Unlocking the therapeutic potential of the Trypanosoma cruzi proline pathway through gene expression knockdown and medicinal chemistry strategies

• Grant number: 25/12443-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 01, 2026
• End date: December 31, 2026
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Ariel Mariano Silber
• Grantee: Ana Carolina Araujo Mengarda
• Supervisor: Maria Belen Cassera
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Georgia, Athens (UGA), United States
• Associated to the scholarship: 22/16258-6 - Potential of ”1- Pyrroline-5-carboxylate synthetase from Trypanosoma cruzi as a therapeutic target, BP.PD

Abstract

Chagas disease is a protozoan disease caused by Trypanosoma cruzi, which infects 6 to 7 million people worldwide. Currently, the only two drugs available for the treatment of the disease are nifurtimox and benznidazole, which have limitations regarding efficacy and tolerance. Therefore, new treatments and therapeutic targets are urgently needed; however, the complexity of the T. cruzi life cycle makes the development of new drugs difficult. In this context, there is an urgent need to know, in depth, the metabolism of this protozoan in order to identify and validate new therapeutic targets. It is known that the amino acid proline (Pro), and the intermediaries of its metabolism, are essential for the survival of T. cruzi. Considering the essential role of the Pro pathway for T. cruzi, identifying small molecules that can inhibit enzymes involved in its biosynthesis and degradation may lead to the development of alternative treatments for Chagas' disease. Given the difficulty in finding novel therapeutics with trypanocidal activity, the objective of this project is to screen a proprietary compound library of novel tetrahydro-¿-carbolines, ¿-carbolines, and other indole alkaloids as a starting point for the development of novel therapies for Chagas disease. This collection was synthetized by Dr. Paul Carlier (University of Illinois at Chicago, United States) in collaboration with Dr. Belen Cassera (University of Georgia, Athens, GA, United States) who is the host researcher for this proposal. In addition, to complement the search for compounds that can inhibit the enzymes of the Pro pathway, knockdown strains for selected enzymes in this pathway will be created as an alternative drug target validation strategy to those proposed in the parental project (Grant number 2022/16258-6). The technology for generating knockdown strains was developed by Dr. Drew Etheridge and his research group (Department of Cellular Biology, University of Georgia, Athens, GA, United States) who is a co-host of this proposal.