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Toxins 2016, 8(9), 248; doi:10.3390/toxins8090248

Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

1
Research and Development, Ophirex, Inc., Corte Madera, CA 94925, USA
2
Center for Exploration and Travel Health, California Academy of Sciences, San Francisco, CA 94118, USA
3
General Medicine, Queen Elizabeth Hospital, King’s Lynn, Norfolk PE30 4ET, UK
4
Yale Center for Molecular Discovery, Yale University, West Haven, CT 06516, USA
5
Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Ana Maria Moura Da Silva
Received: 17 June 2016 / Revised: 11 August 2016 / Accepted: 15 August 2016 / Published: 25 August 2016
(This article belongs to the Section Animal Venoms)
View Full-Text   |   Download PDF [2418 KB, uploaded 25 August 2016]   |  

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. View Full-Text
Keywords: snakebite; field treatment; varespladib; LY315920; methyl-varespladib; LY333013; inhibitor; envenomation; pre-referral; antidote snakebite; field treatment; varespladib; LY315920; methyl-varespladib; LY333013; inhibitor; envenomation; pre-referral; antidote
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lewin, M.; Samuel, S.; Merkel, J.; Bickler, P. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. Toxins 2016, 8, 248.

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