Abstract
Cryptosporidium is one of the leading causes of diarrhoeal disease, which accounts for 200,000 deaths annually. There are currently no efficacious treatments for cryptosporidiosis in patient groups where disease burden is greatest. This large unmet need has led to multiple drug discovery programmes identifying promising new therapeutics. However, some of these novel anti-cryptosporidial’s mode of action are unknown. Understanding the mode of action is a critical step in drug discovery, allowing the initiation of target-based programmes and disregard of undesirable drug targets. In Cryptosporidium, we currently have one unbiased approach to identify a compound's target: thermal proteome profiling. I aimed to expand upon this list, adding to the mode of action toolkit, and adopt the chemical pulldown to test novel compounds and series. To develop and validate this technique we utilised TCDMC-153051 and identified novel targets. I applied this to another compound and identified a putative target of Calibr’s latest late lead compound.Due to the lack of essential targets known in Cryptosporidium the optimal way to identify novel anti-cryptosporidials is by high-throughput screening. I screened two drug libraries, DDU’s in-house kinase-targeting library and the KCGS library, and identified two new hit compounds that have a fast rate of parasite growth inhibition.
Bumped kinase inhibitors are one of the most advanced series in the drug discovery landscape of Cryptosporidium, with late lead BKI-1708 soon to be declared a preclinical candidate. However, there is only indirect evidence that the compounds inhibit their proposed target CpCDPK1. I aimed to validate this target by performing thermal proteome profiling using the original hit compound of the series, BKI-1294. I identified hits and then employed mode of action tools to validate the drug’s target.
| Date of Award | 2026 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Sponsors | Medical Research Council, Wellcome Trust & Royal Society |
| Supervisor | Mattie Christine Pawlowic (Supervisor) & Susan Wyllie (Supervisor) |