DEVELOPMENT OF INTERLEUKIN 6 ANTAGONISTS

长期目标：开发基于肽的白细胞介素6（IL-6）特异性 用于治疗其中IL-6可能有助于 发病机制，如类风湿性关节炎。具有IL-6的肽 然后在动物模型中测试体外拮抗剂活性， 功效由于当肽被降解时，代谢稳定性可能是一个问题， 在体内给药后，将启动类似程序以修饰 最活跃的肽，以最大限度地发挥其活性。如果这些尝试 成功后，计划设计额外的肽模拟物， 口服活性化合物。本研究项目确立的原则 可用于设计其它细胞因子的拮抗剂，因此， 将为设计一种新的 用于选择性操纵免疫系统的药物化合物。 具体目的：（1）鉴定10-15个氨基酸的短序列， 对于IL-6的配体-受体相互作用至关重要。所识别的 将通过固相合成法合成肽，并检测IL-6 IL-6特异性生物测定中的拮抗剂活性。(2)为了检验这一假设 结构预测对于识别 受体-配体相互作用。合成活性肽的类似物 以鉴定最佳表位及其最低结构要求。 (3)为了产生多克隆抗肽抗体以用于进一步的免疫治疗， 目的表位的表征。

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.