A Modular Method for the High-Yield Synthesis of Site-Specific Protein–Polymer Therapeutics
Dr. Yan Pang
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
These authors contributed equally to this work
Search for more papers by this authorDr. Jinyao Liu
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
These authors contributed equally to this work
Search for more papers by this authorYizhi Qi
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
These authors contributed equally to this work
Search for more papers by this authorDr. Xinghai Li
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
Search for more papers by this authorCorresponding Author
Prof. Ashutosh Chilkoti
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
Search for more papers by this authorDr. Yan Pang
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
These authors contributed equally to this work
Search for more papers by this authorDr. Jinyao Liu
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
These authors contributed equally to this work
Search for more papers by this authorYizhi Qi
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
These authors contributed equally to this work
Search for more papers by this authorDr. Xinghai Li
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
Search for more papers by this authorCorresponding Author
Prof. Ashutosh Chilkoti
Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
Search for more papers by this authorAbstract
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.
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