title: The design of antagonist peptide of hIL-6 based on the binding epitope of hIL-6 by computer-aided molecular modeling.
abstract: The interaction between human interleukin-6 (hIL-6) and human interleukin-6 receptor (hIL-6R) is the initial and most specific step in the hIL-6 signaling pathway. Understanding its binding core and interaction mechanism at amino acid level is the basis for designing small IL-6 inhibiting molecules, such as peptides or lead compounds. With Docking method, the complex structure composed of hIL-6 and its alpha-subunit receptor (hIL-6R) was analyzed theoretically. By using structure-based analysis and phage display methods, the loop AB (from Lys67 to Glu81) of hIL-6 was found to be the important binding epitope of hIL-6R. By means of computer-aided design, the mimic antagonist peptide (14 residues) was designed and synthesized. Using multiple myeloma cell line (XG7), IL-6 dependent cell line, as test model, the influence of antagonist peptides on the proliferation of XG7 cells was investigated. The results showed that the synthetic peptide could be competitive to bind to hIL-6R with hIL-6, and the effect was concentration dependent. The theoretical design approach is a powerful alternative to phage peptide library for protein mimics. Such mini-peptide is more amenable to synthetic chemistry and thus may be useful starting points for the design of small organic mimics.
authors.affiliation: Institute of Basic Medical Sciences, P.O. Box 130 (3), Taiping Road, Beijing, PR China.
authors.forename: Jiannan
authors.initials: J
authors.lastname: Feng
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
mesh_terms: D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D000939:Epitopes / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry*; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019947:Receptors, Interleukin-6 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000093242:Interleukin-6 Inhibitors
chemical_list: D000939:Epitopes; D015850:Interleukin-6; D010455:Peptides; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors