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. 1997 Oct;10(4):674–693. doi: 10.1128/cmr.10.4.674

In search of a selective antiviral chemotherapy.

E De Clercq 1
PMCID: PMC172940  PMID: 9336668

Abstract

This article describes several approaches to a selective therapy of virus infections: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU [brivudin]) for the therapy of herpes simplex virus type 1 and varicella-zoster virus infections: (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC [cidofovir]) for the therapy of various DNA virus (i.e., herpesvirus, adenovirus, papillomavirus, polyomavirus, and poxvirus) infections; 9-(2-phosphonylmethoxyethyl)adenine (PMEA [adefovir]) for the therapy of retrovirus, hepadnavirus, and herpesvirus infections; (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for the therapy and prophylaxis of retrovirus and hepadnavirus infections; and nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(IH)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), alpha-anilinophenylacetamide (alpha-APA), and 2',5'bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxat hiole- 2",2"-dioxide)pyrimidine (TSAO) derivatives, and thiocarboxanilides for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. For the clinical use of NNRTIs, some guidelines have been elaborated, such as starting treatment with combinations of different compounds at sufficiently high concentrations to effect a pronounced and sustained suppression of the virus. Despite the diversity of the compounds described here and the different viruses at which they are targeted, they have a number of characteristics in common. As they interact with specific viral proteins, the compounds achieve a selective inhibition of the replication of the virus, which, in turn, should be able to develop resistance to the compounds. However, as has been established for the NNRTIs, the problem of viral resistance may be overcome if the compounds are used from the start at sufficiently high doses, which could be reduced if different compounds are combined. For HIV infections, drug treatment regimens should be aimed at reducing the viral load to such an extent that the risk for progression to AIDS will be minimized, if not avoided entirely. This may result in a real "cure" of the disease but not necessarily of the virus infection, and in this sense, HIV disease may be reduced to a dormant infection, reminiscent of the latent herpesvirus infections. Should virus replication resume after a certain time, the armamentarium of effective anti-HIV and anti-herpesvirus compounds now available, if applied at the appropriate dosage regimens, should make the virus return to its dormant state before it has any chance to damage the host. It is unlikely that this strategy would eradicate the virus and thus "cure" the viral infection, but it definitely qualifies as a cure of the disease.

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Selected References

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  1. Aduma P., Connelly M. C., Srinivas R. V., Fridland A. Metabolic diversity and antiviral activities of acyclic nucleoside phosphonates. Mol Pharmacol. 1995 Apr;47(4):816–822. [PubMed] [Google Scholar]
  2. Ahgren C., Backro K., Bell F. W., Cantrell A. S., Clemens M., Colacino J. M., Deeter J. B., Engelhardt J. A., Hogberg M., Jaskunas S. R. The PETT series, a new class of potent nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 1995 Jun;39(6):1329–1335. doi: 10.1128/aac.39.6.1329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Allaudeen H. S., Kozarich J. W., Bertino J. R., De Clercq E. On the mechanism of selective inhibition of herpesvirus replication by (E)-5-(2-bromovinyl)-2'-deoxyuridine. Proc Natl Acad Sci U S A. 1981 May;78(5):2698–2702. doi: 10.1073/pnas.78.5.2698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Andrei G., Snoeck R., Reymen D., Liesnard C., Goubau P., Desmyter J., De Clercq E. Comparative activity of selected antiviral compounds against clinical isolates of varicella-zoster virus. Eur J Clin Microbiol Infect Dis. 1995 Apr;14(4):318–329. doi: 10.1007/BF02116525. [DOI] [PubMed] [Google Scholar]
