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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.R.L has an ownership stake in Ophirex Inc., a Public Benefit Corporation. The other authors have declared that no competing interests exist.
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