Preclinical evaluation of small molecule inhibitors as early intervention therapeutics against Russell’s viper envenoming in India

Background: Snakebites are problematic in many developing regions, including India, where over half of global snakebite deaths occur. Antivenoms are currently the only licensed treatment for snakebites. However, their use causes several challenges, most notably geographical limitations in efficacy and adverse side effects. Therefore, therapeutic alternatives are urgently needed. Recently, several studies have evaluated small molecule inhibitors (SMIs) and highlighted their promise as safe and effective alternatives to antivenoms. We investigate their potential use against Indian snakes, particularly Russell’s viper (Daboia russelii), responsible for over half of India’s snakebite cases. Methods: Here, we explored the effectiveness of two phase-2-approved SMIs in countering the diverse and variable toxicities of D. russelii from across India. Results: The phospholipase inhibitor varespladib and the metalloproteinase inhibitor marimastat, individually or in combination, effectively counter the toxicities of D. russelii venoms in vitro. Specific drug efficacy varies across geographic regions. These SMIs and their combination prevent lethality caused by the pan-Indian D. russelii, even in rescue experiments where treatment is delayed, in mice. Conclusions: Our findings support the potential use of SMIs as effective, affordable, and accessible future therapies for treating bites from the world’s most medically important snake species.