SERCA plays a crucial role in the toxicity of a betulinic acid derivative with potential antimalarial activity.

Autor: Diedrich D; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil., Wildner AC; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil., Silveira TF; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil., Silva GNS; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil., Santos FD; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil., da Silva EF; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil., do Canto VP; Faculdade de Odontologia, Departamento de Patologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90035-003, Brazil., Visioli F; Faculdade de Odontologia, Departamento de Patologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90035-003, Brazil., Gosmann G; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil., Bergold AM; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil., Zimmer AR; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil., Netz PA; Programa de Pós-graduação em Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, 91501-970, Brazil., Gnoatto SCB; Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90610-000, Brazil. Electronic address: simone.gnoatto@ufrgs.br.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2018 May 01; Vol. 287, pp. 70-77. Date of Electronic Publication: 2018 Mar 28.
DOI: 10.1016/j.cbi.2018.03.014
Abstrakt: Malaria is one of the most significant infectious diseases that affect poor populations in tropical areas throughout the world. Plants have been shown to be a good source for the development of new antimalarial chemotherapeutic agents, as shown for the discovery of quinine and artemisinin derivatives. Our research group has been working with semisynthetic triterpene derivatives that show potential antimalarial activity toward different strains of Plasmodium falciparum by specifically modulating calcium pathways in the parasite. Promising results were obtained for nanomolar concentrations of the semisynthetic betulinic acid derivative LAFIS13 against the P. falciparum 3D7 strain in vitro, with a selectivity index of 18 compared to a mammalian cell line. Continuing these studies, we present here in vitro and in vivo toxicological evaluations of this compound, followed by docking studies with PfATP6, a sarco/endoplasmic reticulum Ca +2 -ATPase (SERCA) protein. LAFIS13 showed an LD 50 between 300 and 50 mg/kg, and the acute administration of 50 mg/kg (i.p.) had no negative effects on hematological, biochemical and histopathological parameters. Based on the results of the in vitro assays, LAFIS13 not exerted significant effects on coagulation parameters of human peripheral blood, but a hemolytic activity was verified at higher concentrations. According to the molecular docking study, the PfATP6 protein may be a target for LAFIS13, which corroborates its previously reported modulatory effects on calcium homeostasis in the parasite. Notably, LAFIS13 showed a higher selectivity for the mammalian SERCA protein than for PfATP6, thus impairing the selectivity between parasite and host. In summary, the direct interaction with calcium pumps and the hemolytic potential of the compound proved to be plausible mechanism of LAFIS13 toxicity.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: