HPMPC (cidofovir),PMEA (adefovir) and Related Acyclic Nucleoside Phosphonate Analogues: A Review of their Pharmacology and Clinical Potential in the Treatment of Viral Infections
Free accessReview articleFirst published online February, 1997
HPMPC (cidofovir),PMEA (adefovir) and Related Acyclic Nucleoside Phosphonate Analogues: A Review of their Pharmacology and Clinical Potential in the Treatment of Viral Infections
The acyclic nucleoside phosphonate (ANP) analogues are broad-spectrum antiviral agents, with potent and selective antiviral activity in vitro and in vivo. The prototype compounds are: (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC, cidofovir), which is active against a wide variety of DNA viruses; 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir), which is active against retro-, herpes- and hepadnaviruses, and (R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA), which is active against retro- and hepadnaviruses. The antiviral action of the ANP analogues is based on a specific interaction of the active diphosphorylated metabolite with the viral DNA polymerase. The long intracellular half-life of the active metabolite accounts for the optimal efficacy in infrequent dosing schedules. The potential of HPMPC as a broad-spectrum anti-DNA virus agent, as originally observed in vitro and in vivo, has been confirmed in clinical trials. HPMPC has recently been commercially released in the USA for the treatment of cytomegalovirus retinitis in AIDS patients. In addition, topical systemic HPMPC is being (or will be) explored for use against other herpesviruses (i.e. herpes simplex virus, Epstein-Barr virus, or varicella-zoster virus), by adenoviruses, or by human papilloma- or polyomaviruses. Intravenous HPMPC is associated with dose-dependent nephrotoxicity, that should be counteracted by prehydration and concomitant administration of probenecid, and by the application of an infrequent dosing schedule. The oral prodrug of PMEA, bis(pivaloyloxymethyl)-PMEA, is currently being evaluated in patients infected with human immunodeficiency virus (HIV) or hepatitis B virus. Finally, preclinical data on the efficacy of PMPA in animal retrovirus models point to its potential usefulness against HIV infections, when given either prophylactically or therapeutically in the treatment of established HIV infections.
AdumaPPConnellyMCSrinivasRV & FridlandA (1995) Metabolic diversity and antiviral activities of acyclic nucleoside phosphonates. Molecular Pharmacology47:816–822.
2.
AndreiGSnoeckRScholsDGoubauPDesmyterJ & De ClercqE (1991) Comparative activity of selected antiviral compounds against clinical isolates of human cytomegalovirus. European Journal of Clinical Microbiology and Infectious Diseases10:1026–1033.
3.
AndreiGSnoeckRGoubauPDesmyterJ & De ClercqE (1992) Comparative activity of various compounds against clinical strains of herpes simplex virus. European Journal of Clinical Microbiology and Infectious Diseases11:143–151.
4.
AndreiGSnoeckR & De ClercqE (1995a) Susceptibilities of several drug-resistant herpes simplex virus type 1 strains to alternative antiviral compounds. Antimicrobial Agents and Chemotherapy39:1632–1635.
5.
AndreiGSnoeckRReymenDLiesnardCGoubauPDesmyterJ & De ClercqE (1995b) Comparative activity of selected antiviral compounds against clinical isolates of varicella-zoster virus. European Journal of Clinical Microbiology and Infectious Diseases14:318–328.
6.
AndreiGSnoeckRVandeputteM & De ClercqE (1996a) Activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)-cytosine (HPMPC, cidofovir) against murine and human polyomavirus replication in vitro. Antiviral Research30:A55.
7.
AndreiGSnoeckRVandeputteM & De ClercqE (1996b) Antiviral activity of various compounds against murine, simian and primate polyomaviruses. Antimicrobial Agents and Chemotherapy (in press).
8.
AwanAR & FieldHJ (1993) Effects of phosphonylmethoxyalkyl derivatives studied with a murine model for abortion induced by equine herpesvirus 1. Antimicrobial Agents and Chemotherapy37:2478–2482.
9.
BabaMMoriSShigetaS & De ClercqE (1987a) Selective inhibitory effect of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and 2′-nor-cyclic GMP on adenovirus replication in vitro. Antimicrobial Agents and Chemotherapy31:337–339.
10.
BabaMKonnoKShigetaS & De ClercqE (1987b) in vitro activity of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine against newly isolated clinical varicella-zoster virus strains. European Journal of Clinical Microbiology6:158–160.
11.
BalzariniJ (1994) Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives. Pharmacy World and Science16:113–126.
12.
BalzariniJ & De ClercqE (1991) 5-Phosphoribosyl 1-pyrophosphate synthetase converts the acyclic nucleoside phosphonates 9-(3-hydroxy-2-phosphonylmethoxypropyl) adenine and 9-(2-phosphonylmethoxyethyl)adenine directly to their antivirally active diphosphate derivatives. Journal of Biological Chemistry266:8686–8689.
13.
