Abstract
The World Health Organization recently listed snakebite envenoming as a Neglected Tropical Disease, proposing strategies to significantly reduce the global burden of this complex pathology by 2030. In this context, effective adjuvant treatments to complement conventional antivenom therapy based on inhibitory molecules for specific venom toxins have gained renewed interest. Varespladib (LY315920) is a synthetic molecule clinically tested to block inflammatory cascades of several diseases associated with elevated levels of secreted phospholipase A2 (sPLA2). Most recently, Varespladib was tested against several whole snake venoms and isolated PLA2 toxins, demonstrating potent inhibitory activity. Herein, we describe the first structural and functional study of the complex between Varespladib and a PLA2-like snake venom toxin (MjTX-II). In vitro and in vivo experiments showed this compound’s capacity to inhibit the cytotoxic and myotoxic effects of MjTX-II from the medically important South American snake, Bothrops moojeni. Crystallographic and bioinformatics analyses revealed interactions of Varespladib with two specific regions of the toxin, suggesting inhibition occurs by physical blockage of its allosteric activation, preventing the alignment of its functional sites and, consequently, impairing its ability to disrupt membranes. Furthermore, based on the analysis of several crystallographic structures, a distinction between toxin activators and inhibitors is proposed.
Highlights
Venomous snakes of medical importance are widely distributed in tropical and sub-tropical countries from Africa, Asia, Latin-America and Oceania, being responsible for an estimated 420,000 to 1,800,000 envenomings every year[1,2]
We describe the crystal structure of MjTX-II, a PLA2-like toxin isolated from Bothrops moojeni[55,56] co-crystallized with Varespladib, revealing two inhibitor molecules interacting with the hydrophobic channel of the dimeric assembly of this toxin, and a comprehensive analysis of other crystal structures of bothropic PLA2-like toxins/inhibitor complexes using bioinformatics approaches
Lys[49] PLA2-like toxins, the intramuscular injection of 50 μg of MjTX-II in mice caused a prominent elevation of plasma creatine kinase activity, indicative of skeletal muscle necrosis (Fig. 1A)
Summary
Venomous snakes of medical importance are widely distributed in tropical and sub-tropical countries from Africa, Asia, Latin-America and Oceania, being responsible for an estimated 420,000 to 1,800,000 envenomings every year[1,2]. In search of alternative and effective adjuvant treatments to complement the conventional antivenom therapy, in vitro and in vivo studies have tested a number of inhibitors against diverse crude venoms, or isolated toxins such as PLA2s23–32, monoclonal antibodies[33,34,35,36] and synthetic molecules[37,38,39,40,41,42,43,44,45,46,47,48] These novel antidotes could be used in the field rapidly after the onset of envenoming, halting the deleterious action of venom toxins in the tissues. Inhibition has been studied using several isolated PLA2 toxins, including a myotoxin isolated from the venom of Bothrops asper[48]
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