A strategic discovery roadmap towards high-quality leads and drug development candidates for kinetoplastid diseases. Part 2: from molecule to confirmed hit.

Given the medical importance and challenges related to kinetoplastid diseases, a strategic roadmap is needed for the identification of high-quality leads and drug development candidates. Within the aim to deliver more compelling proof-of-concept read-outs, this part proposes a systematic flow-chart of laboratory experiments and decision criteria, focusing on African trypanosomiasis, Chagas disease and visceral and cutaneous leishmaniasis. Next to precision experimental design and reporting, an overview is provided of various complementary laboratory models reproducing kinetoplastid infection and disease. Technical aspects of conventional in vitro and in vivo approaches and, more recently, in silico methods are presented with reference to specific preclinical R&D stages from 'hit finding' to 'profiling of a confirmed hit', covering the expertise areas of medicinal chemistry, primary pharmacology, (eco)toxicology, pharmacokinetics and pharmaceutics (Figure 1).