Title:Targets and Patented Drugs for Chemotherapy of Chagas Disease in the Last 15 Years-Period
Volume: 11
Issue: 2
Author(s): Vilma G. Duschak
Affiliation:
Keywords:
Chagas disease, Trypanosoma cruzi, drug targets, patents.
Abstract: Background: The American trypanosomiasis, Chagas disease, is a parasitic infection typically
spread by triatomine vectors affecting millions of people all over Latin America. Existing chemotherapy
is centered on the nitroaromatic compounds benznidazole and nifurtimox that provide
unsatisfactory results and substantial side effects. So, the finding and exploration of novel
ways to challenge this neglected disease is a main priority.
Methods: The biologic and biochemical progress in the scientific knowledge of Trypanosoma
cruzi in the period comprising last 15-years has increased the identification of multiple targets
for Chagas´ disease chemotherapy. In the middle of the best encouraging targets for trypanocidal
drugs, ergosterol biosynthesis pathway and cruzipain, a key cysteine protease (CP) of T.
cruzi, have been pointed out. Unfortunately, recent clinical trials investigating the administration
of pozoconazole and ravuconazole to chronic indeterminate Chagas disease patients revealed
their inferiority compared to the standard drug Benznidazole.
Results: In view of the information gained in the preceding years, a reasonable approach for
the fast development of novel anti-T. cruzi chemotherapy would be focused on K777, the cysteine
proteinase inhibitor (CPI) near to enter to clinical trials, and founded on the clinical
evaluation of combination of known drugs with existing trypanocidal agents to obtain more
efficiency and less secondary effects.
Top series of xanthine have been recently identified as clinical candidate for Chagas disease. In
addition, trypanothione biosynthesis, thiol-dependant redox and polyamine metabolism, the
glycolytic, glyconeogenic, pentose phosphate, lipidic and polyisoprenoid biosynthetic pathways,
and the enzymes from biosynthetic glycoconjugates pathways have been studied. Several
specific enzymes from these particular biosynthetic pathways such as hypoxanthine-guaninephosphoribosyl-
transferase and farnesyl-pyrophosphate synthase, among others, have also been
broadly studied in T. cruzi. Novel synthesized anti-T. cruzi compounds with or without specific
single or multi-target assigned are also described in detail.
Conclusion: In summary, loans on anti-Chagas disease agents focused to specific parasite targets
as their metabolic pathways or specific enzymes will be summarized. Targets will also be
specifically discussed. Patent literature collected and published from 2000 to 2015, alleging
inhibitors for specific T. cruzi targets or trypanocidal activity was achieved over the search
database from Delphion Research intellectual property network including international patents
and the European patent office, Espacenet.
