Inhibitor profiling of the Pseudomonas aeruginosa virulence factor LasB using N-alpha mercaptoamide template-based inhibitors

George Cathcart, Brendan Gilmore, Brett Greer, Patrick Harriott, Brian Walker

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

We report on the synthesis and biological evaluation of a focussed library of N-alpha mercaptoamide containing dipeptides as inhibitors of the zinc metallopeptidase Pseudomonas aeruginosa elastase (LasB, EC 3.4.24.26). The aim of the study was to derive an inhibitor profile for LasB with regard to mapping the S´1 binding site of the enzyme. Consequently, a focussed library of 160 members has been synthesised, using standard Fmoc-solid phase methods (on a Rink-amide resin), in which a subset of amino acids including examples of those with basic (Lys, Arg), aromatic (Phe, Trp), large aliphatic (Val, Leu) and acidic (Asp, Glu) side-chains populated the P´2 position of the inhibitor sequence and all 20 natural amino acids were incorporated, in turn, at the P´1 position. The study has revealed a preference for aromatic and/or large aliphatic amino acids at P´1 and a distinct bias against acidic residues at P´2. Ten inhibitor sequences were discovered that exhibited sub to low micromolar Ki values.
Original languageEnglish
Pages (from-to)6230-6232
Number of pages3
JournalBioorganic & Medicinal Chemistry Letters
Volume19
Issue number21
DOIs
Publication statusPublished - 01 Nov 2009

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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