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, Ki = 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 microM) for SARS CoV and 5.2 log (at 1.25 microM) for HCoV 229E. The crystal structure of TG-0205221 (resolution = 1.93 A) 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.
Yang
Syaulan
S
TaiGen Biotechnology Co., Taipei 114, Taiwan, ROC.
Chen
Shu-Jen
SJ
Hsu
Min-Feng
MF
Wu
Jen-Dar
JD
Tseng
Chien-Te K
CT
Liu
Yu-Fan
YF
Chen
Hua-Chien
HC
Kuo
Chun-Wei
CW
Wu
Chi-Shen
CS
Chang
Li-Wen
LW
Chen
Wen-Chang
WC
Liao
Shao-Ying
SY
Chang
Teng-Yuan
TY
Hung
Hsin-Hui
HH
Shr
Hui-Lin
HL
Liu
Cheng-Yuan
CY
Huang
Yu-An
YA
Chang
Ling-Yin
LY
Hsu
Jen-Chi
JC
Peters
Clarence J
CJ
Wang
Andrew H-J
AH
Hsu
Ming-Chu
MC
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D028941:Coronavirus 229E, Human / Q000187:drug effects; D000086782:Coronavirus 3C Proteases; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014779:Virus Replication / Q000187:drug effects; D009842:Oligopeptides; D011760:Pyrrolidinones
D000998:Antiviral Agents; D002219:Carbamates; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases; D004151:Dipeptides; D014764:Viral Proteins; C513370:(2-tert-butoxy-1-(2-cyclohexyl-1-(1-formyl-2-(2-oxopyrrolidin-3-yl)ethylcarbamoyl)ethylcarbamoyl)propyl)carbamic acid benzyl ester; D009842:Oligopeptides; D011760:Pyrrolidinones