Structures of two coronavirus main proteases: Implications for substrate binding and antiviral drug design

被引：326

作者：

Xue, Xiaoyu ^{[1
,2
]}

Yu, Hongwei ^{[3
]}

Yang, Haitao ^{[1
,2
]}

Xue, Fei ^{[1
,2
]}

Wu, Zhixin ^{[3
]}

Shen, Wei ^{[1
,2
]}

Li, Jun ^{[1
,2
]}

Zhou, Zhe ^{[1
]}

Ding, Yi ^{[1
]}

Zhao, Qi ^{[1
,2
]}

Zhang, Xuejun C. ^{[2
]}

Liao, Ming ^{[3
]}

Bartlam, Mark ^{[1
,2
,4
]}

Rao, Zihe ^{[1
,2
,4
]}

机构：

[1] Tsinghua Univ, Struct Biol Lab, Tsinghua Nankai IBP Joint Res Grp Struct Biol, Beijing 100084, Peoples R China

[2] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China

[3] S China Agr Univ, Coll Vet Med, Lab Avian Med, Guangzhou 510642, Guangdong, Peoples R China

[4] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China

来源：

JOURNAL OF VIROLOGY | 2008年 / 82卷 / 05期

关键词：

D O I：

10.1128/JVI.02114-07

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M-Pro), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) M-Pro and a severe acute respiratory syndrome CoV (SARS-CoV) M-Pro mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M-Pro. A monomeric form of IBV M-Pro was identified for the first time in COV M-Pro, structures. A comparison of these two structures to other available M-Pro structures provides new insights for the design of substrate-based inhibitors targeting CoV M-Pro. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M-Pro and was found to demonstrate in vitro inactivation of IBV M-Pro and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M-Pro.

引用

页码：2515 / 2527

页数：13

共 37 条

[21] Refinement of macromolecular structures by the maximum-likelihood method [J].

Murshudov, GN ;

Vagin, AA ;

Dodson, EJ .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 1997, 53 :240-255

[22] THE 3-DIMENSIONAL STRUCTURE OF RETINOL-BINDING PROTEIN [J].

NEWCOMER, ME ;

JONES, TA ;

AQVIST, J ;

SUNDELIN, J ;

ERIKSSON, U ;

RASK, L ;

PETERSON, PA .

EMBO JOURNAL, 1984, 3 (07) :1451-1454

[23] Processing of X-ray diffraction data collected in oscillation mode [J].

Otwinowski, Z ;

Minor, W .

MACROMOLECULAR CRYSTALLOGRAPHY, PT A, 1997, 276 :307-326

[24] Coronavirus as a possible cause of severe acute respiratory syndrome [J].

Peiris, JSM ;

Lai, ST ;

Poon, LLM ;

Guan, Y ;

Yam, LYC ;

Lim, W ;

Nicholls, J ;

Yee, WKS ;

Yan, WW ;

Cheung, MT ;

Cheng, VCC ;

Chan, KH ;

Tsang, DNC ;

Yung, RWH ;

Ng, TK ;

Yuen, KY .

LANCET, 2003, 361 (9366) :1319-1325

[25]

Pereira HG, 1989, ANDREWES VIRUSES VER, P42

[26]

REED L. J., 1938, AMER JOUR HYG, V27, P493

[27] Substructure solution with SHELXD [J].

Schneider, TR ;

Sheldrick, GM .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2002, 58 :1772-1779

[28] Dissection study on the severe acute respiratory syndrome 3C-like protease reveals the critical role of the extra domain in dimerization of the enzyme - Defining the extra domain as a new target for design of highly specific protease inhibitors [J].

Shi, JH ;

Wei, Z ;

Song, JX .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (23) :24765-24773

[29]

Snijder E. J., 1995, The coronaviridae., P239

[30]

Spaan W. J. M., 2004, VIRUS TAXONOMY, P945

← 1 2 3 4 →