4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection

University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. La Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
Scripps Florida. Department of Chemistry. Jupiter, Florida, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. La Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. La Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. La Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. La Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Anatomia Patológica. Rio de Janeiro, RJ. Brasil .
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. La Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
Scripps Florida. Department of Chemistry. Jupiter, Florida, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. La Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. La Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice.

Keywords in Portuguese

Trypanosoma cruzi
Doença de Chagas
Tratamento
Cardiomiopatias
Infecção

Keywords

Trypanosoma cruzi
Chagas Disease
Treatment
Cardiomiopathy
Infection

Publisher

Public Library of Science

Citation

CALVET, Claudia Magalhães et al. 4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection. PLOS Neglected Tropical Diseases, v.11, n.12, p. 1-12, Dec. 2017.

DOI

10.1371/journal.pntd.0006132

ISSN

1935-2727

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/24755

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Copyright

Open access

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