A Modular Method for the High-Yield Synthesis of Site-Specific Protein-Polymer Therapeutics

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 cl...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie 2016-08, Vol.128 (35), p.10452-10456
Main Authors: Pang, Yan, Liu, Jinyao, Qi, Yizhi, Li, Xinghai, Chilkoti, Ashutosh
Format: Article
Language:eng ; ger
Subjects:
Attachment
Chemical reactions
Chemical synthesis
Chemistry
Conjugates
Conversion
Diabetes
Drugs
Elastin
Fusion protein
Installation
Klick-Chemie
Mice
Modular engineering
Modularity
Peptides
Pharmacokinetics
Pharmacology
Pharmakokinetik
Polymers
Prodrugs
Protein biosynthesis
Protein purification
Proteinmodifikation
Proteins
Purification
Recombinant
Synthesis
Water circulation
Water soluble polymers
Yield
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Die positionsspezifische und stöchiometrische Synthese von Protein/Peptid‐Polymer‐Therapeutika in hohen Ausbeuten gelingt mit einer modularen Methode, die rekombinante Expression, enzymvermittelte Ligation und Klick‐Chemie verbindet. Dieser Ansatz ermöglicht die Konjugation strukturell vielfältiger Polymere an verschiedenste Protein‐ und Peptidwirkstoffe.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201604661