Synthesis and biological evaluation of botulinum neurotoxin a protease inhibitors.
NSC 240898 was previously identified as a botulinum neurotoxin A light chain (BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogues have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of the BoNT/A LC inhibition. The most potent inhibitor against BoNT/A LC in these two series is compound 12 (IC(50) = 2.5 microM, FRET assay), which is 4.4-fold more potent than the lead structure and 11.2-fold more selective for BoNT/A LC versus the anthrax LF metalloproteinase. Structure-activity relationship studies have revealed structural features important to potency and enzyme specificity.
Microbiotix Inc, One Innovation Drive, Worcester, Massachusetts 01605, USA. bli@microbiotix.com
Bing
B
Li
Ramdas
R
Pai
Steven C
SC
Cardinale
Michelle M
MM
Butler
Norton P
NP
Peet
Donald T
DT
Moir
Sina
S
Bavari
Terry L
TL
Bowlin
D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000578:Amidines; D001562:Benzimidazoles; D007211:Indoles; D011480:Protease Inhibitors; D013876:Thiophenes; D019274:Botulinum Toxins, Type A