Schistosoma mansoni Cathepsin B1: design and rational synthesis of new potential inhibitors

• Grant number: 19/26686-2
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2020
• End date: November 30, 2022
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Daniela Goncales Galasse Rando
• Grantee: Daniela Goncales Galasse Rando
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Associated researchers: Conor Caffrey ; Josué de Moraes

Abstract

Schistosomiasis is a neglected disease for which only one drug is available to the treatment, the praziquantel. Previous experience with other infectious diseases has shown that relying upon only one drug is a dangerous approach, even more, when it is frequently employed as prophylactics, as in the case of praziquantel. Consequently, the need for new pharmacological alternatives to treat Schistosomiasis is urgent. This project aims to associate different drug design strategies in the search for new S. mansoni Cathepsin B1 inhibitors. This target is an essential enzyme to the helminth since it is the main digestive enzyme associated with worm nutrition. Virtual Screening (VS) studies are proposed, employing two different compound libraries. The first one will aim FDA approved drugs, associating the VS with drug repositioning, a strategy which may improve and fasten the discovery for new antischistosomal compounds. The second will search for compounds with not explored chemical structures and may provide new chemical insights in the antischistosomal field. In parallel, the synthesis of new molecules, which mixes N-acylhydrazones and Vinyl sulfones characteristics is proposed. To these, previous knowledge about S. mansoni Cathepsin B1 inhibitors (vinyl sulfones) and the Topliss methodology will guide the structures synthesis. Finally, enzymatic inhibition and in vitro and in vivo studies with the worm are planned to be developed in collaborative work with the research groups coordinated by Dr Josué de Moraes, from Universidade de Guarulhos, and by Dr Conor Caffrey, from the University of California in San Diego. (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)

DA COSTA, MARCELA OLIVEIRA LEGRAMANTI; PAVANI, THAIS FERNANDA AMORIM; SCOTT, ANA LIGIA; RAMOS, DEBORA FELICIA VIEIRA; LAZARINI, MARIANA; RANDO, DANIELA GONCALES GALASSE. Nifuroxazide as JAK2 inhibitor: A binding mode proposal and Hel cell proliferation assay. European Journal of Pharmaceutical Sciences, v. 162, JUL 1 2021. (19/26686-2, 13/01875-0)

ROQUINI, VINICIUS; MENGARDA, ANA C. C.; CAJAS, RAYSSA A. A.; MARTINS-DA-SILVA, MILENE F. F.; GODOY-SILVA, JULIA; SANTOS, GUSTAVO A. A.; ESPIRITO-SANTO, MARIA CRISTINA C.; PAVANI, THAIS F. A.; MELO, VANUSA A. A.; SALVADORI, MARIA C. C.; et al. The Existing Drug Nifuroxazide as an Antischistosomal Agent: In Vitro, In Vivo, and In Silico Studies of Macromolecular Targets. MICROBIOLOGY SPECTRUM, v. N/A, p. 12-pg., 2023-07-06. (20/01441-4, 19/25905-2, 19/26686-2, 16/22488-3)