Peptide-based molecules hold great potential as targeted inhibitors of intracellular protein–protein interactions (PPIs). Indeed, the vast diversity of chemical space conferred through their primary, secondary and tertiary structures allows these molecules to be applied to targets that are typically deemed intractable via small molecules.
However, the development of peptide therapeutics has been hindered by their limited conformational stability, proteolytic sensitivity and cell permeability. Several contemporary peptide design strategies are aimed at addressing these issues.
Strategic macrocyclization through optimally placed chemical braces such as olefinic hydrocarbon crosslinks, commonly referred to as staples, may improve peptide properties by (i) restricting conformational freedom to improve target affinities, (ii) improving proteolytic resistance, and (iii) enhancing cell permeability.
As a second strategy, 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, these researchers have combined the strategies to identify the first examples of all-D α-helical stapled and stitched peptides. As a template, they 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, they 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.
Macrocyclization of an all-D linear α-helical peptide imparts cellular permeability
Srinivasaraghavan Kannan, Pietro G. A. Aronica, Simon Ng, Dawn Thean Gek Lian, Yuri Frosi, Sharon Chee, Jiang Shimin, Tsz Ying Yuen, Ahmad Sadruddin, Hung Yi Kristal Kaan, Arun Chandramohan, Jin Huei Wong, Yaw Sing Tan, Zi Wei Chang, Fernando J. Ferrer-Gago, Prakash Arumugam, Yi Han, Shiying Chen, Laurent Rénia, Christopher J. Brown, Charles W. Johannes, Brian Henry, David P. Lane, Tomi K. Sawyer, Chandra S. Verma and Anthony W. Partridge
Chem. Sci., 2020, 11, 5577-5591