Discovery of a dual pathway aggregation mechanism for a therapeutic constrained peptide
| Autor: | Chun-Wan Yen, Lu Dai, Steven Chin, Brian Roper, Elizabeth S. Hecht, Chloe Hu, Cadapakam Venkatramani, Nisana Andersen, Robert Kuhn, Dennis Leung, Fiona Lin, Jason Gruenhagen, Christopher M. Crittenden, Alberto Estevez, Mohammad Al-Sayah, Amin Famili, Lance Cadang, Tao Chen, Shijia Tang, Cinzia Stella, Karthik Nagapudi, Peter Yehl, Richard Vandlen, Peter Liu, Alexis Rohou, Debby P. Chang, Rami N. Hannoush |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Amyloid Chemistry Drug discovery Mechanism (biology) Pharmaceutical Science Peptide 02 engineering and technology 021001 nanoscience & nanotechnology 030226 pharmacology & pharmacy Peptide Fragments Hydrophobic effect 03 medical and health sciences 0302 clinical medicine Covalent bond Biophysics Physical stability Chemical stability Disulfides Peptides 0210 nano-technology Hydrophobic and Hydrophilic Interactions Dual pathway |
| Zdroj: | Journal of Pharmaceutical Sciences. |
| ISSN: | 0022-3549 |
| Popis: | Constrained peptides (CPs) have emerged as attractive candidates for drug discovery and development. To fully unlock the therapeutic potential of CPs, it is crucial to understand their physical stability and minimize the formation of aggregates that could induce immune responses. Although amyloid like aggregates have been researched extensively, few studies have focused on aggregates from other peptide scaffolds (e.g., CPs). In this work, a streamlined approach to effectively profile the nature and formation pathway of CP aggregates was demonstrated. Aggregates of various sizes were detected and shown to be amorphous. Though no major changes were found in peptide structure upon aggregation, these aggregates appeared to have mixed natures, consisting of primarily non-covalent aggregates with a low level of covalent species. This co-existence phenomenon was also supported by two kinetic pathways observed in time- and temperature-dependent aggregation studies. Furthermore, a stability study with 8 additional peptide variants exhibited good correlation between aggregation propensity and peptide hydrophobicity. Therefore, a dual aggregation pathway was proposed, with the non-covalent aggregates driven by hydrophobic interactions, whereas the covalent ones formed through disulfide scrambling. Overall, the workflow presented here provides a powerful strategy for comprehensive characterization of peptide aggregates and understanding their mechanisms of formation. |
| Databáze: | OpenAIRE |
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