Small Molecule Inhibitors as Countermeasures for Botulinum Neurotoxin Intoxication

被引：40
作者：
Li, Bing [1 ]
Peet, Norton P. [1 ]
Butler, Michelle M. [1 ]
Burnett, James C. [2 ]
Moir, Donald T. [1 ]
Bowlin, Terry L. [1 ]
机构：
[1] Microbiotix Inc, Worcester, MA 01605 USA
[2] NCI, SAIC Frederick Inc, Structure Based Drug Discovery Grp, Frederick, MD 21702 USA
来源：
MOLECULES | 2011年 / 16卷 / 01期
关键词：
botulinum neurotoxin; inhibitor; drug discovery; FUNCTION-ORIENTED SYNTHESIS; TOXIN TYPE-A; LIGHT-CHAIN; CLOSTRIDIUM-BOTULINUM; STRUCTURAL-ANALYSIS; NEUROTRANSMITTER RELEASE; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; SYNAPTOTAGMIN-I; MEDICAL ASPECTS;
D O I：
10.3390/molecules16010202
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
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收藏
页码：202 / 220
页数：19
相关论文
共 88 条
  • [1] Efficacy of a novel metalloprotease inhibitor on botulinum neurotoxin B activity
    Adler, M
    Nicholson, JD
    Hackley, BE
    [J]. FEBS LETTERS, 1998, 429 (03) : 234 - 238
  • [2] Structural analysis of botulinum neurotoxin serotype F light chain: Implications on substrate binding and inhibitor design
    Agarwal, R
    Binz, T
    Swaminathan, S
    [J]. BIOCHEMISTRY, 2005, 44 (35) : 11758 - 11765
  • [3] Structural analysis of botulinum neurotoxin type E catalytic domain and its mutant Glu212→Gln reveals the pivotal role of the Glu212 carboxylate in the catalytic pathway
    Agarwal, R
    Eswaramoorthy, S
    Kumaran, D
    Binz, T
    Swaminathan, S
    [J]. BIOCHEMISTRY, 2004, 43 (21) : 6637 - 6644
  • [4] Structure of botulinurn neurotoxin type D light chain at 1.65 Å resolution:: Repercussions for VAMP-2 substrate specificity
    Arndt, JW
    Chai, Q
    Christian, T
    Stevens, RC
    [J]. BIOCHEMISTRY, 2006, 45 (10) : 3255 - 3262
  • [5] Crystal structure of botulinum neurotoxin type G light chain: Serotype divergence in substrate recognition
    Arndt, JW
    Yu, W
    Bi, F
    Stevens, RC
    [J]. BIOCHEMISTRY, 2005, 44 (28) : 9574 - 9580
  • [6] Botulinum toxin as a biological weapon - Medical and public health management
    Arnon, SS
    Schechter, R
    Inglesby, TV
    Henderson, DA
    Bartlett, JG
    Ascher, MS
    Eitzen, E
    Fine, AD
    Hauer, J
    Layton, M
    Lillibridge, S
    Osterholm, MT
    O'Toole, T
    Parker, G
    Perl, TM
    Russell, PK
    Swerdlow, DL
    Tonat, K
    [J]. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2001, 285 (08): : 1059 - 1070
  • [7] BAKRY N, 1991, J PHARMACOL EXP THER, V258, P830
  • [8] Expanding use of botulinum toxin
    Bhidayasiri, R
    Truong, DD
    [J]. JOURNAL OF THE NEUROLOGICAL SCIENCES, 2005, 235 (1-2) : 1 - 9
  • [9] Medical aspects of toxin weapons
    Bigalke, H
    Rummel, A
    [J]. TOXICOLOGY, 2005, 214 (03) : 210 - 220
  • [10] BINZ T, 1994, J BIOL CHEM, V269, P1617
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