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KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library
dc.creator | González-Bacerio J. | spa |
dc.creator | Maluf S.E.C. | spa |
dc.creator | Méndez Y. | spa |
dc.creator | Pascual I. | spa |
dc.creator | Florent I. | spa |
dc.creator | Melo P.M.S. | spa |
dc.creator | Budu A. | spa |
dc.creator | Ferreira J.C. | spa |
dc.creator | Moreno E. | spa |
dc.creator | Carmona A.K. | spa |
dc.creator | Rivera D.G. | spa |
dc.creator | Alonso del Rivero M. | spa |
dc.creator | Gazarini M.L. | spa |
dc.date.accessioned | 2017-12-19T19:36:42Z | |
dc.date.available | 2017-12-19T19:36:42Z | |
dc.date.created | 2017 | |
dc.identifier.issn | 9680896 | |
dc.identifier.uri | http://hdl.handle.net/11407/4264 | |
dc.description.abstract | Malaria 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 (Ki =0.4μM) and an in vitro antimalarial compound as potent as bestatin (IC50 =18μM; without 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 =82μM), 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. © 2017 Elsevier Ltd. | eng |
dc.language.iso | eng | |
dc.publisher | Elsevier Ltd | spa |
dc.relation.isversionof | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85024090017&doi=10.1016%2fj.bmc.2017.06.047&partnerID=40&md5=6e084ac1c6fa5369f3297d4f65008552 | spa |
dc.source | Scopus | spa |
dc.title | KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library | spa |
dc.type | Article in Press | eng |
dc.rights.accessrights | info:eu-repo/semantics/restrictedAccess | |
dc.contributor.affiliation | González-Bacerio, J., Centro de Estudio de Proteínas, Facultad de Biología, Universidad de La Habana, Calle 25 #455 entre I y J, 10400, Vedado, La Habana, Cuba | spa |
dc.contributor.affiliation | Maluf, S.E.C., Departamento de Biofísica, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 7 andar, 04039-032, Vila Mariana, São Paulo, Brazil | spa |
dc.contributor.affiliation | Méndez, Y., Centro de Estudio de Productos Naturales, Facultad de Química, Universidad de La Habana, Zapata y G, 10400 La Habana, Cuba | spa |
dc.contributor.affiliation | Pascual, I., Centro de Estudio de Proteínas, Facultad de Biología, Universidad de La Habana, Calle 25 #455 entre I y J, 10400, Vedado, La Habana, Cuba | spa |
dc.contributor.affiliation | Florent, I., Unité Molécules de Communication et Adaptation des Microorganismes, (MCAM, UMR 7245), Sorbonne Universités, Muséum National Histoire Naturelle, CNRS, CP 52, 57 Rue Cuvier, 75005 Paris, France | spa |
dc.contributor.affiliation | Melo, P.M.S., Departamento de Biofísica, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 7 andar, 04039-032, Vila Mariana, São Paulo, Brazil | spa |
dc.contributor.affiliation | Budu, A., Departamento de Biofísica, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 7 andar, 04039-032, Vila Mariana, São Paulo, Brazil | spa |
dc.contributor.affiliation | Ferreira, J.C., Departamento de Biofísica, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 7 andar, 04039-032, Vila Mariana, São Paulo, Brazil | spa |
dc.contributor.affiliation | Moreno, E., Centro de Inmunología Molecular, Calle 15 esq. 216, Siboney, Playa, La Habana, Cuba, Universidad de Medellín, Carrera 87 #30-65, Medellín, Colombia | spa |
dc.contributor.affiliation | Carmona, A.K., Departamento de Biofísica, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 7 andar, 04039-032, Vila Mariana, São Paulo, Brazil | spa |
dc.contributor.affiliation | Rivera, D.G., Centro de Estudio de Productos Naturales, Facultad de Química, Universidad de La Habana, Zapata y G, 10400 La Habana, Cuba | spa |
dc.contributor.affiliation | Alonso del Rivero, M., Centro de Estudio de Proteínas, Facultad de Biología, Universidad de La Habana, Calle 25 #455 entre I y J, 10400, Vedado, La Habana, Cuba | spa |
dc.contributor.affiliation | Gazarini, M.L., Departamento de Biociências, Universidade Federal de São Paulo, R. Silva Jardim, 136, 11015-020, Vila Mathias, Santos, São Paulo, Brazil | spa |
dc.identifier.doi | 10.1016/j.bmc.2017.06.047 | |
dc.subject.keyword | Antimalarials | eng |
dc.subject.keyword | Combinatorial synthesis | eng |
dc.subject.keyword | Metallo-aminopeptidase inhibitors | eng |
dc.subject.keyword | Multicomponent reactions | eng |
dc.subject.keyword | PfA-M1 | eng |
dc.subject.keyword | Plasmodium falciparum | eng |
dc.publisher.faculty | Facultad de Ciencias Básicas | spa |
dc.abstract | Malaria 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 (Ki =0.4μM) and an in vitro antimalarial compound as potent as bestatin (IC50 =18μM; without 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 =82μM), 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. © 2017 Elsevier Ltd. | eng |
dc.creator.affiliation | Centro de Estudio de Proteínas, Facultad de Biología, Universidad de La Habana, Calle 25 #455 entre I y J, 10400, Vedado, La Habana, Cuba | spa |
dc.creator.affiliation | Departamento de Biofísica, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 7 andar, 04039-032, Vila Mariana, São Paulo, Brazil | spa |
dc.creator.affiliation | Centro de Estudio de Productos Naturales, Facultad de Química, Universidad de La Habana, Zapata y G, 10400 La Habana, Cuba | spa |
dc.creator.affiliation | Unité Molécules de Communication et Adaptation des Microorganismes, (MCAM, UMR 7245), Sorbonne Universités, Muséum National Histoire Naturelle, CNRS, CP 52, 57 Rue Cuvier, 75005 Paris, France | spa |
dc.creator.affiliation | Centro de Inmunología Molecular, Calle 15 esq. 216, Siboney, Playa, La Habana, Cuba | spa |
dc.creator.affiliation | Universidad de Medellín, Carrera 87 #30-65, Medellín, Colombia | spa |
dc.creator.affiliation | Departamento de Biociências, Universidade Federal de São Paulo, R. Silva Jardim, 136, 11015-020, Vila Mathias, Santos, São Paulo, Brazil | spa |
dc.relation.ispartofes | Bioorganic and Medicinal Chemistry | spa |
dc.relation.ispartofes | Bioorganic and Medicinal Chemistry Volume 25, Issue 17, 2017, Pages 4628-4636 | spa |
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dc.type.version | info:eu-repo/semantics/publishedVersion | |
dc.type.driver | info:eu-repo/semantics/other | |
dc.identifier.reponame | reponame:Repositorio Institucional Universidad de Medellín | spa |
dc.identifier.instname | instname:Universidad de Medellín | spa |
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