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![Plots showing the inhibitory activity for the potential drug leads. The hydrolytic activity of SARS-CoV-2 Mpro was measured in the presence of different concentrations of drugs. Curves produce best fits for calculating the IC50 values. Reprinted with permission from Ref. [67]](publication/348238188/figure/fig5/AS:1128651819098125@1646102971487/Plots-showing-the-inhibitory-activity-for-the-potential-drug-leads-The-hydrolytic.png)
Plots showing the inhibitory activity for the potential drug leads. The hydrolytic activity of SARS-CoV-2 Mpro was measured in the presence of different concentrations of drugs. Curves produce best fits for calculating the IC50 values. Reprinted with permission from Ref. [67]
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The COVID-19 pandemic caused by SARS-CoV-2 is responsible for the global health emergency. Here, we explore the diverse mechanisms of SARS-CoV-induced inflammation. We presume that SARS-CoV-2 likely contributes analogous inflammatory responses. Possible therapeutic mechanisms for reducing SARS-CoV-2-mediated inflammatory responses comprise FcR inac...
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Emerging drug design strategies in anti-influenza drug discovery, Acta Pharmaceutica Sinica B, https://doi. Running title Anti-influenza virus drug design strategies. J o u r n a l P r e-p r o o f This article reviews the application of emerging drug design strategies in the discovery of anti-influenza virus drugs, and lists the representative inhi...
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... However, lopinavir/ ritonavir have high protein binding properties, and the plasma concentrations of lopinavir/ritonavir cannot reach the EC 50 value. Lopinavir/ritonavir are also not used for the treatment of COVID-19 because they were ineffective in three randomized controlled trials (RCTs) (Tripathi N, 2022). ...
Main protease (Mpro) is a superior target for anti-SARS-COV-2 drugs. PF-07304814 is a phosphate ester prodrug of PF-00835231 that is rapidly metabolized into the active metabolite PF-00835231 by alkaline phosphatase (ALP) and then suppresses SARS-CoV-2 replication by inhibiting Mpro. PF-07304814 increased the bioavailability of PF-00835231 by enhancing plasma protein binding (PPB). P-glycoprotein (P-gp) inhibitors and cytochrome P450 3A (CYP3A) inhibitors increased the efficacy of PF-00835231 by suppressing its efflux from target cells and metabolism, respectively. The life cycle of SARS-CoV-2 is approximately 4 h. The mechanisms and efficacy outcomes of PF-00835231 occur simultaneously. PF-00835231 can inhibit not only cell infection (such as Vero E6, 293T, Huh-7.5, HeLa+angiotensin-converting enzyme 2 (ACE2), A549+ACE2, and MRC-5) but also the human respiratory epithelial organ model and animal model infection. PF-07304814 exhibits a short terminal elimination half-life and is cleared primarily through renal elimination. There were no significant adverse effects of PF-07304814 administration in rats. Therefore, PF-07304814 exhibits good tolerability, pharmacology, pharmacodynamics, pharmacokinetics, and safety in preclinical trials. However, the Phase 1 data of PF-07304814 were not released. The Phase 2/3 trial of PF-07304814 was also suspended. Interestingly, the antiviral activities of PF-00835231 derivatives (compounds 5–22) are higher than, similar to, or slightly weaker than those of PF-00835231. In particular, compound 22 exhibited the highest potency and had good safety and stability. However, the low solubility of compound 22 limits its clinical application. Prodrugs, nanotechnology and salt form drugs may solve this problem. In this review, we focus on the preclinical data of PF-07304814 and its active metabolite derivatives to hopefully provide knowledge for researchers to study SARS-CoV-2 infection.
... Early therapeutic approaches should emphasize the virus's or host virus's role in the virus's life cycle. Oftentimes, early methods are intended to preserve the RAS equilibrium by inducing ACE2 signaling (Tripathi et al., 2021). ...
... Currently, care should focus on increasing heme oxygenase activity and administering antiviral drugs. That will be the last silver bullet for vaccine production (Tripathi et al., 2021). ...
