Journal article
Design of Wide-Spectrum Inhibitors Targeting Coronavirus Main Proteases
PLoS biology, Vol.3(10), pp.1742-1752
10/01/2005
DOI: 10.1371/journal.pbio.0030324
PMCID: PMC1197287
PMID: 16128623
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 (Mpros), 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 Mpros, 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.
Details
- Title: Subtitle
- Design of Wide-Spectrum Inhibitors Targeting Coronavirus Main Proteases
- Creators
- Haitao Yang - Institute of BiophysicsWeiqing Xie - Shanghai Institute of Organic ChemistryXiaoyu Xue - Institute of BiophysicsKailin Yang - Tsinghua UniversityJing Ma - Tsinghua UniversityWenxue Liang - Shanghai Institute of HematologyQi Zhao - Tsinghua UniversityZhe Zhou - Institute of BiophysicsDuanqing Pei - Guangzhou Institutes of Biomedicine and HealthJohn Ziebuhr - University of WürzburgRolf HilgenfeldKwok Yung YuenLuet WongGuangxia Gao - Institute of BiophysicsSaijuan ChenZhu ChenDawei Ma - Shanghai Institute of Organic ChemistryMark Bartlam - Institute of BiophysicsZihe Rao - Tsinghua University
- Resource Type
- Journal article
- Publication Details
- PLoS biology, Vol.3(10), pp.1742-1752
- Publisher
- Public Library of Science
- DOI
- 10.1371/journal.pbio.0030324
- PMID
- 16128623
- PMCID
- PMC1197287
- ISSN
- 1544-9173
- eISSN
- 1545-7885
- Alternative title
- Inhibitors Targeting Coronavirus Mpros
- Language
- English
- Date published
- 10/01/2005
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696726902771
Metrics
3 Record Views