Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro)

J Med Chem. 2022 Feb 24;65(4):2880-2904. doi: 10.1021/acs.jmedchem.1c00598. Epub 2021 Aug 4.

Abstract

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • COVID-19 / metabolism
  • COVID-19 Drug Treatment
  • Chlorocebus aethiops
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus 3C Proteases / isolation & purification
  • Coronavirus 3C Proteases / metabolism
  • Crystallography, X-Ray
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Glutamine / chemistry
  • Glutamine / pharmacology
  • Humans
  • Ketones / chemistry
  • Ketones / pharmacology
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / enzymology
  • Vero Cells
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Cysteine Proteinase Inhibitors
  • Ketones
  • Peptidomimetics
  • Glutamine
  • 3C-like protease, SARS coronavirus
  • Coronavirus 3C Proteases