A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo
文献类型：期刊论文
| 作者 | Van Dycke, Jana1; Dai, Wenhao2; Stylianidou, Zoe1; Li, Jian2,3; Cuvry, Arno1; Roux, Emma1; Li, Bingqian2; Rymenants, Jasper1; Bervoets, Lindsey1; de Witte, Peter4 |
| 刊名 | VIRUSES-BASEL
 |
| 出版日期 | 2021-09 |
| 卷号 | 13期号:9页码:1852 |
| 关键词 | Caliciviridae antivirals small molecule danio rerio infection |
| DOI | 10.3390/v13091852 |
| 文献子类 | Article |
| 英文摘要 | Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting annually in similar to 219,000 deaths and a societal cost of similar to USD 60 billion, and no antivirals or vaccines are available. Here, we assess the anti-norovirus activity of new peptidomimetic aldehydes related to the protease inhibitor rupintrivir. The early hit compound 4 inhibited the replication of murine norovirus (MNV) and the HuNoV GI.1 replicon in vitro (EC50 similar to 1 mu M) and swiftly cleared the HuNoV GI.1 replicon from the cells. Compound 4 still inhibits the proteolytic activity. We selected a resistant GI.1 replicon, with a mutation (I109V) in a highly conserved region of the viral protease, conferring a low yield of resistance against compound 4 and rupintrivir. After testing new derivatives, compound 10d was the most potent (EC50 nanomolar range). Molecular docking indicated that the aldehyde group of compounds 4 and 10d bind with Cys139 in the HuNoV 3CL protease by a covalent linkage. Finally, compound 10d inhibited the replication of HuNoV GII.4 in infected zebrafish larvae, and PK studies in mice showed an adequate profile. |
| WOS关键词 | REPLICATION ; 3C ; RUPINTRIVIR ; PROTEINS |
| WOS研究方向 | Virology |
| 语种 | 英语 |
| WOS记录号 | WOS:000702111200001 |
| 出版者 | MDPI |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309372]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Liu, Hong; Rocha-Pereira, Joana |
| 作者单位 | 1.Katholieke Univ Leuven, Rega Inst, Lab Virol & Chemotherapy, Dept Microbiol Immunol & Transplantat, B-3000 Leuven, Belgium; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; 3.Nanjing Univ Chinese Med, Coll Pharm, 138 Xianlin Ave, Nanjing 210023, Peoples R China; 4.Katholieke Univ Leuven, Lab Mol Biodiscovery, Dept Pharmaceut & Pharmacol Sci, B-3000 Leuven, Belgium |
| 推荐引用方式 GB/T 7714 | Van Dycke, Jana,Dai, Wenhao,Stylianidou, Zoe,et al. A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo[J]. VIRUSES-BASEL,2021,13(9):1852. |
| APA | Van Dycke, Jana.,Dai, Wenhao.,Stylianidou, Zoe.,Li, Jian.,Cuvry, Arno.,...&Rocha-Pereira, Joana.(2021).A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo.VIRUSES-BASEL,13(9),1852. |
| MLA | Van Dycke, Jana,et al."A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo".VIRUSES-BASEL 13.9(2021):1852. |
入库方式： OAI收割
来源：上海药物研究所
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