Issue 21, 2020

Macrocyclization of an all-d linear α-helical peptide imparts cellular permeability

Abstract

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, 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.

Graphical abstract: Macrocyclization of an all-d linear α-helical peptide imparts cellular permeability

Supplementary files

Article information

Article type
Edge Article
Submitted
17 Dec 2019
Accepted
08 May 2020
First published
11 May 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2020,11, 5577-5591

Macrocyclization of an all-D linear α-helical peptide imparts cellular permeability

S. Kannan, P. G. A. Aronica, S. Ng, D. T. Gek Lian, Y. Frosi, S. Chee, J. Shimin, T. Y. Yuen, A. Sadruddin, H. Y. K. Kaan, A. Chandramohan, J. H. Wong, Y. S. Tan, Z. W. Chang, F. J. Ferrer-Gago, P. Arumugam, Y. Han, S. Chen, L. Rénia, C. J. Brown, C. W. Johannes, B. Henry, D. P. Lane, T. K. Sawyer, C. S. Verma and A. W. Partridge, Chem. Sci., 2020, 11, 5577 DOI: 10.1039/C9SC06383H

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