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Application of structure-based drug design in parasite cysteine protease inhibitor search (cruzain (t. cruzi and CPB (leishmanioses))

Grant number: 13/15650-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): February 01, 2014
Effective date (End): June 30, 2018
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Gustavo Henrique Goulart Trossini
Grantee:Drielli Gomes Vital Fujii
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):17/01181-0 - Virtual screening (vs) and high-throughput screening (HTS) integration in discovery of new drugs against Neglected Tropical Diseases (NTDs), BE.EP.DR

Abstract

Caused by infectious and parasitic agents, neglected diseases are responsible for bringing millions of people to death every year and primarily affect poor countries and developing countries, not arousing the interest of pharmaceutical industries to develop new therapies. Among these, Chagas disease and Leishmaniasis, caused by parasitic flagellate parasites belonging to the family Trypanosomatidae, T. cruzi and Leshmania sp. respectively, are presented as a serious public health problem worldwide. Even endemic in several countries and causing millions of deaths every year, there are still no effective and safe drugs for its treatment. This panorama makes eminent the need for research and development of new drugs for these parasites. The search for chemotherapeutic agents involves the selection of metabolic pathways essential for parasite survival, highlighting the cysteine proteases present in these trypanosomes. The cruzain in T. cruzi and CPB in Leishmaniasis thus appear as biochemical targets promising. The availability of crystallographic structures of cruzain and genomic sequencing of CPB, allows us to use strategies of drug design based on receptor (SBDD) to identify drug candidates for these diseases. Among the modern techniques used SBDD, the virtual screening helps identify and select potent and selective enzyme inhibitors. Thus, it is proposed in this project, from design through SBDD inhibitors cruzain (virtual screening) and CPB (Comparative Modeling / Virtual Screening) and biological assays (enzymatic and parasitic) in identifying candidates trypanocides and antileishmanial agents.