6T2E

Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions

Summary for 6T2E

• Entry DOI: 10.2210/pdb6t2e/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, Stapled peptide GAR300-Gm (3 entities in total)
• Functional Keywords: inhibitor, complex, mdm2, stapled peptides, ugi mcr-based macrocyclizations, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 11848.83

Authors

Groves, R.M.,Ali, M.A.,Atmaj, J.,van Oosterwijk, N.,Domling, A.,Rivera, G.D.,Ricardo, G.M. (deposition date: 2019-10-08, release date: 2020-01-29, Last modification date: 2024-01-24)

Primary citation

Ricardo, M.G.,Ali, A.M.,Plewka, J.,Surmiak, E.,Labuzek, B.,Neochoritis, C.G.,Atmaj, J.,Skalniak, L.,Zhang, R.,Holak, T.A.,Groves, M.,Rivera, D.G.,Domling, A.
Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions.
Angew.Chem.Int.Ed.Engl., 59:5235-5241, 2020

PubMed Abstract: Stapled peptides are chemical entities in-between biologics and small molecules, which have proven to be the solution to high affinity protein-protein interaction antagonism, while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction-based stapling is an effective strategy for the development of α-helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53-MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo- and endo-cyclic hydrophobic moieties at the side chain cross-linkers. The interaction of the Ugi-staple fragments with the target protein was demonstrated by crystallography.

PubMed: 31944488
DOI: 10.1002/anie.201916257

Experimental method

X-RAY DIFFRACTION (2.4 Å)