Screening of a Focused Ubiquitin-Proteasome Pathway Inhibitor Library Identifies Small Molecules as Novel Modulators of Botulinum Neurotoxin Type A Toxicity

Screening of a Focused Ubiquitin-Proteasome Pathway Inhibitor Library Identifies Small Molecules as Novel Modulators of Botulinum Neurotoxin Type A Toxicity

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Botulinum neurotoxins (BoNTs) are known as the most potent bacterial toxins, which can cause potentially deadly disease botulism.BoNT Serotype A (BoNT/A) is the most studied serotype as it is responsible for most human botulism cases, and its formulations are extensively utilized in clinics for therapeutic and cosmetic applications.BoNT/A has the longest-lasting effect in neurons compared to other serotypes, and there has been high interest in understanding how BoNT/A manages to escape protein degradation machinery in neurons for months.

Recent work demonstrated that an E3 ligase, HECTD2, leads to efficient Volleyball - Accessories ubiquitination of the BoNT/A Light Chain (A/LC); however, the dominant activity of a deubiquitinase (DUB), VCIP135, inhibits the degradation of the enzymatic component.Another DUB, USP9X, was also identified as a potential indirect contributor to A/LC degradation.In this study, we screened a focused ubiquitin-proteasome pathway inhibitor library, including Foot Balm VCIP135 and USP9X inhibitors, and identified ten potential lead compounds affecting BoNT/A mediated SNAP-25 cleavage in neurons in pre-intoxication conditions.

We then tested the dose-dependent effects of the compounds and their potential toxic effects in cells.A subset of the lead compounds demonstrated efficacy on the stability and ubiquitination of A/LC in cells.Three of the compounds, WP1130 (degrasyn), PR-619, and Celastrol, further demonstrated efficacy against BoNT/A holotoxin in an in vitro post-intoxication model.

Excitingly, PR-619 and WP1130 are known inhibitors of VCIP135 and USP9X, respectively.Modulation of BoNT turnover in cells by small molecules can potentially lead to the development of effective countermeasures against botulism.