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: 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, Sónia Troeira Henriques, Irina Vetter
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 22 Pg. 11829-42 (May 27 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27026701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Analgesics
• Conotoxins
• Liposomes
• NAV1.8 Voltage-Gated Sodium Channel
• muO-conotoxin MrVIA

Topics

• Amino Acid Sequence
• Analgesics (pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Cell Membrane (metabolism)
• Conotoxins (pharmacology)
• Crystallography, X-Ray
• Electrophysiology
• HEK293 Cells
• Humans
• Liposomes
• Magnetic Resonance Spectroscopy
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• NAV1.8 Voltage-Gated Sodium Channel (chemistry, genetics, metabolism)
• Pain (chemically induced, prevention & control)
• Protein Conformation
• Sequence Homology, Amino Acid