Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?
BACKGROUND
Endemic in Latin America, Chagas disease is now becoming a serious global health problem, and yet has no financial viability for the pharmaceutical industry and remains incurable. In 2012, two antimycotic drugs inhibitors of fungal sterol 14α-demethylase (CYP51) - posaconazole and ravuconazole - entered clinical trials. Availability of the X-ray structure of the orthologous enzyme from the causative agent of the disease, protozoan parasite Trypanosoma cruzi, determined in complexes with posaconazole as well as with several experimental protozoa-specific CYP51 inhibitors opens an excellent opportunity to improve the situation.


METHODS
This article summarizes the information available in PubMed and Google on the outcomes of treatment of the chronic Chagas disease. It also outlines the major features of the T. cruzi CYP51 structure and the possible structure-based strategies for rational design of novel T. cruzi specific drugs.


CONCLUSIONS
There is no doubt that screenings for alternative drug-like molecules as well as mining the T. cruzi genome for novel drug targets are of great value and might eventually lead to groundbreaking discoveries. However, all newly identified molecules must proceed through the long, expensive and low-yielding drug optimization process, and all novel potential drug targets must be validated in terms of their essentiality and druggability. CYP51 is already a well-validated and highly successful target for clinical and agricultural antifungals. With minimal investments into the final stages of their development/trials, T. cruzi-specific CYP51 inhibitors can provide an immediate treatment for Chagas disease, either on their own or in combination with the currently available drugs.
Vanderbilt University, Institute for Global Health, School of Medicine, Center for Structural Biology, Department of Biochemistry , 622 RRB, 23rd at Pierce, Nashville, TN 37232 , USA +1 615 343 1373 ; +1 615 322 4349 ; galina.i.lepesheva@vanderbilt.edu.
Galina I
GI
Lepesheva
D058888:14-alpha Demethylase Inhibitors / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000627:therapeutic use; D014355:Chagas Disease / Q000188:drug therapy*; D015195:Drug Design; D006801:Humans; D014349:Trypanosoma cruzi / Q000187:drug effects
D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D000981:Antiprotozoal Agents