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Research article2003Peer reviewed

Polycationic peptides as inhibitors of mast cell serine proteases

Lundequist A, Juliano MA, Juliano L, Pejler G

Abstract

When mast cells are activated, e.g. during allergic responses, they secrete the serine proteases chymase and tryptase, which both are complex-bound to heparin proteoglycan in vivo. Previous reports have demonstrated potent pro-inflammatory effects of both tryptase and chymase in different animal models, suggesting that these serine proteases may be relevant targets for therapeutic intervention. Recent investigations have shown that heparin-binding compounds can cause tryptase inhibition and it has been suggested that the inhibitory activity of such compounds is due to interference with the binding of heparin to tryptase. Here we tested various polycationic peptides for their ability to inhibit heparin-free human recombinant betaI-tryptase. We demonstrate powerful direct inhibition of tryptase (IC50 values similar to 1-100 nM) by poly-Arg and poly-Lys of different molecular weights. Poly-Arg and poly-Lys showed predominantely competitive inhibition kinetics, although decreases in the k(cat) values for the chromogenic substrate S-2288 were also observed. Peptides built up from heparin-binding motifs were also inhibitors of tryptase, albeit of lower efficiency than poly-Arg/Lys. Tryptase inhibition was strongly dependent on the size of the polycationic peptides. The various polycationic peptides were also inhibitory for heparin-dependent activities of chymase. The tryptase inhibition caused by the polycationic peptides could be reversed by adding heparin. After heparin-induced rescue of tryptase activity, the major part of the tryptase activity was sensitive to inhibition by bovine pancreatic trypsin inhibitor, whereas tryptase before addition of polycationic peptide was completely resistant. Taken together, our findings indicate that polycationic peptides can be used as powerful agents for combined inhibition of mast cell tryptase and chymase. (C) 2003 Elsevier Science Inc. All rights reserved

Published in

Biochemical Pharmacology
2003, Volume: 65, number: 7, pages: 1171-1180
Publisher: PERGAMON-ELSEVIER SCIENCE LTD

      SLU Authors

    • Pejler, Gunnar

      • Department of Molecular Biosciences, Swedish University of Agricultural Sciences

    Publication identifier

    DOI: https://doi.org/10.1016/S0006-2952(03)00044-3

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/1089