A modular method for high yield synthesis of site-specific protein–polymer therapeutics

摘要

A new and versatile method is described to engineer precisely defined protein/peptide–polymer therapeutics by a modular approach that consists of three steps: (1) fuse a protein/peptide of interest with an elastin–like–polypeptide that enables facile purification and high yield; followed by (2) installation of a clickable group at the C–terminus of the recombinant protein/peptide with close to complete conversion by enzyme–mediated ligation; and subsequently (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 structurally diverse water-soluble polymers that prolong the plasma circulation duration of proteins. These protein/peptide–polymer conjugates exhibit significantly improved pharmacokinetics and improved therapeutic effects over the native protein/peptide after administration to mice. The studies reported here provide a facile methodology for synthesis of protein/peptide-polymer conjugates for therapeutic use and other applications.