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 language | English |
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Pages (from-to) | 6230-6232 |
Number of pages | 3 |
Journal | Bioorganic & Medicinal Chemistry Letters |
Volume | 19 |
Issue number | 21 |
DOIs | |
Publication status | Published - 01 Nov 2009 |
ASJC Scopus subject areas
- Biochemistry
- Clinical Biochemistry
- Molecular Biology
- Molecular Medicine
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science