Inhibitory Efficacy of Cyclo Sal-Nucleoside Monophosphates of Aciclovir and Brivudin on DNA Synthesis of Orthopoxviruses

Abstract

Previous studies have shown that cycloSaligenyl-monophosphate (cycloSal-MP) derivatives of aciclovir (ACV), penciclovir (PCV) and brivudin (BVDU) can act as inhibitors of vaccinia virus and cowpox virus replication in vitro. The aim of the present study was to evaluate the inhibatory efficacy on DNA synthesis in vaccinia and cowpox viruses of several cycloSal-pro-nucleotides of ACV and BVDU, which have proven activity against pox viruses. Viral DNA was quantified in treated and non-treated virus-infected cells by semi-quantitative PCR on the basis of the haemag-glutinin protein gene of orthopoxviruses. As result, an inhibitory efficacy on vaccinia and cowpox virus DNA replication could be demonstrated for 3-methyl-cycloSal-ACVMP, 5-H-cycloSal-ACVMP, 6-chloro-7-ECM-cycloSal-3′-OH-BVDUMP, and 6-chloro-7-methyl-cycloSal-3′-OH-BVDUMP. At concentrations of 32–128 mg/ml, 3-methyl-cycloSal-ACVMP and 6-chloro-7-ECM-cycloSal-3′-OH-BVDUMP inhibited synthesis of viral DNA to a similar extent as the well-known inhibitors of pox viruses, cidofovir and 5-iodo-dUrd (deoxyuridine). When concentrations of 128 mg/ml were administered, both test substances diminished the amount of viral genome copies by ≥4 log₁₀ corresponding to ≥99.99% reduction. In conclusion, selected cycloSal-pro-nucleotide derivatives of ACV and BVDU can inhibit orthopoxviral DNA synthesis. The high inhibitory efficacy on both replication of viral DNA and infectious viral particles in cell cultures makes these compounds promising candidates for in vivo experiments.