Polycationic peptides as inhibitors of mast cell serine proteases

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dc.contributor.authorLundequist, A.
dc.contributor.authorJuliano, M. A.
dc.contributor.authorJuliano, L.
dc.contributor.authorPejler, G.
dc.contributor.institutionSwedish Univ Agr Sci
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.date.accessioned2016-01-24T12:33:46Z
dc.date.available2016-01-24T12:33:46Z
dc.date.issued2003-04-01
dc.description.abstractWhen 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.en
dc.description.affiliationSwedish Univ Agr Sci, Ctr Biomed, Dept Vet Med Chem, S-75123 Uppsala, Sweden
dc.description.affiliationUNIFESP, Escola Paulista Med, Dept Biofis, BR-04044020 São Paulo, Brazil
dc.description.affiliationUnifespUNIFESP, Escola Paulista Med, Dept Biofis, BR-04044020 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.format.extent1171-1180
dc.identifierhttp://dx.doi.org/10.1016/S0006-2952(03)00044-3
dc.identifier.citationBiochemical Pharmacology. Oxford: Pergamon-Elsevier B.V., v. 65, n. 7, p. 1171-1180, 2003.
dc.identifier.doi10.1016/S0006-2952(03)00044-3
dc.identifier.issn0006-2952
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/27185
dc.identifier.wosWOS:000182280300015
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofBiochemical Pharmacology
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.subjecttryptaseen
dc.subjectchymaseen
dc.subjectheparinen
dc.subjectpolycationsen
dc.subjectmast cellen
dc.titlePolycationic peptides as inhibitors of mast cell serine proteasesen
dc.typeinfo:eu-repo/semantics/article
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