Hydrocarbon stapled peptide

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. 

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

Figure 9.9 3D-structural diversity of varying subclasses of hydrocarbon-stapled peptides, including double-turn, single-turn, stitch, i,i- -3 single-turn and H-bond surrogate macrocyclizations. 

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. 

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