  5. Ayisi N. K., De Clercq E., Wall R. A., Hughes H., Sacks S. L. Metabolic fate of (E)-5-(2-bromovinyl)-2'-deoxyuridine in herpes simplex virus- and mock-infected cells. Antimicrob Agents Chemother. 1984 Nov;26(5):762–765. doi: 10.1128/aac.26.5.762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. BAUER D. J., STVINCENT L., KEMPE C. H., DOWNIE A. W. PROPHYLACTIC TREATMENT OF SMALL POX CONTACTS WITH N-METHYLISATIN BETA-THIOSEMICARBAZONE (COMPOUND 33T57, MARBORAN). Lancet. 1963 Sep 7;2(7306):494–496. doi: 10.1016/s0140-6736(63)90230-7. [DOI] [PubMed] [Google Scholar]
  7. BAUER D. J. The antiviral and synergic actions of isatin thiosemicarbazone and certain phenoxypyrimidines in vaccinia infection in mice. Br J Exp Pathol. 1955 Feb;36(1):105–114. [PMC free article] [PubMed] [Google Scholar]
  8. Baba M., De Clercq E., Tanaka H., Ubasawa M., Takashima H., Sekiya K., Nitta I., Umezu K., Nakashima H., Mori S. 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 U S A. 1991 Mar 15;88(6):2356–2360. doi: 10.1073/pnas.88.6.2356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Baba M., De Clercq E., Tanaka H., Ubasawa M., Takashima H., Sekiya K., Nitta I., Umezu K., Walker R. T., Mori S. Highly potent and selective inhibition of human immunodeficiency virus type 1 by a novel series of 6-substituted acyclouridine derivatives. Mol Pharmacol. 1991 Jun;39(6):805–810. [PubMed] [Google Scholar]
  10. Baba M., Shigeta S., Yuasa S., Takashima H., Sekiya K., Ubasawa M., Tanaka H., Miyasaka T., Walker R. T., De Clercq E. Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro. Antimicrob Agents Chemother. 1994 Apr;38(4):688–692. doi: 10.1128/aac.38.4.688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Baba M., Tanaka H., De Clercq E., Pauwels R., Balzarini J., Schols D., Nakashima H., Perno C. F., Walker R. T., Miyasaka T. Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative. Biochem Biophys Res Commun. 1989 Dec 29;165(3):1375–1381. doi: 10.1016/0006-291x(89)92756-3. [DOI] [PubMed] [Google Scholar]
  12. Bader J. P., McMahon J. B., Schultz R. J., Narayanan V. L., Pierce J. B., Harrison W. A., Weislow O. S., Midelfort C. F., Stinson S. F., Boyd M. R. Oxathiin carboxanilide, a potent inhibitor of human immunodeficiency virus reproduction. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6740–6744. doi: 10.1073/pnas.88.15.6740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Balzarini J., Baba M., De Clercq E. Differential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains. Antimicrob Agents Chemother. 1995 Apr;39(4):998–1002. doi: 10.1128/aac.39.4.998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Balzarini J., Bernaerts R., Verbruggen A., De Clercq E. Role of the incorporation of (E)-5-(2-iodovinyl)-2'-deoxyuridine and its carbocyclic analogue into DNA of herpes simplex virus type 1-infected cells in the antiviral effects of these compounds. Mol Pharmacol. 1990 Mar;37(3):402–407. [PubMed] [Google Scholar]
  15. Balzarini J., Bohman C., De Clercq E. Differential mechanism of cytostatic effect of (E)-5-(2-bromovinyl)-2'-deoxyuridine, 9-(1,3-dihydroxy-2-propoxymethyl)guanine, and other antiherpetic drugs on tumor cells transfected by the thymidine kinase gene of herpes simplex virus type 1 or type 2. J Biol Chem. 1993 Mar 25;268(9):6332–6337. [PubMed] [Google Scholar]
  16. Balzarini J., Bohman C., Walker R. T., de Clercq E. Comparative cytostatic activity of different antiherpetic drugs against herpes simplex virus thymidine kinase gene-transfected tumor cells. Mol Pharmacol. 1994 Jun;45(6):1253–1258. [PubMed] [Google Scholar]
