Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor

Syaulan Yang, Shu Jen Chen, Min Feng Hsu, Jen Dar Wu, Chien-Te Tseng, Yu Fan Liu, Hua Chien Chen, Chun Wei Kuo, Chi Shen Wu, Li Wen Chang, Wen Chang Chen, Shao Ying Liao, Teng Yuan Chang, Hsin Hui Hung, Hui Lin Shr, Cheng Yuan Liu, Yu An Huang, Ling Yin Chang, Jen Chi Hsu, Clarence J. Peters & 2 others Andrew H J Wang, Ming Chu Hsu

Research output: Contribution to journalArticle

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Abstract

A potent SARS coronavirus (CoV) 3CL protease inhibitor (TG-0205221, K i = 53 nM) has been developed. TG-0205221 showed remarkable activity against SARS CoV and human coronavirus (HCoV) 229E replications by reducing the viral titer by 4.7 log (at 5 μM) for SARS CoV and 5.2 log (at 1.25 μM) for HCoV 229E. The crystal structure of TG-0205221 (resolution = 1.93 Å) has revealed a unique binding mode comprising a covalent bond, hydrogen bonds, and numerous hydrophobic interactions. Structural comparisons between TG-0205221 and a natural peptide substrate were also discussed. This information may be applied toward the design of other 3CL protease inhibitors.

Original languageEnglish (US)
Pages (from-to)4971-4980
Number of pages10
JournalJournal of Medicinal Chemistry
Volume49
Issue number16
DOIs
StatePublished - Aug 10 2006

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SARS Virus
Structure-Activity Relationship
Protease Inhibitors
Antiviral Agents
Human Coronavirus 229E
Crystal structure
Covalent bonds
Hydrophobic and Hydrophilic Interactions
Hydrogen
Hydrogen bonds
Peptides
(2-tert-butoxy-1-(2-cyclohexyl-1-(1-formyl-2-(2-oxopyrrolidin-3-yl)ethylcarbamoyl)ethylcarbamoyl)propyl)carbamic acid benzyl ester
Substrates

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor. / Yang, Syaulan; Chen, Shu Jen; Hsu, Min Feng; Wu, Jen Dar; Tseng, Chien-Te; Liu, Yu Fan; Chen, Hua Chien; Kuo, Chun Wei; Wu, Chi Shen; Chang, Li Wen; Chen, Wen Chang; Liao, Shao Ying; Chang, Teng Yuan; Hung, Hsin Hui; Shr, Hui Lin; Liu, Cheng Yuan; Huang, Yu An; Chang, Ling Yin; Hsu, Jen Chi; Peters, Clarence J.; Wang, Andrew H J; Hsu, Ming Chu.

In: Journal of Medicinal Chemistry, Vol. 49, No. 16, 10.08.2006, p. 4971-4980.

Research output: Contribution to journalArticle

Yang, S, Chen, SJ, Hsu, MF, Wu, JD, Tseng, C-T, Liu, YF, Chen, HC, Kuo, CW, Wu, CS, Chang, LW, Chen, WC, Liao, SY, Chang, TY, Hung, HH, Shr, HL, Liu, CY, Huang, YA, Chang, LY, Hsu, JC, Peters, CJ, Wang, AHJ & Hsu, MC 2006, 'Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor', Journal of Medicinal Chemistry, vol. 49, no. 16, pp. 4971-4980. https://doi.org/10.1021/jm0603926
Yang, Syaulan ; Chen, Shu Jen ; Hsu, Min Feng ; Wu, Jen Dar ; Tseng, Chien-Te ; Liu, Yu Fan ; Chen, Hua Chien ; Kuo, Chun Wei ; Wu, Chi Shen ; Chang, Li Wen ; Chen, Wen Chang ; Liao, Shao Ying ; Chang, Teng Yuan ; Hung, Hsin Hui ; Shr, Hui Lin ; Liu, Cheng Yuan ; Huang, Yu An ; Chang, Ling Yin ; Hsu, Jen Chi ; Peters, Clarence J. ; Wang, Andrew H J ; Hsu, Ming Chu. / Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 16. pp. 4971-4980.
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AU - Chen, Shu Jen

AU - Hsu, Min Feng

AU - Wu, Jen Dar

AU - Tseng, Chien-Te

AU - Liu, Yu Fan

AU - Chen, Hua Chien

AU - Kuo, Chun Wei

AU - Wu, Chi Shen

AU - Chang, Li Wen

AU - Chen, Wen Chang

AU - Liao, Shao Ying

AU - Chang, Teng Yuan

AU - Hung, Hsin Hui

AU - Shr, Hui Lin

AU - Liu, Cheng Yuan

AU - Huang, Yu An

AU - Chang, Ling Yin

AU - Hsu, Jen Chi

AU - Peters, Clarence J.

AU - Wang, Andrew H J

AU - Hsu, Ming Chu

PY - 2006/8/10

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