Synthesis and evaluation of potential inhibitors of trypanosoma cruzi trans-sialidase

• Grant number: 08/00373-3
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2008
• End date: September 30, 2011
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Ivone Carvalho
• Grantee: Ivone Carvalho
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

In the last 20 years parasitic diseases such as Chagas disease, caused by the parasite Trypanosoma cruzi, 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. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MANTOANI, SUSIMAIRE PEDERSOLI; DE ANDRADE, PETERSON; CANTUARIA CHIERRITO, TALITA PEREZ; FIGUEREDO, ANDREZA SILVA; CARVALHO, IVONE. Potential Triazole-based Molecules for the Treatment of Neglected Diseases. Current Medicinal Chemistry, v. 26, n. 23, p. 4403-4434, 2019. (08/00373-3)

JUNQUEIRA, GETLIO G.; CARVALHO, MARCELO R.; DE ANDRADE, PETERSON; LOPES, CARLA D.; CARNEIRO, ZUMIRA A.; SESTI-COSTA, RENATA; SILVA, JOAO S.; CARVALHO, IVONE. Synthesis and in vitro evaluation of novel galactosyl-triazolo-benzenesulfonamides against Trypanosoma cruzi. Journal of the Brazilian Chemical Society, v. 25, n. 10, p. 1872+, OCT 2014. (08/00373-3)