RNA-dependent RNA Polymerase Inhibitors Research Articles

Evaluation of molnupiravir analogues as novel coronavirus (SARS CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study

Evaluation of molnupiravir analogues as novel coronavirus (SARS CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study

Comparative assessment of RNA-dependent RNA polymerase (RdRp) inhibitors under clinical trials to control SARS-CoV2 using rigorous computational workflow.

The devastating effect of SARS-CoV2 continues and the scientific community is pursuing to find the strategy to combat the spread of the virus. The approach is adapted to target this virus with medicine in combination with existing vaccines. For this, the medications that can specifically inhibit an enzyme essential for viral replication ‘RNA-dependant-RNA polymerase (RdRp)’ of SARS-CoV2 are being developed. RdRp is the enzyme commonly found in all RNA viruses but is absent in humans. There are in total 60 different RdRp inhibitors already under clinical trials for combating other RNA viruses, which are sought to even work for SARS-CoV2. These inhibitors are classified as nucleoside/nucleotide analogues and nonnucleoside/nonnucleotide analogues. In this study, all the known RdRp inhibitors were computationally targeted in the native form and their active form making the use of molecular docking, MM-GBSA and molecular dynamics (MD) simulations to find the top two of each nucleoside/nucleotide analogues and nonnucleoside/nonnucleotide analogues. The results showed ribavirin 5′-triphosphate and favipiravir ribonucleoside triphosphate (favipiravir-RTP) to be the top two nucleotide analogues while pimodivir and dihydropyrazolopyridinone analogue 8d were the top two nonnucleosides/non-nucleotide analogues.

Recent advances in the discovery of potent RNA-dependent RNA-polymerase (RdRp) inhibitors targeting viruses.

WHO has declared COVID-19 a pandemic, which has affected the whole world and has caused unprecedented social and economic disruption. Since the emergence of the disease, several druggable targets have been suggested including 3-chymotrypsin-like protease (3CLpro), spike, RNA-dependent RNA polymerase (RdRp), and the papain-like protease (PLpro) computational approach. From the beginning, viral replication has been the main focus for any antiviral drug development for viral diseases, including HCV, influenza virus, zika virus, norovirus, measles, dengue virus, and coronaviruses. This review lists the nucleoside, nucleotide, and non-nucleoside RdRp inhibitor analogues of various viral diseases that may be evaluated for drug development to treat COVID-19.

Discovery of Potential Inhibitors for RNA-Dependent RNA Polymerase of Norovirus: Virtual Screening, and Molecular Dynamics.

Noroviruses are non-enveloped viruses with a positive-sense single-stranded RNA (ssRNA) genome belonging to the genus Norovirus, from the family Caliciviridae, which are accountable for acute gastroenteritis in humans. The Norovirus genus is subdivided into seven genogroups, i.e., (GI-GVII); among these, the genogroup II and genotype 4 (GII.4) strains caused global outbreaks of human norovirus (HuNov) disease. The viral genome comprises three open reading frames (ORFs). ORF1 encodes the nonstructural polyprotein that is cleaved into six nonstructural proteins, which include 3C-like cysteine protease (3CLpro) and a viral RNA-dependent RNA polymerase. ORF2 and ORF3 encode the proteins VP1 and VP2. The RNA-dependent RNA polymerase (RdRp) from noroviruses is one of the multipurpose enzymes of RNA viruses vital for replicating and transcribing the viral genome, making the virally encoded enzyme one of the critical targets for the development of novel anti-norovirus agents. In the quest for a new antiviral agent that could combat HuNov, high throughput virtual screening (HTVS), combined with e-pharmacophore screening, was applied to screen compounds from the PubChem database. CMX521 molecule was selected as a prototype for a similarity search in the PubChem online database. Molecular dynamics simulations were employed to identify different compounds that may inhibit HuNov. The results predicted that compound CID-57930781 and CID-44396095 formed stable complexes with MNV-RdRp within 50 ns; hence, they may signify as promising human norovirus inhibitors.

