Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis

Abstract

Tritryps diseases are devastating parasitic neglected infections caused by Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei subspecies. Together, these parasites affect more than 30 million people worldwide and cause high mortality and morbidity. Leishmaniasis comprises a complex group of diseases with clinical manifestation ranging from cutaneous lesions to systemic visceral damage. Antimonials, the first-choice drugs used to treat leishmaniasis, lead to high toxicity and carry significant contraindications limiting its use. Drug-resistant parasite strains are also a matter for increasing concern, especially in areas with very limited resources. The current scenario calls for novel and/or improvement of existing therapeutics as key research priorities in the field. Although several studies have shown advances in drug discovery towards leishmaniasis in recent years, key knowledge gaps in drug discovery pipelines still need to be addressed. In this review we discuss not only scientific and non-scientific bottlenecks in drug development, but also the central role of public-private partnerships for a successful campaign for novel treatment options against this devastating disease.

Keywords: Chemotherapy; Drug development; Leishmania; Public-private partnership; Trypanosomatids.

Graphical abstract

Fig. 1

Classical pipeline for drug discovery highlighting scientific and non-scientific challenges. The process often starts with basic research in order to (i) identify and validate molecular/biochemical targets (target-based assays) or (ii) develop and validate phenotypic assays (cell-based assays), in which compounds are tested against the whole parasite or a given biological system. Medicinal chemistry experts will then optimize selected compounds (hits). Next steps consist in testing candidates in animal models and assessing their performances by determining pharmacokinetics and pharmacodynamics properties. Finally, a compound is targeted to clinical trials in humans and, once showing a satisfactory profile, it is defined as a drug candidate. The last steps of the pipeline include registration and manufacture of the medicine.

Fig. 2

Profile of DNDi partners. (A) Graph illustrating general distribution of DNDi partners. (B) Distribution of projects by TriTryp diseases. (C) Distribution of partners by each stage of drug discovery pipeline. Pie and bar charts were generated based on data available on DNDi website (www.dndi.org) in December, 2017. Legend: Pharma/Biotech: pharmaceutical and biotechnological companies; PDPs/PPPs: product development partnership and public – private partnership, respectively; NGOs/IOs: non-governmental organizations and international organizations, respectively; Contract Research Organizations: organizations providing support to the pharmaceutical and biotechnology industries.