Active carbonates of polyalkylene oxides for modification of polypeptides
AssigneeEnzon, Inc.
InventorShmuel Zalipsky
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Abstract
Poly(ethylene glycol)-N-succinimide carbonate and its preparation are disclosed. Polyethylene glycol (PEG) is converted into its N-succinimide carbonate derivative. This form of the polymer reacts readily with amino groups of proteins in aqueous buffers. The modified proteins have PEG-chains grafted onto the polypeptide backbone by means of stable, hydrolysis-resistant urethane (carbamate) linkages.
Claims15
A modified polypeptide comprising a polypeptide and a polyalkylene oxide having a molecular weight of less than about 20,000 wherein said polyalkylene oxide is covalently bound to an amine group of the polypeptide by a urethane linkage formed by the process of
- a) treating said polyalkylene oxide with phosgene to form a polyalkylene oxide chloroformate in situ;
- b) reacting said polyalkylene oxide chloroformate with an N-hydroxy-N-dicarboximide followed by triethylamine to form a polyalkylene oxide having a terminal oxycarbonyl-oxy-N-dicarboximide group;
- and
- c) reacting said polyalkylene oxide having a terminal oxycarbonyl-oxy-N-dicarboximide group with said polypeptide whereby said polypeptide and said polyalkylene oxide are covalently coupled said urethane linkage.
A polyethylene glycol-based conjugate comprising a urethane linkage attaching a protein or a polypeptide to a polyethylene glycol having a molecular weight of less than about 20,000 prepared by the process of:
- a) treating said polyethylene glycol with phosgene to form a polyethylene glycol chloroformate in situ;
- b) reacting said polyethylene glycol chloroformate with N-hydroxysuccinimide followed by triethylamine to form a N-succinimide carbonate derivatives of polyethylene glycol;
- and
- c) reacting said N-succinimide carbonate derivatives of polyethylene glycol with said protein or said polypeptide whereby urethane linkages are formed attaching said N-succinimide carbonate derivatives of polyethylene glycol to amino groups on said protein or said polypeptide.
Dependencies are inferred from the claim text.