The clostridial neurotoxins (CNTs) are among the most potent protein toxins known to humans. CNTs include
seven serotypes (A~G) of botulinum toxins (BoNTs), which cause botulism, a flaccid paralysis, and tetanus toxin (TeNT),
which causes spastic paralysis. BoNTs are classified as category A agent and may be used as potential bioterrorism weapons.
On the other hand, the ability of an extremely low dosage of BoNTs (less than 1 ng) to cause reversible partial paralysis
upon injection into muscle has turned BoNTs, in particular serotypes A and B, from deadly agents to novel therapeutic
agents for treatment of a wide range of clinical conditions associated with involuntary muscle spasm and contractions.
In addition to clinical use, they may also be used in cosmetics. Further indications for BoNTs will continue to be
developed, although current BoNT therapies have encountered some limitations due to the pharmacological properties of
BoNTs, such as their ability to elicit immunoresistance in patients upon periodical injections. This review summarizes the
present knowledge of the mechanisms of action of CNTs, with particular focus on the mode of substrate recognition by
CNT catalytic domains and knowledge regarding substrate recognition can be utilized to develop novel BoNT products to
extend its usefulness in therapeutic interventions and overcome the immunoresistance problems.