Abstract
Acyclovir is an effective drug for the treatment of HSV and VZV infections, which after phosphorylation to the triphosphate, inhibits viral DNA polymerase. Acyclovir has low oral bioavailability, therefore prodrugs have been developed, and the L-valyl ester, valaciclovir, recently has been licensed for the treatment of shingles. Ganciclovir is used against CMV, and famciclovir, a lipophilic prodrug of penciclovir, is marketed for shingles. The acyclic nucleoside phosphonates are active against thymidine kinase-resistant viral strains. Promising analogs are PMEA (in clinical trial for the treatment of AIDS) and (S)- HPMPC (good in vivo activity against HSV, VZV, CMV, and EBV). Oligonucleotides incorporating acyclic nucleosides at the 3’t and 5’t-ends, or constituted of amino acyclic nucleosides, are resistant to cleavage by nucleases and may be useful in antisense and/or antigene therapy. HEPT is active against HIV-1: It binds in a hydrophobic pocket on reverse transcriptase, rather than in the polymerase active site. Some acyclic nucleosides are potent inhibitors of purine and pyrimidine nucleoside phosphorylase. These compounds may have a therapeutic niche in combination therapy with antiviral and anticancer nucleosides, and in the treatment of diseases involving the T-cell.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Bean, B. (1992) Antiviral therapy: current concepts and practices.Clin. Microbiol. Rev. 5, 146–182.
van der Sijs, H. and Wiltink, E. H. (1994) Antiviral drugs: present status and future prospects.Int. J. Biochem. 26, 621–630.
Kulikowski, T. (1994) Structure-activity relationships and conformational features of antiherpetic pyrimidine and purine nucleoside analogues. A review.Pharm. World Sci. 16, 127–138.
Montgomery, J. A. (1993) Purine nucleoside phosphorylase: a target for drug design.Med. Res. Rev. 13, 209–228.
Wagstaff, A. J., Faulds, D., and Goa, K. L. (1994) Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy.Drugs 47, 153–205.
Darby, G. (1993) The acyclovir legacy: its contribution to antiviral drug discovery.J. Med Virol. 1(Suppl), 134–138.
Welsby, P. D. (1994) Acyclovir. Is the honeymoon coming to an end?J. Infect. 28, 121–129.
de Ruiter, A. and Thin, R. N. (1994) Genital Herpes. A guide to pharmacological therapy.Drugs 47, 297–304.
Wood, M. J. (1994) Current experience with antiviral therapy for acute herpes zoster.Ann. Neurol. 35(Suppl.), S65-S68.
Snoeck, R., Andrei, G., and De Clercq, E. (1994) Chemotherapy of varicella zoster virus infections.Int. J. Antimicrob. Agents 4, 211–226.
Nikkels, A. F. and Pierard, G. E. (1994) Recognition and treatment of shingles.Drugs 48, 528–548.
Ochiai, H., Kumura, K., and Minamishima, Y. (1992) Murine cytomegalovirus DNA polymerase: purification, characterization and role in the antiviral activity of acyclovir.Antiviral Res. 17, 1–16.
Talarico, C. L., Phelps, W. C., and Biron, K. K. (1993) Analysis of the thymidine kinase genes from acyclovirresistant mutants of varicella-zoster virus isolated from patients with AIDS.J. Virol. 67, 1024–1033.
de Miranda, P. and Good, S. S. (1992) Species differences in the metabolism and disposition of antiviral nucleoside analogues: 1. Acyclovir.Antiviral Chem. Chemother. 3, 1–8.
Domin, B. A., Mahony, W. B., and Zimmerman, T. P. (1991) Desciclovir permeation of the human erythrocyte membrane by nonfacilitated diffusion.Biochem. Pharmacol. 42, 147–152.
Purifoy, D. J. M., Beauchamp, L. M., de Miranda, P., Ertl, P., Lacey, S., Roberts, G., Rahim, S. G., Darby, G., Krenitsky, T. A., and Powell, K. L. (1993) Review of research leading to new anti-herpesvirus agents in clinical development: valaciclovir hydrochloride (256U, the L-valyl ester of acyclovir) and 882C, a specific agent for varicella zoster virus.J. Med. Virol. 1(Suppl.), 139–145.
