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 req uires the association of two distinct homodimeric subunits, and the as sociation of the subunits is inhibited in the presence of a peptide ho mologous to the carboxy terminus of the small subunit. A structural an alog of the inhibitory peptide (BILD 1263) has been shown to inhibit t he replication of HSV-1 at micromolar concentrations in vitro. We used a mouse model of HSV-1 ocular infection to determine the in vivo effi cacy of topical BILD 1263. Treatment of HSV-1 KOS-infected mice result ed 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 cor nea by 10- to 14-fold (P < 0.001). In uninfected mice treated with 5% BILD 1263, we found no evidence of corneal epithelial damage, conjunct ivitis, or blepharitis, and histopathological studies revealed no chan ges in the corneas of these mice. These results show that the peptidom imetic RR inhibitor BILD 1263 is effective in preventing disease, has an antiviral effect in vivo, and has little or no toxicity.