Chemistry

Blocking Botulism

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Science  06 Feb 2009:
Vol. 323, Issue 5915, pp. 689
DOI: 10.1126/science.323.5915.689b

The known antidotes for botulinum neurotoxin (BoNT) exposure are antitoxins, so there is considerable interest in identifying small-molecule inhibitors of its action. All BoNTs consist of a light-chain (LC) protease that is translocated by a heavy-chain (HC) channel. Fischer et al. have used chemical semisynthesis to develop analogs of toosendanin, a traditional Chinese medicine extracted from Melia toosendan that has been reported to inhibit the action of BoNTs in monkeys. Single-molecule assays showed that toosendanin and a more potent tetrahydrofuran derivative inhibited translocation of serotypes A and E of the LC, and two in vivo assays confirmed this activity. However, once the LC cargo was delivered, toosendanin could increase the propensity of the HC channel to remain in an open state that would disrupt endosomal processes. Thus, the binding site for toosendanin apparently depends on the state of the cargo within the chaperone. As this channel-opened state occurs at much higher concentrations (by a factor of about 2000) than does inhibition, further exploration of this class of channel blockers is warranted. — PDS

Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.0812839106 (2008).

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