Jacobson, M. A. (1993) Valaciclovir (BW256U87): the L-valyl ester of acyclovir.J. Med. Virol. 1(Suppl.), 150–153.
Gnann, J. W. (1994) New antivirals with activity against varicella-zoster virus.Ann. Neurol. 35, S69-S72.
de Miranda, P. and Burnette, T. C. (1994) Metabolic fate and pharmacokinetics of the acyclovir prodrug valaciclovir in cynomolgus monkeys.Drug Metab. Dispos. 22, 55–59.
Burnette, T. C. and de Miranda, P. (1994) Metabolic disposition of the acyclovir prodrug valaciclovir in the rat.Drug Metab. Dispos. 22, 60–64.
Weller, S., Blum, M. R., Doucette, M., Burnette, T., Cederberg, D. M., de Miranda, P., and Smiley, M. L. (1993) Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating singleand multiple-dose administration to normal volunteers.Clin. Pharmacol. Ther. 54, 595–605.
Rolan, P. (1995) Pharmacokinetics of new antiherpetic agents.Clin. Pharmacokin. 29, 333–340.
Hostetler, K. Y., Parker, S., Sridhar, C. N., Martin, M. J., Li, J.-L., Stuhmiller, L. M., van Wijk, G. M. T., van den Bosch, H., Gardner, M. F., Aldern, K. A., and Richman, D. D. (1993) Acyclovir diphosphate dimyristoylglycerol: a phospholipid prodrug with activity against acyclovir-resistant herpes simplex virus.Proc. Natl. Acad. Sci. USA 90, 11, 835–11, 839.
Field, A. K., Davies, M. E., DeWitt, C., Perry, H. C., Liou, R., Germershausen, J., Karkas, J. D., Ashton, W. T., Johnston, D. B. R., and Tolman, R. L. (1983) 9-[2-Hydroxy-1 -(hydroxymethyl)ethoxy]methyl guanine: a selective inhibitor of herpes group virus replication.Proc. Natl. Acad. Sci. USA 80, 4139–4143.
Markham, A. and Faulds, D. (1994) Ganciclovir: an update of its therapeutic use in cytomegalovirus infection.Drugs 48, 455–484.
Littler, E., Stuart, A. D., and Chee, M. S. (1992) Human cytomegalovirus UL 97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir.Nature 358, 160–162.
Stolarski, R., Ciesla, J. M., and Shugar, D. (1990) Monophosphates and cyclic phosphates of some antiviral acyclonucleosides: synthesis, conformation and substrate/inhibitor properties in some enzyme systems.Z. Naturforsch. 45, 293–299.
Birnbaum, K. B., Stolarski, R., and Shugar, D. (1994) Structure and conformation of the cyclic phosphate of ganciclovir, a broad-spectrum antiviral agent.Biochim. Biophys. Acta 1200, 55–63 and references therein.
Harnden, M. R., Jarvest, R. L., Bacon, T. H., and Boyd, M. R. (1987) Synthesis and antiviral activity of 9-[4-hydroxy-3-(hydroxymethyl)but-1-y l]purines.J. Med. Chem. 30, 1636–1642.
Bacon, T. H. and Schinazi, R. F. (1993) An overview of the further evaluation of penciclovir against herpessimplex virus and varicella-zoster virus in cell-culture highlighting contrasts with acyclovir.Antiviral Chem. Chemother. 4 (Suppl. 1), 25–36.
Earnshaw, D. L., Bacon, T. H., Darlison, S. J., Edmonds, K., Perkins, R. M., and Vere Hodge, R. A. (1992) Mode of antiviral action of penciclovir in MRC-5 cells infected with herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus.Antimicrob. Agents Chemother. 36, 2747–2757.
Weinberg, A., Bate, B. J., Masters, H. B., Schneider, S. A., Clark, J. C., Wren, C. G., Allaman, J. A., and Levin, M. J. (1992)In vitro activities of penciclovir and acyclovir against herpes simplex virus types 1 and 2.Antimicrob. Agents Chemother. 36, 2037, 2038.
Sutton, D. and Boyd, M. R. (1993) Comparative activity of penciclovir and acyclovir in mice infected intraperitoneally with herpes simplex virus type 1 SC16.Antimicrob. Agents Chemother. 37, 642–645.
