Stapled Peptide Synthesis

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. 

Subsequent to having the desired a,a-diallq lated amino acids available, the synthesis of hydrocarbon-stapled peptides is relatively straightforward and employs solid-phase peptide chemistiy, as illustrated for ATSP-7041 (Scheme 9.2), to provide a feasible route for chemical development. As further detailed below, the hydrocarbon-stapled peptide ATSP-7041 is a dual MDM2/MDMX antagonist that exhibits high potency in vitro and efficacy in vivo in p53-dependent cancer models. 

Scheme 9.2 Synthesis of dual MDM2/MDMX antagonist stapled peptide ATSP-7041.

Kim Y-W, Grossmann TN, Verdine GL (2011) Synthesis of all-hydrocarbon stapled a-helical peptides by ring-closing olefin metathesis. Nat Protocol 6 761-771... 

J.M., Mulder, R.J., Wilce, J.A., Aguilar, M.I., and Perlmutter, P. (2009) Synthesis of stapled betaS-peptides through ringclosing metathesis. Organic Letters, 11,... 

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