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Crystal structure of Bothrops pirajai myotoxin I PrTX-I complexed with inhibitor AZD2716
Structural highlights
FunctionPA2H1_BOTPI Snake venom phospholipase A2 (PLA2) homolog that lacks enzymatic activity, but displays myotoxin and edema-inducing activities in vivo. In vitro neuromuscular activities have also been observed, but they are not found in vivo and can be explained by the destabilization of the muscle membrane by the toxin. The myotoxic activity is inhibited by rosmarinic acid (RA).[1] [2] Publication Abstract from PubMedPhospholipase A(2) (PLA(2)) and PLA(2)-like toxins are key contributors to the local myonecrotic effects induced by Bothrops snake venoms and represent important targets for inhibition. Synthetic molecules such as varespladib (LY315920) and AZD2716 were originally developed as inhibitors of human group IIA PLA(2), with varespladib emerging as a promising candidate for repurposing against venom toxins. Here, we investigated a snake venom Lys49-PLA(2)-like toxin and another potent sPLA(2) inhibitor, AZD2716, using ex vivo neuromuscular blockade assays, microscale thermophoresis, crystallographic, and bioinformatic analyses. Like varespladib, AZD2716 binds the toxin in the micromolar range within the hydrophobic channel (HCh)-which has been reported as the binding site for other inhibitors and fatty acids-adopting a dimeric conformation similar to that observed in other Lys49-PLA(2)-like toxin complexes. Structural comparisons indicate that these ligands block access to HCh, preventing fatty acid binding required for toxin activation. The previously proposed mechanism of action for PLA(2)-like toxins involves fatty acid binding to HCh, leading to conformational changes and solvent exposure of the toxin functional site, which is mainly located at the C-terminus. Thus, physically preventing fatty acid access to HCh can inhibit myotoxic activity. Although AZD2716 and varespladib bind to similar regions in both PLA(2)-like toxins and catalytic sPLA(2)s, they inhibit these proteins through distinct mechanisms due to differences in their functional sites. These findings highlight drug repurposing as a promising strategy for the development of complementary therapies to mitigate the severe local damage associated with snakebite envenoming but are generally applicable to drug discovery and repositioning strategies. Structural and pharmacological analysis of a PLA(2)-like toxin in complex with the sPLA(2) inhibitor AZD2716: Comparisons to varespladib.,Salvador GHM, Pereira ES, Cavalcante WLG, Ortolani PL, Fortes-Dias CL, Lomonte B, Lewin MR, Fontes MRM Biochimie. 2026 Mar 23;245:120-131. doi: 10.1016/j.biochi.2026.03.006. PMID:41881275[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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