In silico, in vitro, and pharmacokinetic studies of UBMC-4, a potential novel compound for treating against Trypanosoma cruzi

dc.creatorBustamante, Christian
dc.creatorDíez-Mejía, Andrés Felipe
dc.creatorArbeláez, Natalia
dc.creatorSoares, Maurilio José
dc.creatorRobledo, Sara M.
dc.creatorOchoa, Rodrigo
dc.creatorVarela-M, Rubén E.
dc.creatorMarín-Villa, Marcel
dc.date2022-08-17T18:28:17Z
dc.date2022-08-17T18:28:17Z
dc.date2022
dc.date.accessioned2023-09-26T23:19:44Z
dc.date.available2023-09-26T23:19:44Z
dc.identifierBUSTAMANTE, Christian et al. In silico, in vitro, and pharmacokinetic studies of UBMC-4, a potential novel compound for treating against Trypanosoma cruzi. Pahogens, v. 11, n. 616, p. 1–21, 2022.
dc.identifier2076-0817
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/54685
dc.identifier10.3390/ pathogens11060616
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8889363
dc.descriptionThe lack of therapeutic alternatives for the treatment of Chagas disease, a neglected disease, drives the discovery of new drugs with trypanocidal activity. Consequently, we conducted in vitro studies using UBMC-4, a potential Trypanosoma cruzi AKT-like pleckstrin homology (PH) domain inhibitory compound found using bioinformatics tools. The half effective concentration (EC50) on intracellular amastigotes was determined at 1.85 nM 1 nM showing low cytotoxicity (LC50) > 40 nM on human cell lines tested. In order to study the lethal effect caused by the compound on epimastigotes, morphological changes were assessed by scanning and transmission electron microscopy. Progressive alterations such as flagellum inactivation, cell size reduction, nuclear structure alteration, condensation of chromatin towards the nuclear periphery, vacuole formation, and mitochondrial swelling with kinetoplast integrity loss were evidenced. In addition, apoptosis-like markers in T. cruzi were assessed by flow cytometry, demonstrating that the effect of UBMC-4 on T. cruzi AKT-like kinase reduced the tolerance to nutritional stress-triggered, apoptosis-like events, including DNA fragmentation, mitochondrial damage, and loss of plasma membrane integrity. After this, UBMC-4 was formulated for oral administration and pharmacokinetics were analyzed in a mouse model. Finally, upon oral administration of 200 mg/kg in mice, we found that a UBMC-4 plasma concentration remaining in circulation beyond 24 h after administration is well described by the two-compartment model. We conclude that UBMC-4 has an effective trypanocidal activity in vitro at low concentrations and this effect is evident in T. cruzi cell structures. In mice, UBMC-4 was well absorbed and reached plasma concentrations higher than the EC50, showing features that would aid in developing a new drug to treat Chagas disease.
dc.formatapplication/pdf
dc.languagepor
dc.publisherMDPI
dc.rightsopen access
dc.subjectTrypanosoma cruzi
dc.subjectUBMC-4 inhibitor
dc.subjectChagas Disease
dc.subjectSerine-Threonine Kinase
dc.subjectDrug Discovery
dc.subjectMolecular Docking
dc.subjectPharmacokinetics
dc.subjectEnfermedad de Chagas
dc.subjectSerina-Treonina Quinasa
dc.subjectDescubrimiento de Drogas
dc.subjectAcoplamiento Molecular
dc.subjectFarmacocinética
dc.subjectDoença de Chagas
dc.subjectSerina-Treonina Quinase
dc.subjectDescoberta de Drogas
dc.subjectAcoplamento Molecular
dc.subjectFarmacocinética
dc.titleIn silico, in vitro, and pharmacokinetic studies of UBMC-4, a potential novel compound for treating against Trypanosoma cruzi
dc.typeArticle


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