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

Antimicrobial Agents and Chemotherapy
Jianmin DuanMichael G Cordingley

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 infect...Continue Reading

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Citations

Nov 17, 2010·Antimicrobial Agents and Chemotherapy·Jocelyne Piret, Guy Boivin
Aug 13, 2013·Expert Opinion on Therapeutic Targets·Sandra K Weller, Robert D Kuchta
Aug 19, 2005·Expert Review of Anti-infective Therapy·Eric Denes, Sylvie Ranger-Rogez
Dec 2, 2004·Expert Opinion on Emerging Drugs·Arun ChakrabartyStephen K Tyring
Dec 23, 2011·British Journal of Haematology·Rob S Sellar, Karl S Peggs
Mar 31, 2016·International Journal of Oral Science·Yu-Chen JiangXiu-Rong Guo
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Sep 8, 2004·Current Opinion in Pharmacology·Guy HewlettHelga Rübsamen-Waigmann
Jul 23, 2004·Antiviral Chemistry & Chemotherapy·Gerald Kleymann

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