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Engineered Cyclotide Blocks Neuronal Excitotoxicity.

Daryl Ariawan1, Julia van der Hoven1, Nicolle Morey1

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Summary
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Modified cyclotides with polyarginines effectively deliver therapeutic peptides into neuronal cells, preventing excitotoxicity and reducing seizure severity in mice. This approach enhances neuroprotection for neurological disorders.

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Area of Science:

  • Biochemistry
  • Neuroscience
  • Peptide Therapeutics

Background:

  • Cyclotides are stable cyclic peptides with potential therapeutic applications.
  • Excitotoxicity, mediated by postsynaptic density protein 95 and NMDA receptors (NMDARs), contributes to neuronal cell death in neurological disorders.
  • Effective intracellular delivery of therapeutic peptides to neurons remains a challenge.

Purpose of the Study:

  • To enhance intracellular delivery of therapeutic peptides using a modified cyclotide backbone.
  • To develop a novel neuroprotective agent targeting the PSD-95/NMDAR interaction.
  • To evaluate the efficacy of the modified cyclotide in preventing excitotoxicity and seizures.

Main Methods:

  • The MCoTI-II cyclotide was modified with a polyarginine backbone for improved cellular uptake.
  • A PSD-95/NMDAR inhibitor sequence (NR2B9c) was grafted into loop 6 of the cyclotide.
  • In vitro studies involved primary neurons treated with N-methyl-D-aspartate (NMDA) and the c5R-NR2B9c cyclotide.
  • In vivo studies utilized a chemically induced seizure model in mice.

Main Results:

  • Polyarginine modification significantly enhanced the uptake of cyclotides into neuronal cells.
  • The NR2B9c-modified cyclotide (c5R-NR2B9c) protected primary neurons from NMDA-induced excitotoxicity.
  • Administration of c5R-NR2B9c in mice increased survival rates and reduced seizure severity.
  • The study demonstrates successful neuroprotection against excitotoxicity via enhanced peptide delivery.

Conclusions:

  • Polyarginine-modified cyclotides serve as effective carriers for intracellular delivery of therapeutic peptides to neurons.
  • This strategy offers a promising approach for developing treatments for neurological disorders characterized by excitotoxicity.
  • The c5R-NR2B9c cyclotide demonstrates potential as a therapeutic agent for neuroprotection.