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Pharmacological characterization and optimization of novel natural compounds with anti-Chagas activity

Grant number: 18/25311-2
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): January 15, 2020
Effective date (End): November 14, 2020
Field of knowledge:Interdisciplinary Subjects
Principal Investigator:Fátima Pereira de Souza
Grantee:Lilian Hernández Alvarez
Supervisor abroad: James H Mckerrow
Home Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
Local de pesquisa : University of California, San Diego (UC San Diego), United States  
Associated to the scholarship:18/03911-8 - Structure-based design of competitive and allosteric inhibitors of cruzain, BP.DR

Abstract

Trypanosoma cruzi is the causative agent of Chagas disease, a neglected infection affecting millions of people in tropical regions. There are several chemotherapeutic agents for the treatment of this disease, but most of them are inefficient and highly toxic. Natural products have traditionally been a rich source for the discovery of new lead substances and, therefore, the approach of testing those "active ingredients" has been implemented also in discovering anti-parasitic drugs. In the present project, we will perform pharmaceutical studies in order to optimize, lead compounds previously discovered from marine microorganisms. Because the remarkable properties of gallinamide as T. cruci parasiticidal and as inhibitor of cruzipain enzyme, preclinical assays will also be performed with this compound. In addition, other lead compounds such as polyketide and steroid derivatives will be tested against cruzain and T. cruzi both in vitro and in vivo. Furthermore, the pharmacokinetics, pharmacodynamics and liver metabolism of these compounds will be assessed in order to evaluated the drug stability. Finally, with the aid of animal models of Chagas disease we intend to optimize the compounds having the lowest acute toxicity profiles. These experiments will provide insights into the design of novel anti-Chagas drugs.