 0 7
CONCLUSION
COVID-19 pandemic has entered a phase beyond con-
tainment, which stresses the need for the availability of effec-
tive antiviral treatments. Worldwide research and collabora-
tion to combat the disease is the need of the hour. The pre-
sent review has focused on the treatment options which are
being considered according to previous treatments of SARS
and MERS. The efficacy and safety of these repurposed
drugs for 2019-nCoV infection patients are now being as-
sessed by further clinical trials. As no specific validated
treatment currently exists, any recommendation needs to be
used with caution
LIST OF ABBREVIATIONS
COVID-19 = Coronavirus Disease 2019
SARS- CoV-2 = Severe Acute Respiratory Syndrome
Coronavirus 2
ACE2 = Angiotensin-Converting Enzyme 2
SARS = Severe Acute Respiratory Syndrome
MERS = Middle East Respiratory Syndrome
ARDS = Acute Respiratory Distress Syndrome
LPV/r = Lopinavir/Ritonavir
RdRp = RNA-dependent RNA Polymerase
IFN-alpha = Interferon-alpha
RDV = Remdesivir
RTV = Ritonavir
IFN = Interferons
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors have no conflicts of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none
REFERENCES
Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao,[1]
X.; Huang, B.; Shi, W.; Lu, R.; Niu, P.; Zhan, F.; Ma, X.; Wang,
D.; Xu, W.; Wu, G.; Gao, G.F.; Tan, W. China Novel Coronavirus
Investigating and Research Team. A novel coronavirus from pa-
tients with pneumonia in China, 2019. N. Engl. J. Med., 2020,
382(8), 727-733.
http://dx.doi.org/10.1056/NEJMoa2001017 PMID: 31978945
https://www.who.int/emergencies/diseases/novel-coron-[2]
avirus-2019/technical-guidance/naming-the-coronavirus-disease-(-
covid-2019)-and-the-virus-that-causes-it2020.
Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.;[3]
Fan, G.; Xu, J.; Gu, X.; Cheng, Z.; Yu, T.; Xia, J.; Wei, Y.; Wu,
W.; Xie, X.; Yin, W.; Li, H.; Liu, M.; Xiao, Y.; Gao, H.; Guo, L.;
Xie, J.; Wang, G.; Jiang, R.; Gao, Z.; Jin, Q.; Wang, J.; Cao, B.
Clinical features of patients infected with 2019 novel coronavirus
in Wuhan, China. Lancet, 2020, 395(10223), 497-506.
http://dx.doi.org/10.1016/S0140-6736(20)30183-5 PMID:
31986264
Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.;[4]
Wang, J.; Liu, Y.; Wei, Y.; Xia, J.; Yu, T.; Zhang, X.; Zhang, L.
Epidemiological and clinical characteristics of 99 cases of 2019
novel coronavirus pneumonia in Wuhan, China: a descriptive
study. Lancet, 2020, 395(10223), 507-513.
http://dx.doi.org/10.1016/S0140-6736(20)30211-7 PMID:
32007143
Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.;[5]
Xiang, H.; Cheng, Z.; Xiong, Y.; Zhao, Y.; Li, Y.; Wang, X.;
Peng, Z. Clinical Characteristics of 138 Hospitalized Patients
With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, Chi-
na. JAMA, 2020, 323(11), 1061-1069.
http://dx.doi.org/10.1001/jama.2020.1585 PMID: 32031570
Liu, K.; Fang, Y.Y.; Deng, Y.; Liu, W.; Wang, M.F.; Ma, J.P.;[6]
Xiao, W.; Wang, Y.N.; Zhong, M.H.; Li, C.H.; Li, G.C.; Liu,
H.G. Clinical characteristics of novel coronavirus cases in tertiary
hospitals in Hubei Province. Chin. Med. J. (Engl.), 2020, 133(9),
1025-1031.
http://dx.doi.org/10.1097/CM9.0000000000000744 PMID:
32044814
Cohen, J.; Normile, D. New SARS- like virus in China triggers[7]
alarm. Science, 2020, 367(6475), 234-235.
