title: Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies.
abstract: Botulinum neurotoxins (BoNTs) are the most lethal biotoxins known to mankind and are responsible for the neuroparalytic disease botulism. Current treatments for botulinum poisoning are all protein based and thus have a limited window of treatment opportunity. Inhibition of the BoNT light chain protease (LC) has emerged as a therapeutic strategy for the treatment of botulism as it may provide an effective post exposure remedy. Using a combination of crystallographic and modeling studies a series of hydroxamates derived from 1-adamantylacetohydroxamic acid (3a) were prepared. From this group of compounds, an improved potency of about 17-fold was observed for two derivatives. Detailed mechanistic studies on these structures revealed a competitive inhibition model, with a K(i)=27 nM, which makes these compounds some of the most potent small molecule, non-peptidic BoNT/A LC inhibitors reported to date.
authors: Department of Chemistry, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Peter
authors: P
authors: Šilhár
authors: Nicholas R
authors: NR
authors: Silvaggi
authors: Sabine
authors: S
authors: Pellett
authors: Kateřina
authors: K
authors: Čapková
authors: Eric A
authors: EA
authors: Johnson
authors: Karen N
authors: KN
authors: Allen
authors: Kim D
authors: KD
authors: Janda
mesh_terms: D000218:Adamantane / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D007700:Kinetics; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D019274:Botulinum Toxins, Type A; D000218:Adamantane