  17. Balzarini J., Brouwer W. G., Dao D. C., Osika E. M., De Clercq E. Identification of novel thiocarboxanilide derivatives that suppress a variety of drug-resistant mutant human immunodeficiency virus type 1 strains at a potency similar to that for wild-type virus. Antimicrob Agents Chemother. 1996 Jun;40(6):1454–1466. doi: 10.1128/aac.40.6.1454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Balzarini J., Brouwer W. G., Felauer E. E., De Clercq E., Karlsson A. Activity of various thiocarboxanilide derivatives against wild-type and several mutant human immunodeficiency virus type 1 strains. Antiviral Res. 1995 Jun;27(3):219–236. doi: 10.1016/0166-3542(95)00006-8. [DOI] [PubMed] [Google Scholar]
  19. Balzarini J., De Clercq E. 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. 1991 May 15;266(14):8686–8689. [PubMed] [Google Scholar]
  20. Balzarini J., De Clercq E., Verbruggen A., Ayusawa D., Seno T. Highly selective cytostatic activity of (E)-5-(2-bromovinyl)-2'-deoxyuridine derivatives for murine mammary carcinoma (FM3A) cells transformed with the herpes simplex virus type 1 thymidine kinase gene. Mol Pharmacol. 1985 Dec;28(6):581–587. [PubMed] [Google Scholar]
  21. Balzarini J., De Clercq E., Verbruggen A., Ayusawa D., Shimizu K., Seno T. Thymidylate synthase is the principal target enzyme for the cytostatic activity of (E)-5-(2-bromovinyl)-2'-deoxyuridine against murine mammary carcinoma (FM3A) cells transformed with the herpes simplex virus type 1 or type 2 thymidine kinase gene. Mol Pharmacol. 1987 Sep;32(3):410–416. [PubMed] [Google Scholar]
  22. Balzarini J., Hao Z., Herdewijn P., Johns D. G., De Clercq E. Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxyethyl)adenine, a potent anti-human immunodeficiency virus compound. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1499–1503. doi: 10.1073/pnas.88.4.1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Balzarini J., Holy A., Jindrich J., Dvorakova H., Hao Z., Snoeck R., Herdewijn P., Johns D. G., De Clercq E. 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4961–4965. doi: 10.1073/pnas.88.11.4961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Balzarini J., Holy A., Jindrich J., Naesens L., Snoeck R., Schols D., De Clercq E. 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. Antimicrob Agents Chemother. 1993 Feb;37(2):332–338. doi: 10.1128/aac.37.2.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Balzarini J., Karlsson A., Meichsner C., Paessens A., Riess G., De Clercq E., Kleim J. P. Resistance pattern of human immunodeficiency virus type 1 reverse transcriptase to quinoxaline S-2720. J Virol. 1994 Dec;68(12):7986–7992. doi: 10.1128/jvi.68.12.7986-7992.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Balzarini J., Karlsson A., Pérez-Pérez M. J., Camarasa M. J., De Clercq E. Knocking-out concentrations of HIV-1-specific inhibitors completely suppress HIV-1 infection and prevent the emergence of drug-resistant virus. Virology. 1993 Oct;196(2):576–585. doi: 10.1006/viro.1993.1513. [DOI] [PubMed] [Google Scholar]
  27. Balzarini J., Karlsson A., Sardana V. V., Emini E. A., Camarasa M. J., De Clercq E. Human immunodeficiency virus 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors may suppress the replication of specific drug-resistant (E138K)RT HIV-1 mutants or select for highly resistant (Y181C-->C181I)RT HIV-1 mutants. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6599–6603. doi: 10.1073/pnas.91.14.6599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Balzarini J., Naesens L., Herdewijn P., Rosenberg I., Holy A., Pauwels R., Baba M., Johns D. G., De Clercq E. Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. Proc Natl Acad Sci U S A. 1989 Jan;86(1):332–336. doi: 10.1073/pnas.86.1.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Balzarini J., Naesens L., Slachmuylders J., Niphuis H., Rosenberg I., Holý A., Schellekens H., De Clercq E. 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. AIDS. 1991 Jan;5(1):21–28. doi: 10.1097/00002030-199101000-00003. [DOI] [PubMed] [Google Scholar]