COVID-19 is a disease triggered by SARS-CoV-2 virus that was discovered in Wuhan City, China, in December 2019. Today, this virus has spread over the globe, and is expanding faster in the United States, Brazil, India, and Russia than in China, where the epidemic started. As with other coronaviruses, this may trigger respiratory tract infections in patients with mild to severe illnesses such as pneumonia and acute respiratory distress syndrome. Currently, there are no effective drugs, therapies, or procedures. However, empirical therapy is used to manage and save lives. Furthermore, earlier treatments including chloroquine, hydroxychloroquine, remdesivir, lopinavir/ritonavir, and favipiravir were advised to help fight COVID-19. Additionally, various molecular methods and in silico procedures have been evaluated for virus targeting. The study assessed all alternative medicines, including immunotherapy, cellular therapy, peptides and peptidomimetics, ketone-based covalent inhibitors, adjuvant medicines, multi-target coronaviral protein targets, Mpro inhibitors, the heme oxygenase mechanism, nano-drug, and Chinese medicine. This study concludes that the above drug targets and therapeutics are distinct and function differently in the battle against COVID-19 viruses. Rather than a single antiviral, a mixture of antivirals with distinct modes of action could be more efficient, while not overlooking their adverse effects.
The severe acute respiratory syndrome coronavirus 2 has caused the new coronavirus disease-2019 (COVID-19) globally to have a higher spreading rate. Recently, the WHO https://www.who.int/emergencies/diseases/novel-coronavirus-2019 announced COVID-19, a pandemic. Several clinical studies have described the pathogenicity, symptoms, diagnostics, and therapeutics of COVID-19 epidemiology. Therefore it is required to report a comparative analysis of available clinical data on a single platform to design effective prognosis, diagnosis, and treatment methods against COVID-19. The present chapter focuses on disease severity among comorbidity cases and its impact on mental health. This study would likely be used to identify influential and unique pathological factors, along with the correlated transmission, diagnosis, and treatment profiles, and ensure an indication or monitoring component in the dynamic evaluation of COVID-19.
Antibiotic resistance against infections caused by microbes has emerged as a global challenge resulting in longer hospitalizations and higher medical cost and mortality. The excessive use of antibiotics has led to the swift progression of antibiotic resistance in bacterial strains. Metallic and metal oxide (M/MO) nanoparticles (NPs) have the potential to provide a pertinent alternative to antibiotics as they interact with the critical cellular organelles and biomolecules such as DNA, enzymes, ribosomes, and lysosomes. This affects the permeability of the cell membrane causing oxidative stress, gene expression, protein activation, and enzyme activation restricting the habitat of microbes. Further, NPs simultaneously target multiple biomolecules at once making them an efficient antibacterial agent against which microbes are unable to develop resistance easily, although the toxicity associated with the M/MO NPs still remains a key challenge for clinical uses. Green synthesis provides an efficient solution to reduce the toxic effects associated with these NPs as it does not use harsh chemicals and environment for the synthesis of NPs. In this work, we have provided a comprehensive review of the green synthesis of M/MO NPs using plants (roots, seeds, barks, flowers) and microbes (bacteria, fungi, algae). The yield of the NPs achieved from the green synthesis is lower than that of conventional methods and significant advancements have been made recently which are delineated in this review for different M/MO NPs. Further, the mechanism of NP interaction with the microbes and their different antimicrobial applications have been discussed in detailed. The present review aims to provide a critical overview of the current state of the large-scale synthesis of the M/MO NPs as well as their different antimicrobial activities.
Concerned organizations and individuals are fully engaged in seeking appropriate measures towards managing Severe Acute Respiratory Syndrome Coronavirus 2 (SAR-CoV-2) infection because of the unprecedented economic and health impact. SAR-CoV-2 Main protease (SARS-CoV-2 Mpro) is unique to the survival and viability of the virus. Therefore, inhibition of Mpro can block the viral propagation.