BalzariniJNaesensLHerdewijnPRosenbergIHolýAPauwelsRBabaMJohnsDG & De ClercqE (1989) Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)-adenine, a selective anti-human immunodeficiency virus agent. Proceedings of the National Academy of Sciences, USA86:332–336.
14.
BalzariniJNaesensL & De ClercqE (1990a) Anti-retrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in vivo increases when it is less frequently administered. International Journal of Cancer46:337–340.
15.
BalzariniJSobisHNaesensLVandeputteM & De ClercqE (1990b) Inhibitory effects of 9-(2-phosphonylmethoxyethyl)-adcnine and 3′-azido-2′,3′-dideoxy-thymidine on tumor development in mice inoculated intracerebrally with Moloney murine sarcoma virus. International Journal of Cancer45:486–489.
16.
BalzariniJHaoZHerdewijnPJohnsDG & De ClercqE (1991a) Intracellular metabolism and mechanism of antiretrovirus action of 9-(2-phosphonylmethoxyethyl)adenine, a potent anti-human immunodeficiency virus compound. Proceedings of the National Academy of Sciences, USA88:1499–1503.
17.
BalzariniJHolýAJindřichJDvořákováHHaoZSnoeckRHerdewijnPJohnsDG & De ClercqE (1991b) 9-[(2RS)-3-Fluoro-2-phosphonylmethoxypropyl]derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo. Proceedings of the National Academy of Sciences, USA88:4961–4965.
18.
BalzariniJNaesensLSlachmuyldersJNiphuisHRosenbergIHolýASchellekensH & De ClercqE (1991c) 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. AIDS5:21–28.
19.
BalzariniJHolýAJindrichJNaesensLSnoeckRScholsD & De ClercqE (1993) Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrobial Agents and Chemotherapy37:332–338.
20.
BalzariniJNavéJ-FBeckerMATatibanaM & De ClercqE (1995) Kinetic properties of adenine nucleotide analogues against purified 5-phosphoribosyl-1-pyrophosphate synthetases from E. coli, rat liver and human erythrocytes. Nucleosides and Nucleotides14:1861–1871.
21.
BalzariniJAquaroSPernoC-FWitvrouwMHolýA & De ClercqE (1996) Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)adenine and 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine against human immunodeficiency virus in different human cell systems. Biochemical and Biophysical Research Communications219:337–341.
22.
Barditch-CrovoPATooleJBurgeeHWachsmanMEbelingDCundyKCJaffeHS & LietmanPS (1995) A randomized, double-blind, placebo-controlled Phase I/II evaluation of 9-[2-(bispivaloyloxymethyl)phosphonylmethoxyethyl]adenine (bis-POM PMEA), an orally bioavailable prodrug of the anti-HIV nucleotide, PMEA. Abstracts of the 8th International Conference on Antiviral Research, Santa Fe, New Mexico, USA, April 23-28 1995. Antiviral Research26:A229.
23.
BesenGFlores-AguilarMAssilKKKuppermanBDGanganPPursleyMMunguiaDVuongCDe ClercqEBergeron-LynnGAzenSP & FreemanWE (1995) Long-term therapy for herpes retinitis in an animal model with high-concentrated liposome-encapsulated HPMPC. Archives of Ophthalmology113:661–668.
24.
BischofbergerNHitchcockMJMChenMSBarkhimerDBCundyKCKentKMLacySALeeWALiZ-HMendelDBSmeeDF & SmithJL (1994) 1-[(S)-2-Hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)mefhyl]cytosine, an intracellular prodrug for (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)-cytosine with improved therapeutic index in vivo. Antimicrobial Agents and Chemotherapy38:2387–2391.
25.
BischofbergerNTsaiC-CFollisKESaboAGrantRFBeckTWDaileyPJ & BlackR (1996) Antiviral efficacy of PMPA in macaques chronically infected with SIV. Abstracts of the 9th International Conference on Antiviral Research, Urabandai, Fukushima, Japan, May 19-24 1996. Antiviral Research30:A42.
26.
BravoFJStanberryLRKierABVogtPE & KernER (1993) Evaluation of HPMPC therapy for primary and recurrent genital herpes in mice and guinea pigs. Antiviral Research21:59–72.
27.
BronsonJJGhazzouliIHitchcockMJMWebbRR & MartinJC (1989) Synthesis and antiviral activity of the nucleotide analogue (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine. Journal of Medicinal Chemistry32:1457–1463.
28.
CaliòRVillaniNBalestraESesaFHolýABalzariniJDe ClercqEPernoC-F & del GobboV (1994) Enhancement of natural killer activity and interferon induction by different acyclic nucleoside phosphonates. Antiviral Research23:77–89.
29.
ČernyJVotrubaIVonkaVRosenbergIOtmarM & HolýA (1990) Phosphonylmefhyl ethers of acyclic nucleoside analogues: inhibitors of HSV-1 induced ribonucleotide reductase. Antiviral Research13:253–264.
30.
CherringtonJMAllenSJMcKeeBH & ChenMS (1994) Kinetic analysis of the interaction between the diphosphate of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, ddCTP, AZTTP & FIAUTP with human DNA polymerases β and γ. Biochemical Pharmacology48:1986–1988.
