Terrab Leila, Wipf Peter
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
ACS Med Chem Lett. 2020 Mar 12;11(3):232-236. doi: 10.1021/acsmedchemlett.9b00583.
The unfolded protein response (UPR) is a cellular stress response mechanism that is critical for cell survival. Pharmacological modulation of the ATPase activity of the chaperone Hsp70 can trigger UPR-mediated cell death, thus removing pathogenic cells in human malignancies, or, alternatively, stimulate survival, thereby preventing apoptosis in neuronal cells and slowing the progress of inflammation, neurodegeneration, and aging. This Viewpoint highlights the complexity of the protein homeostasis network and discusses different approaches for modulating Hsp70 activity, including the use of a chemical reaction development-inspired library of Hsp70 agonists and antagonists.
未折叠蛋白反应（UPR）是一种对细胞存活至关重要的细胞应激反应机制。伴侣蛋白Hsp70的ATP酶活性的药理学调节可触发UPR介导的细胞死亡，从而清除人类恶性肿瘤中的致病细胞，或者，也可刺激细胞存活，从而防止神经元细胞凋亡并减缓炎症、神经退行性变和衰老的进程。本观点强调了蛋白质稳态网络的复杂性，并讨论了调节Hsp70活性的不同方法，包括使用受化学反应开发启发的Hsp70激动剂和拮抗剂文库。
