Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors

Bioorg Med Chem Lett. 2018 Mar 1;28(5):906-909. doi: 10.1016/j.bmcl.2018.01.064. Epub 2018 Feb 1.

Abstract

The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub-micromolar antiviral activity.

Keywords: Covalent inhibitor; Macrocycle; Protease inhibition; Rhinovirus 3C protease; Solid phase synthesis; Structure-based drug design.

MeSH terms

  • 3C Viral Proteases
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Crystallography, X-Ray
  • Cysteine Endopeptidases / metabolism
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Conformation
  • Rhinovirus / drug effects*
  • Rhinovirus / enzymology
  • Structure-Activity Relationship
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / metabolism

Substances

  • Antiviral Agents
  • Cysteine Proteinase Inhibitors
  • Macrocyclic Compounds
  • Viral Proteins
  • Cysteine Endopeptidases
  • 3C Viral Proteases