Journal of Virology vol:87 issue:22 pages:12422-12432
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.