Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure-Activity Relationships, Antiviral Activity, and X-ray Structure Determination
文献类型：期刊论文
| 作者 | Pillaiyar, Thanigaimalai1,2,3; Flury, Philipp1,2,3; Krueger, Nadine4; Su, Haixia5,6; Schaekel, Laura7; Da Silva, Elany Barbosa8; Eppler, Olga1,2,3; Kronenberger, Thales1,2,3; Nie, Tianqing5,6; Luedtke, Stephanie8 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.2c00636 |
| 文献子类 | Article |
| 英文摘要 | ABSTRACT: The main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure???activity relationships of novel small-molecule thioesters as SARSCoV-2 Mpro inhibitors. Compounds 3w and 3x exhibited excellent SARS-CoV-2 Mpro inhibition with kinac/Kiof 58,700 M???1 s???1 (Ki = 0.0141 ??M) and 27,200 M???1 s???1 (Ki = 0.0332 ??M), respectively. In Calu-3 and Vero76 cells, compounds 3h, 3i, 3l, 3r, 3v, 3w, and 3x displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of 3w and 3af with SARS-CoV-2 Mpro was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the Mpro of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections. |
| WOS关键词 | BIOLOGICAL EVALUATION ; DESIGN ; PREDICTION ; DISCOVERY ; DOCKING |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000821451600001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309335]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Pillaiyar, Thanigaimalai; Xu, Yechun |
| 作者单位 | 1.Eberhard Karls Univ Tubingen, Inst Pharm, Pharmaceut Med Chem, Morgenstelle 8, D-72076 Tubingen, Germany; 2.Eberhard Karls Univ Tubingen, Tubingen Ctr Acad Drug Discovery, Morgenstelle 8, D-72076 Tubingen, Germany; 3.Univ Tubingen, Cluster Excellence iFIT EXC 2180 Image Guided & F, D-72076 Tubingen, Germany; 4.Leibniz Inst Primate Res Gottingen, German Primate Ctr, Infect Biol Unit, D-37077 Gottingen, Germany; 5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Mat Med, Stake Key Lab Drug Res, Shanghai 201203, Peoples R China; 7.Univ Bonn, PharmaCtr Bonn, Pharmaceut Inst, Pharmaceut & Med Chem, D-53121 Bonn, Germany; 8.Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA; 9.Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211, Finland; 10.Univ Gottingen, Fac Biol & Psychol, D-37073 Gottingen, Germany |
| 推荐引用方式 GB/T 7714 | Pillaiyar, Thanigaimalai,Flury, Philipp,Krueger, Nadine,et al. Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure-Activity Relationships, Antiviral Activity, and X-ray Structure Determination[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022. |
| APA | Pillaiyar, Thanigaimalai.,Flury, Philipp.,Krueger, Nadine.,Su, Haixia.,Schaekel, Laura.,...&Laufer, Stefan A..(2022).Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure-Activity Relationships, Antiviral Activity, and X-ray Structure Determination.JOURNAL OF MEDICINAL CHEMISTRY. |
| MLA | Pillaiyar, Thanigaimalai,et al."Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure-Activity Relationships, Antiviral Activity, and X-ray Structure Determination".JOURNAL OF MEDICINAL CHEMISTRY (2022). |
入库方式： OAI收割
来源：上海药物研究所
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