The use of peptide-membrane interactions in the design of selective and potent sodium channel inhibitors

The use of peptide-membrane interactions in the design of selective and potent sodium channel inhibitors

The use of peptide-membrane interactions in the design of selective and potent sodium channel inhibitors (#199)

Christina Schroeder ¹

Institute for Molecular Bioscience, Brisbane, QLD, Australia

Peptide toxins isolated from spiders are potent inhibitors of human voltage-gated sodium channels (Na_V). Some of these peptides are selective against subtypes Na_V1.7, reported to be involved in nociception, and may thus have potential as pain therapeutic leads. Peptide toxins can inhibit Na_V activity by blocking the pore domain (i.e, pore blockers) or by binding to the membrane-embedded voltage sensor domain of the sodium channel (i.e. gating-modifier toxins). It is now well established that some gating-modifier toxins also interact with lipid membranes surrounding the voltage-sensor domains. However, it is less well-known to what extent these peptide-lipid interactions are relevant for the inhibitory activity and/or sodium channel selectivity. Using a range of biophysical techniques, we have examined the importance of membrane binding on the inhibitory activity of a subset of peptides, showing a direct correlation between membrane binding affinity and Na_V selectivity, highlighting the importance of considering potential membrane-binding events when designing sodium channel voltage-gating modifier inhibitors. Using this information, we have designed modified gating-modifier toxins with improved potency and off-target selectivity for the therapeutically relevant sodium channel subtype Na_V1.7.

Authors contributing to this presentation.

Schroeder, C

Christina Schroeder received her MSc in Chemistry from University of Kalmar, Sweden in 1998. She relocated to Australia in 1999 to conduct her PhD at the University of Queensland under supervision of Professor Richard Lewis and Professor David Craik working on the development of an omega-conotoxin pharmacophore. After completing her PhD in 2003, she stayed on at UQ until 2006, when she joined Professor Philip Dawson’s laboratory at The Scripps Research Institute, La Jolla, USA to work on developing palmitoylated peptides as chaperones for infantile Batten disease. In 2007, she joined Professor Philip Hogg’s laboratory at the University of New South Wales in Sydney where she worked on the multimerisation of large proteins via disulfide bonds. In 2011 she was recruited back to UQ to join Professor David Craik’s group working on the structural biology and synthesis of disulfide-rich plant- and venom-derived peptides. Dr Schroeder was awarded an Australian Research Council Future Fellowship in 2016 focussed on using bioactive peptides in drug design and to understand the mode of action of toxins binding to sodium channels and their surrounding membranes with the ultimate goal to develop novel non-addictive pain therapeutics.

The use of peptide-membrane interactions in the design of selective and potent sodium channel inhibitors (#199)

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