KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library
dc.creator | Gonzalez-Bacerio, Jorge | |
dc.creator | Maluf, Sarah El Chamy [UNIFESP] | |
dc.creator | Mendez, Yanira | |
dc.creator | Pascual, Isel | |
dc.creator | Florent, Isabelle | |
dc.creator | Melo, Pollyana Maria Saud [UNIFESP] | |
dc.creator | Budu, Alexandre [UNIFESP] | |
dc.creator | Ferreira, Juliana Conrado [UNIFESP] | |
dc.creator | Moreno, Ernesto | |
dc.creator | Carmona, Adriana Karaoglanovic [UNIFESP] | |
dc.creator | Rivera, Daniel G. | |
dc.creator | Rivero, Maday Alonso del | |
dc.creator | Gazarini, Marcos Leoni [UNIFESP] | |
dc.date.accessioned | 2019-08-19T11:49:36Z | |
dc.date.accessioned | 2022-10-07T20:39:42Z | |
dc.date.available | 2019-08-19T11:49:36Z | |
dc.date.available | 2022-10-07T20:39:42Z | |
dc.date.created | 2019-08-19T11:49:36Z | |
dc.date.issued | 2017 | |
dc.identifier | Bioorganic & Medicinal Chemistry. Oxford, v. 25, n. 17, p. 4628-4636, 2017. | |
dc.identifier | 0968-0896 | |
dc.identifier | https://repositorio.unifesp.br/handle/11600/51355 | |
dc.identifier | 10.1016/j.bmc.2017.06.047 | |
dc.identifier | WOS:000407831300009 | |
dc.identifier.uri | http://repositorioslatinoamericanos.uchile.cl/handle/2250/4020768 | |
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 (K-i = 0.4 mu M) and an in vitro antimalarial compound as potent as bestatin (IC50 = 18 mu M | |
dc.description.abstract | 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 = 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. | |
dc.language | eng | |
dc.publisher | Pergamon-Elsevier Science Ltd | |
dc.rights | Acesso restrito | |
dc.subject | Antimalarials | |
dc.subject | Combinatorial synthesis | |
dc.subject | Metallo-aminopeptidase inhibitors | |
dc.subject | Multicomponent reactions | |
dc.subject | PfA-M1 | |
dc.subject | Plasmodium falciparum | |
dc.title | KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library | |
dc.type | Artigo |