Repurposed drug combinations neutralises Russell’s viper venom

India has relied on horse-derived antivenoms to treat snakebites for more than a century. But these treatments are slow, non-specific, and frequently ineffective, especially against regional variations in venom.

Now, a team of researchers from India and Britain has shown that a combination of enzyme-blocking drugs can fully protect mice from the venom of the Russell’s viper, the snake that kills and maims more than any other.

The study¹ is the first to demonstrate that a small molecule inhibitor (SMI) combination can counter the wide spectrum of venom effects across Russell’s Viper populations from different parts of India. The drugs, originally developed for conditions like cancer, pancreatitis, and cardiovascular disease, were administered up to 30 minutes after envenomation and were able to prevent death in all test animals.

“An effective solution for Russell’s viper envenoming would essentially solve India’s snakebite problem,” said Kartik Sunagar, corresponding author and head of the Evolutionary Venomics Lab at the Indian Institute of Science, Bengaluru. “This snake alone accounts for more than half of the country’s estimated 58,000 annual snakebite deaths.”

The drug cocktail

The study used three SMIs: varespladib, which blocks phospholipase A2 (PLA2), an enzyme that breaks down cell membranes and triggers inflammation; marimastat, a metalloprotease inhibitor originally developed to treat cancer; and nafamostat, used in haemodialysis and pancreatitis treatment, which blocks serine proteases and interferes with blood clotting.

The researchers report that the first two were enough to neutralize the venom and they didn’t require nafamostat.

Russell’s viper venom contains a mixture of these enzymes, but their proportions vary significantly by region, a factor that has long confounded the efficacy of conventional antivenoms.

Regional drug mapping

The researchers tested venom samples from seven geographically distinct Russell’s viper populations across India, West Bengal, Madhya Pradesh, Maharashtra, Punjab, Tamil Nadu, Andhra Pradesh, Karnataka and Rajasthan.

They found that the West Bengal venom required both varespladib and marimastat to achieve complete protection. Madhya Pradesh and Maharashtra venoms could be neutralised by either drug on its own. Punjab and Tamil Nadu venoms also responded to either agent individually. Andhra Pradesh and Karnataka venoms were best countered by marimastat alone. Rajasthan venom could be tackled effectively by varespladib alone.

This detailed mapping highlights, for the first time, the geographic specificity of venom composition and treatment response, a major advance in tailoring therapies to India’s complex snakebite landscape.

“What this shows is that enzyme interactions in the venom can be surprisingly interdependent,” said Sunandan Das, a venom biologist at the University of Helsinki, who was not involved in the study. “In some cases, blocking one enzyme renders the other ineffective. That’s a very interesting biological insight and a powerful therapeutic opportunity.”

A historical shift

India’s current antivenom strategy has changed little in 100 years. Developed by immunising horses with venom from a few captive snakes, commercial antivenoms are made against the so-called ‘big four’ — the Russell’s viper, Indian cobra, common krait, and saw-scaled viper — but often fail to account for regional or species-level differences.

“Antivenoms are lifesaving, but they are far from ideal,” said Sunagar. “They’re bulky, need cold chains, require hospital infrastructure, and can trigger severe allergic reactions. And they often don’t neutralise venom effectively if the formulation doesn't match the regional snake.”

In contrast, small molecule inhibitors are stable, portable, and could be administered in the field. They work by directly blocking the toxic enzymes in the venom, buying crucial time for a bite victim to reach medical care.

To simulate real-world scenarios, the team delayed drug administration by 30 minutes after envenoming and still observed complete survival.

Clinical trials for antivenom

The researchers are now in discussions with the Indian Council of Medical Research to initiate clinical trials. If approved, the drugs could offer a scalable, standardised, and more rapidly deployable treatment, potentially marking a big change in how India and other tropical countries respond to venomous bites.

Challenges remain. The drugs have not yet been tested in humans for this indication, and their dosage, delivery, and long-term safety will need rigorous evaluation.

“This approach is modular,” said Sunagar. “We can add or remove inhibitors depending on the snake species and venom profile. That’s a flexibility no existing antivenom can offer.”