Authors:

Hannah Robertson

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About Paper:

Protein-protein interactions (PPls) play essential roles in cellular signaling and are implicated in neurodegenerative disorders such as Huntington's disease (HD). Although peptides have shown promise as PP! modulators due to their high affinity and specificity, their therapeutic potential has been limited by short half-life, rapid elimination, and poor cellular permeability. Proteomimetic polymers, or protein-like polymers (PLPs), have emerged as an alternative strategy to overcome these limitations by functioning as multivalent binders with improved stability and tunable chemistry. A major challenge in applying PLPs to neurodegenerative disease is achieving efficient and selective neuronal targeting. This project focused on the use of the Tet-1 peptide, a short sequence originally identified by phage display for its ability to bind neuronal receptors and undergo neuron-specific internalization. (Spinelli et al., 2025). We investigated the hypothesis that PLPs derived from the Tet-1 peptide sequence would retain neuronal targeting capabilities while enabling improved intracellular delivery relative to the free peptide. Tet-1 peptide sequence conjugated to a norbornene backbone was synthesized via solid phase peptide synthesis and was used as the foundational peptide for PLP synthesis. The monomer was purified by liquid chromatography and characterized with mass spectrometry. Polymers were generated through ring opening metathesis polymerization, fluorescently labeled for cell uptake, and purified using liquid chromatography. Structural and physicochemical characterization was performed using mass spectrometry (LC-TOF), SDS-PAGE, circular dichroism, and dynamic light scattering, while polymerization kinetics were monitored via nuclear magnetic resonance spectroscopy to confirm reproducibility and control. Neuronal uptake was assessed using fluorescence-based assays in neuronal cell models relevant to Huntington's disease. It was found that Tet-1 based PLPs were successfully synthesized, supporting their use as neuron-targeted delivery platforms. Tet1-derived PLPs provide a promising framework for the development of intracellular PP! modulators and expand the applicability of proteomimetic polymers for therapeutic strategies in Huntington's disease.

Source:

Northwestern University

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Co-authors:

Hannah Robertson