http://dx.doi.org/10.1126/science.367.6475.234 PMID: 31949058
World Health Organization (WHO). Novel Coronavirus (2019-n-[8]
CoV) Situation Report – 52,
2020.www.who.int/docs/default-source/coronaviruse/situation-rep
orts/20200312-sitrep-52-covid-19.pdf?sfvrsn=e2bfc9c0_4
Fung, T.S.; Liu, D.X. Human Coronavirus: Host-Pathogen Interac-[9]
tion. Annu. Rev. Microbiol., 2019, 73, 529-557.
http://dx.doi.org/10.1146/annurev-micro-020518-115759 PMID:
31226023
Li, H.; Wang, Y.M.; Xu, J.Y.; Cao, B. 2019 new coronavirus an-[10]
tiviral therapy is available. Zhonghua Jie He He Hu Xi Za Zhi,
2020, 43, E002.
PMID: 32023685
Rosa, S.G.V.; Santos, W.C. Clinical trials on drug repositioning[11]
for COVID-19 treatment. Rev. Panam. Salud Publica, 2020, 44,
e40.
http://dx.doi.org/10.26633/RPSP.2020.40 PMID: 32256547
Martinez, M.A. Compounds with therapeutic potential against nov-[12]
el respiratory 2019 coronavirus. Antimicrob. Agents Chemother.,
2020, 64(5)
http://dx.doi.org/10.1128/AAC.00399-20 PMID: 32152082
Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herr-[13]
ler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.;
Nitsche, A.; Müller, M.A.; Drosten, C.; Pöhlmann, S. SARS- CoV-
-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a
clinically proven protease inhibitor. Cell, 2020, 181(2),
271-280.e8.
http://dx.doi.org/10.1016/j.cell.2020.02.052 PMID: 32142651
Chen, Y.; Liu, Q.; Guo, D. Emerging coronaviruses: Genome[14]
structure, replication, and pathogenesis. J. Med. Virol., 2020,
92(4), 418-423.
http://dx.doi.org/10.1002/jmv.25681 PMID: 31967327
Sanders, J.M.; Monogue, M.L.; Jodlowski, T.Z.; Cutrell, J.B. Phar-[15]
macologic Treatments for Coronavirus Disease 2019
(COVID-19): A Review. JAMA, 2020, 323(18), 1824-1836.
http://dx.doi.org/10.1001/jama.2020.6019 PMID: 32282022
Prajapat, M.; Sarma, P.; Shekhar, N.; Avti, P.; Sinha, S.; Kaur, H.;[16]
Kumar, S.; Bhattacharyya, A.; Kumar, H.; Bansal, S.; Medhi, B.
Drug targets for corona virus: A systematic review. Indian J. Phar-
macol., 2020, 52(1), 56-65.
http://dx.doi.org/10.4103/ijp.IJP_115_20 PMID: 32201449
Dong, L.; Hu, S.; Gao, J. Discovering drugs to treat coronavirus[17]
disease 2019 (COVID-19). Drug Discov. Ther., 2020, 14(1),
8 Infectious Disorders - Drug Targets, 2020, Vol. 20, No. 0 Chopra et al.
58-60.
http://dx.doi.org/10.5582/ddt.2020.01012 PMID: 32147628
Senanayake, S.L. Drug repurposing strategies for COVID-19. Fu-[18]
ture Drug. Discov., 2020, 2(2), FDD40.
Singhal, T. A Review of Coronavirus Disease-2019 (COVID-19).[19]
Indian J. Pediatr., 2020, 87(4), 281-286.
http://dx.doi.org/10.1007/s12098-020-03263-6 PMID: 32166607
Hulseberg, C.E.; Fénéant, L.; Szymańska-de Wijs, K.M.; Kessler,[20]
N.P.; Nelson, E.A.; Shoemaker, C.J.; Schmaljohn, C.S.; Polyak,
S.J.; White, J.M. Arbidol and Other Low-Molecular-Weight
Drugs That Inhibit Lassa and Ebola Viruses. J. Virol., 2019,
93(8), e02185-e18.