Thirty (30) derivatives were built by changing the glucosides in the Meta and para position of quercetin and isohamnetin. Molecular docking analysis was used for the screening of the compounds. Dynamics simulation was performed to assess the stability of the best pose docked complex. Molecular mechanics binding free energy calculation was done by Molecular Mechanics/Poisson-Boltzmann Surface Area (MMPBSA).
Overall analysis showed that the compounds are allosteric inhibitors of SARS-CoV-2 Mpro. Dynamic simulation analysis established the stability of Mpro-ISM-1, Mpro-ISD-3, Mpro-IST-2, Mpro-QM-2, and Mpro-QD-6 complexes with a maximum of 7 hydrogen bonds involved in their interaction. The MMPBSA binding free energies for ISM-1, ISD-3, IST-2, QM-2, and QD-6 were −92.47 ± 9.06, −222.27 ± 32.5, 180.72 ± 47.92, 156.46 ± 49.88 and −93.52 ± 48.75 kcal/mol respectively. All the compounds showed good pharmacokinetic properties, while only ISM-1 inhibits hERG and might be cardio-toxic.
Observations in this study established that the glucoside position indeed influenced the affinity for SARS-CoV-2 Mpro. The study also suggested the potentials of ISD-3, QM-2 and QD-6 as potent inhibitors of the main protease, further experimental and clinical studies are however necessary to validate and establish the need for further drug development processes. Therefore, future studies will be on the chemical synthesis of the compounds and investigation of the in-vitro inhibition of SARS-CoV-2.
Background:
COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Rigorous detection and treatment strategies against SARS-CoV-2 have become very challenging due to continuous evolutions to the viral genome. Therefore, careful genomic analysis is sorely needed to understand transmission, the cellular mechanism of pathogenicity, and the development of vaccines or drugs.
Objective:
In this study, we intended to identify SARS-CoV-2 genome variants that may help understand the cellular and molecular foundation of coronavirus infections required to develop effective intervention strategies.
Methods:
SARS-CoV-2 genome sequences were downloaded from an open-source public database, processed, and analyzed for variants in target detection sites and genes.
Results:
We have identified six unique variants, G---AAC, T---AAC---T, AAC---T, AAC--------T, C----------T, and C--------C, at the nucleocapsid region and eleven major hotspot mutant genes: nsp3, surface glycoprotein, nucleocapsid phosphoprotein, ORF8, nsp6, nsp2, nsp4, helicase, membrane glycoprotein, 3'-5' exonuclease, and 2'-O-ribose methyltransferases. In addition, we have identified eleven major mutant genes that may have a crucial role in SARS-CoV-2 pathogenesis.
Conclusion:
Studying haplotype variants and 11 major mutant genes to understand the mechanism of action of fatal pathogenicity and inter-individual variations in immune responses is inevitable for managing target patient groups with identified variants and developing effective anti-viral drugs and vaccines.
Coronavirus Disease 19 (COVID-19) is associated with high morbidity and mortality rates globally, representing the greatest health and economic challenge today. Several drugs are currently approved for the treatment of COVID-19. Among these, glucocorticoids (GCs) have received particular attention due to their anti-inflammatory and immunosuppressive effects. In fact, GC are widely used in current clinical practice to treat inflammatory, allergic and autoimmune diseases. Major mechanisms of GC action include inhibition of innate and adaptive immune activity. In particular, an important role is played by the inhibition of pro-inflammatory cytokines and chemokines, and the induction of proteins with anti-inflammatory activity.
Overall, as indicated by various national and international regulatory agencies, GCs are recommended for the treatment of COVID-19 in patients requiring oxygen therapy, with or without mechanical ventilation. Regarding the use of GCs for the COVID-19 treatment of non-hospitalized patients at an early stage of the disease, many controversial studies have been reported and regulatory agencies have not recommended their use. The decision to start GC therapy should be based not only on the severity of COVID-19 disease, but also on careful consideration of the benefit/risk profile in individual patients, including monitoring of adverse events.
