Selective inhibition of cytomegaloviruses by 9-(3'-ethylphosphono-1'-hydroxymethyl-1'-propyloxy-methyl)g uanine.
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.
Barnard
D L
DL
Utah State University, Logan.
Huffman
J H
JH
Sidwell
R W
RW
Reist
E J
EJ
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000188:drug therapy; D004279:DNA, Viral / Q000096:biosynthesis; D005347:Fibroblasts / Q000382:microbiology; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology*; D013237:Stereoisomerism; D013997:Time Factors; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; C084462:9-(3'-ethylphosphono-1'-hydroxymethyl-1'-propyloxymethyl)guanine; D015774:Ganciclovir