The Search for Natural and Synthetic Inhibitors That Would Complement Antivenoms as Therapeutics for Snakebite Envenoming

Abstract

A global strategy, under the coordination of the World Health Organization, is being unfolded to reduce the impact of snakebite envenoming. One of the pillars of this strategy is to ensure safe and effective treatments. The mainstay in the therapy of snakebite envenoming is the administration of animal-derived antivenoms. In addition, new therapeutic options are being explored, including recombinant antibodies and natural and synthetic toxin inhibitors. In this review, snake venom toxins are classified in terms of their abundance and toxicity, and priority actions are being proposed in the search for snake venom metalloproteinase (SVMP), phospholipase A2 (PLA2), three-finger toxin (3FTx), and serine proteinase (SVSP) inhibitors. Natural inhibitors include compounds isolated from plants, animal sera, and mast cells, whereas synthetic inhibitors comprise a wide range of molecules of a variable chemical nature. Some of the most promising inhibitors, especially SVMP and PLA2 inhibitors, have been developed for other diseases and are being repurposed for snakebite envenoming. In addition, the search for drugs aimed at controlling endogenous processes generated in the course of envenoming is being pursued. The present review summarizes some of the most promising developments in this field and discusses issues that need to be considered for the effective translation of this knowledge to improve therapies for tackling snakebite envenoming.

In vitro and in vivo preclinical venom inhibition assays identify metalloproteinase inhibiting drugs as potential future treatments for snakebite envenoming by Dispholidus typus

“…The pharmacokinetics of snake envenoming demonstrate that venoms undergo an initial absorption phase when administered through the intramuscular or subcutaneous routes, which are more representative of a snakebite, whereas the intravenous route bypasses the absorption phase to the distribution phase and finally the elimination phase ( Sanhajariya et al, 2018 ). Furthermore, the intravenous pre-incubation assay does not take into account the pharmacokinetics/pharmacodynamics of the unbound test inhibitor ( Gutiérrez et al, 2021 ). Thus, the lack of efficacy observed with prinomastat (compared with marimastat) here, for example, may be the result of a lack of in vivo dose optimisation and thus sub-optimal exposure.…”

Action of Varespladib (LY-315920), a Phospholipase A2 Inhibitor, on the Enzymatic, Coagulant and Haemorrhagic Activities of Lachesis muta rhombeata (South-American Bushmaster) Venom

“…Although the procoagulant action of Viperidae venoms has been mostly associated with the presence of serine proteases in these venoms ( Gutiérrez et al, 2021 ), varespladib can partially prevent the procoagulant action of L. m. rhombeata venom, indicating an eventual role of PLA 2 in these processes. Accordingly, varespladib also contributes to prevent coagulating disorders induced by other groups of snake venoms, e.g., Bothrops (Viperidae-Crotalinae), Daboia , Echis , Oxyuranus , Naja , Pseudechis and Bitis spp., which exhibit high PLA 2 activity ( Bittenbinder et al, 2018 ; Xie et al, 2020 ; Youngman et al, 2020 ; Zdenek et al, 2020 ).…”

In vitro and in vivo venom-inhibition assays identify metalloproteinase-inhibiting drugs as potential treatments for snakebite envenoming by Dispholidus typus

“…Equally, the preclinical model utilised here, consisting of the pre-incubation of drug with venom followed by codelivery intravenously, is largely detached from the clinical scenario of a snakebite. While this is the WHO-recommended method for preclinical assessment of antivenom efficacy, and thus is a logical starting point for assessing preclinical efficacy, this method does not reflect the biodistribution of venom during early envenomation, uses a non-clinically relevant route of venom injection, and does not take into account the pharmacokinetics/pharmacodynamics of the unbound test inhibitor 50 . Thus, the lack of efficacy observed with prinomastat (compared with marimastat) here, for example, may be the result of a lack of dose optimisation and thus sub-optimal exposure.…”