Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California 90089, United States.
Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, United States.
J Med Chem. 2023 Sep 14;66(17):12237-12248. doi: 10.1021/acs.jmedchem.3c00810. Epub 2023 Aug 18.
There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease M plays a pivotal role in SARS-CoV-2 replications, thereby representing an attractive target for antiviral development. We seek to identify novel electrophilic warheads for efficient, covalent inhibition of M. By comparing the efficacy of a panel of warheads installed on a common scaffold against M, we discovered that the terminal alkyne could covalently modify M as a latent warhead. Our biochemical and X-ray structural analyses revealed the irreversible formation of the vinyl-sulfide linkage between the alkyne and the catalytic cysteine of M. Clickable probes based on the alkyne inhibitors were developed to measure target engagement, drug residence time, and off-target effects. The best alkyne-containing inhibitors potently inhibited SARS-CoV-2 infection in cell infection models. Our findings highlight great potentials of alkyne as a latent warhead to target cystine proteases in viruses and beyond.
目前迫切需要改进治疗方法，以更好地控制持续的 COVID-19 大流行。主蛋白酶 M 在 SARS-CoV-2 的复制中起着关键作用，因此成为抗病毒药物开发的一个有吸引力的靶点。我们试图寻找新型亲电弹头，以有效、共价抑制 M。通过比较一组安装在共同支架上的弹头对 M 的功效，我们发现末端炔烃可以作为潜伏弹头共价修饰 M。我们的生化和 X 射线结构分析揭示了炔烃和 M 的催化半胱氨酸之间形成不可逆的乙烯基-硫醚键。基于炔烃抑制剂的可点击探针被开发出来，用于测量靶标结合、药物停留时间和脱靶效应。最好的含炔烃抑制剂在细胞感染模型中强烈抑制 SARS-CoV-2 感染。我们的发现突出了炔烃作为潜伏弹头的巨大潜力，可以针对病毒和其他生物中的半胱氨酸蛋白酶。