In this review we summarize the effects of GCs on the major cellular and molecular components of the inflammatory/immune system, the benefits and the adverse common reactions in the treatment of inflammatory/autoimmune diseases, as well as in the management of COVID-19.
As chemistry progressed over the years, modern society witnessed the significant contribution of women chemists. However, the persisting gender imbalance in the scientific community, attributed to improper societal norms and several other reasons, is a matter of concern. The manuscript highlights some great women chemists, such as Nobel Prize awardees, who have created history through their outstanding research work and are role models for other women. Since women continue to encounter recurring obstacles to moving forward in their area, the "leaky pipeline" of women in chemical science remains problematic. Numerous factors, including having to shoulder the labor of childcare and household work and a lack of awareness of regulations and possibilities, contribute to prejudices and the gender gap in higher-level administrative and decision-making roles. To close the gender gap and empower women chemists, we highlight some initiatives (awards, fellowships, schemes, and grants) that have been put forth by governments, organizations, foundations, companies, industries, and publishing societies. As per statistics, only 4% of female scientists have been awarded the Nobel Prize in chemistry until now. Only 35%, 22%, 14%, 26%, and 5% of women are serving as editors-in-chief, while 38%, 40%, 18%, 22%, and 21% are working as associate editors of the American Chemical Society (ACS), Royal Society of Chemistry (RSC), Wiley, Elsevier, and Springer journals, respectively. A further issue is that women receive far fewer honors in chemistry. To promote a more encouraging atmosphere for women scientists at all career phases, we listed some recommendations that research grant funders, academic institutions, publishers, and scientific organizations can follow. For gender parity, the paper sought to address the current situation of women in the chemical sciences. Women's contributions to chemistry will promote innovation and progress in the field.
Astragali Radix (AR) is a clinically used herbal medicine with multiple immunomodulatory activities that can strengthen the activity and cytotoxicity of natural killer (NK) cells. However, owing to the complexity of its composition, the specific active ingredients in AR that act on NK cells are still not clear. Cell membrane chromatography (CMC) is mainly used to screen the active ingredients in a complex system of herbal medicines. In this study, a new comprehensive two-dimensional (2D) NK-92MI CMC/C18 column/time-of-flight mass spectrometry system was established to screen for potential NK cell activators. To obtain a higher column efficiency, 3-mercaptopropyltrimethoxysilane-modified silica was synthesized to prepare the NK-92MI CMC column. In total, nine components in AR were screened from this system, which could be washed out from the NK-92MI/CMC column after 10 min, and these showed good affinity for NK-92MI/CMC columns. Two representative active compounds of AR, isoastragaloside I and astragaloside IV, promoted the killing effect of NK cells on K562 cells in a dose-dependent manner. It can thus be inferred that isoastragaloside I and astragaloside IV are the main immunomodulatory components of AR. This comprehensive 2D NK-92MI CMC analytical system is a practical method for screening immune cell activators from other herbal medicines with immunomodulatory effects.
Growing evidence indicates that hyperinflammatory syndrome and cytokine storm observed in COVID-19 severe cases are narrowly associated with the disease's poor prognosis. Therefore, targeting the inflammatory pathways seems to be a rational therapeutic strategy against COVID-19. Many anti-inflammatory agents have been proposed, however, most of them suffer from poor bioavailability, instability, short half-life, and undesirable biodistribution resulting in off-target effects. From a pharmaceutical standpoint, the implication of COVID-19 inflammation can be exploited as a therapeutic target and/or a targeting strategy against the pandemic. First, the drug delivery systems can be harnessed to improve the properties of anti-inflammatory agents and deliver them in a safe and efficient manner to their therapeutic targets. Second, the drug carriers can be tailored to develop smart delivery systems able to respond to the microenvironmental stimuli to release the anti-COVID-19 therapeutics in a selective and specific manner. More interestingly, some biosystems can simultaneously repress the hyperinflammation due to their inherent anti-inflammatory potency and endow their drug cargo with a selective delivery to the injured sites.
