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.
Silhár
Peter
P
Department of Chemistry, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Capková
Katerina
K
Salzameda
Nicholas T
NT
Barbieri
Joseph T
JT
Hixon
Mark S
MS
Janda
Kim D
KD
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