http://dx.doi.org/10.1128/JVI.02185-18 PMID: 30700611
Deng, L.; Li, C.; Zeng, Q.; Liu, X.; Li, X.; Zhang, H.; Hong, Z.;[21]
Xia, J. Arbidol combined with LPV/r versus LPV/r alone against
Corona Virus Disease 2019: A retrospective cohort study. J. In-
fect., 2020, 81(1), e1-e5.
http://dx.doi.org/10.1016/j.jinf.2020.03.002 PMID: 32171872
Zhu, Z.; Lu, Z.; Xu, T.; Chen, C.; Yang, G.; Zha, T.; Lu, J.; Xue,[22]
Y. Arbidol monotherapy is superior to lopinavir/ritonavir in treat-
ing COVID-19. J. Infect., 2020, 81(1), e21-e23.
http://dx.doi.org/10.1016/j.jinf.2020.03.060 PMID: 32283143
Delang, L.; Abdelnabi, R.; Neyts, J. Favipiravir as a potential[23]
countermeasure against neglected and emerging RNA viruses. An-
tiviral Res., 2018, 153, 85-94.
http://dx.doi.org/10.1016/j.antiviral.2018.03.003 PMID: 29524445
Furuta, Y.; Komeno, T.; Nakamura, T. Favipiravir (T-705), a[24]
broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn.
Acad., Ser. B, Phys. Biol. Sci., 2017, 93(7), 449-463.
http://dx.doi.org/10.2183/pjab.93.027 PMID: 28769016
Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.;[25]
Hu, Z.; Zhong, W.; Xiao, G. Remdesivir and chloroquine effective-
ly inhibit the recently emerged novel coronavirus (2019-nCoV) in
vitro. Cell Res., 2020, 30(3), 269-271.
http://dx.doi.org/10.1038/s41422-020-0282-0 PMID: 32020029
Cai, Q.; Yang, M.; Liu, D.; Chen, J.; Shu, D.; Xia, J.; Liao, X.;[26]
Gu, Y.; Cai, Q.; Yang, Y.; Shen, C.; Li, X.; Peng, L.; Huang, D.;
Zhang, J.; Zhang, S.; Wang, F.; Liu, J.; Chen, L.; Chen, S.; Wang,
Z.; Zhang, Z.; Cao, R.; Zhong, W.; Liu, Y.; Liu, L. Experimental
Treatment with Favipiravir for COVID-19: An Open-Label Con-
trol Study. Engineering (Beijing), 2020.
http://dx.doi.org/10.1016/j.eng.2020.03.007 PMID: 32346491
Chen, C.; Zhang, Y.; Huang, J.; Yin, P. Favipiravir versus Arbidol[27]
for COVID-19: A Randomized Clinical Trial. https://www.me-
drxiv.org/content/10.1101/2020.03.17.20037432v4
Jacobs, M.; Rodger, A.; Bell, D.J.; Bhagani, S.; Cropley, I.; Filipe,[28]
A.; Gifford, R.J.; Hopkins, S.; Hughes, J.; Jabeen, F.; Johan-
nessen, I.; Karageorgopoulos, D.; Lackenby, A.; Lester, R.; Liu,
R.S.; MacConnachie, A.; Mahungu, T.; Martin, D.; Marshall, N.;
Mepham, S.; Orton, R.; Palmarini, M.; Patel, M.; Perry, C.; Peters,
S.E.; Porter, D.; Ritchie, D.; Ritchie, N.D.; Seaton, R.A.; Sreenu,
V.B.; Templeton, K.; Warren, S.; Wilkie, G.S.; Zambon, M.; Go-
pal, R.; Thomson, E.C. Late Ebola virus relapse causing menin-
goencephalitis: a case report. Lancet, 2016, 388(10043), 498-503,
498-503.
