Repurposed small molecule toxin inhibitors neutralise a diversity of venoms from the Neotropical viperid snake genus Bothrops.

内容摘要

Snakebite globally claims more than 100,000 lives per year and results in morbidity for 400,000 survivors. Current treatment uses antibody-based antivenoms which are constrained by their efficacy, safety, and cost. In this study we evaluated the efficacy of previously described repurposed drugs against viperid snakes of the medically important Bothrops genus. Despite variable toxin representation and bioactivity across this central and south American genus, we found that the lead inhibitors targeting metalloproteinases (marimastat and DMPS) and phospholipases (varespladib) demonstrated pan-species neutralisation in enzymatic assays, whilst nafamostat (serine protease inhibitor) had variable activity. The metalloproteinase inhibitors protected against the procoagulant and haemorrhagic effects of several venoms in phenotypic assays. Collectively these findings demonstrate that repurposed drugs may be of great value as early interventions for the treatment of bothropic envenoming in the Neotropics and thus provide a strong rationale for their progression into future preclinical and clinical evaluation for snakebite indication. Snakebites are a major health problem, particularly in rural parts of tropical countries. Every year, millions of people are bitten by venomous snakes, causing more than 100,000 deaths and leaving many others with permanent disabilities. The World Health Organization classifies snakebite as a neglected tropical disease because, despite its devastating impact, it has received relatively little attention and investment. The only approved treatment for snakebite is antivenom. Antivenom is made by stimulating animals to produce antibodies against snake venom and must be given intravenously in a hospital. While it can be lifesaving, it has important limitations: it is often only effective against certain snake species, can cause serious side effects, and is frequently unavailable where snakebites occur. In remote regions, such as parts of the Amazon, people may have to travel five hours or more before reaching medical care. Earlier treatment could greatly improve survival and reduce permanent injuries. Researchers are therefore investigating new treatments that could be given soon after a bite, before a patient reaches hospital. One promising approach is to repurpose existing small molecule drugs that block the harmful toxins found in snake venom. Three drugs – varespladib, marimastat and DMPS – have already shown promise because they can block two major groups of venom toxins responsible for much of the damage caused by snakebites. Clare et al. wanted to further evaluate the suitability of these drugs, together with another drug called nafamostat, against venom from seven species of Bothrops snakes. Bothrops snakes are responsible for most serious snakebites in Latin America, and their venoms contain a mixture of toxins that damage tissues, disrupt blood clotting and cause severe haemorrhage. The researchers carried out a series of laboratory experiments to measure how well the drugs blocked different venom effects, including toxin activity, blood clotting problems and haemorrhage. Although the venoms varied between snake species, the drugs targeting two major toxin groups consistently worked across all seven species in laboratory tests. In contrast, nafamostat showed more variable effects. The experiments also showed that marimastat and DMPS, which target enzymes responsible for tissue damage and haemorrhage, provided the strongest overall protection. The drugs targeting the other toxin groups also showed promise but require further development. Overall, the findings of Clare et al. suggest that repurposed drugs could become valuable early treatments for Bothrops snakebites in Latin America. Because these medicines can be taken by mouth, they could potentially be given in the community soon after a bite, buying valuable time before patients reach a hospital for antivenom treatment. The study also highlights the need to develop additional drugs that target other important venom toxins, helping pave the way for more effective treatments for snakebite in the future.