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 15 SARS-CoV-2 proteins and analyzed their variation across 27 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.
【초록키워드】 COVID-19, Treatment, Structure, SARS-CoV-2, Coronaviruses, pandemic, Nsp12, Variation, binding site, RNA, Helicase, nsp13, Protein, viral replication, RNA-dependent RNA polymerase, genetic variability, inhibitor, disease, COVID-19 patients, SARS-CoV-2 proteins, portal, replication-transcription complex, overlapping, Threats, other coronaviruses, binding pocket, catalytic site, novel coronaviruses, assumption, component, SARS-CoV-2 protein, selective, pocket, experimental structure, compounding, effective, analyzed, develop, virus, conserved, absence, active against, novel coronavirus, mapped, β-coronavirus, 【제목키워드】 the SARS-CoV-2,