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

Varespladib (LY315920) is a potent inhibitor of human group IIA phospholipase A 2 (PLA 2) originally developed to control inflammatory cascades of diseases associated with high or dysregulated levels of endogenous PLA 2. Recently, varespladib was also found to inhibit snake venom PLA 2 and PLA 2 -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 PLA 2 -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 PLA 2 -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 PLA 2 -like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA 2 and PLA 2 -like toxins. [Display omitted] • An ex vivo assay was used to test the inhibitory activity of varespladib. • Affinity assays demonstrate that inhibitor interacts with the toxin. • Varespaldib binds into hydrophobic channel. • An additional varespladib binds to muscle cell disruption site (MDiS). • An alternative inhibitory mechanism by varespladib is proposed. [ABSTRACT FROM AUTHOR]