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dc.contributor.authorNogueira Santos, Jorge Alexandre
dc.contributor.authorAssis, Diego M.
dc.contributor.authorGouvea, Iuri Estrada
dc.contributor.authorJudice, Wagner A. S.
dc.contributor.authorIzidoro, Mario Augusto
dc.contributor.authorJuliano, Maria Aparecida
dc.contributor.authorSkern, Tim
dc.contributor.authorJuliano, Luiz [UNIFESP]
dc.date.accessioned2016-01-24T14:26:54Z
dc.date.available2016-01-24T14:26:54Z
dc.date.issued2012-03-01
dc.identifierhttp://dx.doi.org/10.1016/j.biochi.2011.10.016
dc.identifier.citationBiochimie. Paris: Elsevier France-editions Scientifiques Medicales Elsevier, v. 94, n. 3, p. 711-718, 2012.
dc.identifier.issn0300-9084
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/34671
dc.description.abstractFoot and mouth disease virus expresses its genetic information as a single polyprotein that is translated from the single-stranded RNA genome. Proteinases contained within the polyprotein then generate the mature viral proteins. the leader protease (Lb(pro)) performs the initial cleavage by freeing itself from the growing polypeptide chain; subsequently, Lb(pro) cleaves the two homologues of the host cell protein eukaryotic initiation factor 4G (eIF4G). We showed that Lb(pro) possesses specific binding sites at the non prime side from S-1 down to S-7 [Santos et al. (2009) Biochemistry, 48, 7948-7958]. Here, we demonstrate that Lb(pro) has high prime side specificity at least down to the S-5' site. Lb(pro) is thus not only one of the smallest papain-like cysteine peptidases but also one of the most specific. It can still however cleave between both K down arrow G and G down arrow R pairs. We further determined the two-step irreversible inhibition (E + I <-> EI -> E - I) kinetic parameters of two known irreversible epoxide-based inhibitors of cysteine proteinases, E64 and CA074 on Lb(pro) that show for the reversible step (E + I <-> EI) K-i = 3.4 mu M and 11.6 mu M, and for the irreversible step (EI -> E-I) k(4) = 0.16 and 0.06 min(-1), respectively. Knowledge of the Lb(pro) specificity led us to extend E64 by addition of the dipeptide R-P. This compound, termed E64-R-P-NH2, irreversibly inhibited Lb(pro) with a K-i = 30 nM and k(4) = 0.01 min(-1) and can serve as the basis for design of specific inhibitors of FMDV replication. (C) 2011 Elsevier Masson SAS. All rights reserved.en
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.sponsorshipInstituto Nacional de Ciencia e Tecnologia em Fluidos Complexos (INCT-Fx) in Brazil
dc.description.sponsorshipAustrian Science Foundation
dc.format.extent711-718
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofBiochimie
dc.rightsAcesso restrito
dc.subjectCysteine proteaseen
dc.subjectFluorescent peptidesen
dc.subjectCathepsinen
dc.subjectPicornavirusen
dc.subjectProtease inhibitorsen
dc.titleFoot and mouth disease leader protease (Lb(pro)): Investigation of prime side specificity allows the synthesis of a potent inhibitoren
dc.typeArtigo
dc.rights.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniv Mogi das Cruzes
dc.contributor.institutionMed Univ Vienna
dc.description.affiliationUniversidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, UNIFESP, BR-04044020 São Paulo, Brazil
dc.description.affiliationUniv Mogi das Cruzes, Ctr Interdisciplinar Invest Bioquim, BR-08780911 Mogi Das Cruzes, Brazil
dc.description.affiliationMed Univ Vienna, Max F Perutz Labs, A-1030 Vienna, Austria
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, UNIFESP, BR-04044020 São Paulo, Brazil
dc.description.sponsorshipIDAustrian Science Foundation: P20889
dc.identifier.doi10.1016/j.biochi.2011.10.016
dc.description.sourceWeb of Science
dc.identifier.wosWOS:000301332200015


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