title: Expanding chemical diversity of conotoxins: peptoid-peptide chimeras of the sodium channel blocker μ-KIIIA and its selenopeptide analogues.
abstract: The μ-conotoxin KIIIA is a three disulfide-bridged blocker of voltage-gated sodium channels (VGSCs). The Lys(7) residue in KIIIA is an attractive target for manipulating the selectivity and efficacy of this peptide. Here, we report the design and chemical synthesis of μ-conopeptoid analogues (peptomers) in which we replaced Lys(7) with peptoid monomers of increasing side-chain size: N-methylglycine, N-butylglycine and N-octylglycine. In the first series of analogues, the peptide core contained all three disulfide bridges; whereas in the second series, a disulfide-depleted selenoconopeptide core was used to simplify oxidative folding. The analogues were tested for functional activity in blocking the Nav1.2 subtype of mammalian VGSCs exogenously expressed in Xenopus oocytes. All six analogues were active, with the N-methylglycine analogue, [Sar(7)]KIIIA, the most potent in blocking the channels while favouring lower efficacy. Our findings demonstrate that the use of N-substituted Gly residues in conotoxins show promise as a tool to optimize their pharmacological properties as potential analgesic drug leads.
authors.affiliation: Faculty of Chemistry, University of Gdansk, Sobieskiego 18, 80-952 Gdansk, Poland. walewska@chem.univ.gda.pl
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Walewska
authors.forename: Tiffany S
authors.initials: TS
authors.lastname: Han
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Zhang
authors.forename: Doju
authors.initials: D
authors.lastname: Yoshikami
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Rolka
mesh_terms: D020916:Conotoxins / Q000737:chemistry*; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D034444:Peptoids / Q000737:chemistry*; D051140:Selenoproteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D020916:Conotoxins; D010455:Peptides; D034444:Peptoids; D051140:Selenoproteins; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels
keywords: Diselenide; Electrophysiology; KIIIA; Peptomers; Selenocysteine; Sodium channels; μ-Conotoxins