Anti-DNA Virus Activity of the 5′-Nucleotide and 3′,5′-Cyclic Nucleotide of 9-<i>β</i>-<i>D</i>-<i>Arabino</i>furanosyladenine

Abstract

9-β-D-Arabinofuranosyladenine-5′-phosphate (ara-AMP) and 9-β-D-arabinofuranosyladenine 3′,5′-cyclic phosphate (cyclic ara-AMP) had significant in vitro activity against types 1 and 2 herpes simplex, pseudorabies, infectious bovine rhinotracheitis, murine and human cytomegalo, vaccinia and myxoma viruses. The drugs were not inhibitory to type 3 adeno, type 3 parainfluenza, or type 13 rhino virus in cell culture. The antiviral activity of the nucleotide and the cyclic nucleotide appeared equivalent to that seen using the known active purine nucleoside 9-β-D- Arabinofurnosyladenine (ara-A) in parallel experiments. Injection of each compound directly into the brains of mice infected intracerebrally with type 1 or type 2 herpes simplex viruses or with vaccinia virus resulted in a highly significant increase in survivors. The intracerebral dose of ara-A was limited by its relative insolubility in aqueous solutions. Intraperitoneal or per os ara-AMP, cyclic ara-AMP or ara-A treatment of mice infected intracerebrally with type 1 herpes simplex virus significantly prevented encephalitis-induced death or prolonged the mean survival time of the animals. Cyclic am-AMP was at least 10-fold more toxic than ara-A and ara-AMP when administered intraperitoneally, but this toxicity was not seen when it was administered per os. All three compounds were also active when administered per os against type 2 herpes simplex virus-induced encephalitis in mice. Topical application of ara-AMP or cyclic ara-AMP inhibited herpes keratitis in experimentally infected rabbits and herpes virus-induced cutaneous lesions in tails of mice. This activity was generally greater than that seen using ara-A tested in simultaneous experiments.