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New insight into the mechanism of action of CP2 in Leishmania: analysis of calcium homeostasis and the respiratory chain

Grant number: 19/21661-1
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): January 31, 2020
Effective date (End): January 30, 2021
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Marcia Aparecida Silva Graminha
Grantee:Angela Maria Arenas Velásquez
Supervisor abroad: Andrew Philip Thomas
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Local de pesquisa : Rutgers The State University of New Jersey, Newark, United States  
Associated to the scholarship:16/19289-9 - Characterization of mechanism of cell death potentially induced by a binuclear antileishmanial cyclopalladated CP2: a contribution to the rational drug development, BP.PD

Abstract

Leishmaniasis is a neglected disease that remains a major health problem around the word. A limited number of effective antileishmanial drugs are available for chemotherapy, and many of them are associated with high toxicity, difficult administration route and low efficacy. Therefore, there is an urgent need to develop a novel safe and effective antileishmanial drug. Previously, we reported the leishmanicidal activity of the cyclopalladated complex [Pd(dmba)(µ-N3)]2 (CP2). The objective of the present study is to investigate the Ca2+ signaling pathway as a possible target of CP2 and to analyze the difference between resistant parasites to CP2. Additionally, inhibition analysis of respiration of CP2-resistance Leishmania in the presence of classical electron transfer complex inhibitors will be used to demonstrate the adaptability of Leishmania and the way by which the parasite tries circumvent the effects induced by CP2. This information are important to understand the involvement of mitochondria in the signals produced downstream of Leishmania topoisomerase IB inhibition by CP2. Ca2+ excess in mitochondria can lead to an increase in reactive oxygen species due to alterations in the redox state of respiratory chain components with collapse of the mitochondrial membrane potential, leading the parasite to cell death. The foregoing will provide us with further information to elucidate the mechanism of action of CP2 and improvement the chemical structure of the antileishmanial compound.