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.