Experimental chemotherapy and approaches to drug discovery for Trypanosoma cruzi infection

In the 100 years since the discovery of Chagas disease, only two drugs have been developed and introduced into clinical practice, and these drugs were introduced over 40 years ago. The tools of drug discovery have improved dramatically in the interim; however, this has not translated into new drugs for Chagas disease. This has been largely because the main practitioners of drug discovery are pharmaceutical companies who are not financially motivated to invest in Chagas disease and other "orphan" diseases. As a result, it has largely been up to academic groups to bring drug candidates through the discovery pipeline and to clinical trials. The difficulty with drug discovery in academia has been the challenge of bringing together the diverse expertise in biology, chemistry, and pharmacology in concerted efforts towards a common goal of developing therapeutics. Funding is often inadequate, but lack of coordination amongst academic investigators with different expertise has also contributed to the slow progress. The purpose of this chapter is to provide an overview of approaches that can be accomplished in academic settings for preclinical drug discovery for Chagas disease. The chapter addresses methods of drug screening against Trypanosoma cruzi cultures and in animal models and includes general topics on compound selection, testing for drug-like properties (including oral bioavailability), investigating the pharmacokinetics and toxicity of compounds, and finally providing parameters to help with triaging compounds.