http://dx.doi.org/10.1016/S0140-6736(16)30386-5 PMID:
27209148
Al-Tawfiq, J.A.; Al-Homoud, A.H.; Memish, Z.A. Remdesivir as[29]
a possible therapeutic option for the COVID-19. Travel Med. In-
fect. Dis., 2020, 34
http://dx.doi.org/10.1016/j.tmaid.2020.101615 PMID: 32145386
Sheahan, T.P.; Sims, A.C.; Graham, R.L.; Menachery, V.D.;[30]
Gralinski, L.E.; Case, J.B.; Leist, S.R.; Pyrc, K.; Feng, J.Y.;
Trantcheva, I.; Bannister, R.; Park, Y.; Babusis, D.; Clarke, M.O.;
Mackman, R.L.; Spahn, J.E.; Palmiotti, C.A.; Siegel, D.; Ray,
A.S.; Cihlar, T.; Jordan, R.; Denison, M.R.; Baric, R.S. Broad-
-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic
coronaviruses. Sci. Transl. Med., 2017, 9(396)
http://dx.doi.org/10.1126/scitranslmed.aal3653 PMID: 28659436
Sheahan, T.P.; Sims, A.C.; Leist, S.R.; Schäfer, A.; Won, J.;[31]
Brown, A.J.; Montgomery, S.A.; Hogg, A.; Babusis, D.; Clarke,
M.O.; Spahn, J.E.; Bauer, L.; Sellers, S.; Porter, D.; Feng, J.Y.;
Cihlar, T.; Jordan, R.; Denison, M.R.; Baric, R.S. Comparative
therapeutic efficacy of remdesivir and combination lopinavir, rito-
navir, and interferon beta against MERS-CoV. Nat. Commun.,
2020, 11(1), 222.
http://dx.doi.org/10.1038/s41467-019-13940-6 PMID: 31924756
de Wit, E.; Feldmann, F.; Cronin, J.; Jordan, R.; Okumura, A.;[32]
Thomas, T.; Scott, D.; Cihlar, T.; Feldmann, H. Prophylactic and
therapeutic remdesivir (GS-5734) treatment in the rhesus macaque
model of MERS-CoV infection. Proc. Natl. Acad. Sci. USA, 2020,
117(12), 6771-6776.
http://dx.doi.org/10.1073/pnas.1922083117 PMID: 32054787
Holshue, M.L.; DeBolt, C.; Lindquist, S.; Lofy, K.H.; Wiesman,[33]
J.; Bruce, H.; Spitters, C.; Ericson, K.; Wilkerson, S.; Tural, A.;
Diaz, G.; Cohn, A.; Fox, L.; Patel, A.; Gerber, S.I.; Kim, L.;
Tong, S.; Lu, X.; Lindstrom, S.; Pallansch, M.A.; Weldon, W.C.;
Biggs, H.M.; Uyeki, T.M.; Pillai, S.K. Washington State 2019-n-
CoV Case Investigation Team. First Case of 2019 Novel Coron-
avirus in the United States. N. Engl. J. Med., 2020, 382(10),
929-936.
http://dx.doi.org/10.1056/NEJMoa2001191 PMID: 32004427
Chu, C.M.; Cheng, V.C.; Hung, I.F.; Wong, M.M.; Chan, K.H.;[34]
Chan, K.S.; Kao, R.Y.; Poon, L.L.; Wong, C.L.; Guan, Y.; Peiris,
J.S.; Yuen, K.Y. HKU/UCH SARS Study Group. Role of lopi-
navir/ritonavir in the treatment of SARS: initial virological and
clinical findings. Thorax, 2004, 59(3), 252-256.
http://dx.doi.org/10.1136/thorax.2003.012658 PMID: 14985565
de Wilde, A.H.; Jochmans, D.; Posthuma, C.C.; Zevenhoven-[35]
Dobbe, J.C.; van Nieuwkoop, S.; Bestebroer, T.M.; van den Hoo-
gen, B.G.; Neyts, J.; Snijder, E.J. Screening of an FDA-approved
compound library identifies four small-molecule inhibitors of Mid-
dle East respiratory syndrome coronavirus replication in cell cul-
ture. Antimicrob. Agents Chemother., 2014, 58(8), 4875-4884.
