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dc.contributor.authorGonzalez-Bacerio, Jorge
dc.contributor.authorMaluf, Sarah El Chamy [UNIFESP]
dc.contributor.authorMendez, Yanira
dc.contributor.authorPascual, Isel
dc.contributor.authorFlorent, Isabelle
dc.contributor.authorMelo, Pollyana Maria Saud [UNIFESP]
dc.contributor.authorBudu, Alexandre [UNIFESP]
dc.contributor.authorFerreira, Juliana Conrado [UNIFESP]
dc.contributor.authorMoreno, Ernesto
dc.contributor.authorCarmona, Adriana Karaoglanovic [UNIFESP]
dc.contributor.authorRivera, Daniel G.
dc.contributor.authorRivero, Maday Alonso del
dc.contributor.authorGazarini, Marcos Leoni [UNIFESP]
dc.identifier.citationBioorganic & Medicinal Chemistry. Oxford, v. 25, n. 17, p. 4628-4636, 2017.
dc.description.abstractMalaria is a global human parasitic disease mainly caused by the protozoon Plasmodium falciparum. Increased parasite resistance to current drugs determines the relevance of finding new treatments against new targets. A novel target is the M1 alanyl-aminopeptidase from P. falciparum (PfA-M1), which is essential for parasite development in human erythrocytes and is inhibited by the pseudo-peptide bestatin. In this work, we used a combinatorial multicomponent approach to produce a library of peptidomimetics and screened it for the inhibition of recombinant PfA-M1 (rPfA-M1) and the in vitro growth of P. falciparum erythrocytic stages (3D7 and FcB1 strains). Dose-response studies with selected compounds allowed identifying the bestatin-based peptidomimetic KBE009 as a submicromolar rPfA-M1 inhibitor (K-i = 0.4 mu M) and an in vitro antimalarial compound as potent as bestatin (IC50 = 18 mu Men
dc.description.abstractwithout promoting erythrocyte lysis). At therapeutic-relevant concentrations, KBE009 is selective for rPfA-M1 over porcine APN (a model of these enzymes from mammals), and is not cytotoxic against HUVEC cells. Docking simulations indicate that this compound binds PfA-M1 without Zn2+ coordination, establishing mainly hydrophobic interactions and showing a remarkable shape complementarity with the active site of the enzyme. Moreover, KBE009 inhibits the M1-type aminopeptidase activity (Ala-7-amido-4-methylcoumarin substrate) in isolated live parasites with a potency similar to that of the antimalarial activity (IC50 = 82 mu M), strongly suggesting that the antimalarial effect is directly related to the inhibition of the endogenous PfA-M1. These results support the value of this multicomponent strategy to identify PfA-M1 inhibitors, and make KBE009 a promising hit for drug development against malaria. (C) 2017 Elsevier Ltd. All rights reserved.en
dc.description.sponsorshipIFS (Sweden)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)pt
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt
dc.publisherPergamon-Elsevier Science Ltd
dc.rightsAcesso restrito
dc.subjectCombinatorial synthesisen
dc.subjectMetallo-aminopeptidase inhibitorsen
dc.subjectMulticomponent reactionsen
dc.subjectPlasmodium falciparumen
dc.titleKBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic libraryen
dc.description.affiliationUniv La Habana, Ctr Estudio Prot, Fac Biol, Calle 25 455 Entre I&J, Havana 10400, Cuba
dc.description.affiliationUniv Fed São Paulo, Dept Biofis, Rua Pedro de Toledo,669,7 Andar, BR-04039032 São Paulo, Brazil
dc.description.affiliationUniv La Habana, Ctr Estudio Prod Nat, Fac Quim, Havana 10400, Cuba
dc.description.affiliationSorbonne Univ, Museum Natl Hist Nat, Unite Mol Commun & Adaptat Microorganismes MCAM, CNRS,UMR 7245, CP 52,57 Rue Cuvier, F-75005 Paris, France
dc.description.affiliationCtr Inmunol Mol, Calle 15 Esq 216, Havana, Cuba
dc.description.affiliationUniv Medellin, Carrera 87 30-65, Medellin, Colombia
dc.description.affiliationUniv Fed São Paulo, Dept Biociencias, R Silva Jardim 136, BR-11015020 São Paulo, Brazil
dc.description.affiliationUnifespUniv Fed São Paulo, Dept Biofis, Rua Pedro de Toledo,669,7 Andar, BR-04039032 São Paulo, Brazil
dc.description.affiliationUnifespUniv Fed São Paulo, Dept Biociencias, R Silva Jardim 136, BR-11015020 São Paulo, Brazil
dc.description.sponsorshipIDIFS: F/4730-1
dc.description.sponsorshipIDIFS: F/4730-2F
dc.description.sponsorshipIDCAPES/MES-CUBA: 169/12
dc.description.sponsorshipIDFAPESP: 2009/54598-9
dc.description.sponsorshipIDFAPESP: 2011/14403-4
dc.description.sponsorshipIDFAPESP: 2013/12913-0
dc.description.sponsorshipIDCNPq: 482400/2013-7
dc.description.sourceWeb of Science

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