31.
CherringtonJMAllenSJWBischofbergerN & ChenMS (1995) Kinetic interaction of the diphosphates of 9-(2-phosphonylrnethoxyethyl)adenine and other anti-HIV active purine congeners with HIV reverse transcriptase and human polymerases a, β and γ. Antiviral Chemistry & Chemotherapy6:217–221.
32.
CherringtonJMMulatoASFullerMD & ChenMS (1996) Novel mutation (K70E) in human immunodeficiency virus type 1 reverse transcriptase confers decreased susceptibility to 9-[2-(phosphonylmethoxy)ethyl]adenine in vitro. Antimicrobial Agents and Chemotherapy40:2212–2216.
33.
CihlářT & ChenMS (1997) Identification of enzymes catalyzing two-step phosphorylation of cidofovir and the effect of cytomegalovirus infection on their activities in host cells. Molecular Pharmacology (in press).
34.
CihlářTVotrubaIHorskáKLiboskaRRosenbergI & HolýA (1992) Metabolism of 1-(S)-(3-hydroxy-2-phosphonylmethoxy-propyl)cytosine (HPMPC) in human embryonic lung cells. Collection of Czechoslovak Chemical Communications57:661–672.
35.
CihlářTRosenbergIVotrubaI & HolýA (1995) Transport of 9-(2-phosphonomethoxyethyl)adenine across plasma membrane of HeLa S3 cells is protein mediated. Antimicrobial Agents and Chemotherapy39:117–124.
36.
ConnellyMCRobbinsBL & FridlandA (1993) Mechanism of uptake of the phosphonate analog (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) in Vero cells. Biochemical Pharmacology46:1053–1057.
37.
CundyKCFishbackJAShawJ-PLeeMLSoikeKFVisorGC & LeeWA (1994a) Oral bioavailability of the antiretroviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) from three formulations of the prodrug bis (pivaloyloxymethyl)-PMEA in fasted male cynomolgus monkeys. Pharmaceutical Research11:839–843.
38.
CundyKCLiZ-H & LeeWA (1994b) Effect of concomitant probenecid on the tissue distribution and urinary excretion of HPMPC in preclinical models. Pharmaceutical Research11(Suppl.):S-449.
39.
CundyKCShawJ-PSt LeeWA (1994c) Oral, subcutaneous and intramuscular bioavailabilities of the antiviral nucleotide analog 9-(2-phosphonylmefhoxyefhyl)adenine in cynomolgus monkeys. Antimicrobial Agents and Chemotherapy38:365–368.
40.
CundyKCPettyBGFlahertyJFisherPEPolisMAWachsmanMLietmanPSLalezariJPHitchcockMJM & JaffeHS (1995a) Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrobial Agents and Chemotherapy39:1247–1252.
41.
CundyKCBarditch-CrovoPWalkerRECollierACEbelingDTooleJ & JaffeHS (1995b) Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients. Antimicrobial Agents and Chemotherapy39:2401–2405.
42.
CundyKCLiZ-HHitchcockMJM & LeeWA (1996a) Pharmacokinetics of cidofovir in monkeys. Evidence for a prolonged elimination phase representing phosphorylated drug. Drug Metabolism and Disposition24:738–744.
43.
CundyKCBidgoodAMLynchGShawJ-PGriffinL & LeeWA (1996b) Pharmacokinetics, bioavailability, metabolism and tissue distribution of cidofovir (HPMPC) and cyclic HPMPC in rats. Drug Metabolism and Disposition24:745–752.
De CastroLMKernERDe ClercqEGhaffarAMayerEPVogtPE & GangemiJD (1991) Phosphonylmethoxyalkyl purine and pyrimidine derivatives for treatment of opportunistic cytomegalovirus and herpes simplex virus infections in murine AIDS. Antiviral Research16:101–114.
46.
De ClercqE (1991) Broad-spectrum anti-DNA virus and antiretrovirus activity of phosphonylmethoxyalkylpurines and -pyrimidines. Biochemical Pharmacology42:963–972.
47.
De ClercqE & HolýA (1991) Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice. Antimicrobial Agents and Chemotherapy35:701–706.
48.
De ClercqEHolýARosenbergISakumaTBalzariniJ & MaudgalPC (1986) A novel selective broad-spectrum anti-DNA virus agent. Nature323:464–467.
49.
De ClercqESakumaTBabaMPauwelsRBalzariniJRosenbergI & HolýA (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Research8:261–272.
50.
De ClercqEHolýA & RosenbergI (1989) Efficacy of phosphonylmethoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infections in vivo. Antimicrobial Agents and Chemotherapy33:185–191.
51.
del GobboVFoliABalzariniJDe ClercqEBalestraEVillaniNMariniSPernoC-F & CaliòR (1991) Immunomodulatory activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a potent anti-HIV nucleoside analogue, on in vivo murine models. Antiviral Research16:65–75.
52.
