Ureido-Based Peptidomimetic Inhibitors 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.

Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing

“…Inhibition of RR activity through blockage of R2 binding to R1 has the potential to be a general chemotherapeutic strategy. The work of Moss et al50, 51, 53, 54 has shown that very high‐affinity ligands for HSV‐R1 that are potent inhibitors of HSV‐RR and viral proliferation54–58 can be developed through optimization of both the N‐terminal and C‐terminal interactions and of the intervening positions linking the two ends, with the latter apparently serving more to properly orient the terminal groups than to bind directly to HSV‐R1 72. We are currently attempting to achieve comparable results for mRR inhibitors, for possible use in cancer chemotherapy,62, 64, 66 and the work of Yang et al67 on M. tuberculosis RR demonstrates that peptide‐based RR inhibitors have potential utility as microbial antibiotics.…”

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

“…In order to evaluate the bioactive conformation around a pyrrolidinemodified asparagine residue, which contributes over 30,000-fold to inhibitor potency, a series of conformationally restricted 5-and 6-membered Freidinger lactams 121 and 122 was designed and prepared by a new synthetic route (Scheme 25). Compounds 121 and 122 were, however, less active than the original peptide inhibitor 120 [95]. …”

Peptidomimetic Inhibitors of Herpes Simplex Virus Ribonucleotide Reductase with Improved in Vivo Antiviral Activity

“…Insertion of an NH group near the N-terminus of compound 1 improved binding potency over 50-fold (cf. compounds 1 and 3 ) . Evidence led us to conclude that this increase in binding potency was due to a hydrogen-bonding interaction between R1 and the NH group.…”