Assessing the Utility of Broad-Acting Inhibitors as Therapeutics in Diverse Venoms

Abstract

Examination of venom constituent bioactivities from diverse venomous animals shows certain highly conserved classes, including enzymes (e.g., phospholipases and metalloproteinases) and pore-forming proteins. While antivenoms targeting other unique and lethal venom components have proven to be life-saving, venom-enzyme-driven tissue damage and morbidity persists. Broad-acting enzyme inhibitors demonstrate the potential to augment antivenom approaches. In this study, we investigate the potential utility of certain broad-acting inhibitors in cubozoa for the first time. Fluorogenic assays were used to determine the phospholipase A2 (PLA2) and matrix metalloproteinase (MMP) activity of the Hawaiian box jellyfish, Alatina alata, and this was compared to representative elapid, viper, and bee venoms. In vitro, evaluation of selected small-molecule inhibitors demonstrated the ability and feasibility of the broad-acting therapeutic doxycycline, which inhibited the PLA2 and MMP activity of A. alata (approximately 50% reduction at 0.1 mM (95% CI 0.06–0.15) and 2.1 mM (95% CI 1.4–3.0), respectively), in addition to both snake venoms. Additionally, copper gluconate broadly inhibited the PLA2 activity of bee, snake, and jellyfish venoms. While all venoms are complex mixtures of bioactive molecules, these studies demonstrate that targeting common class components with broad-acting inhibitors shows promise in clinical and preclinical management.

Keywords

• cubozoa
• phospholipase
• metalloproteinase
• small-molecule inhibitors
• therapeutics