Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors
Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors
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DOI：
10.1021/acs.jmedchem.2c01716
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发表时间：
2022-12-07
影响因子：
7.3
通讯作者：
Liu, Xinyong
中科院分区：
文献类型：
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作者：
Gao, Shenghua;Song, Letian;Liu, Xinyong
SARS-CoV-2的传播不断威胁着人类的生命和健康，小分子抗病毒药物需求旺盛。主要蛋白酶 (Mpro) 是抗 SARS-CoV-2 药物设计的有效且高度保守的靶标。在此，我们报告了有效的共价非肽衍生的 Mpro 抑制剂的发现。设计并合成了一系列含有不同弹头的具有哌嗪骨架的共价化合物。其中，GD-9被认为是最有效的化合物，对Mpro具有显着的酶抑制作用（IC50=0.18μM），并且对SARS-CoV-2具有良好的抗病毒效力（EC50=2.64μM），与瑞德西韦相似（EC50=2.27μM）。此外，与人类半胱氨酸蛋白酶相比，GD-9 对 SARS-CoV-2 Mpro 具有良好的靶点选择性。 X射线共晶结构证实了我们最初的设计理念，即GD-9与Mpro的活性位点共价结合。我们的非肽共价抑制剂为未来开发更有效的 COVID-19 疗法奠定了基础。
The spread of SARS-CoV-2 keeps threatening human life and health, and small-molecule antivirals are in demand. The main protease (Mpro) is an effective and highly conserved target for anti-SARS-CoV-2 drug design. Herein, we report the discovery of potent covalent non-peptide-derived Mpro inhibitors. A series of covalent compounds with a piperazine scaffold containing different warheads were designed and synthesized. Among them, GD-9 was identified as the most potent compound with a significant enzymatic inhibition of Mpro (IC50 = 0.18 mu M) and good antiviral potency against SARS-CoV-2 (EC50 = 2.64 mu M), similar to that of remdesivir (EC50 = 2.27 mu M). Additionally, GD-9 presented favorable target selectivity for SARS-CoV-2 Mpro versus human cysteine proteases. The X-ray co-crystal structure confirmed our original design concept showing that GD-9 covalently binds to the active site of Mpro. Our nonpeptidic covalent inhibitors provide a basis for the future development of more efficient COVID-19 therapeutics.