Potential of ”1- Pyrroline-5-carboxylate synthetase from Trypanosoma cruzi as a therapeutic target

• Grant number: 22/16258-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2023
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Ariel Mariano Silber
• Grantee: Ana Carolina Araujo Mengarda
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 21/12938-0 - Amino acid metabolism in Trypanosoma cruzi: a toolbox to survive in hostile environments, AP.TEM

Abstract

Chagas disease is a protozoan disease caused by Trypanosoma cruzi, which affects 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, the search for new treatments and therapeutic targets is necessary; 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 possible 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. The transport of Pro to the intracellular environment and its catabolism in T. cruzi have already been studied by our group. However, the biosynthesis of Pro in trypanosomatids is less known. Briefly, biosynthesis can occur from glutamate (Glu), by two enzymatic processes: I- Reduction of Glu to semi-aldehyde glutamate, which is converted into ”1-pyrroline-5-carboxylate (P5C) through a non-enzymatic reaction; and II- Reduction from P5C to Pro. The first step can be catalyzed by two separate enzymes, ³-glutamyl kinase and ³-glutamyl phosphate reductase, as occurs in yeast and bacteria, or by a single bifunctional enzyme called ”1-pyrroline-5-carboxylate synthetase (P5CS), that possesses both catalytic activities, as is the case in plants and animals. Recent studies have shown P5CS as a promising target to increase plant resistance to water stress, and for the treatment of human pancreatic ductal adenocarcinoma. However, the literature involving P5CS, T. cruzi and evaluation as a therapeutic target has not yet been fully elucidated. Taking into account the importance of the role of Pro and its metabolic process in T. cruzi, P5CS becomes a promising target to be studied. Thus, we propose the structural analysis of the enzyme via X-ray crystallography and in solution by the low angle X-ray scattering technique. In addition to performing virtual screening assays to search for promising molecules with anti-T. cruzi activity. (AU)