KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library. Issue 17 (1st September 2017)

• Record Type: Journal Article
• Authors: González-Bacerio, Jorge; Maluf, Sarah El Chamy; Méndez, Yanira; Pascual, Isel; Florent, Isabelle; Melo, Pollyana M.S.; Budu, Alexandre; Ferreira, Juliana C.; Moreno, Ernesto; Carmona, Adriana K.; Rivera, Daniel G.; Alonso del Rivero, Maday; Gazarini, Marcos L.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 17(2017)
• Page Start: 4628
• Page End: 4636
• Publication Date: 2017-09-01
• Subjects: AMC 7-amido-4-methylcoumarin -- AP aminopeptidase -- APN M1 alanyl-aminopeptidase -- FT−ICR Fourier transform ion cyclotron resonance -- PfA-M1 APN from P. falciparum -- rPfA-M1 recombinant PfA-M1 -- TLC thin layer chromatography; Antimalarials -- Combinatorial synthesis -- Metallo-aminopeptidase inhibitors -- Multicomponent reactions -- PfA-M1 -- Plasmodium falciparum; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.06.047
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 ( Ki = 0.4 μM) and an in vitro antimalarial compound as potent as bestatin (IC50 = 18 μM; 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 Zn 2+ 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 μM), 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.