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, 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.
authors.affiliation: TaiGen Biotechnology Co., Taipei 114, Taiwan, ROC.
authors.forename: Syaulan
authors.initials: S
authors.lastname: Yang
authors.forename: Shu-Jen
authors.initials: SJ
authors.lastname: Chen
authors.forename: Min-Feng
authors.initials: MF
authors.lastname: Hsu
authors.forename: Jen-Dar
authors.initials: JD
authors.lastname: Wu
authors.forename: Chien-Te K
authors.initials: CT
authors.lastname: Tseng
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Liu
authors.forename: Hua-Chien
authors.initials: HC
authors.lastname: Chen
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Kuo
authors.forename: Chi-Shen
authors.initials: CS
authors.lastname: Wu
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Chang
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chen
authors.forename: Shao-Ying
authors.initials: SY
authors.lastname: Liao
authors.forename: Teng-Yuan
authors.initials: TY
authors.lastname: Chang
authors.forename: Hsin-Hui
authors.initials: HH
authors.lastname: Hung
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Shr
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Liu
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Huang
authors.forename: Ling-Yin
authors.initials: LY
authors.lastname: Chang
authors.forename: Jen-Chi
authors.initials: JC
authors.lastname: Hsu
authors.forename: Clarence J
authors.initials: CJ
authors.lastname: Peters
authors.forename: Andrew H-J
authors.initials: AH
authors.lastname: Wang
authors.forename: Ming-Chu
authors.initials: MC
authors.lastname: Hsu
mesh_terms: 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
chemical_list: 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