title: Rational design of potent mimic peptide derived from monoclonal antibody: antibody mimic design.
abstract: The variable regions of antibody molecules bind antigens with high affinity and specificity. The binding sites are imparted largely to the hypervariable portions (i.e. CDRs) of the variable region. Peptides derived from antibody CDRs can bind antigen with similar specificity acted as mimic of antibody and become drug-designing core, although with markedly lower affinity. In this study, the 3D complex structure of tumor necrosis factor-alpha (TNFalpha) and its neutralizing monoclonal antibody Z12 was modeled using molecular docking method and optimized with molecular mechanism and dynamics method. The binding domains between TNFalpha and Z12 were determined theoretically and functional antigen epitopes were predicted. According to the 3D complex structure of TNFalpha and Z12, a novel antagonist peptide, named PT1, was designed theoretically. The experimental result showed that PT1 possessed significantly binding inhibition of TNFalpha to Z12 and protected L929 cells from the cytotoxic effect of TNFalpha. The designed mimic peptide was more amenable to synthetic chemistry and thus might be useful starting points for the design of smaller organic mimics.
authors.affiliation: Beijing Institute of Basic Medical Sciences, P.O. Box 130 (3), Beijing 100850, PR China.
authors.forename: Jiannan
authors.initials: J
authors.lastname: Feng
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology; D001666:Binding Sites, Antibody; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D017076:Computer-Aided Design; D015195:Drug Design; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha