Exploration of the P1 residue in 3CL protease inhibitors leading to the discovery of a 2-tetrahydrofuran P1 replacement

Bioorg Med Chem. 2024 Feb 15:100:117618. doi: 10.1016/j.bmc.2024.117618. Epub 2024 Jan 29.

Abstract

The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.

Keywords: 3CL(pro); Aldehyde warhead; P1-Gln replacements; SARS‐CoV-2.

MeSH terms

  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • Coronavirus Protease Inhibitors* / chemistry
  • Furans* / chemistry
  • Lactams
  • Peptide Hydrolases
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • Lactams
  • Peptide Hydrolases
  • Protease Inhibitors
  • Furans
  • Coronavirus Protease Inhibitors