Remdesivir for Potential Treatment of COVID-19: A Chemical View

Remdesivir for Potential Treatment of COVID-19: A Chemical View

Highlights

• Remdesivir is inhibitor of SARS-CoV2  life cycle
• Remdesivir is ATP analog
• Remdesivir is in a clinical trial in different countries

COVID-19

Covid-19 is a disease caused by a novel human-infecting betacoronavirus. The coronavirus was identified in Wuhan city of Hubei Province in China, using next-generation sequencing and real-time RT-PCR, in December 2019. Its pandemic disease where more than 2.1 lac people died till now (28 Apr 2020)

Coronaviruses enter host cells by binding to and fusing with cell membranes. Once inside, they subvert the host cell’s machinery to replicate, using the virus’s RNA dependent RNA polymerase (RdRp). RdRp or nsp12 playing catalytic role in replication/transcription of coronavirus and thus helps in synthesizing coronavirus RNA. Some established RdRp inhibitors are Nucleoside analogues such as Remdesivir, favipiravir, penciclovir, ribavirin and galidesivir.

Remdesivir (Gilead), an investigational broad-spectrum IV antiviral drug that is active against SARS-CoV-2 and other corona-viruses in vitro and in animal models.

Remdesivir (GS-5734): Adenosine analogue

An experimental antiviral drug Remdesivir, made by the Bay Area's Gilead Sciences has found to show in vitro activity against SARS-CoV-2.

Remdesivir mimics nucleotide (ATP), added during RNA synthesis and it binds to nucleotide binding pocket of RNA dependent RNA polymerase (RdRp). Hence, it inhibits the synthesis of new RNA strand by RdRp. This terminates corona virus genome replication. One in vitro study claims EC₉₀ value of Remdesivir against COVID-19 in Vero E₆ cells was 1.76 μM, which can be achieved. Coronaviruses have a “proofreading” enzyme (exoribonuclease) that corrects errors in the RNA sequence, potentially limiting the effects of analogues. but remdesivir is able to evade this proofreading. In the laboratory, viral mutation can lead to resistance to remdesivir, but the mutant viruses are less infective. Scientists also found binding side of Remdesivir in RdRp.

A series of clinical trials has been started on account of COVID-19 outbreak. Clinical trials of remdesivir, vitamin C infusion, hydroxychloroquine, ritonavir-lopinavir combination, cobicistat and darunavir has come up with significant dimension on COVID-19 horizon. Given no specific antiviral therapy for COVID-19 and the availability of remdesivir as a potential antiviral agent. Based on pre-clinical studies in SARS-CoV and MERS-CoV infections, this randomized, controlled, double blind trial will evaluate the efficacy and safety of remdesivir in patients hospitalized with mild or moderate COVID-19.

Remdesivir, reportedly had a successful clinical trial in Chicago and has been putting on clinical trials by other coronavirus infected countries. Gilead has initiated two Phase 3 clinical studies to evaluate the safety and efficacy of remdesivir in adults diagnosed with COVID-19 following the U.S. Food and Drug Administration’s (FDA) rapid review and acceptance of Gilead’s investigational new drug (IND) filing. These randomized, open-label, multicenter studies began enrolling patients in March 2020 and will enroll a total of approximately 1,000 patients in the initial phase of the studies, in countries with high prevalence of COVID-19.

Health authorities in China have initiated two clinical trials in patients who have been infected with COVID-19 to determine the safety and efficacy of remdesivir as a potential treatment for the coronavirus. The studies are being coordinated by the China-Japan Friendship Hospital and are being conducted at multiple sites in Hubei province.

The U.S. National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has initiated a Phase 2 adaptive, randomized, double-blind, placebo-controlled trial into remdesivir as a potential treatment for hospitalized adult patients diagnosed with COVID-19.

Journal Reference

1. Ferner Robin E, Aronson Jeffrey K. Remdesivir in covid-19 BMJ 2020; 369 :m1610. doi: https://doi.org/10.1136/bmj.m1610