De OliveiraCBRStevensonDLaBreeLMcDonnellPJ & TrousdaleMD (1996) Evaluation of cidofovir (HPMPC, GS-504) against adenovirus type 5 infection in vitro and in a New Zealand rabbit ocular model. Antiviral Research31:165–172.
53.
EgberinkHBorstMNiphuisHBalzariniJNeuHSchellekensHDe ClercqEHorzinekM & KoolenM (1990) Suppression of feline immunodeficiency virus infection in vivo by 9-(2-phosphonomethoxyethyl)adenine. Proceedings of the National Academy of Sciences, USA87:3087–3091.
54.
FazelyFHaseltineWARodgerRF & RuprechtRM (1991) Postexposure chemoprophylaxis with ZDV or ZDV combined with interferon-α: failure after inoculating rhesus monkeys with a high dose of SIV. Journal of Acquired Immune Deficiency Syndromes4:1093–1097.
55.
FieldHJ (1989) Persistent herpes simplex virus infections and mechanisms of virus drug resistance. European Journal of Clinical Microbiology and Infectious Diseases8:671–680.
56.
FieldHJ & AwanAR (1990) Effective chemotherapy of equine herpesvirus 1 by phosphonylmethoxyalkyl derivatives of adenine demonstrated in a novel murine model for the disease. Antimicrobial Agents and Chemotherapy34:709–717.
57.
Flores-AguilarMHuangJ-SWileyCADe ClercqEVuongCBergeron-LynnGChandlerBMunguiaDDolnakDR & FreemanWR (1994) Long-acting therapy of viral retinitis with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. Journal of Infectious Diseases169:642–647.
58.
FoliASopocioMAndersonBKavlickMSavilleMWWainbergMAGuZCherringtonJMMitsuyaH & YarchoanR (1996). In vitro selection and molecular characterization of human immunodeficiency virus type 1 with reduced sensitivity to 9-[2-(phosphonylmefhoxy)ethyl]adenine (PMEA). Antiviral Research32:91–98.
59.
GangemiJDCozensRMDe ClercqEBalzariniJ & HochkeppelH-K (1989) 9-(2-Phosphonylmethoxyethyl)adenine in the treatment of murine acquired immunodeficiency disease and opportunistic herpes simplex virus infections. Antimicrobial Agents and Chemotherapy33:1864–1868.
60.
Gil-FernándezC & De ClercqE (1987) Comparative efficacy of broad-spectrum antiviral agents as inhibitors of African swine fever virus replication in vitro. Antiviral Research7:151–160.
61.
Gil-FernándezCGarcía-VillalónDDe ClercqERosenbergI & HolýA (1987) Phosphonylmefhoxyalkylpurines and -pyrimidines as inhibitors of African swine fever virus replication in vitro. Antiviral Research8:273–282.
62.
GilliamSE & FieldHJ (1993) The effect of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) on bovine herpesvirus-1 (BHV-1) infection and reactivation in cattle. Antiviral Research20:21–32.
63.
GongY-FMarshallDRSrinivasRV & FridlandA (1994) Susceptibilities of zidovudine-resistant variants of human immunodeficiency virus type 1 to inhibition by acyclic nucleoside phosphonates. Antimicrobial Agents and Chemotherapy38:1683–1687.
64.
GordonYJRomanowskiEAraullo-CruzTSeabergLErzurumSTolmanR & De ClercqE (1991) Inhibitory effect of (S)-HPMPC, (S)-HPMPA and 2′-nor-cyclic GMP on clinical ocular adenoviral isolates is serotype-dependent in vitro. Antiviral Research16:11–16.
65.
GordonYJRomanowskiEG & Araullo-CruzT (1994) Topical HPMPC inhibits adenovirus type 5 in the New Zealand rabbit ocular replication model. Investigative Ophthalmology and Visual Science35:4135–4143.
66.
GordonYJNaesensLDe ClercqEMaudgalPC & VeckeneerM (1996) Treatment of adenoviral conjunctivitis with topical cidofovir. Cornea15:546.
67.
GuZSalomonHCherringtonJMMulatoASChenMSYarchoanRFoliASogocioKM & WainbergMA (1995) K65R mutation of human immunodeficiency virus type 1 reverse transcriptase encodes cross-resistance to 9-(2-phosphonylmethoxyethyl)adenine. Antimicrobial Agents and Chemotherapy39:1888–1891.
68.
HartmannKDonathABeerBEgberinkHFHorzinekMCLutzHHoffmann-FezerGThumI & ThefeldS (1992) Use of two virustatica (AZT, PMEA) in the treatment of FIV and of FeLV seropositive cats with clinical symptoms. Veterinary Immunology and Immunopathology35:167–175.
69.
HartmannKBalzariniJHigginsJDe ClercqE & PedersenNC (1994) In vitro activity of acyclic nucleoside phosphonate derivatives against feline immunodeficiency virus in Crandell feline kidney cells and feline peripheral blood lymphocytes. Antiviral Chemistry & Chemotherapy5:13–19.
