De novo design of ErbB2 epitope targeting fusion protein stabilized by coiled coil structure.
The extracellular cysteine-rich domains of ErbB2 receptors play important roles in ligand binding and receptor dimerization. The aim of the present study was to design a novel peptide exerting cytostatic effect toward ErbB2-overexpressing tumors based on one of the cysteine-rich domain (S1) of ErbB2. In order to create a stable molecule with unique structural and binding property, a chimeric molecule PL45 composed of ErbB2 S1 domain targeting peptide and the five stranded coiled coil domain from cartilage oligomeric matrix protein (COMP) was generated. PL45 was efficiently expressed in Escherichia coli and exhibited remarkable thermal and pH stability. It was capable of interfering with dimerization of ErbB2 and inhibiting the growth of ErbB2-overexpressing tumor cells in vitro and in vivo. The results provide evidence that the coiled coil structure can be used as a new scaffold to stabilize short peptides with potential application for anti-cancer immunotherapy and S1 domain of ErbB2 is a promising target for drug design.
Wang
Jianing
J
Institute of Basic Medical Sciences, Taiping Road 27, Beijing 100850, PR China.
Feng
Jiannan
J
Shi
Ming
M
Qian
Lu
L
Chen
Liyong
L
Yu
Ming
M
Xu
Ruonan
R
Shen
Beifen
B
Guo
Ning
N
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D023041:Xenograft Model Antitumor Assays
D000939:Epitopes; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins