The SARS-CoV-2 replication-transcription complex is a priority target for broad-spectrum pan-coronavirus drugs

Abstract

In the absence of effective treatment, COVID-19 is likely to remain a global disease burden. Compounding this threat is the near certainty that novel coronaviruses with pandemic potential will emerge in years to come. Pan-coronavirus drugs – agents active against both SARS-CoV-2 and other coronaviruses – would address both threats. A strategy to develop such broad-spectrum inhibitors is to pharmacologically target binding sites on SARS-CoV-2 proteins that are highly conserved in other known coronaviruses, the assumption being that any selective pressure to keep a site conserved across past viruses will apply to future ones. Here, we systematically mapped druggable binding pockets on the experimental structure of fifteen SARS-CoV-2 proteins and analyzed their variation across twenty-seven α- and β-coronaviruses and across thousands of SARS-CoV-2 samples from COVID-19 patients. We find that the two most conserved druggable sites are a pocket overlapping the RNA binding site of the helicase nsp13, and the catalytic site of the RNA-dependent RNA polymerase nsp12, both components of the viral replication-transcription complex. We present the data on a public web portal (https://www.thesgc.org/SARSCoV2_pocketome/) where users can interactively navigate individual protein structures and view the genetic variability of drug binding pockets in 3D.

HAP40 orchestrates huntingtin structure for differential interaction with polyglutamine expanded exon 1

“…Multiple sequence alignments were then analysed using Consurf 71 and conservation scores mapped to the HTT-HAP40 (PDBID: 6X9O) structure in Pymol. Ligandable pocket analysis was completed as previously reported 72 . Briefly, HTT-HAP40 model pdb files were loaded in ICM (Molsoft, San Diego).…”

A critical overview of computational approaches employed for COVID-19 drug discovery

“…An insightful recent study has examined the variability of these targets across 58 coronaviruses (CoVs) to support the search for broad spectrum antivirals. 47 The authors have also established an interactive web portal 48 displaying the 3D structures available for 15 of the SARS-CoV-2 proteins with 19 putative drug binding sites mapped on these structures; this set of binding sites was collectively called a SARS-CoV-2 pocketome. This portal is very useful for scientists interested in analyzing these binding sites as part of the future structure based drug discovery efforts.…”

Sequence and structure conservation analysis of the key coronavirus proteins supports the feasibility of discovering broad-spectrum antiviral medications.

“…98 Recently, several studies similar to ours have been published. Also exploring the conservation of coronaviruses, Schapira et al, 99 From their simulations, the authors concluded that developing a pan-inhibitor of M pro based on protein conservation could be extremely challenging due to differences in the dynamics of the binding sites. While this study depicts an interesting consideration in the design of future antiviral medications, it is not supported by any experimental results.…”