ANTILEISHMANIAL PEPTIDES: PLANNING, SYNTHESIS, CHEMICAL AND BIOLOGICAL CHARACTERIZATION OF NEW SYNTHETIC PEPTIDES DIRECTED TO THE MCU (MITOCHONDRIAL CALCIUM UNIPORTER) MOLECULAR TARGET OF LEISHMANIA

• Grant number: 23/02103-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): October 01, 2023
• Effective date (End): September 30, 2025
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Marcia Aparecida Silva Graminha
• Grantee: Ana Laura Dias Ramos
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Leishmaniasis is a highly prevalent neglected disease caused by more than 20 species of protozoan parasites of the genus Leishmania (order: Kinetoplastida; family: Trypanosomatidae) transmitted by the bite of sandflies. The therapeutic treatment of leishmaniasis has several drawbacks, from the limited diversity of drugs currently available to high toxicity, which makes the search for new therapeutic solutions essential. In this context, the design of new leishmanicidal compounds based on essential target proteins proves to be an important strategy to combat this disease. Trypanosomatids have a repertoire of proteins involved in maintaining calcium homeostasis, an important cellular messenger associated with survival and infectivity, which makes this signaling pathway attractive for the development of therapeutic intervention strategies. In trypanosomatids, in addition to acidocalcisomes and endoplasmic reticulum, mitochondria play an important role in maintaining calcium homeostasis. Literature data show that the participation of the MCU complex (Mitochondrial Calcium Uniporter) in this process and genetic studies revealed its essential role in Trypanosoma brucei. Little is known about the structure and importance of MCU to the biology of Leishmania. Thus, Natalia C. C. Coelho, during the development of her doctoral project, carried out molecular modeling and docking analyses for the design of new peptides capable of interacting with MCU selectivity filter region called DIME, thus leading to inhibition of the parasite mitochondrial calcium influx. Therefore, this proposal aims to carry out synthesis, purification and chemical (Mass Spec) and biological characterization (cytotoxicity, anti-Leishmania, anti- Trypanosoma cruzi and anti-Trypanosoma brucei) of these peptides. This proposal is innovative and may contribute to the understanding of the role of the MCU as a potential therapeutic target in the process of drug discovery for the treatment of leishmaniasis.