Shaw, T., Amor, P., Civitico, G., Boyd, M., and Locarnini, S. (1994)In vitro antiviral activity of penciclovir, a novel purine nucleoside, against duck hepatitis B virus.Antimicrob. Agents Chemother. 38, 719–723.
Fowles, S. E., Pierce, D. M., Prince, W. T., and Staniforth, D. (1992) The tolerance to and pharmacokinetics of penciclovir (BRL 39123A), a novel antiherpes agent, administered by intravenous infusion to healthy subjects.Eur. J. Clin. Pharmacol. 43, 513–516.
Safrin, S. and Phan, L. (1993)In vitro activity of penciclovir against clinical isolates of acyclovirresistant and foscarnet-resistant herpes simplex virus.Antimicrob. Agents Chemother. 37, 2241–2243.
Vere Hodge, R. A., Darlison, S. J., Earnshaw, D. L., and Readshaw, S. A. (1993) Use of isotopically chiral [4’t-13C]penciclovir and13C NMR to determine the specificity and absolute configuration of penciclovir phosphate esters formed in HSV-1 and HSV-2-infected cells and by HSV-1-encoded thymidine kinase.Chirality 5, 583–588.
Harrell, A. W., Wheeler, S. M., Pennick, M., Clarke, S. E., and Chenery, R. J. (1993) Evidence that famciclovir (BRL 42810) and its associated metabolites do not inhibit the 6 beta-hydroxylation of testosterone in human liver microsomes.Drug Metab. Dispos. Biol. Fate Chem. 21, 18–23.
Vere Hodge, R. A., Darlison, S. J., and Readshaw, S. A. (1993) Use of isotopically chiral [4’t-13C]famciclovir and13C NMR to identify the chiral monoacetylated intermediates in the conversion of famciclovir to penciclovir by human intestinal wall extract.Chirality 5, 577–582.
Pue, M. A., Pratt, S. K., Fairless, A. J., Fowles, S., Laroche, J., Georgiou, P., and Prince, W. (1994) Linear pharmacokinetics of penciclovir following administration of single oral doses of famciclovir 125, 250, 500 and 750 mg to healthy volunteers.J. Antimicrob. Chemother. 33, 119–127.
Degreef, H., Andrejevic, L., Aoki, F., Arend, J., Ashton, R., De Backer, W., et al. (1994) Famciclovir, a new oral antiherpes drug: Results of the first controlled clinical study demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients.Int. J. Antimicrob. Agents 4, 241–246.
Saltzman, R., Jurewicz, R., and Boon, R. (1994) Safety of famciclovir in patients with herpes zoster and genital herpes.Antimicrob. Agents Chemother. 38, 2454–2457.
Balzarini, J. (1994) Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives.Pharm. World Sci. 16, 113–126.
Kim, C. U., Misco, P. F., Luh, B. Y., and Martin, J. C. (1990) Synthesis of a phosphonate isostere of ganciclovir monophosphate: a highly cytomegalovirus active phosphonate nucleotide analogue.Tetrahedron Lett. 31, 3257–3260.
Kim, C. U., Misco, P. F., Luh, B. Y., Hitchcock, M. J.M, Ghazzouli, I., and Martin, J. C. (1991) A new class of acyclic phosphonate nucleotide analogues: phosphonate isosteres of acyclovir and ganciclovir monophosphates as antiviral agents.J. Med. Chem. 34, 2286–2294.
Reist, E. J., Sturm, P. A., Pong, R. Y., and Sidwell, R. W. (1989) Synthesis of phosphonic acid analogs of acyclovir (ACV) and ganciclovir (DHPG).Nucleosides Nucleotides 8, 919–922.
De Clercq, E., Holy, A., Rosenberg, I., Sakuma, T., Balzarini, J., and Maudgal, P. C. (1986) A novel selective broad-spectrum anti-DNA virus agent.Nature 323, 464–467.
De Clercq, E., Holy, A., and Rosenberg, I. (1989) Efficacy of phosphonylmethoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infectionsin vivo.Antimicrob. Agents Chemother. 33, 185–191.
De Clercq, E., Sakuma, T., Baba, M., Pauwels, R., Balzarini, J., Rosenberg, I., and Holy, A. (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines.Antiviral. Res. 8, 261–272.
