Jia Lee
New York University
Inhibition of Protein Aggregation Using Peptoid Block Copolymers
The aggregation of protein therapeutics is a critical challenge in pharmaceutical development. While covalent attachment of polyethylene glycol minimizes aggregation in many approved therapeutics, it has been associated with immunogenicity and accelerated blood clearance, necessitating alternative stabilization strategies. To avoid covalent conjugation limitations, we propose the use of peptoids (N-substituted glycine oligomers) as non-covalent aggregation inhibitors. Previous work demonstrated the stabilizing potential of block copolymers consisting of sarcosine and tryptophan [1], but tryptophan remains susceptible to protease degradation. A fully abiotic peptoid polymer reduces hydrolysis and offers diverse side chains to optimize the structure beyond canonical amino acids. Using solid-phase peptoid synthesis, our evaluation has two phases. First, we determined the hydrophilic peptoid–N-(2-methoxyethyl) glycine–block length needed to replicate the solubility and stabilization of poly(sarcosine)-block-oligo(L-tryptophan) polymers. Currently, we are attempting to optimize the hydrophobic block by utilizing aromatic side chains. The aggregation will be monitored by absorbance spectroscopy; native structure retention will be evaluated by circular dichroism spectroscopy and lysozyme enzymatic activity assays. Discovery of suitable peptoid block copolymers may result in a cost-effective and modular route to new pharmaceutical excipients for stabilizing protein therapeutics.
The aggregation of protein therapeutics is a critical challenge in pharmaceutical development. While covalent attachment of polyethylene glycol minimizes aggregation in many approved therapeutics, it has been associated with immunogenicity and accelerated blood clearance, necessitating alternative stabilization strategies. To avoid covalent conjugation limitations, we propose the use of peptoids (N-substituted glycine oligomers) as non-covalent aggregation inhibitors. Previous work demonstrated the stabilizing potential of block copolymers consisting of sarcosine and tryptophan [1], but tryptophan remains susceptible to protease degradation. A fully abiotic peptoid polymer reduces hydrolysis and offers diverse side chains to optimize the structure beyond canonical amino acids. Using solid-phase peptoid synthesis, our evaluation has two phases. First, we determined the hydrophilic peptoid–N-(2-methoxyethyl) glycine–block length needed to replicate the solubility and stabilization of poly(sarcosine)-block-oligo(L-tryptophan) polymers. Currently, we are attempting to optimize the hydrophobic block by utilizing aromatic side chains. The aggregation will be monitored by absorbance spectroscopy; native structure retention will be evaluated by circular dichroism spectroscopy and lysozyme enzymatic activity assays. Discovery of suitable peptoid block copolymers may result in a cost-effective and modular route to new pharmaceutical excipients for stabilizing protein therapeutics.
