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)

Abstract

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 μ/ml. At 4 μg/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.