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

• Grant number: 18/25311-2
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: January 15, 2020
• End date: September 14, 2020
• Field of knowledge: Interdisciplinary Subjects
• Principal Investigator: Fátima Pereira de Souza
• Grantee: Lilian Hernández Alvarez
• Supervisor: James H. McKerrow
• Host 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
• Institution abroad: 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. (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)

SHARMA, VANDNA; SHING, BRIAN; HERNANDEZ-ALVAREZ, LILIAN; DEBNATH, ANJAN; PODUST, LARISSA M.. Domain-Swap Dimerization of Acanthamoeba castellanii CYP51 and a Unique Mechanism of Inactivation by Isavuconazole. MOLECULAR PHARMACOLOGY, v. 98, n. 6, p. 770-780, DEC 1 2020. (18/25311-2)

GONZALEZ, JORGE ENRIQUE HERNANDEZ; ALVAREZ, LILIAN HERNANDEZ; LEITE, VITOR B. P.; PASCUTTI, PEDRO GERALDO. Water Bridges Play a Key Role in Affinity and Selectivity for Malarial Protease Falcipain-2. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 11, p. 5499-5512, NOV 23 2020. (16/24587-9, 18/25311-2, 18/03911-8)

DA SILVA, ELANY BARBOSA; SHARMA, VANDNA; HERNANDEZ-ALVAREZ, LILIAN; TANG, ARTHUR H.; STOYE, ALEXANDER; O'DONOGHUE, ANTHONY J.; GERWICK, WILLIAM H.; PAYNE, RICHARD J.; MCKERROW, JAMES H.; PODUST, LARISSA M.. Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi. Journal of Medicinal Chemistry, v. 65, n. 5, p. 15-pg., 2022-03-10. (18/25311-2, 18/03911-8)