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A Modular Method for the High‐Yield Synthesis of Site‐Specific Protein–Polymer Therapeutics
Author(s) -
Pang Yan,
Liu Jinyao,
Qi Yizhi,
Li Xinghai,
Chilkoti Ashutosh
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201604661
Subject(s) - peptide , conjugate , combinatorial chemistry , polymer , chemistry , fusion protein , chemical ligation , peptide synthesis , recombinant dna , click chemistry , biophysics , biochemistry , organic chemistry , biology , mathematical analysis , mathematics , gene
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.