Small Molecule Inhibitors as Countermeasures for Botulinum Neurotoxin Intoxication 英文参考文献.docVIP

Molecules 2011, 16, 202-220; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Review Small Molecule Inhibitors as Countermeasures for Botulinum Neurotoxin Intoxication Bing Li 1,*, Norton P. Peet 1, Michelle M. Butler 1, James C. Burnett 2, Donald T. Moir 1 and Terry L. Bowlin 1 1 Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA 2 Target, Structure-Based Drug Discovery Group, SAIC-Frederick, Inc., National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA; E-Mail: burnettjames@ (J.C.B.) * Author to whom correspondence should be addressed; E-Mail: bli@; Tel.: +1-508-757-2800; Fax: +1-508-757-1999. Received: 30 November 2010; in revised form: 20 December 2010 / Accepted: 29 December 2010 / Published: 30 December 2010 Abstract: Botulinum neurotoxins (BoNTs) are the most potent of known toxins and are listed as category A biothreat agents by the U.S. CDC. The BoNT-mediated proteolysis of SNARE proteins inhibits the exocytosis of acetylcholine into neuromuscular junctions, leading to life-threatening flaccid paralysis. Currently, the only therapy for BoNT intoxication (which results in the disease state botulism) includes experimental preventative antibodies and long-term supportive care. Therefore, there is an urgent need to identify and develop inhibitors that will serve as both prophylactic agents and post- exposure ‘rescue’ therapeutics. This review focuses on recent progress to discover and develop small molecule inhibitors as therapeutic countermeasures for BoNT intoxication. Keywords: botulinum neurotoxin; inhibitor; drug discovery 1. Introduction Botulinum neurotoxins (BoNTs), secreted by the anaerobic spore-forming bacterial Clostridia species botulinum, baratii, and butyricum, are the most poisonous of known biological toxins [1,2], and as a result are listed as category A biothrea