Targeting Key Enzymatic Snake Venom Proteins Using Repurposed Small Molecule Inhibitors: Emerging Adjuncts to...

Snakebite envenoming is a neglected tropical disease causing approximately 81,410-137,880 deaths globally each year and four-fold more disabilities than mortality rate. Despite the availability of antivenoms for treatment, several in vitro and in vivo preclinical studies have shown that their efficacy is limited by many factors including regional venom variation and poor neutralization of major venom toxins. To address these limitations, the potential of alternatives including aptamers, recombinant monoclonal antibodies, camelid antibodies, small molecule inhibitors, and natural product-based inhibitors targeting key venom proteins have been explored. Among these, small molecule inhibitors targeting key enzymatic snake venom proteins are emerging as adjuvants to antivenom treatment. Most of these small molecules are repurposed drugs with established safety, oral bioavailability, and lower cost compared to antivenoms. In this regard, this review tries to compile available information regarding the use of small molecule inhibitors to counteract envenomation with special emphasis on three major enzymatic snake venom protein families: phospholipase A₂, snake venom metalloproteinases, and snake venom serine proteases. In vitro studies have shown that these small molecule inhibitors used either alone or in combination with antivenom can potentially reduce the adverse effects of venom-induced coagulopathy, neurotoxicity, tissue damage, and inflammation. However, critical gaps remain including limited human clinical trial data, uncertain efficacy across diverse venoms, and undefined dosing strategies. Overall, small molecules represent a mechanistically targeted and clinically promising adjunct to antivenom therapy, warranting further validation through randomized trials, pharmacokinetic studies, and development of field-applicable treatment protocols.