Chirality holds the key for potent inhibition of the botulinum neurotoxin serotype a protease.
Botulinum neurotoxin serotype A (BoNT/A) is the most toxic protein known to man and also a bioterrorism agent. As defined by our previous research targeting the etiological agent responsible for BoNT/A intoxication, a protease, we now report on the asymmetric synthesis of four new BoNT/A inhibitors; the most potent of this series is roughly 2-fold more active than the best small molecule inhibitor currently known.
Stowe
G Neil
GN
Department of Chemistry, 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.
Silhár
Peter
P
Hixon
Mark S
MS
Silvaggi
Nicholas R
NR
Allen
Karen N
KN
Moe
Scott T
ST
Jacobson
Alan R
AR
Barbieri
Joseph T
JT
Janda
Kim D
KD
D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D002384:Catalysis; D003013:Clostridium / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D009498:Neurotoxins; D011480:Protease Inhibitors; D019274:Botulinum Toxins, Type A