Selective inhibition of cytomegaloviruses by 9-(3'-ethylphosphono-1'-hydroxymethyl-1'-propyloxy-methyl)g uanine

Abstract

9-(3'-ethylphosphono-1'-hydroxymethyl-1'-propyloxy-methyl)gu anine (SR 3727A) was significantly inhibitory to strain AD169 of human cytomegalovirus (HCMV) utilizing plaque reduction and inhibition of intra- and extracellular virus yield in MRC-5 cells. The 50% effective concentrations (EC50) ranged from 6-17 microM for three laboratory strains of HCMV, whereas the 50% cytotoxic doses were > 4200 microM as determined by viable cell assay and inhibition of radiolabeled precursors into DNA, RNA and protein. EC50 values against ganciclovir-sensitive clinical isolates ranged from 8-47 microM. Against two ganciclovir-resistant strains of HCMV, EC50 values of SR 3727A were 84 and 320 microM; against murine CMV (MCMV); 17 microM and against guinea pig CMV, 56 microM. SR 3727A was most effective when infected cells were treated 24 h or less after virus adsorption. BALB/c mice infected intraperitoneally (i.p.) with a lethal dose of MCMV were treated i.p. with 31.3, 62.5, 125, or 250 mg/kg/day of SR 3727 twice daily for 5 days beginning 4 h pre-virus inoculation. All doses were well tolerated; the 125 and 250 mg/kg/day doses significantly prevented death. In a second experiment, SR 3727 at 125 mg/kg/day markedly reduced titers of recoverable virus from spleens, kidneys, and salivary glands harvested at varying times after virus inoculation.