title: Development of a μO-Conotoxin Analogue with Improved Lipid Membrane Interactions and Potency for the Analgesic Sodium Channel NaV1.8.
abstract: The μO-conotoxins MrVIA, MrVIB, and MfVIA inhibit the voltage-gated sodium channel NaV1.8, a well described target for the treatment of pain; however, little is known about the residues or structural elements that define this activity. In this study, we determined the three-dimensional structure of MfVIA, examined its membrane binding properties, performed alanine-scanning mutagenesis, and identified residues important for its activity at human NaV1.8. A second round of mutations resulted in (E5K,E8K)MfVIA, a double mutant with greater positive surface charge and greater affinity for lipid membranes compared with MfVIA. This analogue had increased potency at NaV1.8 and was analgesic in the mouse formalin assay.
authors.affiliation: From the Institute for Molecular Bioscience and School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia, and.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Deuis
authors.affiliation: From the Institute for Molecular Bioscience and.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Dekan
authors.affiliation: From the Institute for Molecular Bioscience and School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia, and.
authors.forename: Marco C
authors.initials: MC
authors.lastname: Inserra
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Tzong-Hsien
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Marie-Isabel
authors.initials: MI
authors.lastname: Aguilar
authors.affiliation: From the Institute for Molecular Bioscience and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.affiliation: From the Institute for Molecular Bioscience and.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.affiliation: From the Institute for Molecular Bioscience and.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
authors.affiliation: Centre for Advanced Imaging, The University of Queensland, St. Lucia, Queensland 4072, Australia.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mobli
authors.affiliation: From the Institute for Molecular Bioscience and c.schroeder@imb.uq.edu.au.
authors.forename: Christina I
authors.initials: CI
authors.lastname: Schroeder
authors.affiliation: From the Institute for Molecular Bioscience and s.henriques@imb.uq.edu.au.
authors.forename: Sónia Troeira
authors.initials: ST
authors.lastname: Henriques
authors.affiliation: From the Institute for Molecular Bioscience and School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia, and i.vetter@uq.edu.au.
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism*; D020916:Conotoxins / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004594:Electrophysiology; D057809:HEK293 Cells; D006801:Humans; D008081:Liposomes; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D000700:Analgesics; D020916:Conotoxins; D008081:Liposomes; D062559:NAV1.8 Voltage-Gated Sodium Channel; C094740:muO-conotoxin MrVIA
keywords: NaV1.8; lipid-protein interaction; mutagenesis; pain; peptide chemical synthesis; sodium channel; structure-activity relationships; μO-conotoxin MfVIA