Synthesis and evaluation of keto-glutamine analogues as potent inhibitors of severe acute respiratory syndrome 3CLpro

J Med Chem. 2004 Dec 2;47(25):6113-6. doi: 10.1021/jm0494873.

Abstract

The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at the alpha-position were synthesized and tested as reversible inhibitiors against SARS 3CL(pro). Attachment of tripeptide (Ac-Val-Thr-Leu) to these glutamine-based "warheads" generated significantly better inhibitors (4a-c, 8a-d) with IC(50) values ranging from 0.60 to 70 microM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Cysteine Endopeptidases
  • Endopeptidases / chemistry
  • Glutamine / analogs & derivatives*
  • Glutamine / chemical synthesis*
  • Glutamine / chemistry
  • Ketones / chemical synthesis*
  • Ketones / chemistry
  • Models, Molecular
  • Structure-Activity Relationship
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry

Substances

  • Antiviral Agents
  • Ketones
  • Viral Proteins
  • Glutamine
  • Endopeptidases
  • 3C-like proteinase, Coronavirus
  • Cysteine Endopeptidases