Associated organisationsAberystwyth University · Helmholtz Centre for Infection Research · University of DundeeEurope PMC affiliations are not treated as award recipients or mapped locations.
Funding£4.9M
PeriodDec 2020 — Dec 2023
In plain English
AI plain-English summary
Drug hunters are running out of ways to find out exactly how a promising compound works inside a parasite cell. For neglected tropical diseases such as sleeping sickness, Chagas disease, cryptosporidiosis and schistosomiasis, the standard approach is to screen thousands of compounds and pick the ones that kill the parasite — but that leaves a critical gap: nobody knows which protein the compound actually hits, or whether it will cause toxic side effects in humans. This project builds a toolkit that closes that gap. The team will combine genetic screens, chemical proteomics, cell biology and biochemistry into an adaptive matrix that can pinpoint a compound’s molecular target, confirm it stays on that target during optimisation, and flag targets already linked to clinical failure or toxicity. If it works, the platform will let researchers convert phenotypic hits into structure-based drug discovery programmes, find new chemical series for validated targets, and choose rational drug combinations to slow resistance. The result is a faster, safer pipeline for drugs that the market ignores — and a shared resource for the entire international NTD community.
View original technical description
Neglected Tropical Diseases are, by definition, under-invested relative to unmet medical need. Consequently, the Wellcome HIT-NTD flagship must develop and apply the most advanced tools to increase drug discovery efficiency, and make these available to the international NTD drug discovery community. In our opinion, determining compound mode-of-action (MoA) using an intelligent and adaptive matrix of orthogonal genetic, chemical proteomic, cell biological and biochemical assays is one of the most powerful approaches to increase drug discovery efficiency. Our vision, therefore, is to refine and develop this adaptive matrix for kinetoplastid diseases and expand it to other HIT-NTD priorities, namely cryptosporidiosis and schistosomiasis. We believe this will be transformative across these diseases by providing: - The conversion of phenotypic into structure-based drug discovery programmes, allowing the discovery of new chemical series to validated drug targets. - The early triaging of compound series against targets that have failed to translate into the clinic, and against targets that are already over-represented in drug development pipelines. - Confirmation that structure-based drug discovery leads remain on-target and target-specific during optimisation. - Anticipation of potential mechanism-based toxicity liabilities in pre-clinical and clinical development. - Important information for the drug registration process, and the logical selection of partner therapeutics to combat drug resistance.
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