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      A two-component 'double-click' approach to peptide stapling.

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          Abstract

          Peptide cyclization is a useful strategy for the stabilization of short flexible peptides into well-defined bioactive conformations, thereby enhancing their ability to interact with proteins and other important biomolecules. We present an optimized procedure for the stabilization of linear diazido peptides in an α-helical conformation upon reaction with dialkynyl linkers under Cu(I) catalysis. As this procedure generates side chain-cyclized peptides bearing a bis-triazole linkage, it is referred to as 'double-click' stapling. Double-click stapling can enhance the binding affinity, proteolytic stability and cellular activity of a peptide inhibitor. A distinguishing feature of double-click stapling is the efficiency with which peptides bearing different staple linkages can be synthesized, thus allowing for modular control over peptide bioactivity. This protocol describes the double-click reaction between a 1,3-dialkynylbenzene linker and peptides that contain azidoornithine. Subsequent peptide purification and confirmation steps are also described. The entire double-click stapling protocol can be completed in ∼48 h, including two overnight lyophilization steps.

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          Author and article information

          Journal
          Nat Protoc
          Nature protocols
          1750-2799
          1750-2799
          Apr 2015
          : 10
          : 4
          Affiliations
          [1 ] University Chemical Laboratory, University of Cambridge, Cambridge, UK.
          Article
          nprot.2015.033
          10.1038/nprot.2015.033
          25763835

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