How remdesivir blocks SARS-CoV-2’s polymerase

Researchers have used cryo-electron microscopy (cryo-EM) to show how remdesivir, an antiviral that’s shown promise against the novel coronavirus, SARS-CoV-2, binds the viral polymerase (Science 2020, DOI: 10.1126/science.abc1560). Remdesivir is an antiviral designed to act as a prodrug of the nucleotide adenosine. After the drug diffuses into cells, enzymes convert remdesivir to the monophosphate before it disrupts production of new strands of the virus’s RNA. The group, led by researchers at the Chinese Academy of Sciences, Zhejiang University, and Tsinghua University, purified SARS-CoV-2’s RNA-dependent RNA polymerase and showed in vitro that remdesivir inhibits the enzyme from copying RNA. Then the team mixed the enzyme with short lengths of RNA and remdesivir in its monophosphate form (RMP) and analyzed the resulting complex via cryo-EM at 2.5 Å resolution. The imaging study confirms that remdesivir latches onto the primer RNA, stopping the polymerase from lengthening the chain using the template strand as a guide. This shuts down viral reproduction.