Qin Weisong, Feng Jiannan, Li Yan, Lin Zhou, Shen Beifen
Institute of Basic Medical Sciences, P.O. Box 130 (3), Taiping Road, Beijing 100850, PR China.
J Biotechnol. 2006 Aug 20;125(1):57-63. doi: 10.1016/j.jbiotec.2006.01.036. Epub 2006 Mar 7.
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.
肿瘤坏死因子-α（TNF-α）拮抗剂已成为治疗包括类风湿性关节炎、炎症性肠病、克罗恩病等在内的免疫性疾病的药物。低分子量合成肽可模拟TNF-α受体的结合位点并阻断TNF-α的活性。基于TNF-α与其中和单克隆抗体（Mab）Z12的三维复合物结构，合理地从头设计了一种拮抗肽（AP）。所设计的AP具有与Mab Z12相似的结构特征和潜在生物活性。AP能够以剂量依赖的方式竞争性抑制Mab Z12与TNF-α的结合、TNF-α介导的半胱天冬酶激活以及TNF-α诱导的对小鼠L929细胞的细胞毒性。本研究突出了计算辅助方法在设计具有阻断TNF-α有害生物学效应能力的新型肽方面的潜力。
