Isomannide-Based Peptidomimetics as Inhibitors for Human Tissue Kallikreins 5 and 7

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dc.contributor.authorOliveira, Jocelia P. C.
dc.contributor.authorFreitas, Renato F.
dc.contributor.authorMelo, Leandro Silva de
dc.contributor.authorBarros, Thalita G.
dc.contributor.authorSantos, Jorge A. N.
dc.contributor.authorJuliano, Maria A. [UNIFESP]
dc.contributor.authorPinheiro, Sergio
dc.contributor.authorBlaber, Michael
dc.contributor.authorJuliano, Luiz [UNIFESP]
dc.contributor.authorMuri, Estela M. F.
dc.contributor.authorPuzer, Luciano
dc.contributor.institutionUniversidade Federal do ABC (UFABC)
dc.contributor.institutionJohns Hopkins Univ
dc.contributor.institutionUniversidade Federal Fluminense (UFF)
dc.contributor.institutionInst Fed Educ Ciencia & Tecnol Sul Minas Gerais
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionFlorida State Univ
dc.date.accessioned2016-01-24T14:35:16Z
dc.date.available2016-01-24T14:35:16Z
dc.date.issued2014-02-01
dc.description.abstractHuman kallikrein 5 (KLK5) and 7 (KLK7) are potential targets for the treatment of skin inflammation and cancer. Previously, we identified isomannide derivatives as potent and competitive KLK7 inhibitors. the introduction of N-protected amino acids into the isomannide-based scaffold was studied. Some KLK5 inhibitors with submicromolar affinity (K-i values of 0.3-0.7 mu M) were identified, and they were 6- to 13-fold more potent than our previous hits. Enzyme kinetics studies and the determination of the mechanism of inhibition confirmed that the new isomannide-based derivatives are competitive inhibitors of both KLK5 and KLK7. Molecular docking and MD simulations of selected inhibitors into the KLK5 binding site provide insight into the molecular mechanism by which these compounds interact with the enzyme. the promising results obtained in this study open new prospects on the design and synthesis of highly specific KLK5 and KLK7 inhibitors.en
dc.description.affiliationUniv Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP, Brazil
dc.description.affiliationJohns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA
dc.description.affiliationUniv Fed Fluminense, Fac Farm, BR-24220008 Niteroi, RJ, Brazil
dc.description.affiliationInst Fed Educ Ciencia & Tecnol Sul Minas Gerais, BR-37576000 Inconfidentes, MG, Brazil
dc.description.affiliationUniversidade Federal de São Paulo, Dept Biofis, BR-04107001 São Paulo, Brazil
dc.description.affiliationUniv Fed Fluminense, Inst Quim, BR-24220008 Niteroi, RJ, Brazil
dc.description.affiliationFlorida State Univ, Dept Biomed Sci, Tallahassee, FL 32306 USA
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Biofis, BR-04107001 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipJohns Hopkins Malaria Research Institute
dc.description.sponsorshipIDFAPESP: 11/51297-8
dc.description.sponsorshipIDFAPESP: 12/50191-4R
dc.description.sponsorshipIDCNPq: 312701/2009-8
dc.format.extent128-132
dc.identifierhttp://dx.doi.org/10.1021/ml4003698
dc.identifier.citationAcs Medicinal Chemistry Letters. Washington: Amer Chemical Soc, v. 5, n. 2, p. 128-132, 2014.
dc.identifier.doi10.1021/ml4003698
dc.identifier.issn1948-5875
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/37402
dc.identifier.wosWOS:000331493600006
dc.language.isoeng
dc.publisherAmer Chemical Soc
dc.relation.ispartofAcs Medicinal Chemistry Letters
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.subjectSerine proteaseen
dc.subjectkallikreinen
dc.subjectpeptidomimeticsen
dc.subjectinhibitoren
dc.subjectmolecular dynamicsen
dc.titleIsomannide-Based Peptidomimetics as Inhibitors for Human Tissue Kallikreins 5 and 7en
dc.typeinfo:eu-repo/semantics/article
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