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

Abstract

Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and fiscal snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using multiple in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings strongly support the translation of

Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins

“…Duplicate bioassay chromatograms for the B. arietans venom analyses are shown in the Supporting Information in Section S5 ( Figures S13 and S14). In the venom-only analyses, anticoagulation activity was observed as two sharp negative peaks in the bioactivity chromatograms (16.2-16.7 min and 16.7-17.1 min); however, no procoagulation activity was detected, which is consistent with previous findings using this venom [59]. Consequently, of the three SVMP-inhibitors used elsewhere in this study, we only selected marimastat for assessment of toxin inhibition as a control for the PLA 2 -inhibitor varespladib.…”

“…Our data further strengthens recent findings suggesting that small molecule inhibitors, such as varespladib and marimastat, may have broad, cross-species, neutralizing capabilities that make them highly amenable for translation into new "generic" snakebite therapeutics. Given our evidence that both inhibitors have different specificities, our findings further support the concept that a therapeutic combination consisting of both of these Phase II-approved small molecule toxin inhibitors [59] show potential as a new broad-spectrum snakebite treatment.…”

Causes and Consequences of Snake Venom Variation

“…Future broad-spectrum therapeutics will, thus, likely be developed by combining mixtures of these modalities in hybrid antivenom products. Much work remains to be done to strengthen our understanding of snake venoms as drug targets and to settle on the most optimal strategies for developing improved snakebite envenoming therapeutics, including identifying how many of these molecules are required to provide broad neutralization of diverse snake venoms [ 68 , 80 , 83 , 85 ]. However, recent achievements resulting from the mutually enlightening relationship between evolutionary and clinical toxinology provide away forward that may, in the near future, help save many thousands of lives and ease the burden of morbidity caused by snakebite envenoming in the developing tropical world.…”

“…Moreover, several recent studies have demonstrated the highly promising utility of a repurposed Phase II-approved PLA2 inhibitor, varespladib, as a future snakebite therapeutic, as this molecule has been demonstrated to broadly neutralize PLA 2 -mediated pathologies caused by multiple different elapid and viperid venoms [ 81 , 82 ]. Finally, it was recently described that a therapeutic combination of the SVMP inhibitor marimastat and the PLA 2 inhibitor varespladib provide broad preclinical efficacy against lethality caused by a range of geographically diverse viper venoms [ 80 ].…”

“…Ultimately, next-generation snakebite therapeutics may not necessarily be based on only one antitoxin format(e.g., antibodies or small molecule inhibitors), but instead seem likely to be composite products comprising mixtures of different modalities to ensure breadth of toxin neutralization across numerous distinct snakevenoms( Figure 3 )[ 80 , 83 , 84 ]. The recent gains described earlier demonstrate that this is likely achievable in the future as long as sufficient knowledge about venom composition and variation is at hand.…”