New Approaches to Neutralise Haemotoxic Viper Venoms

Casewell, Nicholas nicholas.casewell@lstmed.ac.uk

Albulescu, Laura-Oana

Alomran, Nessrin

Hale, Melissa

Softley, Rowan

Alsolaiss, Jaffer

Crittenden, Edouard

Ainsworth, Stuart Harrison, Robert Centre for Snakebite Research & Interventions (CSRI) Liverpool School of Tropical Medicine Liverpool, UK

Slagboom, Julien

Xie, Chunfang

Kool, Jeroen Division of BioAnalytical Chemistry

Amsterdam Institute for Molecular Medicines and Systems

VU University Amsterdam

Amsterdam, The Netherlands

Snakebite causes upwards of 138,000 deaths every year, and is now recognised by the World Health Organization as a priority neglected tropical disease. The majority of these deaths are caused by snakes that inject haemotoxic venom, predominately viperids, and which result in cardiovascular, haemorrhagic and coagulopathic disturbances. Conventional snakebite therapies, known as antivenoms, consist of polyclonal antibodies harvested from the serum or plasma of animals immunised with venom. While these therapies save tens of thousands of lives every year, they exhibit considerable deficiencies relating to their species-restricted efficacy, poor dose efficacy, high incidence of adverse reactions, and low affordability to the world’s tropical snakebite victims. To begin to address these issues, we first characterised the coagulopathic and enzymatic activities of a wide variety of haemotoxic snake venoms, including representatives from every continent. We then explored the immunological binding and neutralising capability of existing and experimental polyclonal antibody-based antivenoms against these venoms. Our findings revealed surprisingly high levels of cross-reactivity among snake venoms that cause life threatening coagulopathy, and thus raise the potential for developing ‘pathology-specific’, rather than geographical, approaches for conventional antivenom therapy. Finally, given that many haemotoxic venoms rely on snake venom metalloproteinase, serine protease and phospholipase A2 toxins to cause pathology, we investigated the neutralising potential of small molecule-based inhibitors against these enzymes. We find that mixtures of these inhibitors protect against venom-induced lethality for a variety of viperids, and that certain inhibitors show great promise as early, community-based, treatments for particular haemotoxic envenomings.