Bis-imidazoles as molecular probes for peripheral sites of the zinc endopeptidase of botulinum neurotoxin serotype A

摘要: Abstract Botulinum neurotoxin serotype A (BoNTA) is highly toxic, and its antidote currently unavailable. The essential light-chain subunit of BoNTA a zinc endopeptidase that can be used as target for developing antidotes. However, the development high-affinity, small-molecule inhibitors challenging protein–protein complexation. This because polypeptide substrate wraps around circumference upon binding, thereby constituting an unusually large substrate–enzyme interface 4840 A2. To overcome large-interface problem, we propose using zinc-coordination bivalence approaches to design BoNTA. Here report alkylene-linked bis-imidazoles inhibit in two-site binding mode. bis-imidazole tethered with 13 methylene groups, most potent dimers, showed 61% inhibition at concentration 100 μM. results demonstrate presence peripheral site imidazolium group rim active-site cleft. enables use approach improve our previously reported were developed according approach.