Identification of a potent botulinum neurotoxin a protease inhibitor using in situ lead identification chemistry.
[reaction: see text] Botulinum neurotoxins (BoNTs), etiological agents of the deadly food poisoning disease botulism, are the most toxic proteins currently known. By using in situ lead identification chemistry, we have uncovered the first class of inhibitors that displays nanomolar potency. From a 15 microM lead compound, structure-activity relationship studies were performed granting the most potent BoNT/A inhibitor reported to date that displays an inhibition constant of 300 nM.
Boldt
Grant E
GE
Department of Chemistry and Immunology, The Skaggs Institute for Chemical Biology and Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Kennedy
Jack P
JP
Janda
Kim D
KD
D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D001906:Botulism / Q000209:etiology; D020650:Combinatorial Chemistry Techniques; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D011480:Protease Inhibitors; D019274:Botulinum Toxins, Type A