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Pseudosubstrate Peptides Inhibit Akt and Induce Cell Growth Inhibition

2004; American Chemical Society; Volume: 43; Issue: 5 Linguagem: Inglês

10.1021/bi034515p

1943-295X

Yan Luo, Richard A. Smith, Ran Guan, Xuesong Liu, Vered Klinghofer, Jianwei Shen, Charles W. Hutchins, Paul Richardson, Tom Holzman, Saul H. Rosenberg, Vincent L. Giranda,

Quinazolinone synthesis and applications

We have designed peptide inhibitors that potently inhibit Akt both in vitro and inside cells. These peptide inhibitors are selective for Akt versus other closely related kinases. The peptides inhibit the in vitro phosphorylation of a biotinylated Bad peptide by Akt with potency up to 100 nM. We have shown that the binding between Akt1 and these peptide inhibitors requires MgATP. Mutating the two putative Akt phosphorylation sites to Ala (nonsubstrate) in these peptides increases the inhibitory potency while mutating the sites to aspartic acid (phosphorylation mimetic) reduces the potency. When delivered into cells, these peptide inhibitors can inhibit cellular Akt activity and cell growth. Thus, these Akt-specific peptide inhibitors provide prototypes for peptide mimetic drugs as well as very useful tools to dissect cellular functions of Akt.