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

J Med Chem. 2006 Aug 10;49(16):4971-80. doi: 10.1021/jm0603926.

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
  • SARS Virus / 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