Small molecule therapeutics for neutralising venom toxins – a drug discovery approach

Snakebite is a neglected tropical disease affecting ∼5 million people/year and resulting in >100,000 deaths worldwide. Victims are often inhabitants of remote rural areas with limited access to healthcare and antivenom, the only current treatment. While antivenoms are life-saving treatments, they require intravenous administration under medical supervision due to adverse effects, are species-specific, often unavailable and unaffordable in areas with high snakebite incidence, have poor dose efficacy and depend on cold chain. Recently, small molecule toxin inhibitors have attracted interest as potential next-generation snakebite therapeutics. Compared to antivenom, they can exhibit broad-spectrum efficacy against geographically diverse snake venoms, possess higher stability and decreased adverse effects. Their formulation as oral drugs can also aid their fast deployment in the community soon after a bite. Molecules targeting snake venom metalloproteinases (SVMPs, e.g. marimastat, DMPS) as well as phospholipase A2 (PLA2, varespladib) have demonstrated notable preclinical efficacy against multiple medically important snake venoms and two of these drugs have undergone phase I or II clinical trials for snakebite indication. Despite this, the portfolio of snakebite drugs remains extremely limited. Here we describe the first attempt to explore the chemical space of toxin-inhibiting drugs via high-throughput screening of large, diverse commercial drug libraries. We have screened >36K compounds assessing inhibition of SVMP, PLA2 and three-finger toxins, designed >80 analogues over 6 chemical series and selected 3 lead series against SVMPs and one against PLA2s for further characterisation and preclinical testing. Our results support discovery-based approaches and drug optimisation for development of future snakebite therapies.