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 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.
Duan
J
J
Bio-Méga Research Division, Boehringer Ingelheim (Canada) Ltd., Laval, Québec, Canada. jduan@bio-mega.boehringer-ingelheim.ca
Liuzzi
M
M
Paris
W
W
Lambert
M
M
Lawetz
C
C
Moss
N
N
Jaramillo
J
J
Gauthier
J
J
Déziel
R
R
Cordingley
M G
MG
D000212:Acyclovir / Q000494:pharmacology*; D000287:Administration, Topical; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; C114615:BILD 1633 SE; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D012264:Ribonucleotide Reductases; D000212:Acyclovir