Antiviral Research 75 (2007) 30–35 The helicase primase inhibitor, BAY 57-1293 shows potent therapeutic antiviral activity superior to famciclovir in BALB/c mice infected with herpes simplex virus type 1 Subhajit Biswas a , Lyn Jennens b , Hugh J. Field a,∗ a Centre for Veterinary Science, Cambridge University Veterinary School, Madingley Road, Cambridge, CB3 0ES, UK b Arrow Therapeutics Ltd., Britannia House, 7, Trinity Street, London SE1 DB, UK. Received 28 September 2006; accepted 21 November 2006 Abstract BAY 57-1293 represents a new class of potent inhibitors of herpes simplex virus (HSV) that target the virus helicase primase complex. The present study was conducted using the zosteriform infection model in BALB/c mice. The helicase primase inhibitor, BAY 57-1293 was shown to be highly efficacious in this model. The beneficial effects of therapy were obtained rapidly (within 2 days) although the onset of treatment was delayed for 1 day after virus inoculation. The compound given orally, or intraperitoneally once per day at a dose of 15mg/kg for 4 successive days was equally effective or superior to a much higher dose of famciclovir (1 mg/ml, i.e. approximately 140–200 mg/kg/day) given in the drinking water for 7 consecutive days, which, in our hands, is the most effective method for administering famciclovir to mice. In contrast to the vehicle-treated infected mice, all mice that received antiviral therapy looked normal and active with no mortality, no detectable loss of weight and no marked change in ear thickness. BAY 57-1293 and famciclovir reduced the virus titers in the skin to below the level of detection by days 3 and 7 post infection, respectively. In both BAY 57-1293 and famciclovir-treated mice, infectious virus titers in the ear pinna and brainstem remained below the level of detection. Consistent with these findings, BAY 57-1293 also showed a potent antiviral effect in an experiment involving a small number of severely immunocompromised athymic-nude BALB/c mice. © 2006 Elsevier B.V. All rights reserved. Keywords: HSV; Helicase primase; BAY 57-1293; Famciclovir; Antiviral 1. Introduction Herpes simplex virus (HSV) infections cause recurrent cold sores, keratoconjunctivitis and genital herpes and occasion- ally, life-threatening herpes encephalitis. HSV lesions may be chronic in immunocompromised patients and in the latter the infections are prone to become resistant to existing nucleoside and pyrophosphate analogues used for therapy. Approximiately 5% of the isolates from such patients have evidence of resistance (Field, 2001) and there is a particular need in this case to provide alternatives to existing therapy. To date, clinical management of HSV disease comprises chemotherapy using nucleoside or nucleotide or pyrophosphate analogues that exclusively target the viral enzymes thymi- dine kinase (the product of the HSV-1 UL23 gene) and DNA ∗ Corresponding author. Tel.: +44 1223 330810; fax: +44 1223 337610. E-mail address: hjf10@cam.ac.uk (H.J. Field). polymerase (UL30 and the accessory factor UL42). Recently, experiments in immunocompetent animal infection models have suggested that several different compounds which have the novel target, the viral helicase primase complex (the products of HSV-1 UL5, UL8 and UL52 genes) are highly efficacious; indeed, they may be superior to the “gold standard”, acy- clovir (Betz et al., 2002; Crute et al., 2002; Duan et al., 2003; Kleymann et al., 2002; Liuzzi et al., 2004; Spector et al., 1998). Numerous rodent infection models exist for both immuno- competent and immunocompromised hosts in practice, the latter being most important for the development of HSV-resistance in man (reviewed by Field and Brown, 1989). In the present study, we observed that BAY 57-1293, one of the promising helicase primase inhibitors (HPIs) developed to date, is highly effective against HSV-1 infection in immunocompetent BALB/c mice and appeared to be superior to famciclovir, which, in our hands was the most effective compound we had studied to date (Field, 1996). These results confirm and extend previous publications 0166-3542/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.antiviral.2006.11.006