Abstract: Huntington’s Disease (HD) is a fatal inherited neurodegenerative disorder that affects 5 persons per 100,000. A neuroprotective mutant Huntingtin (mtHtt) mimic peptide has been shown in mice models to block binding of mtHtt and valosin containing protein, preventing mitochondrial autophagy in neurons. Peptides have been explored as easily synthesized biocompatible therapeutic agents with more specific targeting than small molecules. However, peptides often fail in translation as they have poor pharmacokinetics and stability, and are vulnerable to proteolysis and clearance due to their small size. A proteomimetic platform for delivering peptides has been developed, termed Protein-like Polymers (PLPs). PLPs are globular, peptide-based structures, assembled around a hydrophobic synthetic core displaying active amino acids for recognition and function. These high-density bottlebrush polymers synthesized from peptide-monomers via ring-opening metathesis polymerization (ROMP) have been shown to render the peptides of interest resistant to proteolysis and degradation due to the packing of the peptides on the polymer backbone. Thus, the PLP is an optimal vehicle for treating HD with peptides, with great implications presented for treating other CNS diseases. Critically, in HD disease cell in vitro assays, the Anti-HD PLP proved to successfully inhibit one of the pathways thought to trigger HD. Anti-HD PLPs also rescued HD cells from death, performing competitively with the free Anti-HD peptide, HV-3, but significantly outlasted peptide in enzyme degradation and stability studies. When compared head-to-head, the Anti-HD PLP’s exceptional stability in vivo outlasted the control Anti-HD peptide that was only detectable for minutes, boasting a half life of almost a week. PLPs showed the same trend in vivo efficacy in HD transgenic mice of outperforming the peptide in behavioral and neuropathological analyses. These data suggest the PLP platform, when employed in Anti-HD mouse models, enhances peptide drug efficacy, providing a robust platform for peptide therapeutic delivery.

Mutant huntingtin mimetic anti-Huntington’s protein-like polymer blocks valosin containing protein binding, rescues HD neurons, and slows onset of neuropathology In vivo

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.