Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite

Abstract

The World Health Organization (WHO) recently added snakebite envenoming to the priority list of Neglected Tropical Diseases (NTD). It is thought that ~75% of mortality following snakebite occurs outside the hospital setting, making the temporal gap between a bite and antivenom administration a major therapeutic challenge. Small molecule therapeutics (SMTs) have been proposed as potential prereferral treatments for snakebite to help address this gap. Herein, we discuss the characteristics, potential uses, and development of SMTs as potential treatments for snakebite envenomation. We focus on SMTs that are secretory phospholipase A2 (sPLA2) inhibitors with brief exploration of other potential drug targets on venom molecules.

A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite

“…Consequently, new strategies capable of circumventing variation in snake venom composition to deliver broad neutralization across snake species, while simultaneously improving the safety, affordability and storage logistics of treatment, are urgently needed 3,47 . Approaches showing signs of promise include the rational design of immunogens to improve the neutralizing breadth of conventional products 48 , the selection of human or humanized toxin-specific monoclonal or oligoclonal antibodies 49,50 , and the use of small molecule inhibitors specific to certain toxin families 12 , such as the PLA 2 -inhibitor varespladib 22,26,27 and the metal chelator DMPS 28 23 , we found both drugs to be equipotent in vitro. We selected marimastat as our candidate for in vivo efficacy experiments due to a number of desirable characteristics that make it amenable for a future field intervention for snakebite, specifically its oral vs.…”

“…Cumulatively, these limitations identify an urgent and compelling need to develop crossgenerically efficacious, stable and affordable, prehospital treatments as an effective means to considerably decrease snakebite mortality and morbidity 12,13 .…”

“…Historically, small molecule toxin inhibitors have received limited attention as potential alternatives to immunoglobulin-based snakebite therapies 12,[21][22][23][24][25] , although recent findings have suggested that a number of Phase-2 approved drugs may hold therapeutic promise 23,[26][27][28] . Perhaps the most notable of these is the PLA 2 -inhibitor, varespladib, which has been widely explored for repurposing as a snakebite therapy, and has shown substantial promise in preclinical models against a number of elapid and viper venoms 22,26,27,29 .…”

Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms

“…The search for inhibitors that block the action of snake venom toxins, and which could be applied in the field rapidly after the onset of envenoming in a snake bite, has become an area of increasingly active research. In this regard, the search for inhibitors that have been developed for diseases whose pathogenesis is associated with endogenous enzymes, such as PLA 2 s and metalloproteinases, represents a potentially cost-and development time-efficient piggy-back approach by taking advantage of previous preclinical and clinical assessments of their safety (see for example [6,24]). Such is the case of the PLA 2 inhibitor Varespladib (LY315920) and its orally available derivative methyl-Varespladib (LY333013), which were developed for the therapy of several unrelated conditions [11,12].…”

Preclinical validation of a repurposed metal chelator as a community-based therapeutic for hemotoxic snakebite

“…Thus, while oral DMPS may still prove to be an effective early intervention for delaying the onset of pathology caused by many viperid snakes, which typically have a high abundance of SVMPs in their venom (21), snakebite victims may still require immediate transport to a healthcare facility in case antivenom therapy is required to neutralize other pathogenic, or even potentially lethal, toxin constituents. Future treatments consisting of mixtures of small molecule inhibitors, each targeting different toxin types, could prove particularly valuable as more generic inhibitors against viper venoms, particularly since such inhibitors with specificities towards different toxin types have recently been described (15,52).…”