title: Reexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: extending towards the β-exosite.
abstract: Botulinum neurotoxins (BoNTs) are the most toxic proteins known to man, exposure to which results in flaccid paralysis. Given their extreme potency, these proteins have become studied as possible weapons of bioterrorism; however, effective treatments that function after intoxication have not progressed to the clinic. Here, we have reexamined one of the most effective inhibitors, 2,4-dichlorocinnamyl hydroxamate, in the context of the known plasticity of the BoNT/A light chain metalloprotease. Our studies have shown that modifications of this compound are tolerated and result in improved inhibitors, with the best compound having an IC(50) of 0.23 μM. Given the inconsistency of structure-activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series.
authors.affiliation: Fox Chase Chemical Diversity Center, Doylestown, PA 18902, USA.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Smith
authors.forename: Dejan
authors.initials: D
authors.lastname: Caglič
authors.forename: Petr
authors.initials: P
authors.lastname: Capek
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sujata
authors.initials: S
authors.lastname: Godbole
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.forename: Tobin J
authors.initials: TJ
authors.lastname: Dickerson
mesh_terms: D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D006877:Hydroxamic Acids / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D019274:Botulinum Toxins, Type A