Abstract
Human American trypanosomiasis, commonly called Chagas disease, is one of the most neglected illnesses in the world and remains one of the most prevalent chronic infectious diseases of Latin America with thousands of new cases every year. The only treatments available have been introduced five decades ago. They have serious, undesirable side effects and disputed benefits in the chronic stage of the disease - a characteristic and debilitating cardiomyopathy and/or megavisceras. Several laboratories have therefore focused their efforts in finding better drugs. Although recent years have brought new clinical trials, these are few and lack diversity in terms of drug mechanism of action, thus resulting in a weak drug discovery pipeline. This fragility has been recently exposed by the failure of two candidates; posaconazole and E1224, to sterilely cure patients in phase 2 clinical trials. Such setbacks highlight the need for continuous, novel and high quality drug discovery and development efforts to discover better and safer treatments. In this article we will review past and current findings on drug discovery for Trypanosoma cruzi made by academic research groups, industry and other research organizations over the last half century. We also analyze the current research landscape that is now better placed than ever to deliver alternative treatments for Chagas disease in the near future.
Highlights
Chagas disease is named after the Brazilian physician Carlos Chagas who first described the disease in 1909 1
Chagas disease is caused by the parasite Trypanosoma cruzi and is considered to be the parasitic infirmity with the biggest social and economic burden in Latin America 2
One high-throughput screen of 200 000 compounds against cruzipain, yielded 921 hit compounds that were subsequently screened by computational docking analysis and revealed 5 chemical scaffolds of common hits. These scaffolds are good starting points for further optimization and evidentiate the advantages of combining biological and bioinformatics analysis for priorization of molecules after an high-throughput screening campaign has been performed 45. In another example of target-based drug discovery, CYP51 from Mycobacterium tuberculosis was screened against a library of 20 000 organic compounds and resulted in two very active compounds 46, of which one (ChemDiv C155-0123) later showed selective inhibitory activity against the T. cruzi orthologous enzyme 47
Summary
Chagas disease is named after the Brazilian physician Carlos Chagas who first described the disease in 1909 1. Trypanosoma cruzi, Chagas disease, benznidazole, nifurtimox, drug discovery, chemotherapy.
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