  30. Balzarini J., Pelemans H., Aquaro S., Perno C. F., Witvrouw M., Schols D., De Clercq E., Karlsson A. Highly favorable antiviral activity and resistance profile of the novel thiocarboxanilide pentenyloxy ether derivatives UC-781 and UC-82 as inhibitors of human immunodeficiency virus type 1 replication. Mol Pharmacol. 1996 Aug;50(2):394–401. [PubMed] [Google Scholar]
  31. Balzarini J., Pelemans H., Karlsson A., De ClercQ E., Kleim J. P. Concomitant combination therapy for HIV infection preferable over sequential therapy with 3TC and non-nucleoside reverse transcriptase inhibitors. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13152–13157. doi: 10.1073/pnas.93.23.13152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Balzarini J., Pelemans H., Pérez-Pérez M. J., San-Félix A., Camarasa M. J., De Clercq E., Karlsson A. Marked inhibitory activity of non-nucleoside reverse transcriptase inhibitors against human immunodeficiency virus type 1 when combined with (-)2',3'-dideoxy-3'-thiacytidine. Mol Pharmacol. 1996 May;49(5):882–890. [PubMed] [Google Scholar]
  33. Balzarini J., Pérez-Pérez M. J., San-Félix A., Schols D., Perno C. F., Vandamme A. M., Camarasa M. J., De Clercq E. 2',5'-Bis-O-(tert-butyldimethylsilyl)-3'-spiro-5''-(4''-amino-1'',2''- oxathiole-2'',2'-dioxide)pyrimidine (TSAO) nucleoside analogues: highlyselective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4392–4396. doi: 10.1073/pnas.89.10.4392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Balzarini J., Pérez-Pérez M. J., Vélazquez S., San-Félix A., Camarasa M. J., De Clercq E., Karlsson A. Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1-specific inhibitors (i.e., TSAO derivatives). Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5470–5474. doi: 10.1073/pnas.92.12.5470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Balzarini J., de Clercq E., Ayusawa D., Seno T. Murine mammary FM3A carcinoma cells transformed with the herpes simplex virus type 1 thymidine kinase gene are highly sensitive to the growth-inhibitory properties of (E)-5-(2-bromovinyl)-2'-deoxyuridine and related compounds. FEBS Lett. 1985 Jun 3;185(1):95–100. doi: 10.1016/0014-5793(85)80747-x. [DOI] [PubMed] [Google Scholar]
  36. Benoit Y., Laureys G., Delbeke M. J., De Clercq E. Oral BVDU treatment of varicella and zoster in children with cancer. Eur J Pediatr. 1985 Jan;143(3):198–202. doi: 10.1007/BF00442138. [DOI] [PubMed] [Google Scholar]
  37. Bischofberger N., Hitchcock M. J., Chen M. S., Barkhimer D. B., Cundy K. C., Kent K. M., Lacy S. A., Lee W. A., Li Z. H., Mendel D. B. 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl] cytosine, an intracellular prodrug for (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine with improved therapeutic index in vivo. Antimicrob Agents Chemother. 1994 Oct;38(10):2387–2391. doi: 10.1128/aac.38.10.2387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Bohman C., Balzarini J., Wigerinck P., Van Aerschot A., Herdewijn P., De Clercq E. Mechanism of cytostatic action of novel 5-(thien-2-yl)- and 5-(furan-2-yl)-substituted pyrimidine nucleoside analogues against tumor cells transfected by the thymidine kinase gene of herpes simplex virus. J Biol Chem. 1994 Mar 18;269(11):8036–8043. [PubMed] [Google Scholar]
  39. Cao Y., Qin L., Zhang L., Safrit J., Ho D. D. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med. 1995 Jan 26;332(4):201–208. doi: 10.1056/NEJM199501263320401. [DOI] [PubMed] [Google Scholar]
  40. Cherrington J. M., Allen S. J., McKee B. H., Chen M. S. Kinetic analysis of the interaction between the diphosphate of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, ddCTP, AZTTP, and FIAUTP with human DNA polymerases beta and gamma. Biochem Pharmacol. 1994 Nov 16;48(10):1986–1988. doi: 10.1016/0006-2952(94)90600-9. [DOI] [PubMed] [Google Scholar]
  41. Connelly M. C., Robbins B. L., Fridland A. Mechanism of uptake of the phosphonate analog (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) in Vero cells. Biochem Pharmacol. 1993 Sep 14;46(6):1053–1057. doi: 10.1016/0006-2952(93)90670-r. [DOI] [PubMed] [Google Scholar]
