DESIGN OF POTENT LIPOPHILIC-PEPTIDE INHIBITORS OF HUMAN NEUTROPHIL ELASTASE - IN-VITRO AND IN-VIVO STUDIES

In keeping with the presence of an extended hydrophobic binding site i n human neutrophil elastase (HNE), a series of lipophilic peptide deri vatives were synthesized. In vitro studies, using an oligopeptide subs trate for HNE, showed that lipidic amino acid derivatives Ib, Ic and I d were potent HNE inhibitors; the lipophilic amino acid trimer conjuga te 1d (IC50 = 1.8 X 10(-10)) was a more powerful inhibitor than the di mer conjugate 1c (IC50 = 2.8 X 10(-10)) which was more potent than the monomer conjugate 1b (IC50 = 2.9 X 10(-9)). When injected intradermal ly to rabbit dermis, compound 1d protected skin elastic fibres against degradation by HNE.