The Benefits and Challenges of PEGylating Small Molecules - Pharmaceutical Technology

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The Benefits and Challenges of PEGylating Small Molecules
Polyethylene glycol (PEG) conjugation is a highly effective technical and commercial strategy to develop macromolecules. The authors explain the benefits and process of PEGylation and how it may be applied to small molecules.

Pharmaceutical Technology

Commercial considerations

Extensive expertise with PEGylated macromolecules has led to the conclusion that no inherent technical or commercial constraints limit the manufacture and scale-up of small-molecule PEGs. The chemistries of these molecules are different (i.e., organic as opposed to aqueous), however, and PEGs must sometimes be built into a small molecule during synthesis. This procedure requires specific expertise. Cost is not expected to significantly affect the commercial feasibility of PEGylated small molecules because costs are well within commercial parameters. Shelf life and stability could actually improve over those of the parent compounds because PEG can be a stabilizing molecule. From a regulatory point of view, the US Food and Drug Administration considers PEG small molecules as new chemical entities (NCEs) subject to the same standards as nonPEGylated NCEs. The technology and molecules can be protected by patents. For example, Nektar has 55 issued patents and 490 applications worldwide that cover polymer structures, polymer linkers, composition of matter, manufacturing, and mechanism and delivery modalities. Thus, patent protection of non-PEGylated drugs is not expected to affect PEGylated drugs' commercial prospects.


PEGylating small molecules is a feasible strategy for enhancing and optimizing current compounds. The technology can be effectively transferred from macromolecules to small molecules to provide a similar range of clinically important benefits such as greater efficacy, reduced side effects, a reduced dosing schedule, and increased patient compliance. The universe of compounds that could be PEGylated is large, but extensive knowledge of structure-activity relationships and PEGylation properties is crucial to tapping this resource. Given the slow rate of new-chemical-entity discovery that currently afflicts the pharmaceutical industry, PEGylating small molecules appears to offer a technically feasible and cost-effective route to the creation of improved drugs.

Timothy Riley, PhD,* is vice-president of PEGylation research, and Jennifer Riggs-Sauthier is director of science and technology at Nektar Therapeutics, 490 Discovery Dr., Huntsville, AL 35806, tel. 800.457.1806, fax 256.533.4805,

*To whom all correspondence should be addressed.

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1. A. Abuchowski et al., "Effect of Covalent Attachment of Polyethylene Glycol on Immunogenicity and Circulating Life of Bovine Liver Catalase," J. Biol. Chem. 252 (11), 3582–3586 (1977).


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