Optimizing drug discovery for snakebite envenoming via a high-throughput phospholipase A2 screening platform

Laura Oana Albulescu, Adam Westhorpe, Rachel H. Clare, Christopher M. Woodley, Nivya James, Jeroen Kool, Neil G. Berry, Paul M. O’Neill, Nicholas R. Casewell*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Snakebite envenoming is a neglected tropical disease that causes as many as 1.8 million envenomings and 140,000 deaths annually. To address treatment limitations that exist with current antivenoms, the search for small molecule drug-based inhibitors that can be administered as early interventions has recently gained traction. Snake venoms are complex mixtures of proteins, peptides and small molecules and their composition varies substantially between and within snake species. The phospholipases A2 (PLA2) are one of the main pathogenic toxin classes found in medically important viper and elapid snake venoms, yet varespladib, a drug originally developed for the treatment of acute coronary syndrome, remains the only PLA2 inhibitor shown to effectively neutralise venom toxicity in vitro and in vivo, resulting in an extremely limited drug portfolio. Here, we describe a high-throughput drug screen to identify novel PLA2 inhibitors for repurposing as snakebite treatments. We present method optimisation of a 384-well plate, colorimetric, high-throughput screening assay that allowed for a throughput of ∼2,800 drugs per day, and report on the screening of a ∼3,500 post-phase I repurposed drug library against the venom of the Russell’s viper, Daboia russelii. We further explore the broad-spectrum inhibitory potential and efficacy of the resulting top hits against a range of medically important snake venoms and demonstrate the utility of our method in determining drug EC50s. Collectively, our findings support the future application of this method to fully explore the chemical space to discover novel PLA2-inhibiting drugs of value for preventing severe pathology caused by snakebite envenoming.

Original languageEnglish
Article number1331224
Pages (from-to)1-14
Number of pages14
JournalFrontiers in Pharmacology
Volume14
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
Copyright © 2024 Albulescu, Westhorpe, Clare, Woodley, James, Kool, Berry, O’Neill and Casewell.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was funded by a UK Medical Research Council-funded Confidence in Concept Award (MC_PC_15040) to NC, and a Wellcome Trust grant (221712/Z/20/Z) awarded to JK, NB, PO’N, and NC. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

FundersFunder number
Wellcome Trust221712/Z/20/Z

    Keywords

    • drug discovery
    • high-throughput screening
    • neglected tropical disease
    • snake venom
    • snakebite envenoming
    • toxin inhibitors

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