70.
HeijtinkRADe WildeGAKruiningJBerkLBalzariniJDe ClercqEHolýA & SchalmSW (1993) Inhibitory effect of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) on human and duck hepatitis B virus infection. Antiviral Research2 :141–153.
71.
HeijtinkRAKruiningJDe WildeGABalzariniJDe ClercqE & SchalmSW (1994) Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture. Antimicrobial Agents and Chemotherapy38:2180–2182.
72.
HitchcockMJMJaffeHSMartinJC & StaggRJ (1996) Cidofovir, a new agent with potent anti-herpesvirus activity. Antiviral Chemistry & Chemotherapy7:115–127.
73.
HoH-TWoodsKLBronsonJJDe BoeckHMartinJC & HitchcockMJM (1992) Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine. Molecular Pharmacology41:197–202.
74.
HolýA & RosenbergI (1987) Synthesis of 9-(2-phosphonylmethoxyedryl)adenine and related compounds. Collection of Czechoslovak Chemical Communications52:2801–2809.
75.
HolýAVotrubaIMertaAČernyJVeselyJVlachJŠediváKRosenbergIOtmarMHřebabeckýHTrávníčekMVonkaVSnoeckR & De ClercqE (1990) Acyclic nucleotide analogues: synthesis, antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro. Antiviral Research13:295–312.
76.
HooverEAEbnerJPZeidnerNS & MuffinsJI (1991) Early therapy of feline leukemia virus infection (FeLV-FAIDS) with 9-(2-phosphonylmethoxyethyl)adenine (PMEA). Antiviral Research16:77–92.
77.
KimCULuhBYMiscoPFBronsonJJHitchcockMJMGhazzouliI & MartinJC (1989) Synthesis and biological activities of phosphonylalkylpurine derivatives. Nucleosides and Nucleotides8:927–931.
78.
KirschLSArevaloJFDe ClercqEChavezEMunguiaDGarciaR & FreemanWR (1995a) Phase I/II study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. American Journal of Ophthalmology119:466–476.
79.
KirschLSArevaloJFChavezEMunguiaDDe ClercqE & FreemanWR (1995b) Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology102:533–542.
80.
KramataPVotrubaIOtováB & HolýA (1996) Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases α, δ & ε. Molecular Pharmacology49:1005–1011.
81.
KuppermanBDAssilKKVuongCBesenGWileyCADe ClercqEBergeron-LynnGConnorJDPursleyMMunguiaD & FreemanWR (1996) Liposome-encapsulated (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine for long-acting therapy of viral retinitis. Journal of Infectious Diseases173:18–23.
82.
LalezariJPDrewWLGlutzerEMinerDSafrinSOwenWFDavidsonJMFisherPE & JaffeHS (1994) Treatment with intravenous (S)-1-[3-hydroxy-2-(phosphonylmethoxypropyl]cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS. Journal of Infectious Diseases170:570–572.
83.
LalezariJPDrewWLGlutzerEJamesCMinerDFlahertyJFisherPECundyKHanniganJMartinJC & JaffeHS (1995) (S)-1-[3-Hydroxy-2-phosphonyl-methoxy)propyl]-cytosine (cidofovir): results of a phase I/II study of a novel antiviral nucleotide analogue. Journal of Infectious Diseases171:788–796.
84.
LalezariJPStaggRKuppermannBHollandGKramerFYouleMRobinsonMNorthfeltDEronJ & JaffeHS (1996) A randomized, controlled trial of cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. Annals of Internal Medicine (in press).
85.
LeeJSMullaneySBronsonRSharpeAHJaenischRBalzariniJDe ClercqE & RuprechtRM (1991) Transplacental antiretroviral therapy with 9-(2-phosphonylmethoxyethyl)adenine is embryotoxic in transgenic mice. Journal of Acquired Immune Deficiency Syndromes4:833–838.
86.
LiSBYangZHFengJSFongCKYLuciaHL & HsiungGD (1990) Activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)-cytosine (HPMPC) against guinea pig cytomegalovirus infection in cultured cells and in guinea pigs. Antiviral Research13:237–252.
LinJ-CDe ClercqE & PaganoJS (1991) Inhibitory effects of acyclic nucleoside phosphonate analogs, including (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, on Epstein-Barr virus replication. Antimicrobial Agents and Chemotherapy35:2440–2443.
89.
LitderEStuartAD & CheeMS (1992) Human cytomegalovirus UL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir. Nature358:160–162.
90.
LurainNSSpaffordLE & ThompsonKD (1994) Mutation in the UL97 open reading frame of human cytomegalovirus strains resistant to ganciclovir. Journal of Virology68:4427–4431.
91.
MaudgalPC & De ClercqE (1991a) Effects of phosphonylmethoxyalkyl-purine and -pyrimidine derivatives on TIC+ and TK - HSV-1 keratitis in rabbits. Antiviral Research16:93–100.
92.