http://dx.doi.org/10.1128/AAC.03011-14 PMID: 24841269
Kim, U.J.; Won, E.J.; Kee, S.J.; Jung, S.I.; Jang, H.C. Combina-[36]
tion therapy with lopinavir/ritonavir, ribavirin and interferon-α for
Middle East respiratory syndrome. Antivir. Ther., 2016, 21(5),
455-459.
http://dx.doi.org/10.3851/IMP3002 PMID: 26492219
Yao, T.T.; Qian, J.D.; Zhu, W.Y.; Wang, Y.; Wang, G.Q. A syste-[37]
matic review of lopinavir therapy for SARS coronavirus and
MERS coronavirus-A possible reference for coronavirus dis-
ease-19 treatment option. J. Med. Virol., 2020, 92(6), 556-563.
http://dx.doi.org/10.1002/jmv.25729 PMID: 32104907
Wang, Z.; Chen, X.; Lu, Y.; Chen, F.; Zhang, W. Clinical charac-[38]
teristics and therapeutic procedure for four cases with 2019 novel
coronavirus pneumonia receiving combined Chinese and Western
medicine treatment. Biosci. Trends, 2020, 14(1), 64-68.
http://dx.doi.org/10.5582/bst.2020.01030 PMID: 32037389
Costanzo, M.; De Giglio, M.A.R.; Roviello, G.N. SARS- CoV-2:[39]
Recent Reports on Antiviral Therapies Based on Lopinavir/Riton-
avir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir,
Favipiravir and other Drugs for the Treatment of the New Coron-
avirus. Curr. Med. Chem., 2020, 27(27), 4536-4541.
http://dx.doi.org/10.2174/0929867327666200416131117 PMID:
32297571
Cao, B.; Wang, Y.; Wen, D.; Liu, W.; Wang, J.; Fan, G.; Ruan,[40]
L.; Song, B.; Cai, Y.; Wei, M.; Li, X.; Xia, J.; Chen, N.; Xiang, J.;
Yu, T.; Bai, T.; Xie, X.; Zhang, L.; Li, C.; Yuan, Y.; Chen, H.; Li,
H.; Huang, H.; Tu, S.; Gong, F.; Liu, Y.; Wei, Y.; Dong, C.;
Zhou, F.; Gu, X.; Xu, J.; Liu, Z.; Zhang, Y.; Li, H.; Shang, L.;
Wang, K.; Li, K.; Zhou, X.; Dong, X.; Qu, Z.; Lu, S.; Hu, X.; Ru-
an, S.; Luo, S.; Wu, J.; Peng, L.; Cheng, F.; Pan, L.; Zou, J.; Jia,
C.; Wang, J.; Liu, X.; Wang, S.; Wu, X.; Ge, Q.; He, J.; Zhan, H.;
Qiu, F.; Guo, L.; Huang, C.; Jaki, T.; Hayden, F.G.; Horby, P.W.;
Zhang, D.; Wang, C. A trial of Lopinavir-Ritonavir in adults hospi-
talized with severe COVID-19. N. Engl. J. Med., 2020, 382(19),
1787-1799.
http://dx.doi.org/10.1056/NEJMoa2001282 PMID: 32187464
Savarino, A.; Boelaert, J.R.; Cassone, A.; Majori, G.; Cauda, R.[41]
Effects of chloroquine on viral infections: an old drug against to-
day’s diseases? Lancet Infect Dis., 2003, 3(11), 722-727.
http://dx.doi.org/10.1016/S1473-3099(03)00806-5
Savarino, A.; Di Trani, L.; Donatelli, I.; Cauda, R.; Cassone, A.[42]
New insights into the antiviral effects of chloroquine. Lancet In-
Pharmacological Strategies for COVID-19 Infectious Disorders - Drug Targets, 2020, Vol. 20, No. 0 9
fect. Dis., 2006, 6(2), 67-69.
http://dx.doi.org/10.1016/S1473-3099(06)70361-9 PMID:
16439323
Singh, A.K.; Singh, A.; Shaikh, A.; Singh, R.; Misra, A. Chloro-[43]
quine and hydroxychloroquine in the treatment of COVID-19 with
or without diabetes: A systematic search and a narrative review
with a special reference to India and other developing countries.
