Discovery and early translation of small molecule toxin inhibitors for use as broadly effective, inexpensive, oral, prehospital snakebite treatments
Dr Nicholas Casewell
Liverpool School of Tropical Medicine, United Kingdom
Small molecule toxin inhibitors offer great potential to rapidly deliver inexpensive, safe and efficacious oral interventions in the community soon after a snakebite, before admission to a healthcare facility.
Despite such promise, only a handful of toxin inhibitors have been robustly explored to date. We will redress this by expanding the chemical space available for snakebite treatments, using a comprehensive drug discovery approach. Using toxin-specific assays, we will screen diverse compound libraries (>50,000 molecules) – including using the Human Pharmacopoeia and Phase-1 approved molecules in a repurposing approach – for hits that demonstrate broad toxin family neutralisation.
We will then rationally identify lead series by defining the toxin-specificity, kinetics, phenotypic potency and medicinal chemistry characteristics of hits, before performing murine preclinical efficacy and pharmacokinetic experiments to rationally define oral dosage regimens of lead candidates capable of achieving systemic inhibitory concentrations throughout a snakebite treatment period.
Finally, we will evaluate therapeutic combinations of lead candidates by performing dose optimisation via PK/PD modelling, preclinical efficacy and drug-drug interactions studies. This comprehensive drug discovery pipeline will deliver a portfolio of lead candidates (and numerous backups) ready for translation into clinical studies to assess their tolerability and efficacy as next-generation snakebite therapeutics.