MaudgalPC & De ClercqE (1991b) (S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine in the therapy of thymidine kinase-positive and -deficient herpes simplex virus experimental keratitis. Investigative Ophthalmology and Visual Science32:1816–1820.
93.
MendelDBBarkhimerDBKernER & ChenMS (1995) Isolation and initial characterization of a herpes simplex virus type 2 (HSV-2) strain with decreased sensitivity to cidofovir. Antiviral Research26:A312.
94.
MendelDBCihlářTMoonK & ChenMS (1996) Cyclic HPMPC (cHPMPC) is hydrolyzed to cidofovir (CDV) by an intracellular cCMP phosphodiesterase. Antiviral Research30:A49.
95.
MertaAVotrubaIRosenbergIOtmarMHřebabeckýHBernaertsR & HolýA (1990) Inhibition of herpes simplex virus DNA polymerase by diphosphates of acyclic phosphonylmethoxyalkyl nucleotide analogues. Antiviral Research13:209–218.
96.
MertaAVotrubaIJindřichJHolýACihlářTRosenbergIOtmarM & HerveTY (1992) Phosphorylation of 9-(2-phosphonomethoxyethyl)adenine and 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine by AMP (dAMP) kinase from L1210 cells. Biochemical Pharmacology44:2067–2077.
97.
MulYMvan MiltenburgRTDe ClercqE & van der VlietPC (1989) Mechanism of inhibition of adenovirus DNA replication by the acyclic nucleoside triphosphate analogue (S)-HPMPA pp: influence of the adenovirus DNA binding protein. Nucleic Acids Research17:8917–8929.
98.
NaesensLBalzariniJRosenbergIHolýA & De ClercqE (1989) 9-(2-Phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP): a novel agent with anti-human immunodeficiency virus activity in vitro and potent anti-Moloney murine sarcoma virus activity in vivo. European Journal of Clinical Microbiology and Infectious Diseases8:1043–1047.
99.
NaesensLBalzariniJHolýARosenbergI & De ClercqE (1990) Antiretroviral efficacy of 9-(2-phosphonylmethoxyethyl) adenine and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine in mice infected with Friend leukemia virus [Abstract]. Journal of Cellular Biochemistry14D(Suppl):140.
100.
NaesensLBalzariniJ & De ClercqE (1991) Single-dose administration of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) in the prophylaxis of retrovirus infection in vivo. Antiviral Research16:53–64.
101.
NaesensLBalzariniJ & De ClercqE (1992) Pharmacokinetics in mice of the anti-retrovirus agent 9-(2-phosphonylmethoxy-ethyl)adenine. Drug Metabolism and Disposition20:747–752.
102.
NaesensLNeytsJBalzariniJHolýARosenbergI & De ClercqE (1993) Efficacy of oral 9-(2-phosphonylmethoxy-ethyl)-2,6-diaminopurine (PMEDAP) in the treatment of retrovirus and cytomegalovirus infections in mice. Journal of Medical Virology39:167–172.
103.
NaesensLBalzariniJBischofbergerN & De ClercqE (1996) Antiretroviral activity and pharmacokinetics in mice of oral bis-(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine, the bis (pivaloyloxymethyl)-ester prodrag of 9-(2-phosphonylmethoxy-ethyl)adenine. Antimicrobial Agents and Chemotherapy40:22–28.
104.
NeytsJSnoeckRScholsDBalzariniJ & De ClercqE (1990) Selective inhibition of human cytomegalovirus DNA synthesis by (S)-1-(3-hydroxy-2-phosphonyhnethoxypropyl)cytosine [(S)-HPMPC] and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG). Virology179:41–50.
105.
NeytsJSnoeckRBalzariniJ & De ClercqE (1991) Particular characteristics of the anti-human cytomegalovirus activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) in vitro. Antiviral Research16:41–52.
106.
NeytsJBalzariniJNaesensL & De ClercqE (1992) Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine and 9-(1,3-dihydroxy-2-propoxyrnethyl)guanine for the treatment of murine cytomegalovirus infection in severe combined immunodeficiency mice. Journal of Medical Virology37:67–71.
107.
NeytsJSobisHSnoeckRVandeputteM & De ClercqE (1993a) Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine in the treatment of intracerebral murine cytomegalovirus infections in immunocompetent and immunodeficient mice. European Journal of Clinical Microbiology and Infectious Diseases12:269–279.
108.
NeytsJStalsFBruggemanC & De ClercqE (1993b) Activity of the anti-HIV agent 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine against cytomegalovirus in vitro and in vivo. European Journal of Clinical Microbiology and Infectious Diseases12:437–446.
109.
PalúGStefanelliSRassuMParolinCBalzariniJ & De ClercqE (1991) Cellular uptake of phosphonylmethoxyalkyl-purine derivatives. Antiviral Research16:115–119.
110.
PauwelsRBalzariniJScholsDBabaMDesmyterJRosenbergIHolýA & De ClercqE (1988) Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents. Antimicrobial Agents and Chemotherapy32:1025–1030.
111.
