College of Pharmacy, Zhejiang University of Technology, Hangzhou 310014, PR China; Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, PR China; Geriatric Medicine Center, Department of Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, PR China.
Biomed Pharmacother. 2024 Nov;180:117448. doi: 10.1016/j.biopha.2024.117448. Epub 2024 Sep 21.
Misfolding and aggregation of specific proteins are associated with liquid-liquid phase separation (LLPS), and these protein aggregates can interfere with normal cellular functions and even lead to cell death, possibly affecting gene expression regulation and cell proliferation. Therefore, understanding the role of LLPS in disease may help to identify new mechanisms or therapeutic targets and provide new strategies for disease treatment. There are several ways to disrupt LLPS, including screening small molecules or small molecule drugs to target the upstream signaling pathways that regulate the LLPS process, selectively dissolve and destroy RNA droplets or protein aggregates, regulate the conformation of mutant protein, activate the protein degradation pathway to remove harmful protein aggregates. Furthermore, harnessing the mechanism of LLPS can improve drug development, including preparing different kinds of drug delivery carriers (microneedles, nanodrugs, imprints), regulating drug internalization and penetration behaviors, screening more drugs to overcome drug resistance and enhance receptor signaling. This review initially explores the correlation between aberrant LLPS and disease, highlighting the pivotal role of LLPS in preparing drug development. Ultimately, a comprehensive investigation into drug-mediated regulation of LLPS processes holds significant scientific promise for disease management.
特定蛋白质的错误折叠和聚集与液-液相分离（LLPS）有关，这些蛋白质聚集体会干扰正常的细胞功能，甚至导致细胞死亡，可能会影响基因表达调控和细胞增殖。因此，了解 LLPS 在疾病中的作用可能有助于确定新的机制或治疗靶点，并为疾病治疗提供新的策略。有几种方法可以破坏 LLPS，包括筛选小分子或小分子药物，以针对调节 LLPS 过程的上游信号通路，选择性溶解和破坏 RNA 液滴或蛋白质聚集体，调节突变蛋白的构象，激活蛋白降解途径以去除有害的蛋白质聚集体。此外，利用 LLPS 的机制可以改善药物开发，包括制备不同种类的药物输送载体（微针、纳米药物、压痕），调节药物的内化和渗透行为，筛选更多的药物来克服耐药性并增强受体信号。本综述最初探讨了异常 LLPS 与疾病之间的相关性，强调了 LLPS 在药物开发中的关键作用。最终，对药物介导的 LLPS 过程的调控进行全面研究，为疾病管理提供了重要的科学前景。
