SummaryThe inhibitory effects of the diphosphates of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its analogues on HIV reverse transcriptase and human DNA polymerases a,~, and y have been studied. The analogues investigated are the diphosphates of 9-(2-phosphonylmethoxypropyl)adenine (PMPApp), 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine (PMPDAPpp), and (2R,5R)-9-[2,5-dihydro-5-(phosphonyl methoxy)-2-furanyl]adenine (D4APpp). These four compounds are much more inhibitory to HIV reverse transcriptase when an RNA template rather than a DNA template is used. The K; values for the four compounds range from 11 to 22 nM with an RNA template. The K; values for ddCTP and AZTTP are 54 nM and 8 nM, respectively. PMEApp and its analogues show varying degrees of inhibition of the human DNA polymerases. The K; values for PMEApp, PMPApp and PMPDAPpp against DNA polymerase a are in the micromolar range, while D4APpp is a poor inhibitor of this enzyme with a K; value of 65.9 11M. The lnhlbltlon of DNA polymerase~by PMEApp, PMPApp and D4APpp is minimal, while PMPDAPpp shows higher inhibition of DNA polymerase~with a K; value of 9.71 11M. The K; values for PMEApp and D4APpp against DNA polymerase yare submicromolar, while PMPApp and PMPDAPpp are much less inhibitory to this enzyme. For comparison, ddCTP was found to be a more potent inhibitor of DNA polymerases~and y than the diphosphates of PMEA and its analogues.

SummaryCidofovir 1-[(S)-3-hydroxy-2-(phosphonomethoxy) propyl] cytosine, HPMPC] is an acyclic cytosine nucleotide analogue with potent in-vitro and in-vivo activity against a broad spectrum of herpesviruses including human cytomegalovirus (HCMV). Cidofovir has recently been shown to delay the progression of HCMV retinitis in AIDS patients. Therefore, the effects of several antiviral compounds (GCV, AZT, ddC, ddl, d4T, 3TC and PMEA) on the anti-HCMV activity of cldofovir were investigated in vitro. Cidofovir in combination with GCV demonstrated synergistic inhibition of HCMV replication. Very little significant antiviral synergy or antagonism was measured for any of the other combinations. Furthermore, none of the combinations showed increased cytotoxicity in comparison with each drug alone. Additionally, the antiviral activity of cidofovir was determined in the presence of several immunosuppressive agents (hydrocortisone, cyclosporine A, methotrexate and mycophenolic acid) that are commonly used in the management of organ transplantation rejection in transplant patients. None of these agents altered the antiviral activity of cidofovir in vitro.