Stapled Peptide Design

Zhang, H., Curreli, F., Zhang, X., Bhattacharya, S., Waheed, A A., Cooper, A., Cowbum, D., Freed, E.O., and Debnath, A.K. (2011) Antiviral activity of a-helical stapled peptides designed from the FlIV-1 capsid dimerization domain. Retrovirology, 8, 28. 

Xu, B and Irving, S.L. (2011) Design and structure of stapled peptides binding to estrogen receptors. Journal of the American Chemical Society, 133, 9696-9699. 

Although target-based methods have their limitations, they still demonstrate great potential in rationally designing new molecular entities especially for new target classes, such as PPIs. A famous example is the stapled peptide technology, which mimics a-helical structures in the PPL Short peptides can be stabilized into a-helical structures with the use of various chemical methods. These structures are almost identical to the natural folding and thus interfere with the PPI [9]. 

Stapled peptides are designed to increase the a-helix content in solution and are expected to produce higher affinity ligands compared to the natural peptide modulators. The following examples demonstrate this correlation, although it should be noted that peptide stapling does not always lead to an increase in affinity. 

Figure 9.4 Design of a,a-alkylated hydrocarbon-stapled peptides for HIV and glu-cokinase therapeutic targets.

Figure 9.6 Design of click-stapled peptides using azide-allg ne cycloaddition and N-terminal macrocyclization using H-bond surrogate methodologies for various intracellular therapeutic targets.

Design of triazole-stapled BCL9 a-helical peptides to target the beta-catenin/B-cell CLL/lymphoma 9 (BCL9) PPL Journal of Medicinal Chemistry, 55,1137-1146 ... 

Figure 9.7 Design of tandem hydrocarbon-stapled ( stitched ) peptides and expansion of click-stapling chemistry, including bis-triazolo-aiyl-stapling, to various intracellular targets.

Figure 9.8 Design of pyrazoline-stapled and bis-thioether macrocyclized peptides...

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