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

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.; Rivero, Maday Alonso del; Gazarini, Marcos L.

doi:10.1016/j.bmc.2017.06.047

Cited by 15 publications

(18 citation statements)

References 39 publications

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“…The possibility for the peptidomimetic to interact with other proteins from T. cruzi also exists. KBE009 inhibits PfA-M1 and its efficacy against Plasmodium falciparum is comparable to that found in this study against T. cruzi [15]. Therefore, it is reasonable to speculate that the peptidomimetic could act on a PfA-M1 orthologous in T. cruzi.…”

Section: Discussionsupporting

confidence: 82%

“…Previously, it was reported that the bestatin-like peptidomimetic KBE009 (Figure 1B) is an inhibitor of Plasmodium falciparum M1 aminopeptidase (PfA-M1) and exerts antimalarial activity in vitro against 3D7 and FcB1 strains [15]. This compound is selective for the plasmodial enzyme over its porcine counterpart, and it is not cytotoxic against human umbilical vein endothelial cells (HUVECs).…”

Section: Introductionmentioning

confidence: 98%

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KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity

González-Bacerio

Arocha²,

Aguado

et al. 2021

Life

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Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC50 = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC50 = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 98%

KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity

González-Bacerio

Arocha²,

Aguado

et al. 2021

Life

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“…Previously [14] and newly synthesized [56] 1,1′-iminodicarboxylic acid analogues 236 were tested for PfA-M1 inhibition and for their in vitro antimalarial activity on the growth of P. falciparum erythrocytic stages (3D7 and FcB1 strains) (Scheme 61). The p53 protein has a key role in protecting cells with oncogenic mutations.…”

Section: Ugi Compounds In Medicinal Chemistrymentioning

confidence: 99%

α-Amino Acids as Synthons in the Ugi-5-Centers-4-Components Reaction: Chemistry and Applications

et al. 2019

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Since the first reports, the Ugi four-component reaction (U-4CR) has been recognized as a keystone transformation enabling the synthesis of peptide mimetics in a single step and with high atom economy. In recent decades, the U-4CR has been a source of inspiration for many chemists fascinated by the possibility of identifying new efficient organic reactions by simply changing one of the components or by coupling in tandem the multicomponent process with a huge variety of organic transformations. Herein we review the synthetic potentialities, the boundaries, and the applications of the U-4CR involving α-amino acids, where the presence of two functional groups—the amino and the carboxylic acids—allowed a 5-center 4-component Ugi-like reaction, a powerful tool to gain access to drug-like multi-functionalized scaffolds.

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“…The co-crystal structure of the early inhibitors show that the Zn 2+ itself is co-ordinated to the enzyme by a catalytic triad of residues His496, His500, and Glu519 while the ZBG of the inhibitor is co-ordinated to the Zn 2+ through metallo-bonds ( Figure 3B, in pink) [74]. For instance, bestatin ( Figure 3C, 8) [79] utilises its hydroxyl and carbonyl oxygen while other peptide-based inhibitors [85][86][87] utilise their carboxylic acid moiety for coordination. Other studies explored the use of phosphonic acids and aminophosphonates (e.g.…”

Section: Pfa-m1 -Flexible Substrate Pockets Provide Key To Potencymentioning

confidence: 99%

Driving antimalarial design through understanding of target mechanism

Calic

Mansouri

Scammells

et al. 2020

Biochemical Society Transactions

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Malaria continues to be a global health threat, affecting approximately 219 million people in 2018 alone. The recurrent development of resistance to existing antimalarials means that the design of new drug candidates must be carefully considered. Understanding of drug target mechanism can dramatically accelerate early-stage target-based development of novel antimalarials and allows for structural modifications even during late-stage preclinical development. Here, we have provided an overview of three promising antimalarial molecular targets, PfDHFR, PfDHODH and PfA-M1, and their associated inhibitors which demonstrate how mechanism can inform drug design and be effectively utilised to generate compounds with potent inhibitory activity.

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

Cited by 15 publications

References 39 publications

KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity

KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity

α-Amino Acids as Synthons in the Ugi-5-Centers-4-Components Reaction: Chemistry and Applications

Driving antimalarial design through understanding of target mechanism

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