title: Lactam-stabilized helical analogues of the analgesic μ-conotoxin KIIIA.
abstract: μ-Conotoxin KIIIA (μ-KIIIA) blocks mammalian voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. Previous structure-activity studies of μ-KIIIA identified a helical pharmacophore for VGSC blockade. This suggested a route for designing truncated analogues of μ-KIIIA by incorporating the key residues into an α-helical scaffold. As (i, i+4) lactam bridges constitute a proven approach for stabilizing α-helices, we designed and synthesized six truncated analogues of μ-KIIIA containing single lactam bridges at various locations. The helicity of these lactam analogues was analyzed by NMR spectroscopy, and their activities were tested against mammalian VGSC subtypes Na(V)1.1 through 1.7. Two of the analogues, Ac-cyclo9/13[Asp9,Lys13]KIIIA7-14 and Ac-cyclo9/13[Lys9,Asp13]KIIIA7-14, displayed μM activity against VGSC subtypes Na(V)1.2 and Na(V)1.6; importantly, the subtype selectivity profile for these peptides matched that of μ-KIIIA. Our study highlights structure-activity relationships within these helical mimetics and provides a basis for the design of additional truncated peptides as potential analgesics.
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Australia.
authors.forename: Keith K
authors.initials: KK
authors.lastname: Khoo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wilson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Zhang
authors.forename: Joszef
authors.initials: J
authors.lastname: Gulyas
authors.forename: Doju
authors.initials: D
authors.lastname: Yoshikami
authors.forename: Jean E
authors.initials: JE
authors.lastname: Rivier
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D020916:Conotoxins / Q000737:chemistry*; D005260:Female; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D056004:Molecular Dynamics Simulation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017433:Protein Structure, Secondary; D051381:Rats; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000700:Analgesics; D020916:Conotoxins; D007769:Lactams; D009842:Oligopeptides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C502265:mu-conotoxin KIIIA, Conus kinoshitai