Terry, B. J., Mazina, K. E., Tuomari, A. V., Haffey, M. L, Hagen, M., Feldman, A., Slusarchyk, W. A., Young, M. G., Zahler, R., and Field, A. K. (1988) Broad-spectrum antiviral activity of the acyclic guanosine phosphonate (R, S)-HPMPG.Antiviral Res. 10, 235–252.
Lin, J. C., De Clercq, E., and Pagano, J. S. (1991) Inhibitory effects of acyclic nucleoside phosphonate analogs, including (S)-l-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, on Epstein-Barr virus replication.Antimicrob. Agents Chemother. 35, 2440–2443.
De Clercq, E.(1993) Therapeutic potential of HPMPC as an antiviral drug.Rev. Med. Virol. 3, 85–96.
Snoeck, R., Andrei, G., Gerard, M., Silverman, A., Hedderman, A., Balzarini, J., Sadzot-Delvaux, C., Tricot, G., Clumeck, N., and De Clercq, E. (1994) Successful treatment of progressive mucocutaneous infection due to acyclovir and foscarnet-resistant herpes simplex virus with (S)-l-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC).Clin. Infect. Dis. 18, 570–578.
Snoeck, R., Gerard, M., Sadzot-Delvaux, C., Andrei, G., Balzarini, J., Reymen, D., Ahadi, N., Debruyn, J. M., Piette, J., Rentier, B., Clumeck, N., and De Clercq, E. (1994) Meningoradiculoneuritis due to acyclovirresistant varicella-zostervirus in an acquired-immunedeficiency-syndrome patients.J. Med. Virol. 42, 338–347.
Merta, A., Votruba, I., Jindrich, J., Holy, A., Cihlar, T., Rosenberg, I., Otmar, M., and Herve, T. Y. (1992) Phosphorylation of 9-(2-phosphonomethoxyethyl) adenine and 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine by AMP(dAMP) kinase from L1210 cells.Biochem. Pharmacol. 44, 2067–2077.
Thormar, H., Balzarini, J., Holy, A., Jindrich, J., Rosenberg, I., Debyser, Z., Desmyter, J., and De Clercq, E. (1993) Inhibition of visna virus replication by 2’t, 3’t-dideoxynucleosides and acyclic nucleoside phosphonate analogs.Antimicrob. Agents Chemother. 37, 2540–2544.
Balzarini, J., Holy, A., Jindrich, J., Naesens, L., Snoeck, R., Schols, D., and De Clercq, E. (1993) Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selectivein vitro andin vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2, 6-diaminopurine.Antimicrob. Agents Chemother. 37, 332–338.
Balzarini, J. and De Clercq, E. (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.J. Biol. Chem. 266, 8686–8689.
Votruba, I., Bernaerts, R., Sakuma, T., De Clercq, E., Merta, A., Rosenberg, I., and Holy, A. (1987) Intracellular phosphorylation of broad-spectrum anti-DNA virus agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and inhibition of viral DNA synthesis.Mol. Pharmacol. 32, 524–529.
Merta, A., Votruba, I., Rosenberg, I., Otmar, M., Hrebabecky, H., Bernaerts, R., and Holy, A. (1990) Inhibition of herpes simplex virus DNA polymerase by diphosphates of acyclic phosphonylmethoxyalkyl nucleotide analogues.Antiviral Res. 13, 209–218.
Cerny, J., Votruba, I., Vonka, V., Rosenberg, I., Otmar, M., and Holy, A. (1990) Phosphonylmethyl ethers of acyclic nucleoside analogues: inhibitors of HSV-1 induced ribonucleotide reductase.Antiviral Res. 13, 253–264.
Yokota, T., Konno, K., Shigeta, S., Holy, A., Balzarini, J., and De Clercq, E. (1994) Inhibitory effects of acyclic nucleoside phosphonate analogs on hepatitis-B virus-DNA synthesis in HB611 cells.Antiviral Chem. Chemother. 5, 57–63.
Pauwels, R., Balzarini, J., Schols, D., Baba, M., Desmyter, J., Rosenberg, I., Holy, A., and De Clercq, E. (1988) Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents.Antimicrob. Agents Chemother. 32, 1025–1030.
Balzarini, J., Naesens, L., Herdewijn, P., Rosenberg, I., Holy, A., Pauwels, R., Baba, M., Johns, D. G., and De Clercq, E. (1989) Markedin vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent.Proc. Natl. Acad. Sci. USA 86, 332–336.
