SARS-CoV-2 木瓜蛋白酶样蛋白酶 (PLpro) 抑制剂和小分子衍生物的抗病毒活性作为药物先导。
SARS-CoV-2 papain-like protease (PLpro) inhibitory and antiviral activity of small molecule derivatives for drug leads.
机构信息
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 USA.
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 USA.
出版信息
Bioorg Med Chem Lett. 2023 Nov 15;96:129489. doi: 10.1016/j.bmcl.2023.129489. Epub 2023 Sep 27.
Abstract
We report here the synthesis and biological evaluation of a series of small molecule SARS-CoV-2 PLpro inhibitors. We compared the activity of selected compounds in both SARS-CoV-1 and SARS-CoV-2 PLpro inhibitory and antiviral assays. We have synthesized and evaluated several new structural variants of previous leads against SARS-CoV-2 PLpro. The replacement of the carboxamide functionality with sulfonamide derivatives resulted in PLpro inhibitors with potent PLpro inhibitory and antiviral activity in VeroE6 cells similar to GRL0617. To obtain molecular insight, we created an optimized model of a potent sulfonamide derivative in the SARS-CoV-2 PLpro active site.
摘要
我们在此报告一系列小分子 SARS-CoV-2 PLpro 抑制剂的合成和生物学评估。我们比较了选定化合物在 SARS-CoV-1 和 SARS-CoV-2 PLpro 抑制和抗病毒测定中的活性。我们已经合成并评估了几种针对 SARS-CoV-2 PLpro 的先前先导化合物的新结构变体。用磺酰胺衍生物替代羧酰胺官能团，得到了对 SARS-CoV-2 PLpro 具有强效 PLpro 抑制和抗病毒活性的抑制剂，其活性与 GRL0617 相似。为了获得分子见解，我们在 SARS-CoV-2 PLpro 的活性位点创建了一个优化的强效磺酰胺衍生物模型。
相似文献
1
SARS-CoV-2 papain-like protease (PLpro) inhibitory and antiviral activity of small molecule derivatives for drug leads.SARS-CoV-2 木瓜蛋白酶样蛋白酶 (PLpro) 抑制剂和小分子衍生物的抗病毒活性作为药物先导。
Bioorg Med Chem Lett. 2023 Nov 15;96:129489. doi: 10.1016/j.bmcl.2023.129489. Epub 2023 Sep 27.
2
Microbial based natural compounds as potential inhibitors for SARS-CoV-2 Papain-like protease (PLpro): a molecular docking and dynamic simulation study.基于微生物的天然化合物作为 SARS-CoV-2 木瓜蛋白酶样蛋白酶 (PLpro) 的潜在抑制剂：分子对接和动态模拟研究。
J Biomol Struct Dyn. 2022;40(24):13848-13858. doi: 10.1080/07391102.2021.1997815. Epub 2021 Nov 3.
3
The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery.GRL0617 与 SARS-CoV-2 PLpro 的复杂结构揭示了抗病毒药物发现的热点。
Nat Commun. 2021 Jan 20;12(1):488. doi: 10.1038/s41467-020-20718-8.
4
Exploring naphthyl derivatives as SARS-CoV papain-like protease (PLpro) inhibitors and its implications in COVID-19 drug discovery.探索萘基衍生物作为 SARS-CoV 木瓜蛋白酶样蛋白酶（PLpro）抑制剂及其在 COVID-19 药物发现中的意义。
Mol Divers. 2022 Feb;26(1):215-228. doi: 10.1007/s11030-021-10198-3. Epub 2021 Mar 6.
5
Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2.强效且选择性抑制 SARS-CoV-2 的木瓜蛋白酶样蛋白酶。
Nat Commun. 2023 Mar 28;14(1):1733. doi: 10.1038/s41467-023-37254-w.
6
Synthesis and Structure-Activity Relationship of Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease with Antiviral Potency.具有抗病毒活性的新型冠状病毒木瓜蛋白酶样蛋白酶共价抑制剂的合成及构效关系
Bioorg Med Chem Lett. 2025 Feb 1;116:130034. doi: 10.1016/j.bmcl.2024.130034. Epub 2024 Nov 21.
7
Chalcone-amide, a privileged backbone for the design and development of selective SARS-CoV/SARS-CoV-2 papain-like protease inhibitors.查尔酮酰胺，一种用于设计和开发选择性 SARS-CoV/SARS-CoV-2 木瓜蛋白酶样蛋白酶抑制剂的优势骨架。
Eur J Med Chem. 2022 Oct 5;240:114572. doi: 10.1016/j.ejmech.2022.114572. Epub 2022 Jul 3.
8
High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors.高通量筛选鉴定出已上市药物为 SARS-CoV-2 PLpro 抑制剂。
Protein Cell. 2021 Nov;12(11):877-888. doi: 10.1007/s13238-021-00836-9. Epub 2021 Apr 17.
9
Identifying structural-functional analogue of GRL0617, the only well-established inhibitor for papain-like protease (PLpro) of SARS-CoV2 from the pool of fungal metabolites using docking and molecular dynamics simulation.利用对接和分子动力学模拟从真菌代谢产物中鉴定出 GRL0617 的结构功能类似物，GRL0617 是唯一一种针对 SARS-CoV2 木瓜样蛋白酶 (PLpro) 的有效抑制剂。
Mol Divers. 2022 Feb;26(1):309-329. doi: 10.1007/s11030-021-10220-8. Epub 2021 Apr 6.
