Chapter 9: Stapled Peptide Inhibitors of Protein–Protein Interactions
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Published:25 Nov 2020
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Special Collection: 2020 ebook collectionSeries: Chemical Biology
M. Wendt, N. M. McLoughlin, and T. N. Grossmann, in Inhibitors of Protein–Protein Interactions, ed. A. Tavassoli, The Royal Society of Chemistry, 2020, ch. 9, pp. 280-304.
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Conformationally constrained α-helical peptides have become important tool molecules in Chemical Biology research. In particular, macrocyclic α-helical peptides that have been constrained via inter-side chain cross-links, so-called stapled peptides, found widespread applications and are considered promising scaffolds for therapeutic applications. Stapled peptides are usually obtained by standard solid-phase peptide synthesis and the introduction of at least two amino acids that allow subsequent macrocyclization. Macrocycles of diverse sizes, functionalities and, architectures can be generated and result in peptides with improved target affinity, proteolytic stability and in some cases, increased cell permeability. In this chapter, the general principles of stapled peptide design are discussed along with notable examples of both one- and two-component peptide stapling reactions. As an example, stapled peptides targeting the protein–protein interaction between the tumor suppressor p53 and MDM2/MDMX are summarized, highlighting the diversity and potential of available stapling approaches.