Crystallographic studies of the enzyme cruzain from T.cruzi in complex with inhibitors

• Grant number: 16/06499-5
• Support type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): June 01, 2016
• Effective date (End): May 31, 2017
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal researcher: Glaucius Oliva
• Grantee: Jonas Coelho Kasmanas
• Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

Chagas disease affects about 12 million people in the Americas, which makes it a major public health problem, in addition to its great potential of human morbidity and mortality. Despite its major impact on public health in countries where poverty is still widespread, Chagas disease has not been the subject of research and development by the large pharmaceuticals industry. Treatment of the disease is made only through benznidazole, distributed by the health care system of Brazil. However, the therapy is still limited and insufficient in various clinical aspects, including limited efficacy and serious side effects. Thus, the development of new and more effective agents against Chagas' disease is needed. After validation of various parasite proteins as therapeutic targets, the enzyme cruzain, a cysteine protease present throughout the development of Trypanosoma cruzi, was selected as target for inhibition studies. Among the methodologies available for the selection of new inhibitor drugs is the Structure Based Drug Design (SBDD) technique. The SBDD method uses various computational techniques, always integrated with the experimental methods of synthesis and evaluation of compounds planned, and have been increasingly used to develop new drugs. In this project we propose the crystallographic structure determination of the cruzain enzyme co-crystallized with some imidazole derivatives, inhibitors developed at the Research and Innovation Center in Biodiversity and Drugs (CIBFar-CEPID). Thus, the aim is to determine the mode of interaction of small molecules with the target protein in order to identify its mechanism of action on the enzyme and enhance the improvement of these inhibitors as to their pharmacodynamics, pharmacokinetic and pharmacological properties.