Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization
文献类型：期刊论文
| 作者 | Yan, Wenzhong4; Qing, Jie1,3; Mei, Hanbing4; Mao, Fei4; Huang, Jin4; Zhu, Jin4; Jiang, Hualiang2,4 ; Liu, Lei1; Zhang, Linqi3; Li, Jian4
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| 刊名 | MOLECULES
 |
| 出版日期 | 2015-06 |
| 卷号 | 20期号:6页码:10342-10359 |
| 关键词 | CypA small molecule inhibitor anti-HCV O-acylation |
| ISSN号 | 1420-3049 |
| DOI | 10.3390/molecules200610342 |
| 文献子类 | Article |
| 英文摘要 | In this work, the relationship between cyclophilin A (CypA) and HCV prompted us to screen a series of small molecule CypA inhibitors which were previously reported by our group. Among them, compound 1, discovered as a non-immunosuppressive anti-HCV agent with an EC50 value of 0.67 M in a virus assay, was selected for further study. Subsequent chemical modification by O-acylation led to a novel class of molecules, among which compound 25 demonstrated the most potent anti-HCV activity in the virus assay (EC50 = 0.19 M), but low cytotoxicity and hERG cardiac toxicity. The following studies (a solution stability assay and a simple pharmacokinetic test together with a CypA enzyme inhibition assay) preliminarily indicated that 25 was a prodrug of 1. To the best of our knowledge, 25 is probably the most potent currently reported small molecule anti-HCV agent acting via the CypA inhibitory mechanism. Consequently, our study has provided a new potential small molecule for curing HCV infection. |
| WOS关键词 | HEPATITIS-C-VIRUS ; HUMAN CYCLOPHILIN-A ; IN-VITRO ; CHEMICAL INHIBITORS ; CYCLOSPORINE-A ; REPLICATION ; INFECTION ; DESIGN ; ISOMERASE ; BINDING |
| 资助项目 | National Natural Science Foundation of China[21222211] ; National Natural Science Foundation of China[21372001] ; National Natural Science Foundation of China[91313303] ; Program for New Century Excellent Talents in University[NCET-12-0853] ; "Shu Guang" project - Shanghai Municipal Education Commission[00000000] ; Shanghai Education Development Foundation[14SG28] ; Fundamental Research Funds for the Central Universities[00000000] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000357992700053 |
| 出版者 | MDPI AG |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276499]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Liu, Lei |
| 作者单位 | 1.Tsinghua Univ, Key Lab Bioorgan Phosphorus Chem & Chem Biol, Tsinghua Peking Ctr Life Sci, Minist Educ,Dept Chem, Beijing 100084, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 3.Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China; 4.E China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Yan, Wenzhong,Qing, Jie,Mei, Hanbing,et al. Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization[J]. MOLECULES,2015,20(6):10342-10359. |
| APA | Yan, Wenzhong.,Qing, Jie.,Mei, Hanbing.,Mao, Fei.,Huang, Jin.,...&Li, Jian.(2015).Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization.MOLECULES,20(6),10342-10359. |
| MLA | Yan, Wenzhong,et al."Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization".MOLECULES 20.6(2015):10342-10359. |
入库方式： OAI收割
来源：上海药物研究所
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