Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor.
Pain therapeutics discovered by molecular mining of the expressed genome of Australian predatory cone snails are providing lead compounds for the treatment of neurological diseases such as multiple sclerosis, shingles, diabetic neuropathy and other painful neurological conditions. The high specificity exhibited by these novel compounds for neuronal receptors and ion channels in the brain and nervous system indicates the high degree of selectivity that this class of neuropeptides can be expected to show when used therapeutically in humans. A lead compound, ACV1 (conotoxin Vc1.1 from Conus victoriae), has entered Phase II clinical trials and is being developed for the treatment for neuropathic pain. ACV1 will be targeted initially for the treatment of sciatica, shingles and diabetic neuropathy. The compound is a 16 amino acid peptide [Sandall et al., 2003. A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo. Biochemistry 42, 6904-6911], an antagonist of neuronal nicotinic acetylcholine receptors. It has potent analgesic activity following subcutaneous or intramuscular administration in several preclinical animal models of human neuropathic pain [Satkunanathan et al., 2005. Alpha conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurons. Brain. Res. 1059, 149-158]. ACV1 may act as an analgesic by decreasing ectopic excitation in sensory nerves. In addition ACV1 appears to accelerate the recovery of injured nerves and tissues.
Livett
Bruce G
BG
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia. b.livett@unimelb.edu.au
Sandall
David W
DW
Keays
David
D
Down
John
J
Gayler
Ken R
KR
Satkunanathan
Narmatha
N
Khalil
Zeinab
Z
D000700:Analgesics / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use; D000818:Animals; D001315:Australia; D020916:Conotoxins / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D052078:Conus Snail; D006801:Humans; D009422:Nervous System Diseases / Q000188:drug therapy*; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000700:Analgesics; D020916:Conotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic