Peptides have been widely explored as therapeutic agents, owing to their potential for tailored specificity and low immunogenicity. Despite their attractive pharmacological profile and intrinsic properties, three issues limit the clinical utility of peptide therapeutics: susceptibility to proteolytic enzymes, an inability to penetrate cells, and rapid, size-dependent excretion by the kidneys. However, few of these strategies (peptide stapling, oligomerization, etc.), can be readily generalized and none have been demonstrated as a promising solution to all three problems. Peptides can be polymerized into macromolecular chains of high density known as brush polymers. The resulting peptide brush polymers form a condensed, globular structure reminiscent of natural globular proteins, with a polymer backbone wrapped in peptide side chains, giving rise to a protein-like display of the amino acid sequence, termed a protein-like polymer (PLP). Peptides arranged in this manner can be protected from degradation by digestive enzymes while maintaining their inherent bioactivity. In this presentation, we will describe a peptide-like polymer for treating Huntington's disease (HD). HD is a fatal autosomal dominant neurodegenerative disorder. Mitochondria are recognized as one of the key targets of mutant huntingtin protein (mtHtt), the disease causative agent, and mitochondrial dysfunction plays a causal role in HD pathogenesis. We recently discovered a PLP that is capable of inhibiting this process of mitochondrial destruction. These engineered peptides were evaluated for efficacy in patient-specific induced pluripotent stem cells (iPSC)-derived neurons harboring expansions in the HTT gene in cell culture. PLP can rescue mouse striatal cells inflicted with mutant Huntington’s protein (HdhQ111) from cell death, showing the prevention of VCP protein binding to mtHtt protein. Furthermore, we tested the degradation kinetics with several enzymes that can cleave the amino acid sequence of the peptide. The anti-HD PLPs displayed very high resistance to multiple proteases compared with the peptide alone. We will describe the synthesis, general approach and implementation of these materials as a generalizable platform technology for peptide delivery to cells and tissues.

Preventing Huntington’s disease using protein-like polymers

2019 Fall National Meeting

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