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

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 mu M) for SARS CoV and 5.2 log (at 1.25 mu M) for...

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Veröffentlicht in:Journal of medicinal chemistry Jg. 49; H. 16; S. 4971 - 4980
Hauptverfasser: Yang, Syaulan, Chen, Shu-Jen, Hsu, Min-Feng, Wu, Jen-Dar, Tseng, Chien-Te K., 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: WASHINGTON Amer Chemical Soc 10.08.2006
Schlagworte:
Animals
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Carbamates - chemical synthesis
Carbamates - chemistry
Carbamates - pharmacology
Cell Line
Chemistry, Medicinal
Chlorocebus aethiops
Coronavirus 229E, Human - drug effects
Crystallography, X-Ray
Cysteine Endopeptidases - chemistry
Dipeptides - chemical synthesis
Dipeptides - chemistry
Dipeptides - pharmacology
Drug Stability
Humans
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Life Sciences & Biomedicine
Mice
Models, Molecular
Molecular Structure
Pharmacology & Pharmacy
Rats
SARS Virus - drug effects
Science & Technology
Structure-Activity Relationship
Viral Proteins - antagonists & inhibitors
Viral Proteins - chemistry
Virus Replication - drug effects
DESIGN
GENOME SEQUENCE
VIRUS
ACUTE RESPIRATORY SYNDROME
PROGRAM
ISSN:0022-2623, 1520-4804
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Zusammenfassung: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 mu M) for SARS CoV and 5.2 log (at 1.25 mu M) for HCoV 229E. The crystal structure of TG- 0205221 (resolution = 1.93 angstrom) 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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0603926