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Review
. 2010 Dec 30;16(1):202-20.
doi: 10.3390/molecules16010202.

Small molecule inhibitors as countermeasures for botulinum neurotoxin intoxication

Bing Li  1 , Norton P Peet, Michelle M Butler, James C Burnett, Donald T Moir, Terry L Bowlin
Affiliations
Review

Small molecule inhibitors as countermeasures for botulinum neurotoxin intoxication

Bing Li et al. Molecules. .

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.

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Figures

Figure 1
Figure 1
Cartoon representations of two types of three-domain organizations of BoNTholotoxins, (a) BoNT/A, left panel, and (b) BoNT/E, right panel. The two structures were obtained from the Protein Data Bank (PDB codes: 3BTA for BoNT/A and 3FFZ for BoNT/E).
Figure 2
Figure 2
Active site of the BoNT/A LC (prepared from PDB code 2IMC) [55].
Figure 3
Figure 3
Chemical structures of toosendanin (1) and its analogs.
Figure 4
Figure 4
AB-ring and CD-ring fragments generated from a function-oriented synthesis (FOS) strategy.
Figure 5
Figure 5
Structures of BoNT inhibitors 6 (bafilomycin A1) and 7 (lomofungin).
Figure 6
Figure 6
Structures of BoNT/A LC inhibitors.
Figure 7
Figure 7
(a) Co-crystal structure of BONT/A LC:8 (PDB code: 2IMA). (b) Co-crystal structure of BONT/A LC:9 (PDB code: 2IMB).
Figure 8
Figure 8
Proposed binding mode for inhibitor 12 (shown in green stick model). Oxygen atoms are red, nitrogen atoms are blue, hydrogen atoms are white, and Zn is cyan. The BoNT/A LC is rendered ribbon. (Reproduced from Li, B. et al. J. Med. Chem.; published by American Chemical Society [54].)
Figure 9
Figure 9
Active site BoNT/A LC inhibitors.
Figure 10
Figure 10
Small molecule BoNT/A LC inhibitors identified using phamacophore-based design.
Figure 11
Figure 11
Covalent inhibitors of BoNT/A LC.
Figure 12
Figure 12
Chemical structure of D-chicoric acid (19).
Figure 13
Figure 13
Small molecule BoNT/B LC inhibitors.
See this image and copyright information in PMC

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