Evaluation of a peptidomimetic ribonucleotide reductase inhibitor with a murine model of herpes simplex virus type 1 ocular disease.
The ribonucleotide reductase (RR) of herpes simplex virus type 1 (HSV-1) is an important virulence factor, being required for neurovirulence, ocular virulence, and reactivation from latency. The RR activity requires the association of two distinct homodimeric subunits, and the association of the subunits is inhibited in the presence of a peptide homologous to the carboxy terminus of the small subunit. A structural analog of the inhibitory peptide (BILD 1263) has been shown to inhibit the replication of HSV-1 at micromolar concentrations in vitro. We used a mouse model of HSV-1 ocular infection to determine the in vivo efficacy of topical BILD 1263. Treatment of HSV-1 KOS-infected mice resulted in significant reductions in the severity and incidence of stromal keratitis and corneal neovascularization. At higher concentrations (5%) BILD 1263 reduced the severity but not the incidence of blepharitis. Treatment with 5% BILD 1263 also reduced viral shedding from the cornea by 10- to 14-fold (P < 0.001). In uninfected mice treated with 5% BILD 1263, we found no evidence of corneal epithelial damage, conjunctivitis, or blepharitis, and histopathological studies revealed no changes in the corneas of these mice. These results show that the peptidomimetic RR inhibitor BILD 1263 is effective in preventing disease, has an antiviral effect in vivo, and has little or no toxicity.
Brandt
C R
CR
Department of Ophthalmology, University of Wisconsin Medical School, Madison 53706, USA. crbrandt@facstaff.wisc.edu
Spencer
B
B
Imesch
P
P
Garneau
M
M
Déziel
R
R
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use* / Q000633:toxicity; D001762:Blepharitis / Q000188:drug therapy; D003315:Cornea / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology; D016849:Keratitis, Herpetic / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000627:therapeutic use* / Q000633:toxicity; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; C090897:BILD 1263; D009842:Oligopeptides; D012264:Ribonucleotide Reductases