Identification of the characteristics that underlie botulinum toxin potency: implications for designing novel drugs.

Botulinum toxin is a uniquely potent substance whose natural site of action is the peripheral cholinergic nerve ending. A substantial amount of information on the cellular, subcellular and molecular aspects of toxin action has been accumulated, and as a result a sound understanding of the basis for toxin potency has been developed. The principal characteristics of the toxin molecule that account for its potency are its ability: a) to be absorbed from the gut with minimal degradation; b) to bind to receptors that maximize the prospects of a pathophysiologic outcome; c) to act by a multiplicative (viz., enzymatic) mechanism; and d) to modify a substrate that is essential for neuronal function. Interestingly, the same properties that account for potency can also be exploited to utilize the toxin as a research tool and as a therapeutic agent. Several specific examples of ways to use the toxin advantageously are presented, including: a) development of oral medications and vaccines; b) analysis of subcellular mechanisms that govern transcytosis; c) identification of cell surface markers characteristic of cholinergic nerve endings; and d) analysis of specific aspects of exocytosis, such as spontaneous quantal release and synchronous quantal release. In all likelihood, further studies on the mechanism of botulinum toxin action will reveal yet further opportunities for utilizing it as a research tool or therapeutic agent.