Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir

TLDR

COVID‑19, caused by SARS‑CoV‑2, has become a global pandemic. The viral RNA‑dependent RNA polymerase (RdRp) is essential for SARS‑CoV‑2 replication and is targeted by the antiviral remdesivir. Cryo‑EM structures of the SARS‑CoV‑2 RdRp in apo form and bound to a 50‑base RNA template‑primer with remdesivir show that remdesivir is incorporated at the first replicated base pair, terminating chain elongation and revealing the replication mechanism and a basis for antiviral design.

Abstract

The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo-electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.