Stapled peptide

Verdine and coworkers reported their first success with Bcl-2 family proteins using a stapled peptide analog of the proapoptotic Bid BH3 domain [37]. The hydrocarbon-crosslinked peptide was shown to bind Bcl-xL at the same binding site as wild-type Bid BH3 and with increased affinity. Importantly, the hydrocarbon crosslink rendered the stapled peptide cell permeable, where the wild-type peptide was not. In cell-based assays, stapled Bid BH3 was shown to sensitize cancer cells to Bax mediated apoptosis. In mice with leukemia xenografts, stapled Bid BH3 treatment consistently suppressed tumor growth. 

Targeting the Transcriptional Hub P-Catenin Using Stapled Peptides... 

Figure 25.5 (a) Starting sequence in phage-display-based affinity optimization with a summary of variations found at least twice in the 32 selected phage sequences (numbers indicate frequency of occurrence), (b) A series of stapled peptide sequences (varied amino acids highlighted in black) including their dissociation constant (Kq) with p-catenin, overall charge (calculated with Marvin 5.2.3, 2009,... 

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 peptide method is included here because it is considered as a promising method for generating leads for PPI targets. 

The a-helix features 3.6 residues per complete turn, which places the i, i -F 4, i -F 7, and i-F 11 side chains on the same face of the folded structure [58]. The stapled peptide covalent cross-links are on one face of an a-helbc, connecting two residues separated by either 1 or 2 a-helical turns (i, i -F 4 or i, i + 7 positions, respectively). Two unnatural amino acids used for the covalent linker introduces four possible combinations in chirality considering the peptide sequencing RR, SS, RS, and SR. A cartoon presentation of these chirality differences is shown in Figure 10.6. The... 

An alternative linker strategy recently employed in the synthesis of stapled peptides is through the incorporation of a triazole bridge, which was constructed through azido-acetylene click chemistry. These new stapled peptides offer enhanced chemical stability and further resistance to proteolysis [49c]. The linker length in these triazole bridge stapled peptides has a similar requirement as the hydrocarbon stapled peptide. 

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