Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 M(pro)).
Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 M(pro)).
复制标题
DOI：
10.1016/j.ejmech.2023.115487
复制
发表时间：
2023-09-05
影响因子：
6.7
通讯作者：
Zhang, Xiangyu
中科院分区：
文献类型：
--
作者：
Zhang, Kuojun;Wang, Tianyu;Li, Maotian;Liu, Mu;Tang, He;Wang, Lin;Ye, Ke;Yang, Jiamei;Jiang, Sheng;Xiao, Yibei;Xie, Youhua;Lu, Meiling;Zhang, Xiangyu
由SARS-CoV-2引起的COVID-19大流行继续对公众健康构成巨大威胁，而全球范围内有各种疫苗可供使用。主蛋白酶（Mpro）已被验证为有效的抗COVID-19药物靶标。利用药物化学和合理的药物设计策略，我们确定了一个喹唑啉-4-酮系列的非肽，非共价SARS-CoV-2 Mpro抑制剂的基础上黄芩素，5，6，7-三羟基-2-苯基-4H-色烯-4-酮。特别是，相对于黄芩素，化合物C7显示出对SARS-CoV-2 Mpro的上级抑制活性（IC 50分别为0.085 ± 0.006和0.966 ± 0.065 μM），以及改善的物理化学和药物代谢及药代动力学（DMPK）性质。此外，C7在SARS-CoV-2感染的Vero E6细胞中抑制病毒复制的效果优于黄芩素（EC 50分别为1.10 ± 0.12和5.15 ± 1.64 μM），且细胞毒性较低（CC 50> 50 μM）。X-射线共晶结构揭示了非共价作用机制，以及黄芩素未观察到的非典型结合模式。这些结果表明，C7代表了开发更有效的SARS-CoV-2 Mpro抑制剂和抗COVID-19药物的有希望的领导者。
The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (Mpro) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 Mpro inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one. In particular, compound C7 exhibits superior inhibitory activity against SARS-CoV-2 Mpro relative to baicalein (IC50 = 0.085 ± 0.006 and 0.966 ± 0.065 μM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, C7 inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC50 = 1.10 ± 0.12 and 5.15 ± 1.64 μM, respectively) with low cytotoxicity (CC50 ＞ 50 μM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that C7 represents a promising lead for development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 drugs.
登录
查看更多内容
DOI：
10.1107/s0907444909029436
发表时间：
2009-10-01
影响因子：
2.2
作者：
Moriarty, Nigel W.;Grosse-Kunstleve, Ralf W.;Adams, Paul D.
通讯作者：
Adams, Paul D.
影响因子：
7.3
作者：
Dahlin JL;Nissink JW;Strasser JM;Francis S;Higgins L;Zhou H;Zhang Z;Walters MA
通讯作者：
Walters MA
影响因子：
4.9
作者：
通讯作者：
--
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1126/science.abg5827
发表时间：
2021-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Drayman N;DeMarco JK;Jones KA;Azizi SA;Froggatt HM;Tan K;Maltseva NI;Chen S;Nicolaescu V;Dvorkin S;Furlong K;Kathayat RS;Firpo MR;Mastrodomenico V;Bruce EA;Schmidt MM;Jedrzejczak R;Muñoz-Alía MÁ;Schuster B;Nair V;Han KY;O'Brien A;Tomatsidou A;Meyer B;Vignuzzi M;Missiakas D;Botten JW;Brooke CB;Lee H;Baker SC;Mounce BC;Heaton NS;Severson WE;Palmer KE;Dickinson BC;Joachimiak A;Randall G;Tay S
通讯作者：
Tay S