Remdesivir Fits Binding Site in SARS-CoV-2 Enzyme

By Will Boggs MD

April 21, 2020

NEW YORK (Reuters Health) - The antiviral drug remdesivir binds to a newly identified section of a SARS-CoV-2 enzyme that is part of the virus' replication and transcription machinery, according to a structural analysis.

The enzyme - RNA-dependent RNA polymerase, also known as nsp12 - catalyzes the synthesis of viral RNA, and possibly uses two other nonstructural proteins, nsp7 and nsp8, as cofactors.

"Nsp12 is therefore considered a primary target for nucleotide analog antiviral inhibitors such as remdesivir, which shows potential for the treatment of COVID-19 viral infections," Dr. Zihe Rao of Tsinghua University, in Beijing, and colleagues write in Science.

In an effort to inform drug design, the team used cryo-electron microscopy to determine the structure of nsp12 in complex with nsp7 and nsp8.

Besides sharing the architecture of the polymerase core with the other coronavirus polymerases, nsp12 possesses a newly identified beta-hairpin domain at its N terminus. Remdesivir possesses a ribose group that enables it to utilize hydrogen bonds to connect to this domain like the polymerase's native substrate.

With remdesivir bound to this domain, the polymerase is effectively prevented from functioning normally. This mechanism may also be applicable to other nucleoside antiviral compounds, note Dr. Rao, also at ShanghaiTech University, in Shanghai, and Nankai University, in Tianjin, and colleagues.

"This target, in addition to other promising drug targets such as the main protease, could support the development of a cocktail of anti-coronavirus treatments that potentially can be used for the discovery of broad-spectrum antivirals," they conclude.

Dr. Miguel Angel Martinez of Hospital Universitari Germans Trias i Pujol, in Badalona, Spain, recently reviewed compounds with therapeutic potential against SARS-CoV-2. He told Reuters Health by email, "The overall structure of this RNA polymerase fits pretty well with those from other coronaviruses; moreover, it shares some structural basis conserved in most of the RNA viruses. However, this paper is relevant because it can be important for the design of new antivirals directed against this polymerase; very small structural differences can be critical to fine-tune the specificity and potency of an inhibitor."

"This is a basic-molecular-biology structural paper that is absolutely essential for the development of specific and potent SARS-CoV-2 antivirals," he said. "Moreover, by using this new structure, in-silico docking experiments may tell us the utility of some repurposing drugs that are planned to be used in future trials."

The study had no commercial funding, and the authors declare no conflicts of interest.

Dr. Rao and co-authors Dr. Quan Wang and Dr. Zhiyong Lou did not respond to a request for comments.

SOURCE: Science, online April 10, 2020.