New Design of Helix Bundle Peptide−Polymer Conjugates

Shu, Jessica Y.; Tan, Cen; DeGrado, William F.; Xu, Ting

doi:10.1021/bm800113g

Cited by 85 publications

(150 citation statements)

References 46 publications

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“…47,48 Two C16 alkyl chains were attached to the peptide N-terminus with a (6)-amino-hexanoic acid linker inserted between the peptide and the double alkyl tail. The resulting amphiphiles are called “1coi-dC16-PEG2K”.…”

Section: Resultsmentioning

confidence: 99%

3-Helix Micelles Stabilized by Polymer Springs

et al. 2012

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Despite increasing demands to employ amphiphilic micelles as nanocarriers and nanoreactors, it remains a significant challenge to simultaneously reduce the particle size and enhance the particle stability. Complementary to covalent chemical bonding and attractive intermolecular interactions, entropic repulsion can be incorporated by rational design in the headgroup of an amphiphile to generate small micelles with enhanced stability. A new family of amphiphilic peptide-polymer conjugates is presented where the hydrophilic headgroup is composed of a 3-helix coiled-coil with poly(ethylene glycol) attached to the exterior of the helix bundle. When micelles form, the PEG chains are confined in close proximity and are compressed to act as a spring to general lateral pressure. The formation of 3-helix bundles determines the location and the directionalities of the force vector of each PEG elastic spring so as to slow down amphiphile desorption. Since each component of the amphiphile can be readily tailored, these micelles provide numerous opportunities to meet current demands for organic nanocarriers with tunable stability in life science and energy science. Furthermore, present studies open new avenues to use energy arising from entropic polymer chain deformation to self-assemble energetically stable single nanoscopic objects, much like repulsion that stabilizes bulk assemblies of colloidal particles.

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Section: Resultsmentioning

confidence: 99%

3-Helix Micelles Stabilized by Polymer Springs

et al. 2012

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“…Depending on the number, molecular weight, and location of the attached PEG chains, these protective effects can accrue without loss of protein biological activity. PEGylation may also confer additional thermodynamic stability to proteins, making some conjugates more resistant to unfolding than their unmodified counterparts (33). One particularly enticing application of PEGylated proteins is in anticancer therapies.…”

Section: Improved Efficacy Of Peg-modified Protein Therapeuticsmentioning

confidence: 99%

Poly(ethylene glycol)-Modified Proteins: Implications for Poly(lactide-co-glycolide)-Based Microsphere Delivery

Pai

Tilton

Przybycien

2009

AAPS J

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Abstract. The reduced injection frequency and more nearly constant serum concentrations afforded by sustained release devices have been exploited for the chronic delivery of several therapeutic peptides via poly(lactide-co-glycolide) (PLG) microspheres. The clinical success of these formulations has motivated the exploration of similar depot systems for chronic protein delivery; however, this application has not been fully realized in practice. Problems with the delivery of unmodified proteins in PLG depot systems include high initial "burst" release and irreversible adsorption of protein to the biodegradable polymer. Further, protein activity may be lost due to the damaging effects of protein-interface and protein-surface interactions that occur during both microsphere formation and release. Several techniques are discussed in this review that may improve the performance of PLG depot delivery systems for proteins. One promising approach is the covalent attachment of poly(ethylene glycol) (PEG) to the protein prior to encapsulation in the PLG microspheres. The combination of the extended circulation time of PEGylated proteins and the shielding and potential stabilizing effects of the attached PEG may lead to improved release kinetics from PLG microsphere system and more complete release of the active conjugate.

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“…To increase their solubility and structural stability, coiled coils have been conjugated with PEGs. Experimentally, the Klok group [62][63][64][65][66], the Kros group [67][68][69][70][71], and the Xu group [72][73][74][75][76] synthesized PEGylated coiled coils, characterized their conformation and structure, and investigated the effect of PEGylation on the self-assembled structures and the interactions with other molecules. Computationally, the sequenced-based programs were developed to predict the existence and structure of coiled coils [77][78][79][80][81][82][83], and MD simulations were performed to study the stability of coiled coils [84][85][86][87][88][89][90][91][92][93].…”

Section: Coiled-coil Peptidesmentioning

confidence: 99%

Molecular Modeling of PEGylated Peptides, Dendrimers, and Single-Walled Carbon Nanotubes for Biomedical Applications

Lee

2014

Polymers

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Polyethylene glycol (PEG) has been conjugated to many drugs or drug carriers to increase their solubility and circulating lifetime, and reduce toxicity. This has motivated many experimental studies to understand the effect of PEGylation on delivery efficiency. To complement the experimental findings and uncover the mechanism that cannot be captured by experiments, all-atom and coarse-grained molecular dynamics (MD) simulations have been performed. This has become possible, due to recent advances in simulation methodologies and computational power. Simulations of PEGylated peptides show that PEG chains wrap antimicrobial peptides and weaken their binding interactions with lipid bilayers. PEGylation also influences the helical stability and tertiary structure of coiled-coil peptides. PEGylated dendrimers and single-walled carbon nanotubes (SWNTs) were simulated, showing that the PEG size and grafting density significantly modulate the conformation and structure of the PEGylated complex, the interparticle aggregation, and the interaction with lipid bilayers. In particular, simulations predicted the structural transition between the dense core and dense shell of PEGylated dendrimers, the phase behavior of self-assembled complexes of lipids, PEGylated lipids, and SWNTs, which all favorably compared with experiments. Overall, these new findings indicate that simulations can now predict the experimentally observed structure and dynamics, as well as provide atomic-scale insights into the interactions of PEGylated complexes with other molecules.

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New Design of Helix Bundle Peptide−Polymer Conjugates

Cited by 85 publications

References 46 publications

3-Helix Micelles Stabilized by Polymer Springs

3-Helix Micelles Stabilized by Polymer Springs

Poly(ethylene glycol)-Modified Proteins: Implications for Poly(lactide-co-glycolide)-Based Microsphere Delivery

Molecular Modeling of PEGylated Peptides, Dendrimers, and Single-Walled Carbon Nanotubes for Biomedical Applications

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