Peptidyl epoxides extended in the P' direction as cysteine protease inhibitors: effect on affinity and mechanism of inhibition

Bioorg Med Chem. 2008 Oct 1;16(19):9032-9. doi: 10.1016/j.bmc.2008.08.031. Epub 2008 Aug 19.

Abstract

Endo peptidyl epoxides, in which the central epoxidic moiety replaces the scissile amide bond of a P(3)-P(3)' peptide, were designed as cysteine proteases inhibitors. The additional P'-S' interactions, relative to those of an exo peptidyl epoxide of the same P(3)-P(1) sequence, significantly improved affinity to the enzymes papain and cathepsin B, but also changed the mode of inhibition from active-site directed inactivation to reversible competitive inhibition. Computational models rationalize the binding affinity and the inhibition mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Cathepsin B / chemistry
  • Cathepsin B / metabolism
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / pharmacology*
  • Papain / chemistry
  • Papain / metabolism
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Epoxy Compounds
  • Peptides
  • Cathepsin B
  • Papain