Repositioning drug strategy against Trypanosoma cruzi: lessons learned from HIV aspartyl peptidase inhibitors

Chagas disease (CD) is an old neglected problem that affects more than 6 million people through 21 endemic countries in Latin America. Despite being responsible for more than 12 thousand deaths per year, the disease disposes basically of two drugs for its treatment, the nitroimidazole benznidazole and the nitrofuran nifurtimox. However, these drugs have innumerous limitations that greatly reduce the chances of cure. In Brazil, for example, only benznidazole is available to treat CD patients. Therefore, some proof-of-concept phase II clinical trials focused on improving the current treatment with benznidazole, also comparing it with repositioned drugs or combining them. Indeed, repositioning already marketed drugs in view of combating neglected tropical diseases is a very interesting approach in the context of decreased time for approval, better treatment options and low cost for development and implementation. After the introduction of human immunodeficiency virus aspartyl peptidase inhibitors (HIV-PIs) in the treatment of acquired immune deficiency syndrome (AIDS), the prevalence and incidence of parasitic, fungal and bacterial co-infections suffered a marked reduction, making these HIV-PIs attractive for drug repositioning. In this line, the present perspective presents the promising and beneficial data concerning the effects of HIV-PIs on the clinically relevant forms of Trypanosoma cruzi (i.e., trypomastigotes and amastigotes) and also highlights the ultrastructural and physiological targets for the HIV-PIs on this parasite. Therefore, we raise the possibility that HIV-PIs could be considered as alternative treatment options in the struggle against CD.