Oral Presentation 8th Venoms to Drugs 2023

Discovery and development of small molecule drugs to neutralise snake venom toxins – next generation snakebite therapeutics (#3)

Rachel H Clare 1 , Laura-Oana Albulescu 1 , Adam Westhorpe 1 , Rohit N Patel 1 , Nada Mosallam 2 , Daniel Chong-Jun-Weng 2 , Ramachandran Gunasekar 2 , Charlotte A Dawson 1 , Steven Hall 1 , Evy Bore 1 , Christopher M Woodley 2 , Nivya James 2 , Edouard Crittenden 1 , Emma L Stars 1 , Paul Rowley 1 , Amy E Marriott 1 , Jeroen Kool 3 , Neil G Berry 2 , Paul M O'Neill 2 , Nicholas R Casewell 1
  1. Centre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Liverpool, Merseryside, United Kingdom
  2. Department of Chemistry, University of Liverpool, Liverpool, Merseryside, United Kingdom
  3. Division of BioAnalytical Chemistry , Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Snakebite is a life-threatening neglected tropical disease, resulting in annually >100,000 deaths. Despite antivenom being the only approved snakebite therapeutic, these animal-derived polyclonal antibody-based therapies have several limitations, i) antivenom requires administration in a healthcare setting due to intravenous delivery and management of severe adverse reactions1, ii) antivenom is raised against specific venoms and thus have species-restrictive efficacy and poor dose efficacy due to venom variation2, iii) access to antivenoms is inconsistent, largely due to high cost and the requirements for refrigeration3. These limitations have led to considerable interest in next generation therapies. A handful of small molecule snake toxin-inhibiting drugs have demonstrated highly promising preclinical efficacy. The potential to administer such drugs orally in snakebite-affected communities offers an exciting new treatment strategy. Of the many components found within medically important snake venom, the three finger toxins (3FTx), phospholipases A2 (PLA2) and snake venom metalloproteinases (SVMP) are considered amongst the most important therapeutic targets due to their role contributing to severe pathology4. However, the chemical space explored to date for snakebite drugs is highly limited, highlighted by the single lead candidate varespladib5 against PLA2 and two candidates for SVMP (DMPS6 and marimastat). To address this limited drug pipeline, we present the progress of three parallel toxin-specific (3FTx, SVMP and PLA2) drug discovery programs, initiated by high-throughput screening of large diverse repurposed drug libraries. Our aim is to broaden the chemical space of hit molecules against SVMP and PLA2 toxins. While for 3FTx we aim to identify the first small molecules to limit the neurotoxicity caused by nicotinic acetylcholine receptor targeting alpha-neurotoxins. To date we have tested over 18,000 drugs against multiple venoms across our three programs, designed ~60 novel analogs across 6 chemical series, and are currently progressing multiple lead series against SVMP and PLA2 toxins into pre-clinical testing.

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