Regulation of a variety of biological processes depends on the protein-protein interactions. Generally, the protein-protein interaction surface is too large to be selectively targeted by small molecule drugs. Besides, protein drug candidates cannot be used directly for this purpose because of their low cellular membrane permeability. Due to these problems, it is imperative to develop the next-generation therapeutic arsenals that combine the membrane permeability of small organic molecules with the broad targetability of protein-based drugs. To overcome this challenge, Verdine et al. designed a novel kind of peptides that were designated as hydrocarbon-stapled α -helical peptides. The synthetic mini-protein can strongly confine its conformation into α -helix by introducing an all-hydrocarbon chemical brace. The pharmacology of the stapled peptides, compared with their unstapled counterpart, is greatly improved, including enhancing proteolytic resistance and cellular permeability. In this paper, we will review the recent advances of the stapled peptides in respect of their chemical synthesis, biophysical properties and pharmaceutical applications of them in the cancer-, and HIV-associated treatment, the regulation of signal pathway and the repression of tumor-activated proteins.

Contents
1 Introduction
2 Synthesis and modification of stapled peptides
2.1 Selection of insertion sites of α-methyl, α-alkenylglycine
2.2 Chemical synthesis of stapled peptides
2.3 Modification on stapled peptides
2.4 Synthesis of long-chain stapled peptides
3 Biophysical properties of stapled peptides
3.1 Conformation of stapled peptides
3.2 High binding affinity to target proteins
3.3 Resistance to proteolytic enzymes
3.4 High cellular permeability
3.5 Characterization of its bioactivity
4 Function and application of stapled peptides
4.1 Application in cancer-associated treatment
4.2 Application in HIV-associated treatment
4.3 Application in regulation of signal pathway
4.4 Application in hepatitis-associated treatment
5 Conclusion and outlook