Site-specific PEGylation of Proteins: Recent Developments

Nischan, Nicole; Hackenberger, Christian P. R.

doi:10.1021/jo502136n

Cited by 101 publications

(85 citation statements)

References 67 publications

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“…However, Asn-PEG is not genetically encodable: Asn-PEGylated peptides and proteins can be prepared via solid-phase peptide synthesis [58] and/or native chemical ligation [59], but not via biological expression. It will be interesting to see whether the correlation between PEG-based stabilization and side-chain orientation relative to OH groups holds for PEGs incorporated site-specifically [60] via chemoselective reactions [61] with genetically encodable amino acids whose structures differ substantially from that of Asn.…”

Section: How Peg Enhances Protein Conformational Stabilitymentioning

confidence: 99%

How PEGylation influences protein conformational stability

Lawrence

Price

2016

Current Opinion in Chemical Biology

103

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PEGylation is an important strategy for enhancing the pharmacokinetic properties of protein therapeutics. The development of chemoselective side-chain modification reactions has enabled researchers to PEGylate proteins with high selectivity at defined locations. However, aside from avoiding active sites and binding interfaces, there are few guidelines for the selection of optimal PEGylation sites. Because conformational stability is intimately related to the ability of a protein to avoid proteolysis, aggregation, and immune responses, it is possible that PEGylating a protein at sites where PEG enhances conformational stability will result in PEG-protein conjugates with enhanced pharmacokinetic properties. However, the impact of PEGylation on protein conformational stability is incompletely understood. This review describes recent advances toward understanding the impact of PEGylation on protein conformational stability, along with the development of structure-based guidelines for selecting stabilizing PEGylation sites.

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Section: How Peg Enhances Protein Conformational Stabilitymentioning

confidence: 99%

How PEGylation influences protein conformational stability

Lawrence

Price

2016

Current Opinion in Chemical Biology

103

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“…The biomacromolecular cargo in these systems are typically sequestered by entrapment, 12 covalent conjugation 9, 17, 18 or electrostatic complexation. 11, 19, 20 Covalent conjugation of PEG polymers, termed PEGylation, 21, 22 has been widely used to increase the circulation lifetimes of biologics and also protect them from degradative enzymes. 23, 24 However, this strategy is not amenable to all biologics because it requires reactive moieties on the biological molecule, the modification of which may unfavorably alter its activity.…”

Section: Introductionmentioning

confidence: 99%

“…11, 19, 20 Covalent conjugation of PEG polymers, termed PEGylation, 21, 22 has been widely used to increase the circulation lifetimes of biologics and also protect them from degradative enzymes. 23, 24 However, this strategy is not amenable to all biologics because it requires reactive moieties on the biological molecule, the modification of which may unfavorably alter its activity. Non-covalent methodologies, such as electrostatic interaction, have also been used to complex biologics, commonly with nucleic acids, where positively charged polymers or lipids are used to form poly- and lipo-plexes.…”

Section: Introductionmentioning

confidence: 99%

Utilizing Inverse Emulsion Polymerization To Generate Responsive Nanogels for Cytosolic Protein Delivery

et al. 2017

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Therapeutic biologics have various advantages over synthetic drugs in terms of selectivity, their catalytic nature and thus, therapeutic efficacy. These properties offer the potential for more effective treatments that may also overcome the undesirable side effects observed due to off-target toxicities of small-molecule drugs. Unfortunately, systemic administration of biologics is challenging due to cellular penetration, renal clearance and enzymatic degradation difficulties. A delivery vehicle that can overcome these challenges and deliver biologics to specific cellular populations has the potential for significant therapeutic impact. In this work, we describe a redox-responsive nanoparticle platform, which can encapsulate hydrophilic proteins and release them only in the presence of a reducing stimulus. We have formulated these nanoparticles using an inverse emulsion polymerization (IEP) methodology, yielding inverse nano-emulsions, or nanogels. We have demonstrated our ability to overcome the liabilities that contribute to activity loss by delivering a highly challenging cargo, functionally active caspase-3, a cysteine protease susceptible to oxidative and self-proteolytic insults, to the cytosol of HeLa cells by encapsulation inside a redox-responsive nanogel.

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“…For example, chemical ligation of synthetic peptides including levulinyllysine to EPO elicited hematopoietic activity superior to native protein [24]. More recent advances in chemo-selective targeting show that the incorporation of canonical and noncanonical amino acids can enhance selectivity while improving PEG architecture [25]. …”

Section: Marketed Protein Delivery Strategiesmentioning

confidence: 99%

Nanotechnology for protein delivery: Overview and perspectives

Shi

et al. 2016

Journal of Controlled Release

327

236

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Protein-based therapeutics have made a significant impact in the treatment of a variety of important human diseases. However, given their intrinsically vulnerable structure and susceptibility to enzymatic degradation, many therapeutic proteins such as enzymes, growth factors, hormones, and cytokines suffer from poor physicochemical/biological stability and immunogenicity that may limit their potential benefits, and in some cases limit their utility. Furthermore, when protein therapeutics are developed for intracellular targets, their internalization and biological activity may be limited by inefficient membrane permeability and/or endosomal escape. Development of effective protein delivery strategies is therefore essential to further enhance therapeutic outcomes to enable widespread medical applications. This review discusses the advantages and limitations of marketed and developmental-stage protein delivery strategies, and provides a focused overview of recent advances in nanotechnology platforms for the systemic delivery of therapeutic proteins. In addition, we also highlight nanoparticle-mediated non-invasive administration approaches (e.g., oral, nasal, pulmonary, and transdermal routes) for protein delivery.

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Site-specific PEGylation of Proteins: Recent Developments

Cited by 101 publications

References 67 publications

How PEGylation influences protein conformational stability

How PEGylation influences protein conformational stability

Utilizing Inverse Emulsion Polymerization To Generate Responsive Nanogels for Cytosolic Protein Delivery

Nanotechnology for protein delivery: Overview and perspectives

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