Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom

Toxins
Matthew LewinDavid J Williams

Abstract

There is an unmet need for economical snakebite therapies with long shelf lives that are effective even with delays in treatment. The orally bioavailable, heat-stable, secretory phospholipase A₂ (sPLA₂) inhibitor, LY333013, demonstrates antidotal characteristics for severe snakebite envenoming in both field and hospital use. A murine model of lethal envenoming by a Papuan taipan (Oxyuranus scutellatus) demonstrates that LY333013, even with delayed oral administration, improves the chances of survival. Furthermore, LY333013 improves the performance of antivenom even after it no longer reverses neurotoxic signs. Our study is the first demonstration that neurotoxicity from presynaptic venom sPLA2S can be treated successfully, even after the window of therapeutic antivenom has closed. These results suggest that sPLA₂ inhibitors have the potential to reduce death and disability and should be considered for the initial and adjunct treatment of snakebite envenoming. The scope and capacity of the sPLA2 inhibitors ability to achieve these endpoints requires further investigation and development efforts.

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Citations

Jul 30, 2019·Frontiers in Immunology·Manuela B PuccaAndreas H Laustsen
May 8, 2020·Science Translational Medicine·Laura-Oana AlbulescuNicholas R Casewell
May 24, 2020·International Journal of Molecular Sciences·Steven Ascoët, Michel De Waard
Mar 29, 2021·Trends in Pharmacological Sciences·Rachel H ClareNicholas R Casewell
Apr 19, 2021·Biochimica Et Biophysica Acta. General Subjects·Guilherme H M SalvadorMarcos R M Fontes
Aug 26, 2021·Toxicon: X·Muhammad HamzaAbdulrazaq G Habib
Sep 28, 2021·Journal of Medicinal Chemistry·Upasana PuzariAshis K Mukherjee
Sep 6, 2020·Toxicon : Official Journal of the International Society on Toxinology·Isadora Caruso Fontana OliveiraYoko Oshima-Franco

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Methods Mentioned

BETA
NMR

Software Mentioned

GraphPad
Prism

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