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

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

Author Gonzalez-Bacerio, Jorge Google Scholar
Maluf, Sarah El Chamy Autor UNIFESP Google Scholar
Mendez, Yanira Google Scholar
Pascual, Isel Google Scholar
Florent, Isabelle Google Scholar
Melo, Pollyana M. S. Autor UNIFESP Google Scholar
Budu, Alexandre Autor UNIFESP Google Scholar
Ferreira, Juliana C. Autor UNIFESP Google Scholar
Moreno, Ernesto Google Scholar
Carmona, Adriana K. Autor UNIFESP Google Scholar
Rivera, Daniel G. Google Scholar
del Rivero, Maday Alonso Google Scholar
Gazarini, Marcos L. Autor UNIFESP Google Scholar
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.
Keywords Antimalarials
Combinatorial synthesis
Metallo-aminopeptidase inhibitors
Multicomponent reactions
Plasmodium falciparum
Language English
Sponsor IFS (Sweden)
FAPESP (Brazil)
CNPq (Brazil)
Grant number IFS: F/4730-1
IFS: F/4730-2F
FAPESP: 2009/54598-9
FAPESP: 2011/14403-4
FAPESP: 2013/12913-0
CNPq: 482400/2013-7
Date 2017
Published in Bioorganic & Medicinal Chemistry. Oxford, v. 25, n. 17, p. 4628-4636, 2017.
ISSN 0968-0896 (Sherpa/Romeo, impact factor)
Publisher Pergamon-Elsevier Science Ltd
Extent 4628-4636
Origin http://dx.doi.org/10.1016/j.bmc.2017.06.047
Access rights Closed access
Type Article
Web of Science ID WOS:000407831300009
URI http://repositorio.unifesp.br/handle/11600/51355

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