The present study reports the activity of
BILD 1633 SE against
acyclovir (ACV)-resistant herpes simplex virus (HSV)
infections in athymic nude (nu/nu) mice.
BILD 1633 SE is a novel
peptidomimetic inhibitor of HSV
ribonucleotide reductase (RR). In vitro, it is more potent than ACV against several strains of wild-type as well as ACV-resistant HSV mutants. Its in vivo activity was tested against cutaneous
viral infections in athymic nude mice infected with the ACV-resistant isolates HSV type 1 (HSV-1) dlsptk and PAAr5, which contain mutations in the viral
thymidine kinase gene and the polymerase gene, respectively. Following cutaneous
infection of athymic nude mice, both HSV-1 dlsptk and PAAr5 induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. A 10-day treatment regimen with ACV 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 PAAr5
infection with a reduction of the area under the concentration-time curve (AUC) of 34 to 48%. The effects of ACV against HSV-1 dlsptk
infection were not significant when it was administered topically and were only marginal when it was given in
drinking water. Treatment under identical conditions with 5% topical
BILD 1633 SE significantly reduced the cutaneous lesions caused by both HSV-1 dlsptk and PAAr5
infections. The effect of
BILD 1633 SE against HSV-1 PAAr5
infections was more prominent and was inoculum and dose dependent, with AUC reductions of 96 and 67% against
infections with 10(6) and 10(7) PFU per inoculation site, respectively.
BILD 1633 SE also significantly decreased the lesions caused by HSV-1 dlsptk
infection (28 to 51% AUC reduction). Combination
therapy with topical
BILD 1633 SE (5%) and ACV in
drinking water (5 mg/ml) produced an
antiviral effect against HSV-1 dlsptk and PAAr5
infections that was more than the sum of the effects of both drugs. This is the first report that a selective HSV RR subunit association inhibitor can be effective against ACV-resistant HSV
infections in vivo.