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Title: KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library
Authors: Gonzalez-Bacerio, Jorge
Maluf, Sarah El Chamy [UNIFESP]
Mendez, Yanira
Pascual, Isel
Florent, Isabelle
Melo, Pollyana Maria Saud [UNIFESP]
Budu, Alexandre [UNIFESP]
Ferreira, Juliana Conrado [UNIFESP]
Moreno, Ernesto
Carmona, Adriana Karaoglanovic [UNIFESP]
Rivera, Daniel G.
Rivero, Maday Alonso del
Gazarini, Marcos Leoni [UNIFESP]
Keywords: Antimalarials
Combinatorial synthesis
Metallo-aminopeptidase inhibitors
Multicomponent reactions
Plasmodium falciparum
Issue Date: 2017
Publisher: Pergamon-Elsevier Science Ltd
Citation: Bioorganic & Medicinal Chemistry. Oxford, v. 25, n. 17, p. 4628-4636, 2017.
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
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.
ISSN: 0968-0896
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