Identification of new peptide amides as selective cathepsin L inhibitors: the first step towards selective irreversible inhibitors?

Bioorg Med Chem Lett. 2013 May 15;23(10):2968-73. doi: 10.1016/j.bmcl.2013.03.041. Epub 2013 Mar 20.

Abstract

A small library of peptide amides was designed to profile the cathepsin L active site. Within the cathepsin family of cysteine proteases, the first round of selection was on cathepsin L and cathepsin B, and then selected hits were further evaluated for binding to cathepsin K and cathepsin S. Five highly selective sequences with submicromolar affinities towards cathepsin L were identified. An acyloxymethyl ketone warhead was then attached to these sequences. Although these original irreversible inhibitors inactivate cathepsin L, it appears that the nature of the warhead drastically impact the selectivity profile of the resulting covalent inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Catalytic Domain / drug effects
  • Cathepsin L / antagonists & inhibitors*
  • Cathepsin L / metabolism
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Molecular Conformation
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amides
  • Cysteine Proteinase Inhibitors
  • Oligopeptides
  • Small Molecule Libraries
  • Cathepsin L