Login / Signup

Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors.

Jerzy OsipiukSaara-Anne AziziSteve DvorkinMichael EndresRobert JedrzejczakKrysten A JonesSoowon KangRahul Singh KathayatYoungchang KimVladislav G LisnyakSamantha L MakiVlad NicolaescuCooper A TaylorChristine TesarYu-An ZhangZhiyao ZhouGlenn RandallKarolina MichalskaScott A SnyderBryan C DickinsonAndrzej Joachimiak
Published in: Nature communications (2021)
The pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to expand. Papain-like protease (PLpro) is one of two SARS-CoV-2 proteases potentially targetable with antivirals. PLpro is an attractive target because it plays an essential role in cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex, and disruption of host responses. We report a substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the SARS-CoV-2 enzyme. We determined the high resolution structure of wild-type PLpro, the active site C111S mutant, and their complexes with inhibitors. This collection of structures details inhibitors recognition and interactions providing fundamental molecular and mechanistic insight into PLpro. All compounds inhibit the peptidase activity of PLpro in vitro, some block SARS-CoV-2 replication in cell culture assays. These findings will accelerate structure-based drug design efforts targeting PLpro to identify high-affinity inhibitors of clinical value.
Keyphrases
  • sars cov
  • respiratory syndrome coronavirus
  • high resolution
  • wild type
  • coronavirus disease
  • emergency department
  • drug delivery
  • mass spectrometry
  • cancer therapy