ANTIVIRAL ACTIVITY OF A SELECTIVE RIBONUCLEOTIDE REDUCTASE INHIBITOR AGAINST ACYCLOVIR-RESISTANT HERPES-SIMPLEX VIRUS TYPE-1 IN-VIVO

The present study reports the activity of BILD 1633 SE against acyclov ir (ACV)-resistant herpes simplex virus (HSV) infections in athymic nu de (nu/nu) mice, BILD 1633 SE is a novel peptidomimetic inhibitor of H SV ribonucleotide reductase (RR). In vitro, it is more potent than ACV against several strains of wild-type as well as ACV-resistant HSV mut ants. Its in vivo activity was tested against cutaneous viral infectio ns in athymic nude mice infected with the ACV-resistant isolates HSV t ype 1 (HSV-1) dlsptk and PAA(r)5, which contain mutations in the viral thymidine kinase gene and the polymerase gene, respectively. Followin g cutaneous infection of athymic nude mice, both HSV-1 dlsptk and PAA( r)S induced significant, reproducible, and persistent cutaneous lesion s that lasted for more than 2 weeks. A 10-day treatment regimen with A CV given topically four times a day as a 5% cream or orally at up to 5 mg/ml in drinking water was partially effective against HSV-1 PAA(r)5 infection with a reduction of the area under the concentration-time c urve (AUC) of 34 to 48%. The effects of ACV against HSV-1 dlsptk infec tion were not significant when it was administered topically and were only marginal when it was given in drinking water. Treatment under ide ntical conditions with 5% topical BILD 1633 SE significantly reduced t he cutaneous lesions caused by both HSV-1 dlsptk and PAA(r)S infection s. The effect of BILD 1633 SE against HSV-1 PAA(r)S infections was mor e prominent and was inoculum and dose dependent, with AUC reductions o f 96 and 67% against infections with 10(6) and 10(7) PFU per inoculati on site, respectively, BILD 1633 SE also significantly decreased the l esions caused by HSV-1 dlsptk infection (28 to 51% AUC reduction). Com bination therapy with topical BILD 1633 SE (5%) and ACV in drinking wa ter (5 mg/ml) produced an antiviral effect against HSV-1 dlsptk. and P AA(r)5 infections that was more than the sum of the effects of both dr ugs. This is the first report that a selective HSV RR subunit associat ion inhibitor can be effective against ACV-resistant HSV infections in vivo.