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Synthesis and evaluation of potential substrates/inhibitors of Trypanosoma cruzi trans-sialidase

Grant number: 07/07146-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2008
Effective date (End): October 31, 2010
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Ivone Carvalho
Grantee:Vanessa Leiria Campo
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


In the last 20 years parasitic diseases such as Chagas disease, caused by the parasite Trypanosoma cruzi, and leishmanioses have represented a threat for human health and socioeconomic development, being an important cause of morbidity and mortality (Boiani et al., 2006). Cellular and molecular biology studies have revealed the presence of specific and essential targets involved in the cycle of life of these parasites. The intracelular parasite T. cruzi develops a surface regulatory enzyme called trans-sialidase, involved in interactions between host cells and the parasite, a key step for invasion process (Previato et al., 2005). T. cruzi can not synthesize sialic acid itself and uses a trans-sialidase enzyme to scavenge this monosaccharide from host glycoconjugates to sialylate acceptors molecules, such as GPI (glycosylphosphatidylinositol)-anchored mucins, that are present in parasite plasma membrane (Pereira et al., 2000). Considering the importance of Trypanosoma cruzi trans-sialidase (TcTS) enzyme as a potential therapeutic target to be explored for the development of selective and effective new molecules for treatment of Chagas disease, the objective of this work is the synthesis of glycosylated amino acids as potential inhibitors of TcTS. Previous studies involving the TcTS enzyme and synthetic glycosylated amino acids and glycopeptides (Campo et al., 2007), together with docking simulations studies led to the rational design of the potential inhibitors 3-O-alfa-Ser-betaGalNAcOMe 13 and 3-O-alfaSer-betaGalNAc-1,4-beta-GlcNAcOMe 14. The synthesized compounds will be submitted to biological assays for evaluation of inhibitory activity of TcTS enzyme, parallel to molecular modeling studies for design of new inhibitors.

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