The SARS-CoV-2 replication-transcription complex is a priority target for broad-spectrum pan-coronavirus drugs
biorxiv(2021)
摘要
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 ( ) where users can interactively navigate individual protein structures and view the genetic variability of drug binding pockets in 3D.
### Competing Interest Statement
The authors have declared no competing interest.
* CoV
: coronavirus
nsp
: non-structural protein
PDB
: Protein Data Bank
Dscore
: Druggability Score
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关键词
sars-cov,replication-transcription,broad-spectrum,pan-coronavirus
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