The analgesic potential of clostridial neurotoxin derivatives.
Botulinum neurotoxins are the most potent acute lethal toxins known, and yet for the last two decades they, and in particular serotype A, have found increasing use in the clinical treatment of diseases or conditions involving neuromuscular or autonomic neuronal transmission. The neurotoxins work by inhibiting the release of acetylcholine from peripheral cholinergic nerve terminals. More recently, the effects on non-cholinergic pathways have been identified, and this has led to an increase in the diseases and syndromes for which botulinum neurotoxins have been found to have clinical utility. In particular, botulinum neurotoxins have been demonstrated to potentially benefit a range of chronic pain syndromes. With the description in the last decade of the biochemical basis of neurotoxin action and the tertiary structure of the toxin molecule, the possibility of designing novel agents utilising selected aspects of toxin function has arisen. This possibility has been pursued in the context of pain relief with the description of a novel hybrid protein derived from botulinum neurotoxin type A, LH(N)/A-ECL, able to selectively target nociceptive afferent neurons and inhibit the release of neurotransmitters involved in pain transmission. This novel derivative of botulinum neurotoxin type A demonstrates prolonged analgesic activity in vivo. This review will consider the evidence for the analgesic properties of the botulinum neurotoxins and their suitability as the basis for novel therapeutic proteins. The general concept of deriving novel therapeutic molecules from the neurotoxins will also be considered.
Foster
Keith A
KA
HPA Porton Down, Salisbury, Wiltshire, SP4 0JG, UK. keith.foster@hpa.org.uk
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D003013:Clostridium / Q000737:chemistry*; D006801:Humans; D009498:Neurotoxins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D000700:Analgesics; D009498:Neurotoxins