KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library
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
Departamento de Biofísica, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 7 andar, 04039-032, Vila Mariana, São Paulo, Brazil
Centro de Estudio de Productos Naturales, Facultad de Química, Universidad de La Habana, Zapata y G, 10400 La Habana, Cuba
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
Centro de Inmunología Molecular, Calle 15 esq. 216, Siboney, Playa, La Habana, Cuba
Universidad de Medellín, Carrera 87 #30-65, Medellín, Colombia
Departamento de Biociências, Universidade Federal de São Paulo, R. Silva Jardim, 136, 11015-020, Vila Mathias, Santos, São Paulo, Brazil
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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.
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