PolisMASpoonerKMBairdBFManischewitzJFJaffeHSFisherPEFalloonJDaveyRTKovacsJAWalkerREWhitcupSMNussenblattRBLaneHC & MasurH (1995) Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria. Antimicrobial Agents and Chemotherapy39:882–886.
112.
ReymenDNaesensLBalzariniJHolýADvořákováH & De ClercqE (1995) Antiviral activity of selected acyclic nucleoside analogues against human herpes virus 6. Antiviral Research28:343–357.
113.
RobbinsBLConnellyMCMarshallDRSrinivasRV & FridlandA (1995a) A human T lymphoid cell variant resistant to the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine shows a unique combination of a phosphorylation defect and increased efflux of the agent. Molecular Pharmacology47:391–397.
114.
RobbinsBLGreenhawJConnellyMC & FridlandA (1995b) Metabolic pathways for activation of the antiviral agent 9-(2-phosphonyhnethoxyethyl)-adenine (PMEA) in human lymphoid cells. Antimicrobial Agents and Chemotherapy39:2304–2308.
115.
SediváKAnanievAVVotrubaIHolýA & RosenbergI (1991) Inhibition of purine nucleoside phosphorylase by phosphonylmethoxyalkyl analogues of nucleotides. International Journal of Purine Pyrimidine Research2:35–39.
116.
SmeeDFMorrisJLBLeonhardtJAMeadJRHolýA & SidwellRW (1992) Treatment of murine cytomegalovirus infections in severe combined immunodeficient mice with ganciclovir (S)-1-[3-hydroxy-2-(phosphonylmethoxy)-propyl]cytosine, interferon & bropirimine. Antimicrobial Agents and Chemotherapy36:1837–1842.
117.
SnoeckRSakumaTDe ClercqERosenbergI & HolýA (1988) (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrobial Agents and Chemotherapy32:1839–1844.
118.
SnoeckRAndreiGGérardMSilvermanAHeddermanABalzariniJSadzot-DelvauxCTricotGClumeckN & De ClercqE (1994) Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnetresistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Clinical Infectious Diseases18:570–578.
119.
SnoeckRvan RanstMAndreiGDe ClercqEDe WitSPoncinM & ClumeckN (1995) Treatment of anogenital papillomavirus infections with an acyclic nucleoside phosphonate analogue. New England Journal of Medicine333:943–944.
120.
SnoeckRAndreiG & De ClercqE (1996a) Patterns of resistance and sensitivity to antiviral compounds of drug-resistant strains of human cytomegalovirus selected in vitro. European Journal of Clinical Microbiology and Infectious Diseases15:574–579.
121.
SnoeckRDe WitSRossiCDachyBO'DohertyENaesensLBalzariniJDe ClercqEGoldmanS & ClumeckN (1996b) Treatment of progressive multifocal leukoencephalopathy (PML) with cidofovir in an AIDS patient. Antiviral Research30:A51.
122.
SnoeckRWellensWDesloovereCvan RanstMDe ClercqE & FeenstraL (1996c) Treatment of severe recurrent laryngeal papillomatosis by local injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (cidofovir). Antiviral Research30:A25.
123.
SoikeKFHuangJ-LZhangJ-YBohmRHitchcockMJM & MartinJC (1991) Evaluation of infrequent dosing regimens with (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine [(S)-HPMPC] on simian varicella infection in monkeys. Antiviral Research16:17–28.
124.
SpiraAIMarxPAPattersonBKMahoneyJKoupRAWolinskySM & HoDD (1996) Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. Journal of Experimental Medicine183:215–225.
125.
SrinivasRVRobbinsBLConnellyMCGongY-FBischofbergerN & FridlandA (1993) Metabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates. Antimicrobial Agents and Chemotherapy37:2247–2250.
126.
StalsFSDe ClercqE & BruggemanCA (1991) Comparative activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)-cytosine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine against rat cytomegalovirus infection in vitro and in vivo. Antimicrobial Agents and Chemotherapy35:2262–2266.
127.
StalsFSZeytinogluAHavenithMDe ClercqE & BruggemanCA (1993) Rat cytomegalovirus-induced pneumonitis after allogeneic bone marrow transplantation: effective treatment with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. Antimicrobial Agents and Chemotherapy37:218–223.
128.
StarrettJETortolaniDRHitchcockMJMMartinJC & MansuriMM (1992) Synthesis and in vitro evaluation of a phosphonate prodrug: bis (pivaloyloxymethyl) 9-(2-phosphonyl-methoxyethyl)adenine. Antiviral Research19:267–273.
129.
StarrettJETortolaniDRRussellJHitchcockMJMWhiterockVMartinJC & MansuriMM (1994) Synthesis, oral bioavailability determination and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). Journal of Medicinal Chemistry37:1857–1864.
130.
SullivanVBironKKTalaricoCStanatSCDavisMPozziLM & CoenDM (1993) A point mutation in the human cytomegalovirus DNA polymerase gene confers resistance to ganciclovir and phosphonylmethoxyalkyl derivatives. Antimicrobial Agents and Chemotherapy37:19–25.
