Advances in the Therapeutic Application of Small-Molecule Inhibitors and Repurposed Drugs against Snakebite

Abstract

The World Health Organization has declared snakebite as a neglected tropical disease. Antivenom administration is the sole therapy against venomous snakebite; however, several limitations of this therapy reinforce the dire need for an alternative and/or additional treatment against envenomation. Inhibitors against snake venoms have been explored from natural resources and are synthesized in the laboratory; however, repurposing of small-molecule therapeutics (SMTs) against the principal toxins of snake venoms to inhibit their lethality and/or obnoxious effect of envenomation has been garnering greater attention owing to their established pharmacokinetic properties, low-risk attributes, cost-effectiveness, ease of administration, and storage stability. Nevertheless, SMTs are yet to be approved and commercialized for snakebite treatment. Therefore, we have systematically reviewed and critically analyzed the scenario of small synthetic inhibitors and repurposed drugs against snake envenomation from 2005 to date and proposed novel approaches and commercialization strategies for the development of efficacious therapies against snake envenomation.

Unraveling the Reaction Mechanism of Russell’s Viper Venom Factor X Activator: A Paradigm for the Reactivity of Zinc Metalloproteinases?

“…Interestingly, this coordination mode is mimicked by hydroxamate-based inhibitors such as batimastat or marimastat, which were developed as antineoplastic drug candidates targeting the human matrix metalloproteinases but failed at clinical trials. These drugs are under investigation to treat snakebite, as they are highly efficient in inhibiting the SVMPs in vitro and in vivo. ,, The drug candidate’s carbonyl group resembles the substrate’s carbonyl group, and the hydroxamic acid hydroxyl group resembles the hydroxide ion (TS2, Figure D and SI, Figure S3). The fact that these drug candidates precisely mimic the rate-limiting transition state of the whole cycle reinforces the strategy of inspiring drug discovery on the rate-limiting transition states determined through accurate QM/MM calculations.…”

“…Although initially designed for inhibiting human extracellular matrix metalloproteinases (MMPs), these were used for repurposing based on the high degree of sequence identity shared by MMPs and SVMPs. However, all failed in the clinical trials due to toxicity problems brought on by off-target effects. , …”

“…However, all failed in the clinical trials due to toxicity problems brought on by off-target effects. 19,20 Russell's Viper and Its Venom. This paper focuses on one of the leading actors of the problem, Russell's viper (RV), a large and beautiful snake that is responsible for most snakebites that occur in the vicinity of the agricultural lands and villages 4,9,12,21,22 where its primary dietary preference, rats and mice, grow.…”

Catalytically Active Snake Venom PLA2 Enzymes: An Overview of Its Elusive Mechanisms of Reaction

“…It is particularly relevant for avoiding myotoxicity, a severe condition sometimes coupled with neurotoxicity, , consequences of envenomation caused by several snakes of the Elapidae, Viperidae, Atractaspididae, and sometimes Colubridae families. − Nevertheless, the antivenom treatment has significant drawbacks: it is costly, needs inpatient administration by trained physicians, refrigerated transport and storage, and its efficacy is limited to the species used in the animal immunization and frequently causes anaphylactic reactions . Alternatives based on small molecule inhibitors of central venom toxins, such as the svPLA 2 discussed in this Perspective, are being developed to overcome some of these limitations. , …”

“…5 Alternatives based on small molecule inhibitors of central venom toxins, such as the svPLA 2 discussed in this Perspective, are being developed to overcome some of these limitations. 1,11 Snake venoms are cocktails of bioactive molecules. The venom of each species is unique, and intraspecific variations are common.…”