Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Virology, ANTIVIRAL ACTIVITY, MURINE GAMMAHERPESVIRUS, HERPESVIRUS, CIDOFOVIR, ANALOGS, EBV, REPLICATION, INHIBITION, PHOSPHORYLATION, IDENTIFICATION, Animals, Antiviral Agents, Apoptosis, Blotting, Western, Cells, Cultured, Cidofovir, Cyclic AMP, Cytosine, Gammaherpesvirinae, Herpesviridae Infections, Humans, Kidney, Lymphoma, B-Cell, Mice, Mice, Inbred BALB C, NIH 3T3 Cells, Organophosphonates, Organophosphorus Compounds, Prodrugs, Tumor Virus Infections, Virus Activation, Virus Replication, 06 Biological Sciences, 07 Agricultural and Veterinary Sciences, 11 Medical and Health Sciences, 30 Agricultural, veterinary and food sciences, 31 Biological sciences, 32 Biomedical and clinical sciences

Abstract:

Acyclic nucleoside phosphonates (ANPs), such as HPMPC, are an important group of broad-spectrum antiviral agents with activity against DNA viruses. In this report, we present the in vitro potency of novel ANPs against γ-herpesviruses, including Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus (EBV), and three animal γ-herpesviruses. HPMP-5-azaC, 3-deaza-HPMPA and their cyclic derivatives emerged as highly potent anti-γ-herpesvirus agents. Interestingly, cyclic prodrugs of ANPs exhibited reduced activities against EBV P3HR-1 strain, but not against EBV Akata strain. Cell culture metabolism studies with HPMPC and cyclic HPMPC revealed that these differences were attributed to an altered drug metabolism in P3HR-1 cells after EBV reactivation and more specifically to a reduced hydrolysis of cyclic HPMPC by cyclic CMP phosphodiesterase. We did not correlate this effect to phosphodiesterase downregulation, nor to functional mutations. Instead, altered cAMP levels in P3HR-1 cells indicated a competitive inhibition of the phosphodiesterase by this cyclic nucleotide. Finally, both HPMPC and HPMP-5-azaC emerged as highly effective inhibitors in vivo through significant inhibition of murine γ-herpesvirus replication and dissemination. In the current need of potent anti-γ-herpesvirus antivirals, our findings underlined the requirement of appropriate surrogate viruses for antiviral susceptibility testing and highlighted HPMP-5-azaC as a promising compound for future clinical development.