Study the inhibition ubiquinone biosynthesis in Leishmania (L.) amazonensis as a strategy in the discovery of new therapeutic targets

• Grant number: 21/01877-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2021
• End date: March 31, 2024
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Alejandro Miguel Katzin
• Grantee: Juliana Tonini Mesquita
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/22452-1 - Biosynthesis of isoprenoids in Plasmodium falciparum: evaluation of possible targets to obtain new anti-malarial drugs, AP.TEM

Abstract

Leishmaniasis is a parasitic disease caused by protozoa the genus Leishmania that represents an important problem public health. The treatment is considered a major challengedue to the limited therapeutic arsenal and serious adverse effects. The Leishmaniasis is related topoverty and the pharmaceutical industry has no interest due to the low financial return. According to the World Health Organization is considered a neglected disease due to the need toprioritize the development of new drugs. Based on this problem, there is urgency and to needsearch new therapies. The Leishmania is distinguished from mammalian cells in that it has aunique mitochondria and this makes it an important therapeutic target. In the inner membrane of the mitochondria is found ubiquinone which plays an important role in the electron transportchain. Atovaquone is a drug that blocks mitochondrial electron transport, inhibiting pyrimidine synthesis, preventing DNA synthesis and leading to the death of the protozoan. Based on this information, the drug atovaquone and/or analogs were chosen to be evaluated, as well as the inhibitors ubiquinone biosynthesis (4-hydroxybenzoate analogs, statins and bisphosphonates). This work aims to evaluate the efficacy of these drugs in Leishmania (L.) amazonensis, seeking proof of concept to elucidate the mechanism of action and evaluate the association of atovaquone and/or analogs with inhibitors ubiquinone biosynthesis. If the combination or concomitant use shows promising results, in vivo studies will be done, which may contribute with new alternatives to treat Cutaneous Leishmaniasis. (AU)