Development of HER2-antagonistic peptides as novel anti-breast cancer drugs by in silico methods.
An antagonistic peptide called HRAP that binds to the human HER2 molecule was designed by our computational method. In silico docking study demonstrated the specific interaction of HRAP with the dimerization domain in the HER2 molecule. Interestingly, HRAP inhibited proliferation of HER2-overexpressed human breast cancer cell lines. However, it had little cellular cytotoxicity (apoptosis inducibility). The cell proliferation inhibition was associated with the suppression of phosphorylation of PTEN and Akt. Thus, HRAP is the first HER2-binding small peptide antagonist rationally designed by a computer-aided SBDD method and is useful for the development of peptide mimetics to generate novel anti-breast cancer drugs.
Nakajima
Hiroo
H
Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto 602-0841, Japan. hiro@koto.kpu-m.ac.jp
Mizuta
Naruhiko
N
Sakaguchi
Koichi
K
Fujiwara
Ikuya
I
Yoshimori
Atsushi
A
Takahashi
Satoshi
S
Takasawa
Ryoko
R
Tanuma
Sei-ichi
S
D029681:Arabidopsis Proteins / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D019204:GTP-Binding Proteins / Q000627:therapeutic use*; D018734:Genes, erbB-2 / Q000502:physiology; D006801:Humans; D009842:Oligopeptides / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use*
D029681:Arabidopsis Proteins; D009842:Oligopeptides; D010455:Peptides; C553899:acetyl-prolyl-hisitidyl-alanyl-histidyl-phenylalaninamide; C506621:hypersensitive response-assisting protein, Arabidopsis; D019204:GTP-Binding Proteins