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

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.

Defining the Pandemic at the State Level: Sequence-Based Epidemiology of the SARS-CoV-2 virus by the Arizona COVID-19 Genomics Union (ACGU)

“…One of the nsp12 mutations at residue 323 (P → L) identified in 69 AZ sequences was previously associated with SARS-CoV-2 sequences from Europe 25 . We did not find nsp12 mutations at sites predicted to be the contact interface with remdesivir 33 . Finally, the 2 isolates with nsp14 mutation at residue 233 (F → L) were the same sequences harboring the spike RBD A475V mutation.…”

“…Studies of SARS-CoV replication demonstrate that nsp14 regulates replication fidelity through its 3'-to-5' exonuclease activity 31,32 . Mutations in nsp7, nsp8, nsp12, and nsp14 may therefore have an effect on viral RNA synthesis and susceptibility to antiviral treatments such as remdesivir 33 . We identified several non-synonymous mutations in nsp7 residue 25 (S → L) and 26 (S → F), but none in nsp8 ( Figure 5B).…”

In silico detection of SARS-CoV-2 specific B-cell epitopes and validation in ELISA for serological diagnosis of COVID-19

“…Third, conformational B-cell epitopes were predicted with DiscoTope2 on molecular structures of SARS-CoV-2 proteins 8 . The unprecedented speed at which experimental SARS-CoV-2 structures have been solved and deposited in the PDB allowed us to predict epitopes on 13 proteins (Table S3) [9][10][11][12] . Coverage was further extended to all proteins except E envelope protein, ORF9b and ORF14, by including high-quality homology models obtained with the Robetta platform and ab-initio models from the CASP-commons competition ( Table S3) 13,14 .…”

Cryo-EM structure of the SARS-CoV-2 3a ion channel in lipid nanodiscs

“…These targets have well characterized functions and, particularly for Spike, evidence for neutralizing antibodies in con-valescent patient serum. The availability of highresolution structures of these targets, some in complex with drug candidates or neutralizing antibodies, has yielded mechanistic insight into their function and provided a platform for structure-guided drug design [1][2][3][4][5][6] . However, expanding of the range of SARS-CoV-2 drug targets may accelerate therapeutic discovery and increase diversity of available drugs to mitigate against the potential evolution of drug-resistant viral strains 7 .…”