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. Peters; Andrew H.J. Wang; Ming Chu Hsu

doi:10.1021/jm0603926

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

Microbiology And Immunology

Research output: Contribution to journal › Article › peer-review

84 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 language	English (US)
Pages (from-to)	4971-4980
Number of pages	10
Journal	Journal of medicinal chemistry
Volume	49
Issue number	16
DOIs	https://doi.org/10.1021/jm0603926
State	Published - Aug 10 2006

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/jm0603926

Cite this

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

Yang, S, Chen, SJ, Hsu, MF, Wu, JD, Tseng, CTK, 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

@article{6f998df4e8fa4db1804ae4b6e0d84e65,

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

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 {\AA}) 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.",

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

year = "2006",

month = aug,

day = "10",

doi = "10.1021/jm0603926",

language = "English (US)",

volume = "49",

pages = "4971--4980",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "16",

}

TY - JOUR

T1 - Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor

AU - Yang, Syaulan

AU - Chen, Shu Jen

AU - Hsu, Min Feng

AU - Wu, Jen Dar

AU - Tseng, Chien Te K.

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

Y1 - 2006/8/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33746886624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746886624&partnerID=8YFLogxK

U2 - 10.1021/jm0603926

DO - 10.1021/jm0603926

M3 - Article

C2 - 16884309

AN - SCOPUS:33746886624

SN - 0022-2623

VL - 49

SP - 4971

EP - 4980

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 16

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this