Ureido-Based Peptidomimetic Inhibitors of Herpes Simplex Virus Ribonucleotide Reductase:  An Investigation of Inhibitor Bioactive Conformation

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 co...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1996-05, Vol.39 (11), p.2178-2187
Main Authors: Moss, Neil, Beaulieu, Pierre, Duceppe, Jean-Simon, Ferland, Jean-Marie, Gauthier, Jean, Ghiro, Elise, Goulet, Sylvie, Guse, Ingrid, Llinàs-Brunet, Montse, Plante, Raymond, Plamondon, Louis, Wernic, Dominik, Déziel, Robert
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
herpes simplex virus
Medical sciences
Pharmacology. Drug treatments
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Summary: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 β-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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm950825x