Botulinum neurotoxin A protease: discovery of natural product exosite inhibitors.
A new mechanistic class of BoNT/A zinc metalloprotease inhibitors, from Echinacea, exemplified by the natural product d-chicoric acid (I1) is disclosed. A detailed evaluation of chicoric acid's mechanism of inhibition reveals that the inhibitor binds to an exosite, displays noncompetitive partial inhibition, and is synergistic with a competitive active site inhibitor when used in combination. Other components found in Echinacea, I3 and I4, were also inhibitors of the protease.
Department of Chemistry, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Peter
P
Silhár
Katerina
K
Capková
Nicholas T
NT
Salzameda
Joseph T
JT
Barbieri
Mark S
MS
Hixon
Kim D
KD
Janda
D001685:Biological Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002109:Caffeic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002726:Chlorogenic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003014:Clostridium botulinum / Q000201:enzymology*; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D001685:Biological Factors; D002109:Caffeic Acids; D006877:Hydroxamic Acids; D010636:Phenols; D011480:Protease Inhibitors; D013386:Succinates; D002726:Chlorogenic Acid; D019274:Botulinum Toxins, Type A; C100435:chicoric acid; C515101:caftaric acid