靶向诱导蛋白降解作为药物开发新策略

发布时间：2018-07-03 04:27

本文选题：泛素E连接酶 + 蛋白降解　；参考：《药学学报》2017年12期

【摘要】：基于机制药物研发的核心问题是寻找和发现可靠的药物靶标。随着基因组学和蛋白质组学的理论及实验技术的快速发展,有不少非酶蛋白被确定为药物靶标。这些非酶蛋白类药物靶标难以用传统的、通过占据活性位点的调控方式来设计和发现疾病治疗药物。近年来,利用人体自身的泛素-蛋白酶体系统靶向诱导目的蛋白降解方法,可实现对众多非酶蛋白的有效抑制,成为创新药物研究的又一新的亮点。该方法通过设计靶向诱导蛋白降解的缀合物,该缀合物含有双功能单元分别识别和结合目的蛋白和泛素E3连接酶,诱导泛素化复合体组装,实现对特定的目的蛋白泛素化,最后诱导目的蛋白降解。这一创新的药物直接调控体内蛋白含量的策略极大拓展了潜在药物靶标的范围,为创新药物研究提供了广阔的新思路。
[Abstract]:The core problem of drug development based on mechanism is to find and find reliable drug target. With the rapid development of genomics and proteomics, many non-enzymatic proteins have been identified as drug targets. These non-enzyme protein drug targets are difficult to design and discover disease treatment drugs by occupying active sites. In recent years, the method of targeting and inducing the degradation of target protein by Ubiquitin proteasome system in human body can effectively inhibit many non-enzyme proteins and become a new bright spot in the research of innovative drugs. By designing a conjugate targeting to induce protein degradation, the conjugate contains a bifunctional unit to recognize and bind the target protein and ubiquitin E3 ligase, respectively, to induce the assembly of the ubiquitin complex. Finally, the degradation of the target protein was induced. This innovative strategy of direct regulation of protein content in the body greatly expands the range of potential drug targets and provides a broad new idea for the research of innovative drugs.
【作者单位】：中国药科大学江苏省药物分子设计与成药性优化重点实验室;中国药科大学药学院药物化学系;
【基金】：国家自然科学基金资助项目(81230078,81602948)
【分类号】：R91

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