Structural basis for phospholipase A-like toxin inhibition by the synthetic compound Varespladib (LY315920).

The World Health Organization recently listed snakebite envenoming as a Neglected Tropical Disease, proposing strategies to significantly reduce the global burden of this complex pathology by 2030. In this context, effective adjuvant treatments to complement conventional antivenom therapy based on inhibitory molecules for specific venom toxins have gained renewed interest. Varespladib (LY315920) is a synthetic molecule clinically tested to block inflammatory cascades of several diseases associated with elevated levels of secreted phospholipase A (sPLA).

Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A.

A need exists to develop specific and clinically useful inhibitors of toxic enzymes present in snake venoms, responsible for severe tissue damage and life-threatening effects occurring in thousands of people suffering envenomations globally. LY315920 (Varespladib, S-5920, A-001), a low molecular weight drug developed to inhibit several human secreted phospholipases A (PLAs), was recently shown to also inhibit PLAs in whole snake venoms with high potency, yet no studies have examined its direct effect on purified snake venom PLAs. This work evaluated the ability of LY315920 to neutralize the enzymatic and toxic activities of three isolated PLA toxins of structural groups I (pseudexin) and II (crotoxin B and myotoxin I), and their corresponding whole venoms.

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

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 () demonstrates that LY333013, even with delayed oral administration, improves the chances of survival.