3C Protease of Enterovirus 68: Structure-Based Design of Michael Acceptor Inhibitors and Their Broad-Spectrum Antiviral Effects against Picornaviruses
文献类型：期刊论文
| 作者 | Tan, Jinzhi1,7; George, Shyla1,7; Kusov, Yuri1,7; Perbandt, Markus1,8,9; Anemueller, Stefan1,7; Mesters, Jeroen R.1,7; Norder, Helene10; Coutard, Bruno2,3,4; Lacroix, Celine5; Leyssen, Pieter5 |
| 刊名 | JOURNAL OF VIROLOGY
 |
| 出版日期 | 2013-04 |
| 卷号 | 87期号:8页码:4339-4351 |
| ISSN号 | 0022-538X |
| DOI | 10.1128/JVI.01123-12 |
| 文献子类 | Article |
| 英文摘要 | We have determined the cleavage specificity and the crystal structure of the 3C protease of enterovirus 68 (EV68 3C(pro)). The protease exhibits a typical chymotrypsin fold with a Cys...His...Glu catalytic triad; its three-dimensional structure is closely related to that of the 3C(pro) of rhinovirus 2, as well as to that of poliovirus. The phylogenetic position of the EV68 3C(pro) between the corresponding enzymes of rhinoviruses on the one hand and classical enteroviruses on the other prompted us to use the crystal structure for the design of irreversible inhibitors, with the goal of discovering broad-spectrum antiviral compounds. We synthesized a series of peptidic alpha,beta-unsaturated ethyl esters of increasing length and for each inhibitor candidate, we determined a crystal structure of its complex with the EV68 3C(pro), which served as the basis for the next design round. To exhibit inhibitory activity, compounds must span at least P3 to P1'; the most potent inhibitors comprise P4 to P1'. Inhibitory activities were found against the purified 3C protease of EV68, as well as with replicons for poliovirus and EV71 (50% effective concentration [EC50] = 0.5 mu M for the best compound). Antiviral activities were determined using cell cultures infected with EV71, poliovirus, echovirus 11, and various rhinovirus serotypes. The most potent inhibitor, SG85, exhibited activity with EC(50)s of approximate to 180 nM against EV71 and approximate to 60 nM against human rhinovirus 14 in a live virus-cell-based assay. Even the shorter SG75, spanning only P3 to P1', displayed significant activity (EC50 = 2 to 5 mu M) against various rhinoviruses. |
| WOS关键词 | HEPATITIS-A VIRUS ; CORONAVIRUS MAIN PROTEINASE ; MOLECULAR REPLACEMENT ; HUMAN RHINOVIRUS-87 ; CRYSTAL-STRUCTURE ; GENE-PRODUCT ; RNA ; FEATURES ; QUALITY ; DRUGS |
| 资助项目 | European Commission[LSHG-CT-2004-511960] ; European Commission[HEALTH-F3-2010-260644] ; Schleswig-Holstein Innovation Fund[00000000] ; Chinese Academy of Sciences[2010T1S6] ; Agency for Innovation by Science and Technology (IWT)[00000000] |
| WOS研究方向 | Virology |
| 语种 | 英语 |
| WOS记录号 | WOS:000316671000020 |
| 出版者 | AMER SOC MICROBIOLOGY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277677]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Hilgenfeld, Rolf |
| 作者单位 | 1.Med Univ Lubeck, Inst Biochem, Ctr Struct & Cell Biol Med, D-23538 Lubeck, Germany; 2.Ctr Natl Rech Sci, Lab Architecture & Fonct Macromol Biol, UMR 6098, Marseille, France; 3.Univ Aix Marseille 1, Marseille, France; 4.Univ Aix Marseille 2, F-13284 Marseille 07, France; 5.Katholieke Univ Leuven, Rega Inst Med Res, Louvain, Belgium; 6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China 7.Med Univ Lubeck, German Ctr Infect Res, D-23538 Lubeck, Germany; 8.Med Univ Lubeck, Lab Struct Biol Infect & Inflammat, Hamburg, Germany; 9.Univ Hamburg, Lab Struct Biol Infect & Inflammat, Hamburg, Germany; 10.Gothenburg Univ, Dept Clin Microbiol, Sahlgrenska Acad, Gothenburg, Sweden; |
| 推荐引用方式 GB/T 7714 | Tan, Jinzhi,George, Shyla,Kusov, Yuri,et al. 3C Protease of Enterovirus 68: Structure-Based Design of Michael Acceptor Inhibitors and Their Broad-Spectrum Antiviral Effects against Picornaviruses[J]. JOURNAL OF VIROLOGY,2013,87(8):4339-4351. |
| APA | Tan, Jinzhi.,George, Shyla.,Kusov, Yuri.,Perbandt, Markus.,Anemueller, Stefan.,...&Hilgenfeld, Rolf.(2013).3C Protease of Enterovirus 68: Structure-Based Design of Michael Acceptor Inhibitors and Their Broad-Spectrum Antiviral Effects against Picornaviruses.JOURNAL OF VIROLOGY,87(8),4339-4351. |
| MLA | Tan, Jinzhi,et al."3C Protease of Enterovirus 68: Structure-Based Design of Michael Acceptor Inhibitors and Their Broad-Spectrum Antiviral Effects against Picornaviruses".JOURNAL OF VIROLOGY 87.8(2013):4339-4351. |
入库方式： OAI收割
来源：上海药物研究所
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