Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity

被引：60

作者：

Gao, Shenghua ^{[1
,2
]}

Sylvester, Katharina ^{[3
,4
]}

Song, Letian ^{[1
]}

Claff, Tobias ^{[3
,4
]}

Jing, Lanlan ^{[1
]}

Woodson, Molly ^{[5
,6
]}

Weisse, Renato H. ^{[7
]}

Cheng, Yusen ^{[1
]}

Schaekel, Laura ^{[3
,4
]}

Petry, Marvin ^{[3
,4
]}

Guetschow, Michael ^{[3
,4
]}

Schiedel, Anke C. ^{[3
,4
]}

Straeter, Norbert ^{[7
]}

Kang, Dongwei ^{[1
]}

Xu, Shujing ^{[1
]}

Toth, Karoly ^{[5
,6
]}

Tavis, John ^{[5
,6
]}

Tollefson, Ann E. ^{[5
,6
]}

Mueller, Christa E. ^{[3
,4
]}

Liu, Xinyong ^{[1
]}

Zhan, Peng ^{[1
]}

机构：

[1] Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, Jinan 250012, Peoples R China

[2] Shandong Univ, Shenzhen Res Inst, Shenzhen 518057, Guangdong, Peoples R China

[3] Univ Bonn, Dept Pharmaceut & Med Chem, PharmaCtr Bonn, D-53113 Bonn, Germany

[4] Univ Bonn, Dept Pharmaceut & Med Chem, Pharmaceut Inst, D-53113 Bonn, Germany

[5] St Louis Univ, Sch Med, Dept Mol Microbiol & Immunol, St Louis, MO 63103 USA

[6] St Louis Univ, Inst Drug & Biotherapeut Innovat, St Louis, MO 63103 USA

[7] Univ Leipzig, Ctr Biotechnol & Biomed, Inst Bioanalyt Chem, D-04103 Leipzig, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 19期

基金：

中国博士后科学基金;

关键词：

AMP Exception; MODELS;

D O I：

10.1021/acs.jmedchem.2c01146

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The continuous spread of SARS-CoV-2 calls for more direct-acting antiviral agents to combat the highly infectious variants. The main protease (Mpro) is an promising target for anti-SARS-CoV-2 drug design. Here, we report the discovery of potent non-covalent nonpeptide Mpro inhibitors featuring a 1,2,4-trisubstituted piperazine scaffold. We systematically modified the non-covalent hit MCULE5948770040 by structure-based rational design combined with multisite binding and privileged structure assembly strategies. The optimized compound GC-14 inhibits Mpro with high potency (IC50 = 0.40 mu M) and displays excellent antiviral activity (EC50 = 1.1 mu M), being more potent than Remdesivir. Notably, GC-14 exhibits low cytotoxicity (CC50 > 100 mu M) and excellent target selectivity for SARS-CoV-2 Mpro (IC50 > 50 mu M for cathepsins B, F, K, L, and caspase 3). X-ray co-crystal structures prove that the inhibitors occupy multiple subpockets by critical non-covalent interactions. These studies may provide a basis for developing a more efficient and safer therapy for COVID-19.

引用

页码：13343 / 13364

页数：22

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