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 106 and 107 PFU per inoculation site, respectively. BILD 1633 SE also significantly decreased the lesions caused by HSV-1dlsptk 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.
Nucleoside analogs such as acyclovir (ACV) and penciclovir and prodrugs thereof have been approved as drugs of choice for the treatment of herpes simplex virus (HSV) infections (1, 11). While nucleoside-based therapeutics are quite effective for the treatment of primary and recurrent mucocutaneous infections, present medications are not effective for the treatment of nucleoside-resistant herpesvirus infections in immunocompromised individuals (4,5,29). Moreover, nucleoside-based antiviral therapeutics have limited effects on the establishment of latent HSV infections (6,17,31). Therefore, significant improvements in therapy may be achievable with distinct inhibitors with improved efficacy and pharmacokinetic (PK) properties and a new mechanism of action. We have reported previously on the discovery of specific non-nucleoside-based inhibitors of the HSV type 1 (HSV-1) helicase-primase (10). This enzyme is composed of the virus-encoded UL5, UL8, and UL52 gene products, which are all essential for HSV DNA replication and growth (3,7,9,19,23). The most optimized aminothiazolyl-phenyl compounds exhibited potent antiviral activity against a series of HSV strains analyzed in vitro, including HSV-1 and HSV-2 strains that are ACV r . One of the inhibitors, BILS 179 BS, showed antiviral activity in murine models of wild-type HSV disease after oral administration (10), but its activity against ACV r HSV disease had not been evaluated. In the present report, we provide a detailed examination of the PK and pharmacodynamic properties of a helicase-primase inhibitor, BILS 45 BS, in a mouse model of ACV r HSV infection. PK studies were done with hairless mice, where BILS 45 BS demonstrated in vivo efficacy against wild-type HSV-1 infection with a 50% effective dose (ED 50 ) of 56 mg/kg. The athymic nude mouse model was chosen for the present study because ACV r HSV-1 fails to induce significant disease in normal mice (2, 14-16). In addition, since ACV r HSV infections cause significant disease mainly in the immunocompromised patient population, information obtained with these immunodeficient animals may have clinical relevance (14-16). Our results show that BILS 45 BS, an analog structurally related to BILS 179 BS, exhibited excellent oral efficacy against ACV r HSV-1 infections in nude mice, highlighting the potential of this novel class of antiherpetic agents for the treatment of ACV r HSV disease in humans. MATERIALS AND METHODSCell culture and viruses. All of the cell culture reagents and media used in this study were obtained from Gibco BRL (Burlington, Ontario, Canada). Cells were from the American Type Culture Collection (Manassas, Va.). Vero (African green monkey kidney) cells were grown in Dulbecco's modified Eagle's medium supplemented with 8% fetal bovine serum, 100 U of penicillin per ml, 100 g of streptomycin sulfate per ml, and 100 g of kanamycin sulfate per ml. Baby hamster kidney (BHK) 21/C13 (ATCC CCL10) cells were grown in ␣-MEM instead of Dulbecco's modified Eagle's medium. All cells were grown at 37°C in an ...
A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (Ki) for inhibitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19-24) inhibited HIV-1 replication in cell culture assays with 50% effective concentrations (EC50) = 3.7-35 nM. This series of inhibitors was found to exhibit poor bioavailability (< 10%) in the rat, following oral administration. The synthesis and biological properties of these compounds are discussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HIV protease inhibitors.
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