title: Structure and function of μ-conotoxins, peptide-based sodium channel blockers with analgesic activity.
abstract: μ-Conotoxins block voltage-gated sodium channels (VGSCs) and compete with tetrodotoxin for binding to the sodium conductance pore. Early efforts identified µ-conotoxins that preferentially blocked the skeletal muscle subtype (NaV1.4). However, the last decade witnessed a significant increase in the number of µ-conotoxins and the range of VGSC subtypes inhibited (NaV1.2, NaV1.3 or NaV1.7). Twenty µ-conotoxin sequences have been identified to date and structure-activity relationship studies of several of these identified key residues responsible for interactions with VGSC subtypes. Efforts to engineer-in subtype specificity are driven by in vivo analgesic and neuromuscular blocking activities. This review summarizes structural and pharmacological studies of µ-conotoxins, which show promise for development of selective blockers of NaV1.2, and perhaps also NaV1.1,1.3 or 1.7.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville VIC 3052, Australia.
authors.forename: Brad R
authors.initials: BR
authors.lastname: Green
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D020916:Conotoxins / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D052078:Conus Snail / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000473:pathology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000700:Analgesics; D020916:Conotoxins; D020033:Protein Isoforms; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels