Half-Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation

Peptides and proteins constitute a vast pool of excellent drug candidates. Evolution has equipped these molecules with superior drug‐like properties such as high specificity and potency. However, native peptides and proteins suffer from an inadequate pharmacokinetic profile, and their outstanding ph...

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Bibliographic Details
Published in:ChemMedChem 2016-11, Vol.11 (22), p.2474-2495
Main Authors: van Witteloostuijn, Søren B., Pedersen, Søren L., Jensen, Knud J.
Format: Article
Language:English
Subjects:
Alternatives
Biological Products - chemistry
Biological Products - metabolism
biopharmaceuticals
drug delivery
Half-Life
half-life extension
Humans
Molecular Structure
peptides
Peptides - chemistry
Peptides - metabolism
Polyethylene Glycols - chemistry
proteins
Proteins - chemistry
Proteins - metabolism
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Summary:Peptides and proteins constitute a vast pool of excellent drug candidates. Evolution has equipped these molecules with superior drug‐like properties such as high specificity and potency. However, native peptides and proteins suffer from an inadequate pharmacokinetic profile, and their outstanding pharmacological potential can only be realized if this issue is addressed during drug development. To overcome this challenge, a variety of half‐life extension techniques relying on covalent chemical modification have been developed. These methods include PEGylation, fusion to unstructured polypeptide‐based PEG mimetics, conjugation of large polysaccharides, native‐like glycosylation, lipidation, fusion to albumin or the Fc domain of IgG, and derivatization with bio‐orthogonal moieties that direct self‐assembly. This review provides an overview of available conjugation chemistries, biophysical properties, and safety data associated with these concepts. Moreover, the effects of these modifications on peptide and protein pharmacokinetics are demonstrated through key examples. An alternative direction: Despite the commercial success of PEGylation, new strategies for extending the half‐lives of biopharmaceuticals are warranted. In this review, we describe the available alternatives with an emphasis on conjugation chemistry, biophysical properties, and biological compatibility.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201600374