Oral bioavailability and in vivo efficacy of the helicase-primase inhibitor BILS 45 BS against acyclovir-resistant herpes simplex virus type 1.
This study investigated the oral bioavailability and efficacy of BILS 45 BS, a selective herpes simplex virus (HSV) helicase-primase inhibitor, against acyclovir (ACV)-resistant (ACV(r)) infections mediated by the HSV type 1 (HSV-1) dlsptk and PAA(r)5 mutant strains. In vitro, the compound was more potent than ACV against wild-type clinical and laboratory HSV-1 strains and ACV(r) HSV isolates, as determined by a standard plaque reduction assay, with a mean 50% effective concentration of about 0.15 microM. The oral bioavailability of BILS 45 BS in hairless mice was 49%, with a peak concentration in plasma of 31.5 microM after administration of a single dose of 25 mg/kg. Following cutaneous infection of nude mice, both the HSV-1 dlsptk and PAA(r)5 mutant strains induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. Oral treatment with ACV (100 or 125 mg/kg/day, three times a day by gavage) did not affect either mutant-induced infection. In contrast, BILS 45 BS at an oral dose of 100 mg/kg/day almost completely abolished cutaneous lesions mediated by both ACV(r) HSV-1 mutants. The 50% effective doses of BILS 45 BS were 56.7 and 61 mg/kg/day against dlsptk- and PAA(r)5-induced infections, respectively. Taken together, our results demonstrate very effective oral therapy of experimental ACV(r) HSV-1 infections in nude mice and support the potential use of HSV helicase-primase inhibitors for the treatment of nucleoside-resistant HSV disease in humans.
Duan
Jianmin
J
Research and Development, Boehringer Ingelheim Ltd., Laval, Québec, Canada H7S 2G5. jduan@lav.boehringer-ingelheim.com
Liuzzi
Michel
M
Paris
William
W
Liard
Francine
F
Browne
Abigail
A
Dansereau
Nathalie
N
Simoneau
Bruno
B
Faucher
Anne-Marie
AM
Cordingley
Michael G
MG
D000212:Acyclovir / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D019915:DNA Primase; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy*; D018259:Herpesvirus 1, Human / Q000254:growth & development*; D051379:Mice; D008819:Mice, Nude; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014764:Viral Proteins
D000998:Antiviral Agents; C477783:BILS 45 BS; D004791:Enzyme Inhibitors; D011725:Pyridines; D013844:Thiazoles; D014764:Viral Proteins; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases; D000212:Acyclovir