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Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS- CoV-2 by Remdesivir

Authors: Yin et al. Link to paper: https://www.biorxiv.org/content/10.1101/2020.04.08.032763v1

Journal/ Pre-Print: bioRxiv

Key Words: cryo-EM, RdRp complex, Remdesivir

Research Highlights 

1. Cryo-EM structure of the apo non-structural protein (nsp)12-nsp-7-nsp8 RNA-dependent RNA polymerase (RdRp) complex

2. Cryo-EM structure of RNA template recognition by the RdRp complex

3. Cryo-EM structure of the direct acting antiviral Remdesivir bound to the RdRp complex – this provides clarity to previous models of this interaction

Summary 

This paper shows cryo-EM structures of the viral RNA-dependent RNA polymerase (RdRp) required for SARS-CoV-2 replication to 2.5-2.8 Å resolution. The structures of the SARS-CoV-2 RdRp either in the apo form or in complex with a 50-base template-primer RNA and Remdesivir are reported. The recent Science paper Gao et al. 2020 (link below) shows most of these findings, however this is the first structure of Remedsivir in complex. This reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is incorporated into the first replicated base pair and terminates the chain elongation. This structure provides rational template for drug design and allows the authors to potentially explain the relative potency of other RdRp inhibitors such as EIDD-2801 which has a 3-10 fold increased potency over Remedsivir in in blocking viral replication.

Impact for SARS-CoV2/COVID19 research efforts

Treat of SARS-CoV2/COVID19 positive individuals

Study Type

· In vitro study

Strengths and limitations of the paper

Novelty: Cryo-EM structure of SARS-CoV-2 RdRp complex with Remdesivir

Standing in the field: Structure of SARS-CoV-2 RdRp in this paper is in agreement with the structure of an earlier published paper (Gao et al.; https://science.sciencemag.org/content/early/2020/04/09/science.abb7498) and demonstrates some of the modelling of Remedesivir carried out in that Science paper to be incorrect.

Appropriate statistics: Yes

Viral model used: Protein production of SARS-CoV-2 nsp12, nsp8, nsp8 in insect SF9 or E. coli BL21 cells

Translatability: Basis to design potent inhibitors for SARS-CoV-2 RdRp

Main limitations: Modelling – as was seen in the Gao et al. study modelling of inhibitors into structures can have its limitations and the predicted basis of the increased potency of EIDD-2801 is not from a cryo-EM structure but rather a rationalised model again.