131.
ThormarHBalzariniJHolýAJindřichJRosenbergIDebyserZDesmyterJ & De ClercqE (1993) Inhibition of visna virus replication by 2′,3′-dideoxynucleosides and acyclic nucleoside phosphonate analogs. Antimicrobial Agents and Chemotherapy37:2540–2544.
132.
ThormarHBalzariniJDebyserZWitvrouwMDesmyterJ & De ClercqE (1995a) Inhibition of visna virus replication and cytopathic effect in sheep choroid plexus cell cultures by selected anti-HIV agents. Antiviral Research27:49–57.
133.
ThormarHGeorgssonGPálssonPABalzariniJNaesensLTorsteinsdóttirS & De ClercqE (1995b) Inhibitory effect of 9-(2-phosphonylmethoxyethyl)adenine on visna virus infection in lambs: a model for in vivo testing of candidate anti-human immunodeficiency virus drugs. Proceedings of the National Academy of Sciences, USA92:3283–3287.
134.
TsaiC-CFollisKESaboAGrantRFBartzCNolteREBenvenisteRE & BischofbergerN (1994a) Pre-exposure prophylaxis with 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against simian immunodeficiency virus infection in macaques. Journal of Infectious Diseases169:260–266.
135.
TsaiC-CFollisKEGrantRSaboANolteRBartzCBischofbergerN & BenvenisteR (1994b) Comparison of the efficacy of AZT and PMEA treatment against acute SIVmne infection in macaques. Journal of Medical Primatology23:175–183.
136.
TsaiC-CFollisKESaboABeckTWGrantRFBischofbergerNBenvenisteRE & BlackR (1995a) Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)-adenine. Science270:1197–1199.
137.
TsaiC-CFollisKESaboAGrantR & BischofbergerN (1995b) Efficacy of 9-(2-phosphonyhmethoxyethyl)adenine (PMEA) treatment against chronic simian immunodeficiency virus infection in macaques. Journal of Infectious Diseases171:1338–1343.
138.
VahlenkampTWDerondeABalzariniJNaesensLDe ClercqEvan EijkMJTHorzinekMC & EgberinkHF (1995) (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine is a potent inhibitor of feline immunodeficiency virus infection. Antimicrobial Agents and Chemotherapy39:746–749.
139.
van CutsemESnoeckRvan RanstMFitenPOpdenakkerGGeboesKJanssensJRutgeertsRVantrappenG & De ClercqE (1995) Successful treatment of a squamous papilloma of the hypopharynx-esophagus by local injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. Journal of Medical Virology45:230–235.
140.
van RompayKKAMarthasMLRamosRAMandellCPMcGowanEKJoyeSM & PedersenNC (1992) Simian immunodeficiency virus (SIV) infection of infant rhesus macaques as a model to test antiretroviral drug prophylaxis and therapy: oral 3′-azido-3′-deoxythymidine prevents SIV infection. Antimicrobial Agents and Chemotherapy36:2381–2386.
141.
van RompayKKACherringtonJMMarthasMLBerardiCJMulatoASSpinnerATararaRPCanfieldDRTelmSBischofbergerN & PedersenNC (1996) 9-[2-(phosphonylmethoxy) adenine therapy of established Simian immunodeficiency virus infection in infant rhesus macaques. Antimicrobial Agents and Chemotherapy40:2586–2591.
142.
VotrubaIBernaertsRSakumaTDe ClercqEMertaARosenbergI & HolýA (1987) Intracellular phosphorylation of broad-spectrum anti-DNA virus agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and inhibition of viral DNA synthesis. Molecular Pharmacology32:524–529.
143.
WachsmanMPettyBGCundyKCJaffeHSFisherPEPastelakA & LietmanPS (1996) Pharmacokinetics, safety and bioavailability of HPMPC (cidofovir) in human immunodeficiency virus-infected subjects. Antiviral Research29:153–161.
144.
XiongXSmithJL & ChenMS (1995) The consequence of incorporation of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine by human cytomegalovirus DNA polymerase on DNA elongation. Abstracts of the 8th International Conference on Antiviral Research, Santa Fe, New Mexico, USA, April 23-28 1995. Antiviral Research26:A321.
145.
XiongXSmithJLKimCHuangE & ChenMS (1996) Kinetic analysis of the interaction of cidofovir diphosphate with human cytomegalovirus DNA polymerase. Biochemical Pharmacology51:1563–1567.
146.
YokotaTKonnoKChonanEMochizukiSKojimaKShigetaS & De ClercqE (1990) Comparative activities of several nucleoside analogs against duck hepatitis B virus in vitro. Antimicrobial Agents and Chemotherapy34:1326–1330.
147.
YokotaTMochizukiSKonnoKMoriSShigetaS & De ClercqE (1991) Inhibitory effects of selected antiviral compounds on human hepatitis B virus DNA synthesis. Antimicrobial Agents and Chemotherapy35:394–397.
