title: Structure-based design of irreversible, tripeptidyl human rhinovirus 3C protease inhibitors containing N-methyl amino acids.
abstract: Tripeptide-derived molecules incorporating N-methyl amino acid residues and C-terminal Michael acceptor moieties were evaluated as irreversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). Such compounds displayed good 3CP inhibition activity (k(obs)/[I] up to 610,000 M(-1) s(-1)) and potent in vitro antiviral properties (EC50 approaching 0.03 microM) when tested against HRV serotype-14.
authors.affiliation: Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: S E
authors.initials: SE
authors.lastname: Webber
authors.forename: T J
authors.initials: TJ
authors.lastname: Prins
authors.forename: R
authors.initials: R
authors.lastname: Zhou
authors.forename: J T
authors.initials: JT
authors.lastname: Marakovits
authors.forename: J G
authors.initials: JG
authors.lastname: Tikhe
authors.forename: S A
authors.initials: SA
authors.lastname: Fuhrman
authors.forename: A K
authors.initials: AK
authors.lastname: Patick
authors.forename: D A
authors.initials: DA
authors.lastname: Matthews
authors.forename: C E
authors.initials: CE
authors.lastname: Ford
authors.forename: E L
authors.initials: EL
authors.lastname: Brown
authors.forename: S L
authors.initials: SL
authors.lastname: Binford
authors.forename: J W
authors.initials: JW
authors.lastname: Meador
authors.forename: R A
authors.initials: RA
authors.lastname: Ferre
authors.forename: S T
authors.initials: ST
authors.lastname: Worland
mesh_terms: D000086042:3C Viral Proteases; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D012229:Rhinovirus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins
chemical_list: D010455:Peptides; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases