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. 2010 Dec 17;5(12):1183-91.
doi: 10.1021/cb1002366. Epub 2010 Oct 22.

Symptomatic relief of botulinum neurotoxin/a intoxication with aminopyridines: a new twist on an old molecule

Alexander V Mayorov  1 , Bert Willis, Antonia Di Mola, Derek Adler, Jennifer Borgia, Olin Jackson, Jie Wang, Yongyi Luo, Lei Tang, Richard J Knapp, Chandra Natarajan, Michael C Goodnough, Noam Zilberberg, Lance L Simpson, Kim D Janda
Affiliations

Symptomatic relief of botulinum neurotoxin/a intoxication with aminopyridines: a new twist on an old molecule

Alexander V Mayorov et al. ACS Chem Biol. .

Abstract

Botulinum neurotoxins (BoNT) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. BoNT/A is the most toxic protein known to man and has been classified by the Centers of Disease Control (CDC) as one of the six highest-risk threat agents for bioterrorism. Of particular concern is the apparent lack of clinical interventions that can reverse cellular intoxication. Efforts to uncover molecules that can act within an intoxicated cell so as to provide symptomatic relief to BoNT/A are paramount. Aminopyridines have shown clinical efficacy for multiple sclerosis treatment as well as BoNT/A intoxication; yet, aminopyridines for BoNT/A treatment has been abandoned because of blood brain barrier (BBB) penetration producing undesired neurotoxic side effects. Two aminopyridines (5 and 11) exhibited inhibitory activity toward Shaker-IR voltage-gated potassium (K(V)1.x) channels with potencies similar to that of the previous "gold-standard", 3,4-diaminopyridine (3,4-DAP), including reversal of symptoms from BoNT-induced paralysis in phrenic nerve-hemidiaphragm preparations. Importantly, pharmacokinetic experiments revealed a lack of BBB penetration of 5, which is a significant advancement toward resolving the neurotoxicity issues associated with prolonged 3,4-DAP treatments. Finally, 5 was found to be as effective as 3,4-DAP in rescuing BoNT-poisoned mice in the mouse lethality assay, signifying an optimized balance between the undesired permeability across the BBB and the required permeability across lipid cellular membranes. The results demonstrate that 5 is the most promising small molecule K(+) channel inhibitor discovered to date for the treatment of BoNT/A intoxication.

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Figures

Figure 1
Figure 1
Structures of the leading small molecule K+ channel inhibitors 1–3, and the experimental analogues 4–12.
Figure 2
Figure 2
Rescue of BoNT/A intoxicated mice. The data represents the mean ± S.E. (n = 10). The differences between all group pairs are statistically significant (P ≤ 0.001), with the exception of the 3,4-DAP and 5 groups with respect to one another.
Figure 3
Figure 3
Dose-response curves for inhibition of Shaker channels by 3,4-DAP, 5, and 11. The data represents the mean ± S.E. (n = 5).
Figure 4
Figure 4
Concentration (ng/mL) of substrate in mouse plasma and brain tissue after i.p. administration of 3,4-DAP and analogues 5 and 11 at 3.0 mg/kg (non-serial sampling). The data represents the mean ± S.E. (n = 3).
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