title: Toward the discovery of dual inhibitors for botulinum neurotoxin A: concomitant targeting of endocytosis and light chain protease activity.
abstract: Dyngo-4a™ has been found to be an endocytic inhibitor of BoNT/A neurotoxicity through dynamin inhibition. Herein, we demonstrate this molecule to have a previously unrecognized dual activity against BoNT/A, dynamin-protease inhibition. To establish the importance of this dual activity, detailed kinetic analysis of Dyngo-4a's inhibition of BoNT/A metalloprotease as well as cellular and animal toxicity studies have been described. The research presented is the first polypharmacological approach to counteract BoNT/A intoxication.
authors.affiliation: Departments of Chemistry and Immunology and Microbial Sciences, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. kdjanda@scripps.edu.
authors.forename: Hajime
authors.initials: H
authors.lastname: Seki
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hixon
authors.forename: Sabine
authors.initials: S
authors.lastname: Pellett
authors.forename: Marek
authors.initials: M
authors.lastname: Remes
authors.forename: Eric A
authors.initials: EA
authors.lastname: Johnson
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
chemical_list: D006835:Hydrazones; D009284:Naphthols; C568360:dyngo-4a; D045726:Metalloproteases; D019274:Botulinum Toxins, Type A; D034281:Dynamins