Design, synthesis, and evaluation of a novel series of macrocyclic inhibitors of norovirus 3CL protease

Eur J Med Chem. 2017 Feb 15;127:41-61. doi: 10.1016/j.ejmech.2016.12.033. Epub 2016 Dec 21.

Abstract

Norovirus infections have a major impact on public health worldwide, yet there is a current dearth of norovirus-specific therapeutics and prophylactics. This report describes the discovery of a novel class of macrocyclic inhibitors of norovirus 3C-like protease, a cysteine protease that is essential for virus replication. SAR, structural, and biochemical studies were carried out to ascertain the effect of structure on pharmacological activity and permeability. Insights gained from these studies have laid a solid foundation for capitalizing on the therapeutic potential of the series of inhibitors described herein.

Keywords: 3CLprotease; Macrocyclic inhibitors; Norovirus.

MeSH terms

  • Animals
  • Chemistry Techniques, Synthetic
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Macrocyclic Compounds / chemical synthesis*
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / metabolism
  • Macrocyclic Compounds / pharmacology*
  • Mice
  • Molecular Docking Simulation
  • Norovirus / drug effects
  • Norovirus / enzymology*
  • Permeability
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology*
  • Protein Conformation
  • RAW 264.7 Cells
  • Structure-Activity Relationship
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry
  • Viral Proteins / metabolism

Substances

  • Macrocyclic Compounds
  • Protease Inhibitors
  • Viral Proteins
  • Cysteine Endopeptidases
  • 3C proteases