Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics

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.

以蛋白水解靶向嵌合体（proteolysis-targeting chimera, PROTAC）为代表的靶向蛋白质降解（Targeted protein degradation, TPD）是一类新兴的药物发现平台。PROTAC分子通常包含连接于E3泛素连接酶（E3 ligase）配体的靶蛋白配体，可将靶蛋白招募至E3泛素连接酶，进而诱导靶蛋白发生泛素化与降解。本研究中，我们采用PROTAC策略开发了针对多种病毒关键宿主因子的广谱抗病毒药物，以及靶向病毒特有蛋白的病毒特异性抗病毒药物。