De novo design TNF-alpha antagonistic peptide based on the complex structure of TNF-alpha with its neutralizing monoclonal antibody Z12.
Tumor necrosis factor-alpha (TNF-alpha) antagonists have become therapeutic drugs for immunological diseases including rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, etc. Low molecular weight synthetic peptides can mimic the binding sites of TNF-alpha receptors and block the activity of TNF-alpha. Based on the 3-D complex structure of TNF-alpha with its neutralizing monoclonal antibody (Mab) Z12, an antagonistic peptide (AP) was rationally de novo designed. The designed AP possessed similar structural character and potential bioactivity with Mab Z12. AP could competitively inhibit the binding of Mab Z12 to TNF-alpha, TNF-alpha-meditated caspase activation and TNF-alpha-induced cytotoxicity on murine L929 cells with a dose-dependent fashion. This study highlights the potential of computation-aided method for the design of novel peptides with the ability to block the deleterious biological effects of TNF-alpha.
Qin
Weisong
W
Institute of Basic Medical Sciences, P.O. Box 130 (3), Taiping Road, Beijing 100850, PR China.
Feng
Jiannan
J
Li
Yan
Y
Lin
Zhou
Z
Shen
Beifen
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology
D000911:Antibodies, Monoclonal; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases