Abstract：
:PEGylation is a clinically proven strategy for increasing the therapeutic efficacy of protein-based medicines. Our approach to site-specific PEGylation exploits the thiol selective chemistry of the two cysteine sulfur atoms from an accessible disulfide. It involves two key steps: (1) disulfide reduction to release the two cystine thiols, and (2) bis-alkylation to give a three-carbon bridge to which PEG is covalently attached. During this process, irreversible denaturation of the protein does not occur. Mechanistically, the conjugation is conducted by a sequential, interactive bis-alkylation using alpha,beta-unsaturated-beta'-mono-sulfone functionalized PEG reagents. The combination of: - (a) maintaining the protein's tertiary structure after reduction of a disulfide, (b) bis-thiol selectivity of the PEG reagent, and (c) PEG associated steric shielding ensure that only one PEG molecule is conjugated at each disulfide. Our studies have shown that peptides, proteins, enzymes and antibody fragments can be site-specifically PEGylated using a native and accessible disulfide without destroying the molecules' tertiary structure or abolishing its biological activity. As the stoichiometric efficiency of our approach also enables recycling of any unreacted protein, it offers the potential to make PEGylated biopharmaceuticals as cost-effective medicines.
journal_name
Adv Drug Deliv Revjournal_title
Advanced drug delivery reviewsauthors
Brocchini S,Godwin A,Balan S,Choi JW,Zloh M,Shaunak Sdoi
10.1016/j.addr.2007.06.014subject
Has Abstractpub_date
2008-01-03 00:00:00pages
3-12issue
1eissn
0169-409Xissn
1872-8294pii
S0169-409X(07)00134-2journal_volume
60pub_type
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journal_title：Advanced drug delivery reviews
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journal_title：Advanced drug delivery reviews
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journal_title：Advanced drug delivery reviews
pub_type： 杂志文章,评审
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journal_title：Advanced drug delivery reviews
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journal_title：Advanced drug delivery reviews
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