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Journal of Virology, March 2008, p. 2515-2527, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02114-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Structures of Two Coronavirus Main Proteases: Implications for Substrate Binding and Antiviral Drug Design{triangledown}

Xiaoyu Xue,1,2,{dagger} Hongwei Yu,3,{dagger} Haitao Yang,1,2 Fei Xue,1,2 Zhixin Wu,3 Wei Shen,1,2 Jun Li,1,2 Zhe Zhou,1 Yi Ding,1 Qi Zhao,1,2 Xuejun C. Zhang,2 Ming Liao,3 Mark Bartlam,1,2,4 and Zihe Rao1,2,4*

Tsinghua-Nankai-IBP Joint Research Group for Structural Biology, Tsinghua University, Beijing 100084, China,1 National Laboratory of Biomacromolecules, Institute of Biophysics (IBP), Chinese Academy of Sciences, Beijing 100101, China,2 Laboratory of Avian Medicine, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China,3 College of Life Sciences, Nankai University, Tianjin 300071, China4

Received 25 September 2007/ Accepted 12 December 2007

Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (Mpro), 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) Mpro and a severe acute respiratory syndrome CoV (SARS-CoV) Mpro mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of Mpro. A monomeric form of IBV Mpro was identified for the first time in CoV Mpro structures. A comparison of these two structures to other available Mpro structures provides new insights for the design of substrate-based inhibitors targeting CoV Mpros. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV Mpro and was found to demonstrate in vitro inactivation of IBV Mpro 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 Mpro.

* Corresponding author. Mailing address: Laboratory of Structural Biology, Life Sciences Building, Tsinghua University, Beijing 100084, China. Phone: 86 10 62771493. Fax: 86 10 62773145. E-mail: raozh{at}xtal.tsinghua.edu.cn

{triangledown} Published ahead of print on 19 December 2007.

{dagger} These authors contributed equally.

Journal of Virology, March 2008, p. 2515-2527, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02114-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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