Yu Wenying, Zhao Yucheng, Ye Hui, Wu Nanping, Liao Yixian, Chen Nannan, Li Zhiling, Wan Ning, Hao Haiping, Yan Honggao, Xiao Yibei, Lai Maode
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing210009, China.
Department of Resources Science of Traditional Chinese Medicines and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing210009, China.
J Med Chem. 2022 Dec 22;65(24):16252-16267. doi: 10.1021/acs.jmedchem.2c00954. Epub 2022 Dec 12.
The two proteases, PL and M, of SARS-CoV-2 are essential for replication of the virus. Using a structure-based co-pharmacophore screening approach, we developed a novel dual-targeted inhibitor that is equally potent in inhibiting PL and M of SARS-CoV-2. The inhibitor contains a novel warhead, which can form a covalent bond with the catalytic cysteine residue of either enzyme. The maximum rate of the covalent inactivation is comparable to that of the most potent inhibitors reported for the viral proteases and covalent inhibitor drugs currently in clinical use. The covalent inhibition appears to be very specific for the viral proteases. The inhibitor has a potent antiviral activity against SARS-CoV-2 and is also well tolerated by mice and rats in toxicity studies. These results suggest that the inhibitor is a promising lead for development of drugs for treatment of COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的两种蛋白酶PL和M对该病毒的复制至关重要。我们采用基于结构的共同药效团筛选方法，开发了一种新型双靶点抑制剂，它在抑制SARS-CoV-2的PL和M方面具有同等效力。该抑制剂含有一个新型弹头，可与这两种酶的催化半胱氨酸残基形成共价键。共价失活的最大速率与报道的针对该病毒蛋白酶的最有效抑制剂以及目前临床使用的共价抑制剂药物相当。共价抑制似乎对病毒蛋白酶具有高度特异性。该抑制剂对SARS-CoV-2具有强大的抗病毒活性，并且在毒性研究中，小鼠和大鼠对其耐受性良好。这些结果表明，该抑制剂是开发治疗2019冠状病毒病（COVID-19）药物的一个有前景的先导物。