Potency of Three Brown Seaweeds Species as the Inhibitor of RNA-dependent RNA Polymerase of SARS-CoV-2

The objective of this study was to evaluate the binding activity of bioactive compounds from three brown seaweed on RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 by docking method. The bioactive identification of Sargassum cristaefolium, S. echinocarpum, and Padina australis was carried out using HPLC-HRMS. The ligand structures in PDB format were obtained from the PubChem website and the RdRp from the RCSB website. The binding affinity of the interaction of bioactive components with the RdRp Covid-19 was determined by docking method using AutoDock Vina on PyRx software. The visualization of 2D and 3D interactions between ligands and macromolecules were carried out with the Biovia Discovery Studio and PyMol software. The decoction of S. cristaefolium, S. echinocarpum, and P. australis contained ninety one compounds, and there were twenty compounds with a strong affinity for RdRp. Rhamnetin was a compound of the Sargassum species have the strongest binding affinity of -7.6 kcal/mol. Its affinity bonds were hydrogen bonds in Val315, Arg349, Phe396, Asn628, and hydrophobic bonds in the form of bonds to - and -alkyl from Pro461. Taribavirin bound to RdRp in hydrogen bonds at Thr393, Thr394, and Phe396 and bound hydrophobically to -alkyl from Cys395. Rhamnetin has the same binding affinity region as taribavirin, which was the subdomain finger of the RdRp. In conclusion, rhamnetin is a compound of Sargassum sp that can inhibit the replication and transcription of RdRp SARS-CoV-2 and further studies using the molecular dynamics method on the mechanism of interaction between rhamnetin and the viral RdRp of SARS-CoV-2 are mandatory.

Vaccines and Treatment of Coronavirus Disease 2019

In December 2019, a new strain of betacoronavirus, severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19), emerged in Wuhan, China. Subsequently, the virus quickly spread worldwide and the World Health Organization declared COVID-19 a global pandemic on March 11, 2020. In response to the pandemic, many researchers are working on repurposing existing drugs to alter the course of severe COVID-19, and are testing experimental treatments. Among antiviral agents, remdesivir, an RNA-dependent RNA polymerase inhibitor, showed clinical benefit in a randomized clinical trial. In October 2020, the Food and Drug Administration approved remdesivir for treating hospitalized patients with COVID-19, making it the first drug approved for the disease. The race to produce safe, effective vaccines is also progressing at unprecedented speed, with over 200 under development and 45 candidates already being tested in human clinical trials (as of October 2020).

Computational investigation for identification of potential phytochemicals and antiviral drugs as potential inhibitors for RNA-dependent RNA polymerase of COVID-19

Since the SARS/MERS epidemic, scientists across the world have been racing to identify the novel-CoVs as it has been predicted that next epidemic can very well be a result from a new mutation of CoV, for which hundred mutations have already been discovered, and the same fear has come true with world facing a raging pandemic due to COVID-19, an infectious disease caused by a newly discovered coronavirus. COVID-19 or Severe acute respiratory syndrome coronavirus2 (SARS-CoV-2), is a single stranded RNA virus. COVID −19 is highly contagious and has resulted in current global pandemic with almost no country of the world unaffected by this virus. Owing to the lack of effective therapeutics or vaccines, the best measures to control human coronaviruses remain a strong public health surveillance system coupled with rapid diagnostic testing and quarantine/social; distancing/lockdowns as and when necessary. In the present study, we have used the insilico approach for the prediction of novel drug molecules from available antiviral drugs and also from natural compounds that can be best target against RNA-dependent RNA-polymerase (Pol/RdRp) protein of SARS-CoV-2 which can be suitable drugs for the treatment of COVID-19 virus. From the current study we observed that three antiviral and three phyto-chemicals have minimum binding energy with the target protein which were further evaluated in molecular dynamics studies and could specifically bind to RdRp protein of COVID-19. Based on results we suggest that these drugs may act as best or novel inhibitor that may be used for the treatment of SARS-CoV-2. Communicated by Ramaswamy H. Sarma

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).

Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial

ObjectiveTo assess the efficacy and safety of favipiravir in adults with mild-to-moderate coronavirus disease 2019 (COVID-19). MethodsIn this randomized, open-label, parallel-arm, multicenter, phase 3 trial, adults (18–75 years) with RT-PCR confirmed COVID-19 and mild-to-moderate symptoms (including asymptomatic) were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2−14: 800 mg BID) plus standard supportive care versus supportive care alone. The primary endpoint was time to the cessation of viral shedding; time to clinical cure was also measured. ResultsFrom May 14 to July 3, 2020, 150 patients were randomized to favipiravir (n = 75) or control (n = 75). Median time to the cessation of viral shedding was 5 days (95% CI: 4 days, 7 days) versus 7 days (95% CI: 5 days, 8 days), P = 0.129, and median time to clinical cure was 3 days (95% CI: 3 days, 4 days) versus 5 days (95% CI: 4 days, 6 days), P = 0.030, for favipiravir and control, respectively. Adverse events were observed in 36% of favipiravir and 8% of control patients. One control patient died due to worsening disease. ConclusionThe lack of statistical significance on the primary endpoint was confounded by limitations of the RT-PCR assay. Significant improvement in time to clinical cure suggests favipiravir may be beneficial in mild-to-moderate COVID-19.

