Pseudosubstrate peptides inhibit Akt and induce cell growth inhibition.
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.
Luo
Yan
Y
Department R47S AP9A, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. yan.luo@abbott.com
Smith
Richard A
RA
Guan
Ran
R
Liu
Xuesong
X
Klinghofer
Vered
V
Shen
Jianwei
J
Hutchins
Charles
C
Richardson
Paul
P
Holzman
Tom
T
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
D000255:Adenosine Triphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000235:genetics; D001667:Binding, Competitive / Q000235:genetics; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics; D006367:HeLa Cells; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine / Q000235:genetics; D013379:Substrate Specificity / Q000235:genetics
D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D010455:Peptides; D011518:Proto-Oncogene Proteins; D001224:Aspartic Acid; D012694:Serine; D006639:Histidine; D000255:Adenosine Triphosphate; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3