6KZU

Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled alpha-helical peptide modality

Summary for 6KZU

• Entry DOI: 10.2210/pdb6kzu/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, 2JN-DAL-E03-DTY-2JN-DSG-TDF-DGL-MK8-DLE-DLE-2JN (3 entities in total)
• Functional Keywords: e3 ligase, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 15399.60

Authors

Jiang, S.,Brown, C.J. (deposition date: 2019-09-25, release date: 2019-10-16, Last modification date: 2023-11-22)

Primary citation

Kannan, S.,Aronica, P.G.A.,Ng, S.,Gek Lian, D.T.,Frosi, Y.,Chee, S.,Shimin, J.,Yuen, T.Y.,Sadruddin, A.,Kaan, H.Y.K.,Chandramohan, A.,Wong, J.H.,Tan, Y.S.,Chang, Z.W.,Ferrer-Gago, F.J.,Arumugam, P.,Han, Y.,Chen, S.,Renia, L.,Brown, C.J.,Johannes, C.W.,Henry, B.,Lane, D.P.,Sawyer, T.K.,Verma, C.S.,Partridge, A.W.
Macrocyclization of an all-d linear alpha-helical peptide imparts cellular permeability.
Chem Sci, 11:5577-5591, 2020

PubMed 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 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.

PubMed: 32874502
DOI: 10.1039/c9sc06383h

Experimental method

X-RAY DIFFRACTION (1.79 Å)