We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (M^Pro), a highly conserved protease among various CoVs, is essential for viral replication and pathogenesis, making it a prime target for antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 M^Pro. Among them, MPD2 was demonstrated to effectively reduce M^Pro protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing M^Pro protein levels in SARS-CoV-2-infected A549-ACE2 cells. MPD2 also displayed potent antiviral activity against various SARS-CoV-2 strains and exhibited enhanced potency against nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights the potential of targeted protein degradation of M^Pro as an innovative approach for developing antivirals that could fight against drug-resistant viral variants.

中文翻译：

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发现 SARS-CoV-2 主要蛋白酶的一流 PROTAC 降解剂

过去二十年里，我们目睹了三起冠状病毒 (CoV) 爆发，其中包括由 SARS-CoV-2 引起的 COVID-19 大流行。主蛋白酶（M ^Pro）是多种冠状病毒中高度保守的蛋白酶，对于病毒复制和发病机制至关重要，使其成为抗病毒药物开发的主要靶点。在这里，我们利用蛋白水解靶向嵌合体 (PROTAC) 技术开发一类新型小分子抗病毒药物，可诱导 SARS-CoV-2 M ^Pro降解。其中，MPD2被证明可以有效降低293T细胞中M ^Pro蛋白水平，依赖于时间依赖性、CRBN介导和蛋白酶体驱动的机制。此外，MPD2 在降低SARS-CoV-2 感染的 A549-ACE2 细胞中M ^Pro蛋白水平方面表现出显着的功效。 MPD2 还对各种 SARS-CoV-2 毒株表现出有效的抗病毒活性，并对 nirmatrelvir 耐药病毒表现出增强的效力。总体而言，这项概念验证研究强调了 M ^Pro靶向蛋白质降解作为开发抗病毒药物的创新方法的潜力，该抗病毒药物可以对抗耐药病毒变体。