Discussion

The development of new drugs to treat kinetoplastid and many other infectious diseases has been hampered by a severe lack of robustly validated drug targets. This has left drug discovery programs heavily reliant upon phenotypic screening to identify suitable chemical start points. Development and optimisation of phenotypically-active compounds is also hindered by lack of information regarding mechanism(s) of action (MoA) and molecular target(s). Specifically, knowledge of molecular targets is often crucial in developing strategies to overcome issues such as poor pharmacokinetics and toxicity. When targets of phenotypically-active compounds are identified, target- and structure-based drug discovery programmes can be initiated allowing optimisation based on selectivity over human orthologues. Thus, MoA studies can effectively integrate these two, often disconnected, approaches to drug discovery. Furthermore, understanding the MoA is critical in developing appropriate combination therapies of the future. Historically, MoA studies have been of secondary consideration for drugs being developed for NTD. If these studies were carried out at all, they were initiated after the development of pre-clinical or clinical candidates. Over the last 6 years, my group have developed an integrated drug target deconvolution platform, employing a range of established and new methodologies encompassing high-throughput genetics, cell biology and chemical proteomics. Using this platform our aim is to provide MoA input and information in real-time for on-going drug discovery programmes. This enables the data we provide to guide and indeed drive the evolution of the best possible drug candidates. Details of my group’s integrated approach to drug target identification in kinetoplastids will be provided and I will describe how we are transitioning this approach to study MoA in Cryptosporidium, Plasmodium and Schistosoma.