Effect of oral treatment with (S)-HPMPA, HDP-(S)-HPMPA or ODE-(S)-HPMPA on replication of murine cytomegalovirus or human cytomegalovirus in animal models. Antivir. Res

We utilized BALB/c mice infected with murine CMV (MCMV) or severe combined immunodeficient (SCID) mice implanted with human fetal tissue and infected with HCMV to determine the efficacy of (S)-9-[3-hydroxy-2-(phophonomethoxy)propyl]adenine ((S)-HPMPA), hexadecyloxypropyl-(S)-HPMPA (HDP-(S)-HPMPA), or octadecyloxyethyl-(S)-HPMPA (ODE-(S)-HPMPA). In MCMV-infected BALB/c mice, oral HDP-(S)-HPMPA at 30 mg/kg significantly reduced mortality when started 24- 48 h post inoculation. In the experimental HCMV infection, oral administration of vehicle or 10 mg/kg of (S)-HPMPA, HDP-(S)-HPMPA or ODE-(S)-HPMPA was initiated 24 h after infection and continued for 28 consecutive days. Cidofovir (CDV), at 20 mg/kg given i.p., was used as a positive control. HDP-(S)-HPMPA or ODE-(S)-HPMPA significantly reduced viral replication compared to vehicle treated mice, while oral (S)-HPMPA was ineffective. Keywords cytomegalovirus; antiviral; animal models; phosphonate nucleotides Synthesis of orally active alkoxyalkyl esters of cidofovir (CDV) and (S)-9-[3-hydroxy-2-(phophonomethoxy)propyl]adenine ((S)-HPMPA) have resulted in modified compounds that are highly effective in vitro against both orthopoxviruses and cytomegalovirus (CMV) (Beadle et al., 2006, Keith et al., 2004). The EC50 values of (S)-HPMPA, hexadecyloxypropyl-(S)-HPMPA (HDP-(S)-HPMPA), octadecyloxyethyl-(S)-HPMPA (ODE-(S)-HPMPA) and CDV against murine CMV (MCMV) and HCMV, respectively, were 0.16, 0.002, 0.003 and 0.04 fo