DEVELOPMENT OF INTERLEUKIN 6 ANTAGONISTS

长期目标：开发基于多肽的白介素6(IL-6)特异性 用于治疗IL-6可能参与的疾病的抑制剂 发病机制，如类风湿性关节炎。含有IL-6的多肽 体外拮抗剂活性将在动物模型中进行测试 功效。因为代谢稳定性可能是当肽被 在体内给药，将启动一个模拟程序来修改 最活跃的多肽，以最大限度地发挥其活性。如果这些尝试是 成功后，额外的多肽仿制药的设计计划导致 口服活性化合物。在本研究项目中确立的原则 可用于设计其他细胞因子的拮抗剂，因此， 将为设计一类新的 用于选择性操纵免疫系统的药物化合物。 具体目标：(1)鉴定10-15个氨基酸的短序列， 在IL-6的配体-受体相互作用中起关键作用。被识别的人 将用固相合成法合成多肽，并检测IL-6 IL-6特异性生物测定中的拮抗活性。(2)检验假设 这种结构预测对于确定 受体-配体的相互作用。活性多肽类似物的合成 确定最佳表位及其最低结构要求。 (3)制备多克隆抗肽抗体，为进一步研究奠定基础 对感兴趣的表位进行表征。

Long term objective: To develop peptide-based interleukin 6 (IL-6)-specific inhibitors for the treatment of diseases in which IL-6 might contribute to the pathogenesis, such as rheumatoid arthritis. Peptides with IL-6 antagonist activity in vitro will then be tested in animal models for efficacy. Since metabolic stability may be a concern when peptides are administered in vivo, an analog program will be initiated to modify the most active peptides to maximize their activity. If these attempts are successful, the design of additional peptidomimetics is planned to lead to orally active compounds. Principles established in this research project could be used for the design of antagonists for other cytokines, and thus, will provide useful information for the design of a new class of pharmaceutical compounds for selective manipulation of the immune system. Specific Aims: (1) To identify short sequences of 10-15 amino acids that are crucial for ligand-receptor interaction of IL-6. The identified peptides will be synthesized by solid phase synthesis and tested for IL-6 antagonist activity in IL-6-specific bioassays. (2) To test the hypothesis that structural prediction is useful for the identification of receptor-ligand interaction sits. To synthesize analogs of active peptides to identify the optimum epitope and its minimal structural requirements. (3) To generate polyclonal anti-peptide antibodies for further characterization of the epitopes of interest.