Ruthenium Compounds Differentially Inhibit Group IA and IIA Snake Venom Phospholipase A₂ Anticoagulant Activity

Neurotoxicity caused by snake venom phospholipase A₂ (PLA₂) activity derived from coral snakes (e.g., Micrurus tener, Micrurus fulvius, group IA PLA₂) and some rattlesnakes (e.g., Crotalus scutulatus, group IIA PLA₂) is medically significant. Of interest, the catalytic site of PLA₂ also binds to activated clotting factor X, causing anticoagulation. Given that ruthenium (Ru)-containing compounds have been demonstrated to inactivate hemotoxic venoms in a solvent-dependent manner (e.g., 0.9% NaCl, phosphate-buffered saline), we wished to determine if RuCl₃ would cause solvent-dependent inhibition of snake venom group IA and group IIA PLA₂ in human plasma with thrombelastography. It was determined that RuCl₃ significantly decreased the anticoagulant effects of group IA PLA₂ derived from M. tener and M. fulvius venoms in the presence of 0.9% NaCl, but not phosphate-buffered saline. In contrast, group IIA PLA₂ anticoagulant activity derived from C. scutulatus venom was inhibited by RuCl₃ in both solvents. It is concluded that the different ions formed by RuCl₃ in different solvents may interact with novel disulfide bridges unique to group IA and IIA PLA₂ or through some other mechanism. In vivo validation of Ru-based enzyme inhibitor effects on neurotoxicity associated with either group IA or IIA remains a critical translational issue.