10
Identification of novel human USP2 inhibitor and its putative role in treatment of COVID-19 by inhibiting SARS-CoV-2 papain-like (PLpro) protease.鉴定新型人类 USP2 抑制剂及其通过抑制 SARS-CoV-2 木瓜样（PLpro）蛋白酶在治疗 COVID-19 中的潜在作用。
Comput Biol Chem. 2020 Dec;89:107376. doi: 10.1016/j.compbiolchem.2020.107376. Epub 2020 Sep 13.
引用本文的文献
1
Design, synthesis and SARS-CoV‑2 main protease inhibitory activities of 2-arylthiomethyl-6-bromoindole derivatives.2-芳基硫甲基-6-溴吲哚衍生物的设计、合成及对严重急性呼吸综合征冠状病毒2主要蛋白酶的抑制活性
Mol Divers. 2025 Aug 13. doi: 10.1007/s11030-025-11308-1.
2
Viral deubiquitinating proteases and the promising strategies of their inhibition.病毒去泛素化蛋白酶及其抑制的潜在策略。
Virus Res. 2024 Jun;344:199368. doi: 10.1016/j.virusres.2024.199368. Epub 2024 Apr 11.
3
Identification of Triazolopyrimidinyl Scaffold SARS-CoV-2 Papain-Like Protease (PL) Inhibitor.三唑并嘧啶骨架的新型严重急性呼吸综合征冠状病毒2（SARS-CoV-2）木瓜蛋白酶样蛋白酶（PL）抑制剂的鉴定
Pharmaceutics. 2024 Jan 25;16(2):169. doi: 10.3390/pharmaceutics16020169.
4
Oral Molnupiravir and Nirmatrelvir/Ritonavir for the Treatment of COVID-19: A Literature Review with a Focus on Real-World Evidence.口服莫努匹拉韦和奈玛特韦/利托那韦治疗新冠肺炎：一项侧重于真实世界证据的文献综述
Infect Dis Rep. 2023 Oct 25;15(6):662-678. doi: 10.3390/idr15060061.
本文引用的文献
1
Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study.帕罗韦德治疗成人重症新型冠状病毒肺炎的疗效和安全性：一项多中心随机对照研究
Lancet Reg Health West Pac. 2023 Apr;33:100694. doi: 10.1016/j.lanwpc.2023.100694. Epub 2023 Feb 6.
2
Recent Drug Development and Medicinal Chemistry Approaches for the Treatment of SARS-CoV-2 Infection and COVID-19.最近用于治疗 SARS-CoV-2 感染和 COVID-19 的药物开发和药物化学方法。
ChemMedChem. 2022 Nov 18;17(22):e202200440. doi: 10.1002/cmdc.202200440. Epub 2022 Oct 13.
3
COVID-19 in 2022-The Beginning of the End or the End of the Beginning?2022年的新冠疫情——是结束的开始还是开始的结束？
JAMA. 2022 Jun 28;327(24):2389-2390. doi: 10.1001/jama.2022.9655.
4
Pyronaridine Protects against SARS-CoV-2 Infection in Mouse.咯萘啶对小鼠感染新型冠状病毒具有保护作用。
ACS Infect Dis. 2022 Jun 10;8(6):1147-1160. doi: 10.1021/acsinfecdis.2c00091. Epub 2022 May 24.
5
Recommendations for the Management of Drug-Drug Interactions Between the COVID-19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications.新型冠状病毒抗病毒药物奈玛特韦/利托那韦（Paxlovid）与合并用药的药物相互作用管理建议。
Clin Pharmacol Ther. 2022 Dec;112(6):1191-1200. doi: 10.1002/cpt.2646. Epub 2022 Jun 7.
6
Inhibitors of SARS-CoV-2 PLpro.严重急性呼吸综合征冠状病毒2型木瓜蛋白酶样蛋白酶（SARS-CoV-2 PLpro）抑制剂
Front Chem. 2022 Apr 26;10:876212. doi: 10.3389/fchem.2022.876212. eCollection 2022.
7
Targeting papain-like protease for broad-spectrum coronavirus inhibition.针对木瓜蛋白酶样蛋白酶的广谱冠状病毒抑制作用。
Protein Cell. 2022 Dec;13(12):940-953. doi: 10.1007/s13238-022-00909-3. Epub 2022 Apr 6.
8
Nirmatrelvir Plus Ritonavir: First Approval.奈玛特韦片/利托那韦片：首次获批。
Drugs. 2022 Apr;82(5):585-591. doi: 10.1007/s40265-022-01692-5.
9
Potential Inhibitors Targeting Papain-Like Protease of SARS-CoV-2: Two Birds With One Stone.靶向严重急性呼吸综合征冠状病毒2木瓜蛋白酶样蛋白酶的潜在抑制剂：一石二鸟。
Front Chem. 2022 Feb 23;10:822785. doi: 10.3389/fchem.2022.822785. eCollection 2022.
10
Prescribing Nirmatrelvir-Ritonavir: How to Recognize and Manage Drug-Drug Interactions.奈玛特韦利托那韦片的处方：如何识别和管理药物相互作用。
Ann Intern Med. 2022 May;175(5):744-746. doi: 10.7326/M22-0281. Epub 2022 Mar 1.
Zotero 插件