Diabetes Metab. Syndr., 2020, 14(3), 241-246.
http://dx.doi.org/10.1016/j.dsx.2020.03.011 PMID: 32247211
Zhou, D.; Dai, S.M.; Tong, Q. COVID-19: a recommendation to[44]
examine the effect of hydroxychloroquine in preventing infection
and progression The Journal of antimicrobial chemotherapy,
2020, 75(7), 1667-1670.
Devaux, C.A.; Rolain, J.M.; Colson, P.; Raoult, D. New insights[45]
on the antiviral effects of chloroquine against coronavirus: what to
expect for COVID-19? Int. J. Antimicrob. Agents, 2020, 55(5)
http://dx.doi.org/10.1016/j.ijantimicag.2020.105938 PMID:
32171740
Gao, J.; Tian, Z.; Yang, X. Breakthrough: Chloroquine phosphate[46]
has shown apparent efficacy in treatment of COVID-19 associated
pneumonia in clinical studies. Biosci. Trends, 2020, 14(1), 72-73.
http://dx.doi.org/10.5582/bst.2020.01047 PMID: 32074550
Gautret, P.; Lagier, J.C.; Parola, P.; Hoang, V. T.; Meddeb, L.;[47]
Mailhe, M. Hydroxychloroquine and azithromycin as a treatment
of COVID-19: results of an open-label non-randomized clinical
trial Int J Antimicrob Agents, 2020, 56(1), 105949.
http://dx.doi.org/10.1016/j.ijantimicag.2020.105949
Chen, J.; Liu, D.; Liu, L.; Liu, P.; Xu, Q.; Xia, L. A pilot study of[48]
hydroxychloroquine in treatment of patients with common coron-
avirus disease-19 (COVID-19). J Zhejiang Univ Med Sci., 2020,
49(2), 215-219.
http://dx.doi.org/10.3785/j.issn.1008-9292.2020.03.03 PMID:
32391667
Rossignol, J.F. Nitazoxanide, a new drug candidate for the treat-[49]
ment of Middle East respiratory syndrome coronavirus. J. Infect.
Public Health, 2016, 9(3), 227-230.
http://dx.doi.org/10.1016/j.jiph.2016.04.001 PMID: 27095301
Sarma, P.; Prajapat, M.; Avti, P.; Kaur, H.; Kumar, S.; Medhi, B.[50]
Therapeutic options for the treatment of 2019-novel coronavirus:
An evidence-based approach. Indian J. Pharmacol., 2020, 52(1),
1-5.
http://dx.doi.org/10.4103/ijp.IJP_119_20 PMID: 32201439
Nguyen, M.H.; Wright, T.L. Therapeutic advances in the manage-[51]
ment of hepatitis B and hepatitis C. Curr. Opin. Infect. Dis., 2001,
14(5), 593-601.
http://dx.doi.org/10.1097/00001432-200110000-00014 PMID:
11964881
Spiegel, M.; Pichlmair, A.; Mühlberger, E.; Haller, O.; Weber, F.[52]
The antiviral effect of interferon-beta against SARS- coronavirus
is not mediated by MxA protein. J. Clin. Virol., 2004, 30(3),
211-213.
http://dx.doi.org/10.1016/j.jcv.2003.11.013 PMID: 15135736
Cinatl, J.; Morgenstern, B.; Bauer, G.; Chandra, P.; Rabenau, H.;[53]
Doerr, H.W. Treatment of SARS with human interferons. Lancet,
2003, 362(9380), 293-294.
http://dx.doi.org/10.1016/S0140-6736(03)13973-6 PMID:
12892961
Chan, J.F.; Yao, Y.; Yeung, M.L.; Deng, W.; Bao, L.; Jia, L.; Li,[54]
F.; Xiao, C.; Gao, H.; Yu, P.; Cai, J.P.; Chu, H.; Zhou, J.; Chen,
H.; Qin, C.; Yuen, K.Y. Treatment With Lopinavir/Ritonavir or In-
terferon-β1b Improves Outcome of MERS-CoV Infection in a
Nonhuman Primate Model of Common Marmoset. J. Infect. Dis.,
2015, 212(12), 1904-1913.