The Binding of Remdesivir to SARS-CoV-2 RNA-Dependent RNA Polymerase May Pave The Way Towards the Design of Potential Drugs for COVID-19 Treatment.

We seek to provide an understanding of the binding mechanism of Remdesivir, as well as structural and conformational implications on SARS-CoV-2 virus RNA-dependent RNA polymerase upon its binding and identify its crucial pharmacophoric moieties. The coronavirus disease of 2019 (COVID-19) pandemic had infected over a million people, with 65,000 deaths as of the first quarter of 2020. The current limitation of effective treatment options with no approved vaccine or targeted therapeutics for the treatment of COVID-19 has posed serious global health threats. This has necessitated several drug and vaccine development efforts across the globe. To date, the farthest in the drug development pipeline is Remdesivir. We performed the molecular dynamics simulation, quantified the energy contributions of binding site residues using per-residue energy decomposition calculations, and subsequently generated a pharmacophore model for the identification of potential SARS-CoV-2 virus RNA-dependent RNA polymerase inhibitors. Integrative molecular dynamics simulations and thermodynamic calculations coupled with advanced post-molecular dynamics analysis techniques were employed. Our analysis showed that the modulatory activity of Remdesivir is characterized by an extensive array of high-affinity and consistent molecular interactions with specific active site residues that anchor Remdemsivir within the binding pocket for efficient binding. These residues are ASP452, THR456, ARG555, THR556, VAL557, ARG624, THR680, SER681, and SER682. Results also showed that Remdesivir binding induces minimal individual amino acid perturbations, subtly interferes with deviations of C-α atoms, and restricts the systematic transition of SARS-CoV-2 RNA-dependent RNA polymerase from the "buried" hydrophobic region to the "surface-exposed" hydrophilic region. We also mapped a pharmacophore model based on the observed high-affinity interactions with SARSCoV- 2 virus RNA-dependent RNA polymerase, which showcased the crucial functional moieties of Remdesivir and was subsequently employed for virtual screening. The structural insights and the provided optimized pharmacophoric model would augment the design of improved analogs of Remdesivir that could expand treatment options for COVID-19.

Identification of potential inhibitors of Zika virus NS5 RNA-dependent RNA polymerase through virtual screening and molecular dynamic simulations

Zika virus (ZIKV) is one of the mosquito borne flavivirus with several outbreaks in past few years in tropical and subtropical regions. The non-structural proteins of flaviviruses are suitable active targets for inhibitory drugs due to their role in pathogenicity. In ZIKV, the non-structural protein 5 (NS5) RNA-Dependent RNA polymerase replicates its genome. Here we have performed virtual screening to identify suitable ligands that can potentially halt the ZIKV NS5 RNA dependent RNA polymerase (RdRp). During this process, we searched and screened a library of ligands against ZIKV NS5 RdRp. The selected ligands with significant binding energy and ligand-receptor interactions were further processed. Among the selected docked conformations, top five was further optimized at atomic level using molecular dynamic simulations followed by binding free energy calculations. The interactions of ligands with the target structure of ZIKV RdRp revealed that they form strong bonds within the active sites of the receptor molecule. The efficacy of these drugs against ZIKV can be further analyzed through in-vitro and in-vivo studies.

Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach

The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5′-triphosphate-5′-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.

Past, Present, and Future of Remdesivir: An Overview of the Antiviral in Recent Times.

In the current COVID-19 pandemic, evidence to justify the use of any specific antiviral drug with proven efficacy is not yet available. Antiviral drug development always remains a challenge to the scientists. Remdesivir has emerged as a promising molecule, based on results of clinical trials and observational studies and has receieved marketing approval for COVID-19 treatment under “emergency use authorization” in countries such as United States. Remdesivir is a newer antiviral drug that acts as an RNA-dependent RNA polymerase (RdRp) inhibitor targeting the viral genome replication process. Therapeutic efficacy was first demonstrated by suppressing viral replication in Ebola-infected rhesus monkeys. It is available for parenteral use with reasonable safety and tolerability profile. Multiple clinical trials are going on in many countries to evaluate its safety, efficacy and tolerability. Positive outcome will make the drug capable of meeting the demand generated by both the current pandemic and future outbreak.How to cite this articleChoudhury S, Chakraborty DS, Lahiry S, Chatterjee S. Past, Present, and Future of Remdesivir: An Overview of the Antiviral in Recent Times. Indian J Crit Care Med 2020;24(7):570–574.

