Prolonging the Action of Protein and Peptide Drugs by a Novel Approach of Reversible Polyethylene Glycol Modification

Polyethylene glycol (PEG)-conjugated therapeutic peptides/proteins have been shown to exhibit clinical properties superior to those of their corresponding unmodified parent molecules. However, the desirable pharmacological features gained by protein PEGylation become irrelevant if conjugates are ina...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-09, Vol.279 (37), p.38118-38124
Main Authors: Tsubery, Haim, Mironchik, Marina, Fridkin, Mati, Shechter, Yoram
Format: Article
Language:English
Subjects:
Anhydrides - pharmacology
Animals
Blood Glucose - metabolism
Chromatography, High Pressure Liquid
Chromatography, Thin Layer
Exenatide
Fluorenes - chemical synthesis
Fluorenes - pharmacology
Glucose - metabolism
Human Growth Hormone - chemistry
Humans
Hydrogen-Ion Concentration
Hydrolysis
Maleimides - chemical synthesis
Maleimides - pharmacology
Mice
Models, Chemical
Peptides - chemistry
Peptides - pharmacology
Polyethylene Glycols - chemistry
Propionates - pharmacology
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Spectrophotometry
Succinimides - pharmacology
Temperature
Time Factors
Ultraviolet Rays
Venoms - chemistry
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Summary:Polyethylene glycol (PEG)-conjugated therapeutic peptides/proteins have been shown to exhibit clinical properties superior to those of their corresponding unmodified parent molecules. However, the desirable pharmacological features gained by protein PEGylation become irrelevant if conjugates are inactivated or cannot reach their target tissues. Here we describe the design and synthesis of MAL-FMS-OSU. This bifunctional agent enables PEG chains to be linked to peptides and proteins through a slowly hydrolysable chemical bond. PEG-FMS-peptide/protein conjugates thus formed undergo spontaneous hydrolysis at a slow rate upon incubation at pH 8.5, 37 °C with a t½ value of 8–14 ± 2 h, generating the unmodified parent molecule. The validity of this approach was studied with exendin-4 and human growth hormone. A single subcutaneous administration of PEG40,000-FMS-exendin-4 facilitated a prolonged and stable reduction in glucose levels in mice (t½ = 30 ± 2 h) and exceeded the effect obtained by the same dose of the native hormone by 7–8 times.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M405155200