
Journal of Pharmaceutical Sciences
Fecha de publicación: 27 de febrero de2021
DOI: https://doi.org/10.1016/j.xphs.2020.12.041
Autores: Shijia Tang , Elizabeth S. Hecht, Chun-Wan Yen, Nisana Andersen, Steven Chin, Lance Cadang, Brian Roper, Alberto Estevez, Alexis Rohou, Debby Chang, Lu Dai, Peter Liu, Mohammad Al-Sayah, Karthik Nagapudi, Fiona Lin, Amin Famili, Chloe Hu, Robert Kuhn, Cinzia Stella, Christopher M. Crittenden, Jason A. Gruenhagen, Cadapakam Venkatramani, Rami N. Hannoush, Dennis Leung, Richard Vandlen, Peter Yehl
Background: 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.
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