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 t he HSV RR large subunit and consequently prevent subunit association a nd 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 potenc y 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 al so provides evidence for the bioactive conformation around two importa nt amino acid residues contained in our inhibitors. A tert-butyl group , which contributes 100-fold to inhibitor potency but does not directl y bind to the large subunit, favors an extended beta-strand conformati on that is prevalent in solution and in the bound state. More signific antly, the bioactive conformation around a pyrrolidine-modified aspara gine residue, which contributes over 30 000-fold to inhibitor potency, is elucidated through a series of conformationally restricted analogu es.