COVALENT INHIBITION OF BOTULINUM NEUROTOXIN A - EXPLORATION OF WARHEAD REACTIVITY AND FUNCTION USING A BIFUNCTIONAL APPROACH.

ABSTRACT:

Introduction and objectives

Botulinum neurotoxin A (BoNT/A) is extremely toxic possessing an estimated intravenous LD₅₀ of 1-2 ng/kg and as such has been designated a category A bioterrorism agent.^{1, 2} BoNT/A also possesses an extremely long half-life and persists within muscle neurons for months to >1 year.³ Because of BoNT/A longevity, we have utilized covalent inhibition as a means to abrogate BoNT/A's toxicity. To this end, we describe an approach to designing inhibitors that possess both electrophilic warheads and metal-binding groups for the bifunctional inhibition of BoNT/A.

Methods

Small molecule inhibitors that possessed electrophilic moieties were designed, using X-ray crystallography as guidance, to target both the zinc metal-bindi

SUBMITTER: Turner LD 

PROVIDER: S-EPMC8183569 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature