Solid-phase library synthesis, screening, and selection of tight-binding reduced peptide bond inhibitors of a recombinant Leishmania mexicana cysteine protease B

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dc.contributor.authorHilaire, PMS
dc.contributor.authorAlves, L. C.
dc.contributor.authorHerrera, F.
dc.contributor.authorRenil, M.
dc.contributor.authorSanderson, S. J.
dc.contributor.authorMottram, J. C.
dc.contributor.authorCoombs, G. H.
dc.contributor.authorJuliano, M. A.
dc.contributor.authorJuliano, L.
dc.contributor.authorArevalo, J.
dc.contributor.authorMeldal, M.
dc.contributor.institutionCarlsberg Lab
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniv Peruana Cayetano Heredia
dc.contributor.institutionUniv Glasgow
dc.date.accessioned2016-01-24T12:33:23Z
dc.date.available2016-01-24T12:33:23Z
dc.date.issued2002-05-09
dc.description.abstractA one-bead-two-compound inhibitor library was synthesized by the split-mix method for the identification of inhibitors of a recombinant cysteine protease from Leishmania mexicana, CPB2.8DeltaCTE. the inhibitor library was composed of octapeptides with a centrally located reduced bond introduced by reductive amination of the resin-bound amines with Fmoc amino aldehydes. the library was screened on solid phase, and less than 1% of the library contained active compounds. the inhibitors displayed great specificity in the subsites flanking the enzyme catalytic triad with Cha and Ile/Leu preferred in P-2, Phe in P-1, Cha and Ile/Leu in P-1', and Ile/Leu in P-2'. Some of the inhibitors were resynthesized, and the kinetics of inhibition were determined in solution-phase assays. Most of the inhibitors had micromolar K-i values, and a few inhibited the enzyme at nanomolar concentrations. One inhibitor, DKHF(CH2NH)LLVK (K-i = 1 muM), was tested for antiparasite efficacy and shown to affect parasite survival with an IC50 of approximately 50 muM.en
dc.description.affiliationCarlsberg Lab, Dept Chem, DK-2500 Valby, Denmark
dc.description.affiliationEscola Paulista Med, Dept Biophys, BR-0404420 São Paulo, Brazil
dc.description.affiliationUniv Peruana Cayetano Heredia, Mol & Cellular Lab Trypanosomatids, URB Ingn, Lima, Peru
dc.description.affiliationUniv Glasgow, Div Infect & Immun, Glasgow G12 8QQ, Lanark, Scotland
dc.description.affiliationUniv Glasgow, Anderson Coll, Wellcome Ctr Mol Parasitol, Glasgow G11 6NU, Lanark, Scotland
dc.description.affiliationUnifespEscola Paulista Med, Dept Biophys, BR-0404420 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.format.extent1971-1982
dc.identifierhttp://dx.doi.org/10.1021/jm0110901
dc.identifier.citationJournal of Medicinal Chemistry. Washington: Amer Chemical Soc, v. 45, n. 10, p. 1971-1982, 2002.
dc.identifier.doi10.1021/jm0110901
dc.identifier.issn0022-2623
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/26870
dc.identifier.wosWOS:000175488900004
dc.language.isoeng
dc.publisherAmer Chemical Soc
dc.relation.ispartofJournal of Medicinal Chemistry
dc.rightsAcesso restrito
dc.titleSolid-phase library synthesis, screening, and selection of tight-binding reduced peptide bond inhibitors of a recombinant Leishmania mexicana cysteine protease Ben
dc.typeArtigo
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