Efficacy of 2'-nor-cyclicGMP in treatment of experimental herpes virus infections.

ABSTRACT

9-[(2-Hydroxy-1,3,2-dioxaphosphorinan-5-yl)oxymethyl]guanine P-oxide (2'-nor-cGMP), the cyclic phosphate of 2'-nor-deoxyguanosine (2'-NDG) was synthesized by phosphorylation of 2'-NDG and evaluated for antiherpetic activity in cell cultures and in animal protection studies. 2'-nor-cGMP was effective in cell culture against both thymidine kinase deficient and wild-type herpes simplex virus type 1 strains and also against herpes simplex virus type 2. The anti-herpes activity of 2'-nor-cGMP against thymidine kinase deficient HSV-1 was confirmed by animal protection studies. Also, in comparative cell culture protection studies, the ED50 (microM) of 2'-nor-cGMP was approximately 10-fold lower than that of 2'-NDG against three strains of varicella zoster virus. In addition, 2'-nor-cGMP was effective orally in preventing HSV-1 orofacial infection and HSV-2 genital infection of mice. Topical therapeutic applications of 2'-nor-cGMP prevented orofacial HSV-1 lesion development in mice and development of HSV-2 genital lesions in guinea pigs. Subcutaneous application of 2'-nor-cGMP to intracerebral HSV-1 challenged weanling mice significantly prolonged survival. These studies indicate that 2'-nor-cGMP is not dependent on viral thymidine kinase for its antiviral activity and is highly effective in preventing experimental HSV infections.