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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antiviral Agents / chemical synthesis*
-
Antiviral Agents / chemistry
-
Antiviral Agents / pharmacology
-
Carbamates / chemical synthesis*
-
Carbamates / chemistry
-
Carbamates / pharmacology
-
Cell Line
-
Chlorocebus aethiops
-
Coronavirus 229E, Human / drug effects
-
Coronavirus 3C Proteases
-
Crystallography, X-Ray
-
Cysteine Endopeptidases / chemistry*
-
Dipeptides / chemical synthesis*
-
Dipeptides / chemistry
-
Dipeptides / pharmacology
-
Drug Stability
-
Humans
-
Hydrogen Bonding
-
Hydrophobic and Hydrophilic Interactions
-
Mice
-
Models, Molecular
-
Molecular Structure
-
Rats
-
Severe acute respiratory syndrome-related coronavirus / drug effects
-
Structure-Activity Relationship
-
Viral Proteins / antagonists & inhibitors*
-
Viral Proteins / chemistry*
-
Virus Replication / drug effects
Substances
-
(2-tert-butoxy-1-(2-cyclohexyl-1-(1-formyl-2-(2-oxopyrrolidin-3-yl)ethylcarbamoyl)ethylcarbamoyl)propyl)carbamic acid benzyl ester
-
Antiviral Agents
-
Carbamates
-
Dipeptides
-
Viral Proteins
-
Cysteine Endopeptidases
-
Coronavirus 3C Proteases