title: Ureido-based peptidomimetic inhibitor of herpes simplex virus ribonucleotide reductase: an investigation of inhibitor bioactive conformation.
abstract: We have been investigating peptidomimetic inhibitors of herpes simplex virus (HSV) ribonucleotide reductase (RR). These inhibitors bind to the HSV RR large subunit and consequently prevent subunit association and subsequent enzymatic activity. This report introduces a new series of compounds that contain an extra nitrogen (a ureido function) at the inhibitor N-terminus. This nitrogen improves inhibitor binding potency 50-fold over our first published inhibitor series. Evidence supports that this improvement in potency results from a new hydrogen-bonding contact between the inhibitor and the RR large subunit. This report also provides evidence for the bioactive conformation around two important amino acid residues contained in our inhibitors. A tert-butyl group, which contributes 100-fold to inhibitor potency but does not directly bind to the large subunit, favors an extended beta-strand conformation that is prevalent in solution and in the bound state. More significantly, the bioactive conformation around a pyrrolidine-modified asparagine residue, which contributes over 30 000-fold to inhibitor potency, is elucidated through a series of conformationally restricted analogues.
authors.affiliation: Bio-Méga/Boehringer Ingelheim Research Inc., Laval, Québec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Moss
authors.forename: P
authors.initials: P
authors.lastname: Beaulieu
authors.forename: J S
authors.initials: JS
authors.lastname: Duceppe
authors.forename: J M
authors.initials: JM
authors.lastname: Ferland
authors.forename: J
authors.initials: J
authors.lastname: Gauthier
authors.forename: E
authors.initials: E
authors.lastname: Ghiro
authors.forename: S
authors.initials: S
authors.lastname: Goulet
authors.forename: I
authors.initials: I
authors.lastname: Guse
authors.forename: M
authors.initials: M
authors.lastname: Llinàs-Brunet
authors.forename: R
authors.initials: R
authors.lastname: Plante
authors.forename: L
authors.initials: L
authors.lastname: Plamondon
authors.forename: D
authors.initials: D
authors.lastname: Wernic
authors.forename: R
authors.initials: R
authors.lastname: Déziel
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018139:Simplexvirus / Q000201:enzymology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives*
chemical_list: D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D046911:Macromolecular Substances; D009842:Oligopeptides; D014508:Urea; D012264:Ribonucleotide Reductases