Discovery of a dual pathway aggregation mechanism for a therapeutic constrained peptide

Chen, Tao; Tang, Shijia; Hecht, Elizabeth S.; Yen, Chun-Wan; Andersen, Nisana; Chin, S.; Cadang, Lance; Roper, Brian; Estevez, Alberto; Rohou, Alexis; Chang, Debby P.; Dai, Lu; Liu, Peter; Al‐Sayah, Mohammad H.; Nagapudi, Karthik; Lin, Fiona L.; Famili, Amin; Hu, Chloe; Kuhn, Robert W.; Stella, Cinzia; Crittenden, Christopher M.; Gruenhagen, Jason; Venkatramani, Cadapakam J.; Hannoush, Rami N.; Leung, Dennis; Vandlen, Richard; Yehl, Peter

doi:10.1016/j.xphs.2020.12.041

Cited by 4 publications

(3 citation statements)

References 48 publications

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“…It is composed of a 30-residue linear peptide having three internal disulfide bonds with an overall molecular weight of 3.4 kDa. This peptide is highly prone to aggregation via multiple pathways, forming both amorphous non-covalent aggregates as well as oligomers formed from covalent disulfide scrambling [ 42 ]. As a result, the ability to overcome these risks and develop a stable high-concentration formulation of GNE-A would be highly valuable.…”

Section: Resultsmentioning

confidence: 99%

“…However, both formulations exhibited a slight increase in observed particle size over time at the higher temperature accelerated condition of 37 • C. In order to quantitate the aggregation state and monomer content of GNE-A more closely, the samples were also analyzed via SEC. As can be seen in Figure 6, the GNE-A monomer concentration remains relatively stable under these conditions, although a slight reduction was seen for the samples stored at 37 covalent disulfide scrambling [42]. As a result, the ability to overcome these risks and develop a stable high-concentration formulation of GNE-A would be highly valuable.…”

Section: Gne-a Nanosuspensionsmentioning

confidence: 99%

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A New Approach for Preparing Stable High-Concentration Peptide Nanoparticle Formulations

Hu,

Zang,

Tam

et al. 2023

Pharmaceuticals

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The subcutaneous administration of therapeutic peptides would provide significant benefits to patients. However, subcutaneous injections are limited in dosing volume, potentially resulting in high peptide concentrations that can incur significant challenges with solubility limitations, high viscosity, and stability liabilities. Herein, we report on the discovery that low-shear resonant acoustic mixing can be used as a general method to prepare stable nanoparticles of a number of peptides of diverse molecular weights and structures in water without the need for extensive amounts of organic solvents or lipid excipients. This approach avoids the stability issues observed with typical high-shear, high-intensity milling methods. The resultant peptide nanosuspensions exhibit low viscosity even at high concentrations of >100 mg/mL while remaining chemically and physically stable. An example nanosuspension of cyclosporine nanoparticles was dosed in rats via a subcutaneous injection and exhibited sustained release behavior. This suggests that peptide nanosuspension formulations can be one approach to overcome the challenges with high-concentration peptide formulations.

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Section: Resultsmentioning

confidence: 99%

Section: Gne-a Nanosuspensionsmentioning

confidence: 99%

A New Approach for Preparing Stable High-Concentration Peptide Nanoparticle Formulations

Hu,

Zang,

Tam

et al. 2023

Pharmaceuticals

Self Cite

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“…For many peptide‐based drugs, constrained peptides are used that often contain disulphide bonds and can be prone to aggregation and scrambling. ME–MS using the ZipChip has been used to successfully identify covalently linked aggregates [93]. In addition to the commercially available ME–MS, there have been other peptide characterization methods made using new chip designs.…”

Section: Me–ms Applicationmentioning

confidence: 99%

Concepts and recent advances in microchip electrophoresis coupled to mass spectrometry: Technologies and applications

et al. 2022

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The online coupling of microchip electrophoresis (ME) as a fast, highly efficient, and low-cost miniaturized separation technique to mass spectrometry (MS) as an information-rich and sensitive characterization technique results in ME-MS an attractive tool for various applications. In this paper, we review the basic concepts and latest advances in technology for ME coupled to MS during the period of 2016-2021, covering microchip materials, structures, fabrication techniques, and interfacing to electrospray ionization (ESI)-MS and matrix-assisted laser desorption/ionization-MS. Two critical issues in coupling ME and ESI-MS include the electrical connection used to define the electrophoretic field strength along the separation channel and the generation of the electrospray for MS detection, as well as, a miniaturized ESI-tip. The recent commercialization of ME-MS in zone electrophoresis and isoelectric focusing modes has led to the widespread application of these techniques in academia and industry. Here we summarize recent applications of ME-MS for the separation and detection of antibodies, proteins, peptides, carbohydrates, metabolites, and so on. Throughout the paper these applications are discussed in the context of benefits and limitations of ME-MS in comparison to alternative techniques.

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Regulatory Issues for Peptide Drugs

Jois

2022

AAPS Advances in the Pharmaceutical Sciences Series

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Discovery of a dual pathway aggregation mechanism for a therapeutic constrained peptide

Cited by 4 publications

References 48 publications

A New Approach for Preparing Stable High-Concentration Peptide Nanoparticle Formulations

A New Approach for Preparing Stable High-Concentration Peptide Nanoparticle Formulations

Concepts and recent advances in microchip electrophoresis coupled to mass spectrometry: Technologies and applications

Regulatory Issues for Peptide Drugs

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