Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/18640
Title: Stairway to Heaven or Hell? Perspectives and Limitations of Chagas Disease Chemotherapy
Authors: Salomão, Kelly
Menna-Barreto, Rubem Figueiredo Sadok
Castro, Solange Lisboa de
Affilliation: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Abstract: In this review, we intend to provide a general view of the evolution of experimental studies in the area of chemotherapy for Chagas disease. We can follow the process of drug development through three phases. The first phase began almost at the same time as the discovery made by Carlos Chagas and proceeds to 1970, during which time an extensive list of compounds was subjected to preclinical and clinical trials. The second phase began with the introduction of nifurtimox and benznidazole into the clinical setting, followed with the search for alternative drugs. In this phase, a dichotomy existed between rational and empirical approaches in preclinical studies. The third phase began with the unravelling of the T. cruzi genome. The development of transgenic parasites has allowed the development of solid HTS protocols, and the establishment of bioluminescent T. cruzi has allowed in vivo drug evaluations using a reduced number of animals. Among the wide variety of compounds subjected to preclinical studies, we have discovered azolic and non-azolic inhibitors of sterol C14α-demethylase (CYP51) and nitro compounds. Two compounds evaluated during the second phase, namely, MK-436 and allopurinol, could be revisited. Clinical studies of posaconazole and E1224 yielded disappointing results, and it is critical to understand the reason for their failure as a monotherapy. Currently, the combination and repositioning of drugs with different mechanisms of action are complementary approaches. The use of drug combinations, particularly those of nitro compounds with CYP51 inhibitors, is considered a real alternative for the treatment of Chagas disease.
Keywords: Chemotherapy
Chagas Disease
Trypanosoma cruzi
High throughput screening
C14α-demethylase inhibitors
nitroheterocycles
azoles
keywords: Quimioterapia
Doença de Chagas
Trypanosoma cruzi
Azóis
Nitro-heterociclos
Rastreio de alto rendimento
Issue Date: 2016
Publisher: Bentham Science Publishers
Citation: SALOMÃO, Kelly Sampaio; MENNA-BARRETO, Rubem Figueiredo Sadok; CASTRO, Solange Lisboa de. Stairway to Heaven or Hell? Perspectives and Limitations of Chagas Disease Chemotherapy. Current Topics in Medicinal Chemistry, v.16, 24p, 2016.
ISSN: 1568-0266
Copyright: restricted access
Appears in Collections:IOC - Artigos de Periódicos

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