Superactivation of the botulinum neurotoxin serotype A light chain metalloprotease: a new wrinkle in botulinum neurotoxin.
Small molecules based upon a 2-acylguanidine-5-phenyl thiophene scaffold that can activate the light chain metalloprotease of botulinum neurotoxin serotype A (BoNT LC/A) by an apparent reduction in Km are reported. On the basis of structure-activity relationships and the activation profile, one or more molecules of activator specifically bind to a defined site on the toxin, causing the observed rate enhancement. With the ever-growing clinical uses of BoNT, compounds such as those reported here may provide a method for combating the emerging adaptive immune responses to BoNT.
Department of Chemistry, The Skaggs Institute for Chemical Biology, La Jolla, California 92037, USA.
Laura A
LA
McAllister
Mark S
MS
Hixon
Jack P
JP
Kennedy
Tobin J
TJ
Dickerson
Kim D
KD
Janda
D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D002384:Catalysis; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D045726:Metalloproteases / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
D013876:Thiophenes; D045726:Metalloproteases; D019274:Botulinum Toxins, Type A