http://dx.doi.org/10.1093/infdis/jiv392 PMID: 26198719
Loutfy, M.R.; Blatt, L.M.; Siminovitch, K.A.; Ward, S.; Wolff,[55]
B.; Lho, H.; Pham, D.H.; Deif, H.; LaMere, E.A.; Chang, M.;
Kain, K.C.; Farcas, G.A.; Ferguson, P.; Latchford, M.; Levy, G.;
Dennis, J.W.; Lai, E.K.; Fish, E.N. Interferon alfacon-1 plus corti-
costeroids in severe acute respiratory syndrome: a preliminary
study. JAMA, 2003, 290(24), 3222-3228.
http://dx.doi.org/10.1001/jama.290.24.3222 PMID: 14693875
Yamamoto, M.; Matsuyama, S.; Li, X.; Takeda, M.; Kawaguchi,[56]
Y.; Inoue, J.I.; Matsuda, Z. Identification of nafamostat as a po-
tent inhibitor of Middle East respiratory syndrome coronavirus S
protein-mediated membrane fusion using the split-protein-based
cell-cell fusion assay. Antimicrob. Agents Chemother., 2016,
60(11), 6532-6539.
http://dx.doi.org/10.1128/AAC.01043-16 PMID: 27550352
Hoffmann, M.; Schroeder, S.; Kleine-Weber, H.; Müller, M.A.;[57]
Drosten, C.; Pöhlmann, S. Nafamostat mesylate blocks activation
of SARS- CoV-2: new treatment option for COVID-19. Antimi-
crob. Agents Chemother., 2020, 64(6), e00754-e20.
http://dx.doi.org/10.1128/AAC.00754-20 PMID: 32312781
Doi, K.; Ikeda, M.; Hayase, N.; Moriya, K.; Morimura, N.[58]
COVID-UTH Study Group. Nafamostat mesylate treatment in
combination with favipiravir for patients critically ill with
Covid-19: a case series. Crit. Care, 2020, 24(1), 392.
http://dx.doi.org/10.1186/s13054-020-03078-z PMID: 32620147
Li, H.; Zhou, Y.; Zhang, M.; Wang, H.; Zhao, Q.; Liu, J. Updated[59]
Approaches against SARS- CoV-2. Antimicrob. Agents Che-
mother., 2020, 64(6), e00483-e20.
http://dx.doi.org/10.1128/AAC.00483-20 PMID: 32205349
Zhou, N.; Pan, T.; Zhang, J.; Li, Q.; Zhang, X.; Bai, C.; Huang,[60]
F.; Peng, T.; Zhang, J.; Liu, C.; Tao, L.; Zhang, H. Glycopeptide
antibiotics potently inhibit cathepsin L in the late endosome/lyso-
some and block the entry of Ebola virus, Middle East respiratory
syndrome coronavirus (MERS-CoV), and severe acute respiratory
syndrome coronavirus (SARS- CoV). J. Biol. Chem., 2016,
291(17), 9218-9232.
http://dx.doi.org/10.1074/jbc.M116.716100 PMID: 26953343
Zhang, J.; Ma, X.; Yu, F.; Liu, J.; Zou, F.; Pan, T. Teicoplanin po-[61]
tently blocks the cell entry of 2019-nCoV. bioRxiv, 2020.
http://dx.doi.org/10.1101/2020.02.05.935387
https://www.mohfw.gov.in/pdf/RevisedNationalClinicalManage-[62]
mentGuidelineforCOVID1931032020.pdf2020.
https://clinicaltrials.gov/2020.[63]
Omolo, C.A.; Soni, N.; Fasiku, V.O.; Mackraj, I.; Govender, T.[64]
Update on therapeutic approaches and emerging therapies for
SARS- CoV-2 virus. Eur. J. Pharmacol., 2020, 883
http://dx.doi.org/10.1016/j.ejphar.2020.173348 PMID: 32634438
