Potential RNA-dependent RNA polymerase inhibitors as prospective therapeutics against SARS-CoV-2

Abstract

<jats:p> <jats:bold>Introduction.</jats:bold> The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics.</jats:p> <jats:p> <jats:bold>Aim.</jats:bold> To identify drugs against COVID-19, we performed an <jats:italic>in silico</jats:italic> virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication.</jats:p> <jats:p> <jats:bold>Methodology.</jats:bold> Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the <jats:italic>in silico</jats:italic> virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the <jats:italic>in silico</jats:italic> virtual screen.</jats:p> <jats:p> <jats:bold>Results.</jats:bold> The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects.</jats:p> <jats:p> <jats:bold>Conclusion.</jats:bold> Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our <jats:italic>in silico</jats:italic> findings.</jats:p>

Identifying and repurposing antiviral drugs against severe acute respiratory syndrome coronavirus 2 with in silico and in vitro approaches

“…The cryo-electron microscopic structure of the SARS-CoV-2 polymerase complex consisting of nsp12 (RdRp), nsp7, and nsp8 was reported in May 2020 [ 33 ]. Virtual screening has selected many approved drugs that were anticipated to bind to RdRp, including nilotinib, saquinavir, tipranavir, lonafarnib, tegobuvir, olysio, cepharanthine, filibuvir, ornipressin, lypressin, examorelin, polymyxin B1, nacortocin, cistinexine, cisatracurium, bedoradrine, palbociclib, quinupristin, dactinomycin, sirolimus, cetrorelix, rifampin, nebivolol, and sofosbuvir [ [34] , [35] , [36] , [37] , [38] , [39] ].…”

Molecular mechanisms of the novel coronavirus SARS-CoV-2 and potential anti-COVID19 pharmacological targets since the outbreak of the pandemic

“…Enisamium was shown to inhibit the activity of the SARS-CoV-2 RNA polymerase and its active metabolite exhibits similar efficacy with remdesivir triphosphate, it is approved in 11 countries and does not require intravenous administration, unlike remdesivir ( Walker et al, 2020 ). In silico approaches have also been used to identify novel inhibitors, either by screening clinically used polymerase inhibitors, or FDA approved drugs and/or natural compounds ( Kar et al, 2020 ; Pokhrel et al, 2020 ; Ruan et al, 2020 ; Zhang et al, 2020b ).…”

An overview of potential therapeutic agents to treat COVID-19

“…Computer-aided drug screening is being extensively used to discover new drugs and repurpose existing ones targeting RdRp in order to treat COVID-19. in silico virtual screening by Pokhrel et al indicated that quinupristin bound across the conserved RNA tunnel of RdRp, possibly resulting in the arrest of viral replication (64). Elfiky cited ribavirin, sofosbuvir, remdesivir, tenofovir, galidesivir, and the guanosine derivative (IDX-184) as potent drugs for COVID-19 therapy since they tightly bind to SARS-CoV-2 RdRp in a model (65).…”