Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics.
Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics.
复制标题
DOI：
10.1016/j.chom.2023.05.030
复制
发表时间：
2023-06
影响因子：
30.3
通讯作者：
Nan Zhao;J. Ho;Fanye Meng;Simin Zheng;A. Kurland;Lu Tian;Martha G Rea-Moreno;Xiangyang Song;Ji-Seon Seo;H. Kaniskan;A. J. T. te Velthuis;D. Tortorella;Ya-Wen Chen;Jeffrey R. Johnson;Jian Jin;Ivan Marazzi
中科院分区：
文献类型：
--
作者：
Nan Zhao;J. Ho;Fanye Meng;Simin Zheng;A. Kurland;Lu Tian;Martha G Rea-Moreno;Xiangyang Song;Ji-Seon Seo;H. Kaniskan;A. J. T. te Velthuis;D. Tortorella;Ya-Wen Chen;Jeffrey R. Johnson;Jian Jin;Ivan Marazzi
靶向蛋白降解（TPD），如蛋白水解靶向嵌合体（PROTAC）所示，是一种新兴的药物发现平台。PROTAC分子通常含有与E3连接酶配体连接的靶蛋白配体，将靶蛋白募集至E3连接酶以诱导其泛素化和降解。在这里，我们应用PROTAC方法开发针对许多病毒的关键宿主因子的广谱抗病毒药物和针对独特病毒蛋白的病毒特异性抗病毒药物。对于宿主导向的抗病毒药物，我们鉴定了一种小分子降解剂FM-74-103，它可以选择性降解人GSPT 1（一种翻译终止因子）。FM-74-103介导的GSPT 1降解抑制RNA和DNA病毒。在病毒特异性抗病毒药物中，我们开发了基于病毒RNA寡核苷酸的双功能分子（Destroyers）。作为原理的证明，病毒启动子序列的RNA模拟物被用作异双功能分子以募集和靶向流感病毒聚合酶用于降解。这项工作突出了TPD在合理设计和开发下一代抗病毒药物方面的广泛用途。
Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically contain a target protein ligand linked to an E3 ligase ligand, recruit a target protein to the E3 ligase to induce its ubiquitination and degradation. Here, we applied PROTAC approaches to develop broad-spectrum antivirals targeting key host factors for many viruses and virus-specific antivirals targeting unique viral proteins. For host-directed antivirals, we identified a small-molecule degrader, FM-74-103, that elicits selective degradation of human GSPT1, a translation termination factor. FM-74-103-mediated GSPT1 degradation inhibits both RNA and DNA viruses. Among virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). As a proof of principle, RNA mimics of viral promoter sequences were used as heterobifunctional molecules to recruit and target influenza viral polymerase for degradation. This work highlights the broad utility of TPD to rationally design and develop next-generation antivirals.