Title:Stairway to Heaven or Hell? Perspectives and Limitations of Chagas Disease Chemotherapy
Volume: 16
Issue: 20
Author(s): Kelly Salomao, Rubem Figueiredo Sadok Menna-Barreto and Solange Lisboa de Castro
Affiliation:
Keywords:
Chemotherapy, Chagas disease, Trypanosoma cruzi, High throughput screening, C14α-demethylase inhibitors, nitroheterocycles,
azoles.
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.