Study Design Characteristics and Pharmacological Mechanisms in International Clinical Trials Registry Platform: Registered Clinical Trials on Antiviral Drugs for COVID-19.

ObjectiveThis study aimed to evaluate the pharmacological mechanisms of antiviral drugs against the novel coronavirus disease (COVID-19) and the study designs in clinical trials registered with the International Clinical Trials Registry Platform (ICTRP).MethodsClinical trials involving antiviral drugs for treating COVID-19 were retrieved from the ICTRP database. For each trial, the study design, number of participants, primary endpoints, source register, antiviral mechanism, and results were evaluated.ResultsOn June 10, 2020, 145 eligible clinical trials were retrieved from the ICTRP, of which 99 (68.3%) were randomized trials, 109 (75.2%) were parallel assignment trials, 38 (26.2%) were double or single blinded, 130 (89.7%) involved two groups, and 75 (51.6%) included more than 100 participants; and clinical improvement or recovery and virus-negative conversion were the two most common endpoints, accounting for 40.7% and 18.6%, respectively. The drugs were divided according to the antiviral mechanism into HIV reverse transcriptase inhibitors, RNA-dependent RNA polymerase inhibitors, HIV protease inhibitors (PIs), hepatitis C virus NS3 PIs, and anti-influenza drugs.ConclusionThe design characteristics of clinical trials of antiviral drugs for treating COVID-19 as well as the mechanism of action and antiviral efficacy of the drugs were evaluated in this study. The results of these trials could constitute a reference for future clinical trials to be executed on COVID-19 treatment and prevention.

SARS-CoV-2 Treatment Approaches: Numerous Options, No Certainty for a Versatile Virus.

SARS-CoV-2 is the most recent coronavirus which crossed the species barrier in 2019 and provoked a still ongoing and dangerous pandemic known as coronavirus disease 2019 (COVID-19). The SARS-CoV-2 infection has triggered an impressive amount of clinical and experimental studies to identify an effective and safe therapy to stop the pandemic spread. Hence, numerous trials and studies have scrutinized the analogies between SARS-CoV-2 and other corona viruses or the host-virus interactions and their similarities with immune system disorders. Still, the pathogenic mechanisms behind SARS-CoV-2 have been partially deciphered and the current therapies have not yet met the initial enthusiastic expectations. So far COVID-19 therapies have targeted various pathogenic mechanisms, namely the neutralization of ACE2 receptors or SARS-CoV-2 spike protein epitopes, the disruption of the endocytic pathways using hydroxychloroquine, arbidol, or anti-Janus kinase inhibitors, the inhibition of RNA-dependent RNA polymerase using nucleotide analogues such as remdesivir, immunosuppressive drugs or molecules acting on the immune response (corticoids, interferons, monoclonal antibodies against inflammatory cytokines, mesenchymal stem cells) and convalescent plasma administration together with numerous drugs with unproven effect against SARS-CoV-2 but with potential antiviral activities (antiretrovirals, antimalarial drugs, antibiotics, etc.). Nevertheless, these therapies have been associated with side effects and contradictory results. At the same time a specific SARS-CoV-2 vaccine is a long-term solution requiring clinical validation and important investments together with appropriate strategies to promote the confidence in the safety of the new vaccine. The article revises the current state of SARS-CoV-2 therapeutic options but advises towards a more cautious and individualized treatment approach centred on the clinical features, immune particularities, and the risk-benefit balance.

Development of antibody-based assays for high throughput discovery and mechanistic study of antiviral agents against yellow fever virus

