title: Synthesis and evaluation of keto-glutamine analogues as potent inhibitors of severe acute respiratory syndrome 3CLpro.
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.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Jain
authors.forename: Hanna I
authors.initials: HI
authors.lastname: Pettersson
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Aull
authors.forename: Pascal D
authors.initials: PD
authors.lastname: Fortin
authors.forename: Carly
authors.initials: C
authors.lastname: Huitema
authors.forename: Lindsay D
authors.initials: LD
authors.lastname: Eltis
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Parrish
authors.forename: Michael N G
authors.initials: MN
authors.lastname: James
authors.forename: David S
authors.initials: DS
authors.lastname: Wishart
authors.forename: John C
authors.initials: JC
authors.lastname: Vederas
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000737:chemistry; D005973:Glutamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D007659:Ketones; D014764:Viral Proteins; D005973:Glutamine; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases