ArticleToxicon : official journal of the International Society on Toxinology2021
COVALENT INHIBITION OF BOTULINUM NEUROTOXIN A - EXPLORATION OF WARHEAD REACTIVITY AND FUNCTION USING A BIFUNCTIONAL APPROACH.
Article in Toxicon : official journal of the International Society on Toxinology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors at 2 institutions in 2 countries.
Funding
Abstract
INTRODUCTION AND
objectivesBotulinum neurotoxin A (BoNT/A) is extremely toxic possessing an estimated intravenous LD
methodsSmall molecule inhibitors that possessed electrophilic moieties were designed, using X-ray crystallography as guidance, to target both the zinc metal-binding region and Cys165 within the active site of BoNT/A. Synthesized compounds were evaluated for covalent inhibition using a continuous SNAPtide FRET assay
resultsSeveral electrophilic warhead types were confirmed to inhibit BoNT/A LC covalently with substantial differences in time-dependent inhibition between the WT and C165A variant. A trend in warhead reactivity was reflected in inhibitor stability and toxicity. Compounds exhibited moderate potency in a BoNT/A neuronal cellular assay but were not further explored due to undesirable therapeutic potential.
conclusionsA fundamental framework for the bifunctional covalent inhibition of BoNT/A LC has been established. This approach has potential to be translated to other small molecule metal-binding inhibitors of BoNT/A LC with the vision that different pharmacophores, possessing improved physicochemical properties, will address BoNT/As toxicity and longevity within cells.
Indexed as
Identifiers
34103769PMC8183569W3125149750What OpenQuestion holds
Registered trials
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