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Discovery of Dipeptides as Potent Botulinum Neurotoxin A Light-Chain Inhibitors.

ABSTRACT: The botulinum neurotoxin, the caustic agent that causes botulism, is the most lethal toxin known to man. The neurotoxin composed of a heavy chain (HC) and a light chain (LC) enters neurons and cleaves SNARE proteins, leading to flaccid paralysis, which, in severe occurrences, can result in death. A therapeutic target for botulinum neurotoxin (BoNT) intoxication is the LC, a zinc metalloprotease that directly cleaves SNARE proteins. Herein we report dipeptides containing an aromatic connected to the N-terminus via a sulfonamide and a hydroxamic acid at the C-terminus as BoNT/A LC inhibitors. On the basis of a structure-activity relationship study, 33 was discovered to inhibit the BoNT/A LC with an IC₅₀ of 21 nM. X-ray crystallography analysis of 30 and 33 revealed that the dipeptides inhibit through a competitive mechanism and identified several key intermolecular interactions.

SUBMITTER: Amezcua M

PROVIDER: S-EPMC7883461 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Discovery of Dipeptides as Potent Botulinum Neurotoxin A Light-Chain Inhibitors.

Amezcua Martin M Cruz Ricardo S RS Ku Alex A Moran Wilfred W Ortega Marcos E ME Salzameda Nicholas T NT

ACS medicinal chemistry letters 20210127 2

The botulinum neurotoxin, the caustic agent that causes botulism, is the most lethal toxin known to man. The neurotoxin composed of a heavy chain (HC) and a light chain (LC) enters neurons and cleaves SNARE proteins, leading to flaccid paralysis, which, in severe occurrences, can result in death. A therapeutic target for botulinum neurotoxin (BoNT) intoxication is the LC, a zinc metalloprotease that directly cleaves SNARE proteins. Herein we report dipeptides containing an aromatic connected to ...[more]

PMID: 33603978

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