| Autor: |
Kannan, Srinivasaraghavan, Aronica, Pietro G. A., Ng, Simon, Thean, Dawn, Frosi, Yuri, Chee, Sharon, Shimin, Jiang, Yuen, Tsz Ying, Sadruddin, Ahmad, Kaan, Hung Yi Kristal, Chandramohan, Arun, Wong, Jin Huei, Tan, Yaw Sing, Ferrer, Fernando J., Arumugam, Prakash, Han, Yi, Chen, Shiying, Brown, Christopher J., Johannes, Charles W., Henry, Brian, Lane, David P., Sawyer, Tomi K., Verma, Chandra S., Partridge, Anthony W. |
| Rok vydání: |
2019 |
| Popis: |
Peptide-based inhibitors hold great potential for targeted modulation of intracellular protein-protein interactions (PPIs) by leveraging vast chemical space relative to primary structure via sequence diversity as well as conformationally through varying secondary and tertiary structures. However, the development of peptide therapeutics has been hindered because of their limited conformational stability, proteolytic sensitivity and cell permeability. Several contemporary peptide design strategies address these issues to varying degrees. Strategic macrocyclization through optimally placed chemical braces such as olefinic hydrocarbon crosslinks, commonly referred to as staples, may address these issues by i) restricting conformational freedom to improve target affinities, ii) improving proteolytic resistance, and iii) enhancing cell permeability. Conversely, molecules constructed entirely from D-amino acids are hyper-resistant to proteolytic cleavage, but generally lack conformational stability and membrane permeability. Since neither approach is a complete solution, we have combined these strategies to identify the first examples of all-D α-helical stapled and stitched peptides. As a template, we used a recently reported all D-linear peptide that is a potent inhibitor of the p53-Mdm2 interaction, but is devoid of cellular activity. To design both stapled and stitched all-D-peptide analogues, we used computational modelling to predict optimal staple placement. The resultant novel macrocyclic all D-peptide was determined to exhibit increased α-helicity, improved target binding, complete proteolytic stability and, most notably, cellular activity. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
