Update on two Wellcome trust grants for developing novel snakebite treatments
The grants were obtained by Jeroen kool, Nick Casewell and Chris Ulens
06/14/2021 | 11:46 AM
Jeroen Kool (VU), Nick Casewell (Liverpool School of Tropical Medicine) and Chris Ulens KULeuven) recently obtained two Wellcome trust grants of in total 4.2 Meuro on developing novel snakebite treatments. The first Wellcome grant started this month and deals with the development of protein biopharmaceutical drugs for snakebite treatment. This project is entitled "Design, selection and validation of nicotinic acetylcholine receptor mimicking molecules as novel ‘decoy receptor’ therapies for treating snakebite".
One of the most common lethal snakebite pathologies is neurotoxicity, which is the result of neurotoxins blocking nerve transmission, commonly via interaction with nicotinic acetylcholine receptors (nAChRs). We will use molecules that mimic the structural components of nAChRs that are important for toxin binding to generically inhibit the functional activity of venom neurotoxins. Our pilot data demonstrates that such ‘decoy receptors’ offer great potential to generically neutralize venom neurotoxins irrespective of snake species (unlike antivenom). We will use structural and informatic guided approaches to rationally design a panel of acetylcholine receptor binding proteins, nAChR ligand binding domains, and peptide mimotopes, before measuring their binding affinity to venom neurotoxins. We will then identify the toxins they capture using analytical approaches, before demonstrating that they effectively prevent binding to nAChRs. Thereafter, we will use in vivo efficacy studies to robustly assess whether mixtures of lead decoy receptors protect mice from venom lethality, as either solo or adjunct therapies. We anticipate that our inhibitory mixtures will exhibit superiority over antivenom by neutralizing neurotoxins irrespective of the snake species and at lower therapeutic doses. This project therefore has the potential to generate a single, generic, eminently translatable therapy for treating neurotoxic snakebites worldwide.
The other Welcome trust grant entitled "Discovery and early translation of small molecule toxin inhibitors for use as broadly effective, inexpensive, oral, prehospital snakebite treatments" will start later this year and will be a drug discovery project focusing on small-molecule inhibitors able to neutralize pathological venom toxin enzymes.
Small molecule toxin inhibitors offer great potential to rapidly deliver inexpensive, safe and efficacious oral interventions in the community soon after a snakebite, prior to subsequent admission to a healthcare facility. Despite such promise, only a handful of toxin inhibitors have been robustly explored to date. We redress this here by expanding the chemical space available for snakebite treatments by employing 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 neutralization. Thereafter, we will 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 optimization via PK/PD modelling, and 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.
Picture from the snake was made by Jory van Thiel.
From left to right: Chris Ulens,Nick Casewell and Jeroen Kool