Chagas Disease: Progress and New Perspectives

F.      Sanchez-Sancho; N.   E.   Campillo; J.   A.   Paez

Abstract

Chagas disease, also known as American trypanosomiasis, is caused by infection with the protozoan parasite Trypanosoma cruzi. The Pan American Health Organization (PAHO) estimates that currently 7.7 million of people have Trypanosoma cruzi infection in the 21 endemic countries from the southern and southwestern United States to central Argentina and Chile. The only approved therapeutics for the treatment of Chagas disease are two nitroheterocyclic compounds as a nitrofuran (nifurtimox; Lampit) and a nitroimidazole (benznidazole; Rochagan). However, the anti-Trypanosoma cruzi activities of these compounds were discovered empirically over three decades ago. The treatment of Chagas disease with nifurtimox or benznidazole is unsatisfactory because of their limited efficacy in the prevalent chronic stage of the disease and their toxic side effects. In this context, this article will review the current knowledge of the different aspects involved in this illness, such as Trypanosoma cruzi transmission, physiology and biochemistry of the etiological agent, epidemiological aspects and current treatments for American trypanosomiasis. An important section of this review will focus on the different strategies in drug discovery for Chagas disease, including methodology, in vitro screening studies against whole parasites, novel rationally developed approaches on the basis of the increasing knowledge of the biochemistry of Trypanosoma cruzi and the recent progress in the understanding and validation of several targets for the therapy of Chagas disease. A summary of the most relevant drug targets such as sterol biosynthesis pathway, cysteine protease pathway, pyrophosphate metabolism and purine salvage pathway will be reviewed. Moreover, recent studies regarding other strategies currently under development including thiol-dependent redox metabolism, lysophospholipid analogues and DNA binders will also be discussed.

Keywords: Chagas disease, Trypanosoma cruzi, drug discovery, cruzaine, ergosterol, HGPRT, trypanothione, Pentose phosphate