Journal
JOURNAL OF PROTEOME RESEARCH
Volume 20, Issue 8, Pages 4212-4215Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.1c00206
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Funding
- Natural Sciences and Engineering Research Council of Canada [ALLRP 555329-20]
- EMBL
- AbbVie [1097737]
- Bayer AG
- Boehringer Ingelheim
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU
- EFPIA through the Innovative Medicines Initiative 2 Joint Undertaking [875510]
- Janssen
- Merck KGaA (aka EMD in Canada and US)
- Pfizer
- Takeda
- Wellcome Trust [106169/ZZ14/Z]
- Genentech
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The strategy of targeting highly conserved binding sites on SARS-CoV-2 proteins can lead to the development of drugs that work against multiple coronaviruses; the two most conserved binding sites are the RNA binding site of the helicase nsp13 and the catalytic site of the RNA-dependent RNA polymerase nsp12.
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 alpha- and beta-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.
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