Novel drug discovery for Chagas disease

ABSTRACT

Introduction: Chagas disease is a chronic infection associated with long-term morbidity. Increased funding and advocacy for drug discovery for neglected diseases have prompted the introduction of several important technological advances, and Chagas disease is among the neglected conditions that has mostly benefited from technological developments. A number of screening campaigns, and the development of new and improved in vitro and in vivo assays, has led to advances in the field of drug discovery.

Areas covered: This review highlights the major advances in Chagas disease drug screening, and how these are being used not only to discover novel chemical entities and drug candidates, but also increase our knowledge about the disease and the parasite. Different methodologies used for compound screening and prioritization are discussed, as well as novel techniques for the investigation of these targets. The molecular mechanism of action is also discussed.

Expert opinion: Technological advances have been executed with scientific rigour for the development of new in vitro cell-based assays and in vivo animal models, to bring about novel and better drugs for Chagas disease, as well as to increase our understanding of what are the necessary properties for a compound to be successful in the clinic. The gained knowledge, combined with new exciting approaches toward target deconvolution, will help identifying new targets for Chagas disease chemotherapy in the future.

KEYWORDS:

• Trypanosoma cruzi
• Chagas disease drug discovery
• high content screening
• target deconvolution

Article highlights

• Chagas disease is a neglected tropical disease with limited funding for drug discovery and development and for which only old and unsafe drugs exist. Despite years of intensive research, there are very few validated molecular targets, making viability-based assays the major screening strategy available.

• High content screening has helped to increase the number of hits and leads issued from Chagas disease drug discovery; it offers advantages, such as higher sensitivity and improved translation to in vivo models.

• Screening campaigns for Chagas disease have resulted in the selection of a large proportion of CYP51 inhibitors, however recent clinical studies have shown these inhibitors to have unsustained efficacy in patients.

• Secondary assays are important in the profiling of antichagasic compounds for determining the killing kinetics and spectrum of activity against T. cruzi strains, and increase data translation to in vivo models.

• New technologies for target deconvolution and identification of compounds emerging from phenotypic screens can aid in the understanding of a compound mechanism of action and lead to the discovery of new drug targets in Trypanosoma cruzi.

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Acknowledgements

The authors would like to thank Lucio Freitas Junior for critically reviewing the manuscript.

Financial and competing interests disclosure

C Haddad Franco has received a doctorate scholarship from the Brazilian Research Council (CNPq). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.