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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

Xiaoyu Xue,^1,2, Hongwei Yu,^3, 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 Rao^1,2,4*

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 (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^pros. 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.

Published ahead of print on 19 December 2007.

These authors contributed equally.

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