Naesens, L., Balzarini, J., and De Clercq, E. (1994) Therapeutic potential of PMEA as an antiviral drug.Rev. Med. Virol. 4, 147–159.
Gong, Y.-F., Marshall, D. R., Srinivas, R. V., and Fridland, A. (1994) Susceptibilities of zidovudineresistant variants of human immunodeficiency virus type 1 to inhibition by acyclic nucleoside phosphonates.Antimicrob. Agents Chemother. 38, 1683–1687.
Calio, R., Villani, N., Balestra, E., Sesa, F., Holy, A., Balzarini, J., De Clercq, E., Perno, C. F., and Del Gobbo, V. (1994) Enhancement of natural killer activity and interferon induction by different acyclic nucleoside phosphonates.Antiviral Res. 23, 77–89.
Gangemi, J. D., Cozens, R. M., De Clercq, E., Balzarini, J., and Hochkeppel, H.-K. (1989) 9-(2-Phosphonylmethoxyethyl)adenine in the treatment of murine acquired immunodeficiency disease and opportunistic herpes simplex virus infections.Antimicrob. Agents Chemother. 33, 1864–1868.
Cihlar, T., Rosenberg, I., Votruba, I., and Holy, A. (1995) Transport of 9-(2-phosphonomethoxyethyl) adenine across plasma-membrane of HeLa S3 cells is protein-mediated.Antimicrob. Agents Chemother. 39, 117–124.
Neyts, J. and De Clercq, E. (1994) Mechanism of action of acyclic nucleoside phosphonates against herpes virus replication.Biochem. Pharmacol. 47, 39–41.
Balzarini, J, Perno, C.-F., Schols, D., and De Clercq, E. (1991) Activity of acyclic nucleoside phosphonate analogues against human immunodeficiency virus in monocyte/macrophages and peripheral blood lymphocytes.Biochem. Biophys. Res. Commun. 178, 329–335.
Balzarini, J., Holy, A., Jindrich, J., Dvorakova, H., Hao, Z., Snoeck, R., Herdewijn, P., Johns, D. G., and De Clercq, E. (1991) 9-[(2RS)-3-Fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agentsin vitro andin vivo.Proc. Natl. Acad. Sci. USA 88, 4961–4965.
Heijtink, R. A., Kruining, J., Dewilde, G. A., Balzarini, J., De Clercq, E., and Schalm, S. W. (1994) Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis-B virus and duck hepatitis-B virus-infections in tissue-culture.Antimicrob. Agents Chemother. 38, 2180–2182.
Starrett, J. E., Tortolani, D. R., Hitchcock, M. J. M., Martin, J. C., and Mansuri, M. M. (1992) Synthesis andin vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine.Antiviral Res. 19, 267–273.
Srinivas, R. V., Robbins, B. L., Connelly, M. C., Gong, Y.-F., Bischofberger, N., and Fridland, A. (1993) Metabolism andin vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates.Antimicrob. Agents Chemother. 37, 2247–2250.
Srinivas, R. V., Robbins, B. L., Connelly, M. C., Gong, Y.-F., Bischofberger, N., and Fridland, A. (1994) Pivaloyloxymethyl esters of acyclic nucleoside phosphonates.Intl. Antiviral News. 2, 53–55.
Uhlmann, E. and Peyman, A. (1990) Antisense oligonucleotides: a new therapeutic principle.Chem. Rev. 90, 543–584.
Augustyns, K., Van Aerschot, A., Van Schepdael, A., Urbanke, C., and Herdewijn, P. (1991) Influence of the incorporation of (S)-9-(3, 4-dihydroxybutyl)-adenine on the enzymatic stability and base-pairing properties of oligodeoxynucleotides.Nucleic Acids Res. 19, 2587–2593
Vandendriessche, F., Augustyns, K. Van Aerschot, A., Busson, R., Hoogmartens, J., and Herdewijn, P. (1993) Acyclic oligonucleotides: possibilities and limitations.Tetrahedron 49, 7223–7238.
Egholm, M., Buchardt, O., Nielsen, P. E., and Berg, R. H. (1992) Peptide nucleic acids (PNA). Oligonucleotide analogues with an achiral peptide backbone.J. Am. Chem. Soc. 114, 1895–1897.
