In the classic novella "The Strange Case of Dr. Jekyll and Mr. Hyde", Robert Louis Stevenson paints a stark picture of the duality of good and evil within a single man. Botulinum neurotoxin (BoNT), the most potent known toxin, possesses an analogous dichotomous nature: It shows a pronounced morbidity and mortality, but it is used with great effect in much lower doses in a wide range of clinical scenarios. Recently, tremendous strides have been made in the basic understanding of the structure and function of BoNT, which have translated into widespread efforts towards the discovery of biomacromolecules and small molecules that specifically modulate BoNT activity. Particular emphasis has been placed on the identification of inhibitors that can counteract BoNT exposure in the event of a bioterrorist attack. This Review summarizes the current advances in the development of therapeutics, including vaccines, peptides, and small-molecule inhibitors, for the prevention and treatment of botulism.

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 voltagegated 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. KeywordsBotulinum Neurotoxin; aminopyridine; K + channel inhibitors * To whom correspondence should be addressed. Phone: (+1) 858-784-2516. Fax: (+1) 858-784-2595. kdjanda@scripps.edu. SUPPORTING INFORMATION AVAILABLE Synthetic and computational procedures, HPLC traces and 1 H/ 13 C NMR spectra of compounds 4-12; additional details for the biological evaluation of compounds 5 and 11. This material is available free of charge via the Internet at

In seiner klassischen Erzählung “Der Seltsame Fall des Dr. Jekyll und Mr. Hide” beschreibt Robert Louis Stevenson einen gespaltenen Menschen zwischen Gut und Böse. Botulinum‐Neurotoxin (BoNT), der wirksamste bekannte Giftstoff, ist von ähnlich zwiespältiger Natur: BoNT zeigt einerseits eine ausgeprägte Morbidität und Mortalität, kommt andererseits aber – wenn auch in viel geringeren Dosen – in einem breiten Spektrum klinischer Szenarien zum Einsatz. In jüngerer Zeit sind enorme Fortschritte beim Verständnis der Struktur und Funktion von BoNT erzielt worden, die eine intensive Erforschung von biomakromolekularen und niedermolekularen Modulatoren der BoNT‐Aktivität nach sich zogen. Ein Schwerpunkt dieser Projekte lag auf der Identifizierung von Inhibitoren, die einer BoNT‐Exposition, z. B. im Falle eines bioterroristischen Anschlags, entgegenwirken können. Dieser Aufsatz fasst die aktuellen Fortschritte bei der Entwicklung von Therapeutika zur Prävention und Behandlung von Botulismus zusammen, mit einem Schwerpunkt auf Impfstoffen sowie peptidischen und niedermolekularen Inhibitoren.

Organic chemistry Z 0200The Strange Case of the Botulinum Neurotoxin: Using Chemistry and Biology to Modulate the Most Deadly Poison -[159 refs.]. -(WILLIS, B.; EUBANKS, L. M.; DICKERSON*, T. J.; JANDA, K. D.; Angew. Chem., Int. Ed. 47 (2008) 44, 8360-8379; Dep. Chem., Scripps Res. Inst.,