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 K. 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. PetersAndrew H.J. Wang, Ming Chu Hsu

Research output: Contribution to journalArticle

57 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Yang, S., Chen, S. J., Hsu, M. F., Wu, J. D., Tseng, C. T. K., Liu, Y. F., Chen, H. C., Kuo, C. W., Wu, C. S., Chang, L. W., Chen, W. C., Liao, S. Y., Chang, T. Y., Hung, H. H., Shr, H. L., Liu, C. Y., Huang, Y. A., Chang, L. Y., Hsu, J. C., ... Hsu, M. C. (2006). Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor. Journal of Medicinal Chemistry, 49(16), 4971-4980. https://doi.org/10.1021/jm0603926