μ-conotoxin KIIIA peptidomimetics that block human voltage-gated sodium channels

Knuhtsen, A., Whiting, R., McWhinnie, F. S., Whitmore, C., Smith, B. O. , Green, A. C., Timperley, C. M., Kinnear, K. I. and Jamieson, A. G. (2021) μ-conotoxin KIIIA peptidomimetics that block human voltage-gated sodium channels. Peptide Science, 113(1), e24203. (doi: 10.1002/pep2.24203)

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Abstract

Peptidomimetics designed to target voltage‐gated sodium channels have attracted significant attention as potential analgesics. However, voltage‐gated sodium channel (VGSC)‐blocking activity of these compounds has mainly been assessed using rat and/or mice homologs. In this study, we developed a novel series of conformationally constrained peptidomimetic analogues of the μ‐conotoxin KIIIA and assessed their activity against human VGSCs. Two of the mimetics block the currents of hNav1.4 and hNav1.6 channels. NMR derived structures of the mimetics provided excellent insight into the structural requirements for bioactivity. A lactam‐constrained analogue, previously reported to be active in mice, did not block the corresponding human VGSC. This work highlights important differences in VGSCs between species and validates the potential of peptidomimetics as human analgesics.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Knuhtsen, Dr Astrid and Jamieson, Dr Andrew and Smith, Dr Brian and McWhinnie, Mr Fergus
Authors: Knuhtsen, A., Whiting, R., McWhinnie, F. S., Whitmore, C., Smith, B. O., Green, A. C., Timperley, C. M., Kinnear, K. I., and Jamieson, A. G.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Peptide Science
Publisher:Wiley
ISSN:2475-8817
ISSN (Online):2475-8817
Published Online:24 October 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Peptide Science 113(1): e24203
Publisher Policy:Reproduced under a Creative Commons Licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
304896EPSRC-IAA: Early Stage Commercialisation of a PET Imaging Agent for the Detection of Cardiovascular Disease and CancerAndrew SutherlandEngineering and Physical Sciences Research Council (EPSRC)EP/R511705/1Chemistry