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Antimicrobial Agents and Chemotherapy, June 2003, p. 1798-1804, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1798-1804.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Oral Bioavailability and In Vivo Efficacy of the Helicase-Primase Inhibitor BILS 45 BS against Acyclovir-Resistant Herpes Simplex Virus Type 1

Jianmin Duan,* Michel Liuzzi, William Paris, Francine Liard, Abigail Browne, Nathalie Dansereau, Bruno Simoneau, Anne-Marie Faucher, and Michael G. Cordingley

Research and Development, Boehringer Ingelheim (Canada) Ltd., Laval, Québec, Canada H7S 2G5

Received 24 October 2002/ Returned for modification 30 December 2002/ Accepted 20 March 2003

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 (ACVr) infections mediated by the HSV type 1 (HSV-1) dlsptk and PAAr5 mutant strains. In vitro, the compound was more potent than ACV against wild-type clinical and laboratory HSV-1 strains and ACVr HSV isolates, as determined by a standard plaque reduction assay, with a mean 50% effective concentration of about 0.15 µM. The oral bioavailability of BILS 45 BS in hairless mice was 49%, with a peak concentration in plasma of 31.5 µM after administration of a single dose of 25 mg/kg. Following cutaneous infection of nude mice, both the HSV-1 dlsptk and PAAr5 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 ACVr HSV-1 mutants. The 50% effective doses of BILS 45 BS were 56.7 and 61 mg/kg/day against dlsptk- and PAAr5-induced infections, respectively. Taken together, our results demonstrate very effective oral therapy of experimental ACVr 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.

* Corresponding author. Mailing address: Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 rue Cunard, Laval, Québec, Canada H7S 2G5. Phone: (450) 682-4640. Fax: (450) 682-8434. E-mail: jduan{at}lav.boehringer-ingelheim.com.

Antimicrobial Agents and Chemotherapy, June 2003, p. 1798-1804, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1798-1804.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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