Despite the availability of a highly effective yellow fever virus (YFV) vaccine, outbreaks of yellow fever frequently occur in Africa and South America with significant mortality, highlighting the pressing need for antiviral drugs to manage future outbreaks. To support the discovery and development of antiviral drugs against YFV, we characterized a panel of rabbit polyclonal antibodies against the three YFV structural proteins and five non-structural proteins and demonstrated these antibody reagents in conjunction with viral RNA metabolic labeling, double-stranded RNA staining and membrane floatation assays as powerful tools for investigating YFV polyprotein processing, replication complex formation, viral RNA synthesis and high throughput discovery of antiviral drugs. Specifically, the proteolytic processing of the viral polyprotein can be analyzed by Western blot assays. The predominant nuclear localization of NS5 protein as well as the relationship between intracellular viral non-structural protein distribution and foci of YFV RNA replication can be revealed by immunofluorescence staining and membrane flotation assays. Using an antibody against YFV NS4B protein as an example, in-cell western and high-content imaging assays have been developed for high throughput discovery of antiviral agents. A synergistic antiviral effect of an YFV NS4B-targeting antiviral agent BDAA and a NS5 RNA-dependent RNA polymerase inhibitor (Sofosbuvir) was also demonstrated with the high-content imaging assay. Apparently, the antibody-based assays established herein not only facilitate the discovery and development of antiviral agents against YFV, but also provide valuable tools to dissect the molecular mechanism by which the antiviral agents inhibit YFV replication.

Directly Acting Antivirals for COVID-19: Where Do We Stand?

The outbreak of a novel coronavirus (SARS-CoV-2) in Wuhan, China in December 2019 has now become a pandemic with no approved therapeutic agent. At the moment, the genomic structure, characteristics, and pathogenic mechanisms of SARS-CoV-2 have been reported. Based upon this information, several drugs including the directly acting antivirals have been proposed to treat people with coronavirus disease 2019 (COVID-19). This rapid review aims to describe the directly acting antivirals that have been examined for use in the management of COVID-19. Searches were conducted in three electronic databases, supplemented with a search on arXiv, bioRxiv, medRxiv, ChinaXiv, ClinicalTrials.gov, and Chinese Clinical Trial Registry for studies examining the use of antivirals in COVID-19 to identify for case reports, case series, observational studies, and randomized controlled studies describing the use of antivirals in COVID-19. Data were extracted independently and presented narratively. A total of 98 studies were included, comprising of 38 published studies and 60 registered clinical trials. These drugs include the broad spectrum antivirals such as umifenovir, protease inhibitors such as lopinavir/ritonavir as well as the RNA-dependent RNA polymerase inhibitors, remdesivir, and favipiravir. Other drugs that have been used include the nucleosidase inhibitors and polymerase acidic endonuclease inhibitors which are currently approved for prevention of influenza infections. While some of the drugs appear promising in small case series and reports, more clinical trials currently in progress are required to provide higher quality evidence.

In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials

Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CLpro) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CLpro based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients. Communicated by Ramaswamy H. Sarma

Advances in the possible treatment of COVID-19: A review.

The emergence of the global pandemic caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has put a challenge to identify or derive the therapeutics for its prevention and treatment. Despite the unprecedented advances in the modern medicinal system, currently, there are no proven effective therapies. However, rapid research on SARS-CoV-2 epidemiology help unveiling some new targets for potential drug therapies. Many drugs have been screened, and even their clinical trials are going on at an exceptional pace. Amongst these RNA-dependent RNA polymerase inhibitors (favipiravir and remdesivir) and steroids especially dexamethasone showed promising effects. The biological agents like tocilizumab, interferons, and convalescent plasma prove to be beneficial in viral clearance. Moreover, many immunomodulatory and viral S protein targeting vaccines have their ongoing clinical trials. The establishment of various in vitro and in vivo models for preclinical studies can additionally help the current research. The volume and the pace of the clinical trials launched to evaluate the safety and efficacy of various agents against coronavirus disease 2019 (COVID-19) reflect the need for high-quality evidence for various therapies to be practiced by clinicians. This study aims to sum up all the current advances in the global medicinal system against the COVID-19.

RNA-Dependent RNA Polymerase as a Target for COVID-19 Drug Discovery.

COVID-19 respiratory disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global health issue since it emerged in December 2019. While great global efforts are underway to develop vaccines and to discover or repurpose therapeutic agents for this disease, as of this writing only the nucleoside drug remdesivir has been approved under Emergency Use Authorization to treat COVID-19. The RNA-dependent RNA polymerase (RdRP), a viral enzyme for viral RNA replication in host cells, is one of the most intriguing and promising drug targets for SARS-CoV-2 drug development. Because RdRP is a viral enzyme with no host cell homologs, selective SARS-CoV-2 RdRP inhibitors can be developed that have improved potency and fewer off-target effects against human host proteins and thus are safer and more effective therapeutics for treating COVID-19. This review focuses on biochemical enzyme and cell-based assays for RdRPs that could be used in high-throughput screening to discover new and repurposed drugs against SARS-CoV-2.