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. 2005 Oct;3(10):e324.
doi: 10.1371/journal.pbio.0030324. Epub 2005 Sep 6.

Design of wide-spectrum inhibitors targeting coronavirus main proteases

Haitao Yang  1 , Weiqing Xie, Xiaoyu Xue, Kailin Yang, Jing Ma, Wenxue Liang, Qi Zhao, Zhe Zhou, Duanqing Pei, John Ziebuhr, Rolf Hilgenfeld, Kwok Yung Yuen, Luet Wong, Guangxia Gao, Saijuan Chen, Zhu Chen, Dawei Ma, Mark Bartlam, Zihe Rao
Affiliations

Design of wide-spectrum inhibitors targeting coronavirus main proteases

Haitao Yang et al. PLoS Biol. 2005 Oct.

Erratum in

  • PLoS Biol. 2005 Nov;3(11):e428

Abstract

The genus Coronavirus contains about 25 species of coronaviruses (CoVs), which are important pathogens causing highly prevalent diseases and often severe or fatal in humans and animals. No licensed specific drugs are available to prevent their infection. Different host receptors for cellular entry, poorly conserved structural proteins (antigens), and the high mutation and recombination rates of CoVs pose a significant problem in the development of wide-spectrum anti-CoV drugs and vaccines. CoV main proteases (M(pro)s), which are key enzymes in viral gene expression and replication, were revealed to share a highly conservative substrate-recognition pocket by comparison of four crystal structures and a homology model representing all three genetic clusters of the genus Coronavirus. This conclusion was further supported by enzyme activity assays. Mechanism-based irreversible inhibitors were designed, based on this conserved structural region, and a uniform inhibition mechanism was elucidated from the structures of Mpro-inhibitor complexes from severe acute respiratory syndrome-CoV and porcine transmissible gastroenteritis virus. A structure-assisted optimization program has yielded compounds with fast in vitro inactivation of multiple CoV M(pro)s, potent antiviral activity, and extremely low cellular toxicity in cell-based assays. Further modification could rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-related diseases.

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Figures

Figure 1
Figure 1. Structures of Inhibitors and Their Interactions with SARS-CoV Mpro
(A) The structures of compounds I2, N1, and N3. (B) A stereo view showing I2 bound into the substrate-binding pocket of the SARS-CoV Mpro at 2.7 Å. The I2 inhibitor is shown in gold and covered by an omit map contoured at 1.0 σ. Residues forming the substrate-binding pocket are shown in silver. (C) A stereo view showing N1 bound into the substrate-binding pocket of the SARS-CoV Mpro at 2.0 Å. The N1 inhibitor is shown in gold and covered by an omit map contoured at 1.0 σ. Residues forming the substrate-binding pocket are shown in silver. Two water molecules (in red) form hydrogen bonds with N1. (D) Detailed view of the interactions between the N1 and SARS-CoV Mpro. The N1 inhibitor is shown in green. Hydrogen bonds are shown as dashed lines, and interaction distances are given. The covalent bond is labeled in red.
Figure 2
Figure 2. Surface Representation of Native SARS-CoV Mpro and Inhibitor Complexes
(A) Surface representation of conserved substrate-binding pockets of five CoV Mpros. Background is SARS-CoV Mpro. Red: identical residues among the five CoV Mpros; magenta: substitution in one CoV Mpro; orange: substitution in two CoV Mpros. The S1, S2, S4, and S1′ subsites and residues forming the substrate-binding pocket are labeled. (B) Surface representation of SARS-CoV Mpro (blue) complexed with N1 (green). Water molecules are shown as red spheres. The P1–P5 and P1′ groups and residues forming the substrate-binding pocket are labeled. (C) Surface representation of SARS-CoV Mpro (blue) in complex with N3 (green). Labels are the same as in Figure 2B.
Figure 3
Figure 3. The Structure of TGEV Mpro in Complex with N1
A stereo view showing N1 bound into the substrate-binding pocket of the TGEV Mpro at 2.7 Å. The N1 inhibitor is shown in gold and covered by an omit map contoured at 1.0 σ. Residues forming the substrate-binding pocket are shown in silver. The red sphere represents a water molecule that is hydrogen bonded to N1.
Figure 4
Figure 4. Cell-Based Assays of N3 against HCoV-229E, FIPV, and MHV-A59
Inhibition of replication of three CoVs under high-multiplicity single-cycle growth conditions (MOI = 3) and protection of DBT cells from MHV infection under low-multiplicity growth conditions (MOI = 0.01). (A) Reduction of HCoV-229E titer in MRC-5 cell culture by N3. (B) Reduction of FIPV titer in FCWF cell culture by N3. (C) Reduction of MHV-A59 titer in DBT cell culture by N3. In (A–C), infections were done at an MOI of 3 TCID50 per cell, and titers were determined at 14 h postinfection. (D) Plaque-reduction assay of MHV-A59. FCWF, F. catus whole fetus; MOI, multiplicity of infection.
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