title: A Modular Method for the High-Yield Synthesis of Site-Specific Protein-Polymer Therapeutics.
abstract: A versatile method is described to engineer precisely defined protein/peptide-polymer therapeutics by a modular approach that consists of three steps: 1) fusion of a protein/peptide of interest with an elastin-like polypeptide that enables facile purification and high yields; 2) installation of a clickable group at the C terminus of the recombinant protein/peptide with almost complete conversion by enzyme-mediated ligation; and 3) attachment of a polymer by a click reaction with near-quantitative conversion. We demonstrate that this modular approach is applicable to various protein/peptide drugs and used it to conjugate them to structurally diverse water-soluble polymers that prolong the plasma circulation duration of these proteins. The protein/peptide-polymer conjugates exhibited significantly improved pharmacokinetics and therapeutic effects over the native protein/peptide upon administration to mice. The studies reported here provide a facile method for the synthesis of protein/peptide-polymer conjugates for therapeutic use and other applications.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Pang
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
authors.forename: Jinyao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
authors.forename: Xinghai
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA. chilkoti@duke.edu.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chilkoti
mesh_terms: D049452:Green Fluorescent Proteins / Q000737:chemistry*; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D010455:Peptides; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols
keywords: click chemistry; diabetes; pharmacokinetics; prodrugs; protein modification