Development of a μO-conotoxin analogue with improved lipid membrane interactions and potency for the analgesic target NaV1.8

Jennifer R. Deuis, Zoltan Dekan, Marco C. Inserra, Tzong-Hsien Lee, Marie-Isabel Aguilar, David J. Craik, Richard J. Lewis, Paul F. Alewood, Mehdi Mobli, Christina I. Schroeder, Sonia Troeira Henriques, Irina Vetter

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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.
Original languageEnglish
Pages (from-to)11829-11842
Number of pages14
JournalJournal of Biological Chemistry
Volume291
Issue number22
DOIs
Publication statusPublished - 27 May 2016

Keywords

  • lipid-protein interaction
  • mutagenesis
  • pain
  • peptide chemical synthesis
  • sodium channel
  • μO-conotoxin MfVIA
  • NaV1.8
  • structure-activity relationships

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