A critical review of the development of specific chemotherapeutic approaches for the management of
American Trypanosomiasis or
Chagas disease is presented, including controversies on the pathogenesis of the disease, the initial efforts that led to the development of currently available drugs (
nifurtimox and
benznidazole), limitations of these
therapies and novel approaches for the development of anti-Trypanosoma cruzi drugs, based on our growing understanding of the biology of this parasite. Among the later, the most promising approaches are
ergosterol biosynthesis inhibitors such as
posaconazole and
ravuconazole, poised to enter clinical trials for chronic
Chagas disease in the short term; inhibitors of
cruzipain, the main
cysteine protease of T. cruzi, essential for its survival and proliferation in vitro and in vivo;
bisphosphonates, metabolic stable
pyrophosphate analogs that have trypanocidal activity through the inhibition of the parasite's
farnesyl-pyrophosphate synthase or
hexokinase; inhibitors of
trypanothione synthesis and redox metabolism and inhibitors of
hypoxanthine-
guanine phosphoribosyl-
transferase, an essential
enzyme for
purine salvage in T. cruzi and related organisms. Finally, the economic and political challenges faced by development of drugs for the treatment of
neglected tropical diseases, which afflict almost exclusively poor populations in developing countries, are analyzed and recent potential solutions for this conundrum are discussed.