Chemotherapy for Chagas Disease: therapeutic failures to benznidazole and screening of candidates for treatment alternatives

• Grant number: 13/13333-8
• Support Opportunities: Regular Research Grants
• Duration: November 01, 2013 - October 31, 2015
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Bianca Silvana Zingales
• Grantee: Bianca Silvana Zingales
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Iolanda Midea Cuccovia ; Leoberto Costa Tavares

Abstract

Benznidazole (BZ) is the frontline drug used against Trypanosoma cruzi, the causative agent of Chagas disease, which affects 10 million people in Latin America. However, treatment failures are frequently reported, attributed mainly to the diversity of drug susceptibility within natural parasite populations and/or the development of drug resistance. Evidence of our group indicate that an ABC transporter (TcABCG1) participates in the process of natural resistance to BZ. Others have shown that alterations of a gene encoding a mitochondrial nitroreductase (TcNTR) play a central role in acquired resistance to this drug. Both studies have been performed in a limited number of T. cruzi strains, whose genetic diversity is widely recognized. In this context, one of the goals of this proposal is to characterize the nucleotide sequence and genomic organization of TcABCG1 and TcNTR genes in parasite strains belonging to different genetic lineages (DTUs TcI-TcVI) and in isolates recovered from patients before and after treatment with BZ (treatment failure). This information has implications for future therapeutic strategies. The second goal of the proposal is the screening of drug candidates for Chagas disease. Two laboratories of the University of São Paulo have synthesized some derivatives of different chemical classes, which have shown in vitro anti-trypanosomal activity to epimastigote forms of the Y strain (TcII). We intend to screen the activity of 30 or more of these compounds against epimastigote and intracellular amastigote forms belonging to T. cruzi lineages prevalent in human patients (TcI, TcII and TcV), and evaluate the citotoxicity of promising drugs to mammalian cells in culture. The drug screening method of intracellular parasites will utilize parasites that express the E. coli ²-galactosidase gene. The enzyme activity will be monitored spectrophotometrically. Active compounds will be further explored. (AU)

Scientific publications

(5)

(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)

PETRAVICIUS, PAMELA O.; COSTA-MARTINS, ANDRE G.; SILVA, MARCELO N.; REIS-CUNHA, JOAO L.; BARTHOLOMEU, DANIELLA C.; TEIXEIRA, MARTA M. G.; ZINGALES, BIANCA. Mapping benznidazole resistance in trypanosomatids and exploring evolutionary histories of nitroreductases and ABCG transporter protein sequences. Acta Tropica, v. 200, DEC 2019. (13/13333-8)

FRANCO, JAQUES; FERREIRA, RENATA C.; IENNE, SUSAN; ZINGALES, BIANCA. ABCG-like transporter of Trypanosoma cruzi involved in benznidazole resistance: Gene polymorphisms disclose inter-strain intragenic recombination in hybrid isolates. INFECTION GENETICS AND EVOLUTION, v. 31, p. 198-208, APR 2015. (13/13333-8, 09/01230-4)

ZINGALES, BIANCA; AQUINO ARAUJO, RAFAEL GOMES; MORENO, MARGOTH; FRANCO, JAQUES; NASCIMENTO AGUIAR, PEDRO HENRIQUE; NUNES, SOLANGE LESSA; SILVA, MARCELO NUNES; IENNE, SUSAN; MACHADO, CARLOS RENATO; BRANDAO, ADEILTON. A novel ABCG-like transporter of Trypanosoma cruzi is involved in natural resistance to benznidazole. Memórias do Instituto Oswaldo Cruz, v. 110, n. 3, p. 433-444, MAY 2015. (13/13333-8)

PALACE-BERL, FANNY; MESQUITA PASQUALOTO, KERLY FERNANDA; JORGE, SALOMAO DORIA; ZINGALES, BIANCA; ZORZI, RODRIGO ROCHA; SILVA, MARCELO NUNES; FERREIRA, ADILSON KLEBER; DE AZEVEDO, RICARDO ALEXANDRE; TEIXEIRA, SARAH FERNANDES; TAVARES, LEOBERTO COSTA. Designing and exploring active N `-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 96, p. 330-339, MAY 26 2015. (14/06061-4, 13/13333-8)

PALACE-BERL, FANNY; MESQUITA PASQUALOTO, KERLY FERNANDA; ZINGALES, BIANCA; MORAES, CAROLINA BORSOI; BURY, MARIANA; FRANCO, CAIO HADDAD; DA SILVA NETO, ADELSON LOPES; MURAYAMA, JOAO SUSSUMU; NUNES, SOLANGE LESSA; SILVA, MARCELO NUNES; et al. Investigating the structure-activity relationships of N `-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 144, p. 29-40, JAN 20 2018. (14/06061-4, 13/13333-8)