CHAPTER 8: Double-click Stapled Peptides for Inhibiting Protein–Protein Interactions
Published:14 Dec 2017
K. Sharma, D. L. Kunciw, W. Xu, M. M. Wiedmann, Y. Wu, H. F. Sore, ... D. R. Spring, in Cyclic Peptides: From Bioorganic Synthesis to Applications, ed. J. Koehnke, J. Naismith, and W. A. van der Donk, The Royal Society of Chemistry, 2017, pp. 164-187.
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Protein–protein interactions (PPIs) have traditionally been referred to as “undruggable” mainly due to the large contact surfaces involved and the lack of well-defined binding sites. Research in this area has led to the development of a number of effective strategies for inhibiting PPIs. This chapter describes one of these methodologies developed in the Spring group: two-component double-click peptide stapling. This involves constraining short linear peptides by covalently linking two of their non-proteogenic amino acid side chains with a dialkyne linker utilizing Cu-catalyzed click chemistry. The advantage of this technique is that the properties of the stapled peptide can be modified via the linker group. This technique was successfully applied to target the oncogenic p53–MDM2 interaction. An optimization of the peptide sequence in addition to the use of different functionalized linkers resulted in biologically active stapled peptides. This Cu-catalyzed stapling technique was extended to develop a metal-free stapling methodology utilizing strain-promoted click chemistry and hence eliminating the use of cytotoxic copper. Finally, the Cu-catalyzed double-click stapling technique was used to synthesize non-α-helical constrained peptides to target the substrate-recognition domain of tankyrase to antagonize Wnt signaling, and the transcription factor HNF1β/Importin α PPI.