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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library

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Gonzalez-Bacerio, Jorge ; Maluf, Sarah El Chamy ; Mendez, Yanira ; Pascual, Isel ; Florent, Isabelle ; Melo, Pollyana M. S. ; Budu, Alexandre ; Ferreira, Juliana C. ; Moreno, Ernesto ; Carmona, Adriana K. ; Rivera, Daniel G. ; del Rivero, Maday Alonso ; Gazarini, Marcos L.
Total Authors: 13
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry; v. 25, n. 17, p. 4628-4636, SEP 1 2017.
Web of Science Citations: 2

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; 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. (AU)

FAPESP's process: 11/14403-4 - Processment of plasmatic proteins by Plasmodium
Grantee:Pollyana Maria Saud Melo
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 13/12913-0 - Calcium-calmodulin of Plasmodium falciparum: identification of ligands and participation in the host-parasite signalling
Grantee:Alexandre Budu
Support type: Scholarships in Brazil - Post-Doctorate