Selective inhibition of human cytomegalovirus DNA synthesis by (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC] and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG).
The novel acyclic nucleoside phosphonate, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC], is a potent and selective inhibitor of human cytomegalovirus (CMV) replication in cell culture. (S)-HPMPC inhibits CMV DNA synthesis in a concentration-dependent manner within the concentration range of 0.04-4 micrograms/ml. At 4 micrograms/ml, viral DNA synthesis is completely suppressed. (S)-HPMPC proved more inhibitory to CMV replication and CMV DNA synthesis than 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG, ganciclovir), the current drug of choice for the treatment of CMV infections. Both compounds affected cell proliferation and cellular DNA synthesis only at a concentration that was 100- to 500-fold higher than the antivirally effective concentrations. In accord with the postulated target (viral DNA synthesis) for its antiviral action, (S)-HPMPC did not prevent immediate early antigen expression in CMV-infected cells. A limited exposure time (as short as 6 hr postinfection) of the CMV-infected cells to (S)-HPMPC sufficed to afford a pronounced and prolonged inhibition of viral DNA synthesis and virus replication. This gives (S)-HPMPC a definite advantage over DHPG, which only afforded a weak and transient inhibition of CMV DNA synthesis and virus replication after it had been exposed to the cells for a short exposure time. The long-lasting antiviral action of (S)-HPMPC is a unique property that opens new therapeutic modalities for the treatment of virus infections.
Neyts
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Snoeck
R
R
Schols
D
D
Balzarini
J
J
De Clercq
E
E
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000302:isolation & purification; D004261:DNA Replication / Q000187:drug effects*; D004279:DNA, Viral / Q000187:drug effects / Q000302:isolation & purification; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology*; D006801:Humans; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*
D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D004247:DNA; D000077404:Cidofovir; D015774:Ganciclovir