Oral bioavailability and in vivo efficacy of the helicase-primase inhibitor BILS 45 BS against acyclovir-resistant herpes simplex virus type 1.

Abstract

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.

• Authors: Jianmin Duan, Michel Liuzzi, William Paris, Francine Liard, Abigail Browne, Nathalie Dansereau, Bruno Simoneau, Anne-Marie Faucher, Michael G Cordingley
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 47 Issue 6 Pg. 1798-804 (Jun 2003) ISSN: 0066-4804 [Print] United States
• PMID: 12760851 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• BILS 45 BS
• Enzyme Inhibitors
• Pyridines
• Thiazoles
• Viral Proteins
• DNA Primase
• helicase-primase, Human herpesvirus 1
• DNA Helicases
• Acyclovir

Topics

• Acyclovir (pharmacology)
• Administration, Oral
• Animals
• Antiviral Agents (administration & dosage, pharmacokinetics, pharmacology)
• Area Under Curve
• Biological Availability
• DNA Helicases (antagonists & inhibitors)
• DNA Primase
• Dose-Response Relationship, Drug
• Drug Resistance, Viral
• Enzyme Inhibitors (administration & dosage, pharmacokinetics, pharmacology)
• Female
• Herpes Simplex (drug therapy)
• Herpesvirus 1, Human (growth & development)
• Mice
• Mice, Nude
• Pyridines (administration & dosage, pharmacokinetics, pharmacology)
• Thiazoles (administration & dosage, pharmacokinetics, pharmacology)
• Viral Proteins