Structural and Functional Evaluation of the Effects of Glycosome Blockers in Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum

• Grant number: 25/00260-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2025
• End date: December 31, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Beatriz Simonsen Stolf
• Grantee: Juliana Mendes Sousa
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Leishmaniases are a group of neglected diseases endemic in 97 countries, with an annual incidence of approximately 1.5 million cases for the cutaneous form and 300,000 for the visceral form. In Brazil, they represent a serious public health issue, with current therapies often being ineffective, toxic, and difficult to administer, highlighting the need for the identification of new therapeutic targets. Glycosomes are organelles of protozoa from the Trypanosomatidae family that house most of the enzymes involved in the glycolytic pathway and other metabolic pathways. These enzymes are produced in the cytoplasm and transported to the glycosome with the aid of PEX proteins, with the PEX5-PEX14 interaction being essential for this transport. Recent studies have developed a 3D pharmacophore model that simulates this interaction, leading to the synthesis of compounds capable of blocking the PEX5-PEX14 interaction. In vitro assays with promastigotes of L. (L.) amazonensis and L. (L.) infantum, as well as with intracellular amastigotes of L. (L.) amazonensis (unpublished data), revealed four compounds capable of significantly reducing parasite viability and showing favorable selectivity indices compared to two mammalian cell lines. This project aims to evaluate the leishmanicidal activity of these compounds in an in vivo infection model with Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum. Additionally, we will investigate ultrastructural and functional alterations in the parasites related to the proposed mechanism of action, such as impacts on energy metabolism (ATP levels) and enzymatic compartmentalization in the glycosome. The results may contribute to the development of safer and more effective therapies for the cutaneous and visceral forms of leishmaniasis, addressing a critical need in endemic countries such as Brazil.