title: Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation.
abstract: Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.
authors: Research and Development, Ophirex, Inc., Corte Madera, CA 94925, USA. matt@ophirex.com.|Center for Exploration and Travel Health, California Academy of Sciences, San Francisco, CA 94118, USA. matt@ophirex.com.
authors: Matthew
authors: M
authors: Lewin
authors: General Medicine, Queen Elizabeth Hospital, King's Lynn, Norfolk PE30 4ET, UK. paulshania@yahoo.co.uk.
authors: Stephen
authors: S
authors: Samuel
authors: Yale Center for Molecular Discovery, Yale University, West Haven, CT 06516, USA. janie.merkel@yale.edu.
authors: Janie
authors: J
authors: Merkel
authors: Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA. bicklerp@anesthesia.ucsf.edu.
authors: Philip
authors: P
authors: Bickler
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000037:antagonists & inhibitors / Q000201:enzymology; D007211:Indoles / Q000494:pharmacology*; D007651:Keto Acids; D051379:Mice; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000378:metabolism*; D011355:Prodrugs / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D030162:Reptilian Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012909:Snake Bites / Q000188:drug therapy* / Q000201:enzymology; D013997:Time Factors; D014757:Viper Venoms / Q000037:antagonists & inhibitors / Q000201:enzymology
chemical_list: D000085:Acetates; D000931:Antidotes; D004546:Elapid Venoms; D007211:Indoles; D007651:Keto Acids; D064801:Phospholipase A2 Inhibitors; D011355:Prodrugs; D030162:Reptilian Proteins; D014757:Viper Venoms; C053972:micrurus venom; C545088:varespladib methyl; C117948:varespladib; D054467:Phospholipases A2
keywords: LY315920; LY333013; antidote; envenomation; field treatment; inhibitor; methyl-varespladib; pre-referral; snakebite; varespladib