Abstract
Chagas disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi, and is the most important parasitic infection in Latin America. The current drugs, benznidazole and nifurtimox, are characterized by limited efficacy and toxic side-effects, and treatment failures are frequently observed. The urgent need for new therapeutic approaches is being met by a combined effort from the academic and commercial sectors, together with major input from not-for-profit drug development consortia. With the disappointing outcomes of recent clinical trials against chronic Chagas disease, it has become clear that an incomplete understanding of parasite biology and disease pathogenesis is impacting negatively on the development of more effective drugs. In addition, technical issues, including difficulties in establishing parasitological cure in both human patients and animal models, have greatly complicated the assessment of drug efficacy. Here, we outline the major questions that need to be addressed and discuss technical innovations that can be exploited to accelerate the drug development pipeline.
Highlights
Five to eight million people in Latin America are infected with the protozoan parasite Trypanosoma cruzi, the aetiologic agent of Chagas disease (Hashimoto and Yoshioka, 2012; Bern, 2015)
From the drug development perspective, there are a number of important questions relating to the T. cruzi life-cycle that need to be addressed: (i) Is it necessary to kill all developmental forms to produce a curative outcome? (ii) Are all developmental forms susceptible to trypanocidal compounds? (iii) Is there a point in the life-cycle during chronic stage infections where the parasites enter a biochemically quiescent or dormant phase? The T. cruzi life-cycle involves a series of differentiation steps, in which the parasite passes through both replicative and non-replicative stages
Adipose tissue has been implicated as a possible reservoir of recrudescence in other parasitic infections, including African trypanosomiasis (Trindade et al 2016; Tanowitz et al 2017); further work will be required before definitive conclusions can be drawn about the situation in T. cruzi
Summary
AMANDA F. FRANCISCO, SHIROMANI JAYAWARDHANA, MICHAEL D. LEWIS, MARTIN C. TAYLOR and JOHN M. KELLY* Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK (Received 26 May 2017; revised 11 July 2017; accepted 14 July 2017; first published online 23 August 2017)
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