Buchardt, O., Egholm, M., Berg, R. H., and Nielsen, P. E. (1993) Peptide nucleic acids (PNAs) and their potential applications in biotechnology.Trends Biotechnol. 11, 384–386.
Wittung, P., Nielsen, P. E., Buchardt, O., Egholm, M., and Norden, B. (1994) DNA-like double helix formed by peptide nucleic acid.Nature 368, 561–563.
Dueholm, K. L., Egholm, M., Behrens, C., Christensen, L., Hansen, H. F., Vulpius, T., Petersen, K. H., Berg, R. H., Nielsen, P. E., and Buchardt, O. (1994) Synthesis of peptide nucleic acid monomers containing the four natural nucleobases: thymine, cytosine, adenine, and guanine and their oligomerization.J. Org. Chem. 59, 5767–5773.
Baba, M., Tanaka, H., De Clercq, E., Pauwels, R., Balzarini, J., Schols D., Nakashima, H., Perno, C.-F., Walker, R. T., and Miyasaka, T. (1989) Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative.Biochem. Biophys. Res. Commun. 165, 1375–1381.
Miyasaka, T., Tanaka, H., Baba, M., Hayakawa, H., Walker, R. T., Balzarini, J., and De Clercq, E. (1989) A novel lead for specific anti-HIV-1 agents: l-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine.J. Med. Chem. 32, 2507–2509.
Tanaka, H., Baba, M., Saito, S., Miyasaka, T., Takashima, H., Sekiya, K., Ubasawa, M., Nitta, I., Walker, R. T., Nakashima, H., and De Clercq, E. (1991) Specific anti-HIV-1 “acyclonucleosides” which cannot be phosphorylated: synthesis of some deoxy analogues of l-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine.J. Med. Chem. 34, 1508–1511.
Baba, M., De Clercq, E., Tanaka, H., Ubasawa, M., Takashima, H., Sekiya, K., Nitta, I., Umezu, K., Nakashima, H., Mori, S., Shigeta, S., Walker, R. T., and Miyasaka, T. (1991) Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase.Proc. Natl. Acad. Sci. USA 88, 2356–2360.
Boyer, P. L., Currens, M. J., McMahon, J. B., Boyd, M. R., and Hughes, S. H. (1993) Analysis of nonnucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase.J. Virol. 67, 2412–2420.
Tarrago-Litvak, L., Andreola, M.-L., Nevinsky, G. A., Sarih-Cottin, L., and Litvak, S. (1994) The reverse transcriptase of HIV-1: from enzymology to therapeutic intervention.FASEB J. 8, 497–503.
Turtle, J. V. and Krenitsky, T. A. (1984) Effects of acyclovir and its metabolites on purine nucleoside phosphorylase.J. Biol. Chem. 259, 4065–4069.
Bzowska, A., Kulikowska, E., Shugar, D., Bing-Yi, C., Lindborg, B., and Johansson, N. G. (1991) Acyclonucleoside analogue inhibitors of mammalian purine nucleoside phosphorylase.Biochem. Pharmacol. 41, 1791–1803.
Ealick, S. E., Babu, Y. S., Bugg, C. E., Erion, M. D., Guida, W. C., Montgomery, J. A., and Secrist, J. A. (1991) III Application of crystallographic and modeling methods in the design of purine nucleoside phosphorylase inhibitors.Proc. Natl. Acad. Sci. USA 88, 11, 540–11, 544.
Kelley, J. L., Linn, J. A., McLean, E. W., and Turtle, J. V. (1993) 9-[(Phosphonoalkyl)benzyl]guanines. Multisubstrate analogue inhibitors of human erythrocyte purine nucleoside phosphorylase.J. Med. Chem. 36, 3455–3463.
Naguib, F. N. M., Levesque, D. L., Wang, E.-C., Panzica, R. P., and el Kouni, M. H. (1993) 5-Benzylbarbituric acid derivatives, potent and specific inhibitors of uridine phosphorylase.Biochem. Pharmacol. 46, 1273–1283.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Freeman, S., Gardiner, J.M. Acyclic nucleosides as antiviral compounds. Mol Biotechnol 5, 125–137 (1996). https://doi.org/10.1007/BF02789061
Issue Date:
DOI: https://doi.org/10.1007/BF02789061