Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib

Abstract

Varespladib (LY315920) is a potent inhibitor of human group IIA phospholipase A₂ (PLA₂) originally developed to control inflammatory cascades of diseases associated with high or dysregulated levels of endogenous PLA₂. Recently, varespladib was also found to inhibit snake venom PLA₂ and PLA₂-like toxins. Herein, ex vivo neuromuscular blocking activity assays were used to test the inhibitory activity of varespladib. The binding affinity between varespladib and a PLA₂-like toxin was quantified and compared with other potential inhibitors for this class of proteins. Crystallographic and bioinformatic studies showed that varespladib binds to PrTX-I and BthTX-I into their hydrophobic channels, similarly to other previously characterized PLA₂-like myotoxins. However, a new finding is that an additional varespladib binds to the MDiS region, a particular site that is related to muscle cell disruption by these toxins. The present results further advance the characterization of the molecular interactions of varespladib with PLA₂-like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA₂ and PLA₂-like toxins.