  42. Cundy K. C., Bidgood A. M., Lynch G., Shaw J. P., Griffin L., Lee W. A. Pharmacokinetics, bioavailability, metabolism, and tissue distribution of cidofovir (HPMPC) and cyclic HPMPC in rats. Drug Metab Dispos. 1996 Jul;24(7):745–752. [PubMed] [Google Scholar]
  43. Cundy K. C., Li Z. H., Hitchcock M. J., Lee W. A. Pharmacokinetics of cidofovir in monkeys. Evidence for a prolonged elimination phase representing phosphorylated drug. Drug Metab Dispos. 1996 Jul;24(7):738–744. [PubMed] [Google Scholar]
  44. D'Aquila R. T., Hughes M. D., Johnson V. A., Fischl M. A., Sommadossi J. P., Liou S. H., Timpone J., Myers M., Basgoz N., Niu M. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Ann Intern Med. 1996 Jun 15;124(12):1019–1030. doi: 10.7326/0003-4819-124-12-199606150-00001. [DOI] [PubMed] [Google Scholar]
  45. DAVIES W. L., GRUNERT R. R., HAFF R. F., MCGAHEN J. W., NEUMAYER E. M., PAULSHOCK M., WATTS J. C., WOOD T. R., HERMANN E. C., HOFFMANN C. E. ANTIVIRAL ACTIVITY OF 1-ADAMANTANAMINE (AMANTADINE). Science. 1964 May 15;144(3620):862–863. doi: 10.1126/science.144.3620.862. [DOI] [PubMed] [Google Scholar]
  46. DE Clercq E., Descamps J., DE Somer P., Holyacute A. (S)-9-(2,3-Dihydroxypropyl)adenine: An Aliphatic Nucleoside Analog with Broad-Spectrum Antiviral Activity. Science. 1978 May 5;200(4341):563–565. doi: 10.1126/science.200.4341.563. [DOI] [PubMed] [Google Scholar]
  47. Davey R. T., Jr, Chaitt D. G., Reed G. F., Freimuth W. W., Herpin B. R., Metcalf J. A., Eastman P. S., Falloon J., Kovacs J. A., Polis M. A. Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother. 1996 Jul;40(7):1657–1664. doi: 10.1128/aac.40.7.1657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. De Clercq E What can be Expected from Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) in the Treatment of Human Immunodeficiency Virus Type 1 (HIV-1) Infections? Rev Med Virol. 1996 Jun;6(2):97–117. doi: 10.1002/(SICI)1099-1654(199606)6:2<97::AID-RMV168>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
  49. De Clercq E. Antiviral therapy for human immunodeficiency virus infections. Clin Microbiol Rev. 1995 Apr;8(2):200–239. doi: 10.1128/cmr.8.2.200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. De Clercq E. Antivirals for the treatment of herpesvirus infections. J Antimicrob Chemother. 1993 Jul;32 (Suppl A):121–132. doi: 10.1093/jac/32.suppl_a.121. [DOI] [PubMed] [Google Scholar]
  51. De Clercq E., Balzarini J. Knocking out human immunodeficiency virus through non-nucleoside reverse transcriptase inhibitors used as single agents or in combinations: a paradigm for the cure of AIDS? Farmaco. 1995 Nov;50(11):735–747. [PubMed] [Google Scholar]
  52. De Clercq E. Broad-spectrum anti-DNA virus and anti-retrovirus activity of phosphonylmethoxyalkylpurines and -pyrimidines. Biochem Pharmacol. 1991 Aug 8;42(5):963–972. doi: 10.1016/0006-2952(91)90276-b. [DOI] [PubMed] [Google Scholar]
  53. De Clercq E., Cools M., Balzarini J., Marquez V. E., Borcherding D. R., Borchardt R. T., Drach J. C., Kitaoka S., Konno T. Broad-spectrum antiviral activities of neplanocin A, 3-deazaneplanocin A, and their 5'-nor derivatives. Antimicrob Agents Chemother. 1989 Aug;33(8):1291–1297. doi: 10.1128/aac.33.8.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. De Clercq E., Descamps J., De Somer P., Barr P. J., Jones A. S., Walker R. T. (E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent. Proc Natl Acad Sci U S A. 1979 Jun;76(6):2947–2951. doi: 10.1073/pnas.76.6.2947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. De Clercq E. HIV inhibitors targeted at the reverse transcriptase. AIDS Res Hum Retroviruses. 1992 Feb;8(2):119–134. doi: 10.1089/aid.1992.8.119. [DOI] [PubMed] [Google Scholar]
  56. De Clercq E. HIV resistance to reverse transcriptase inhibitors. Biochem Pharmacol. 1994 Jan 20;47(2):155–169. doi: 10.1016/0006-2952(94)90001-9. [DOI] [PubMed] [Google Scholar]
  57. De Clercq E., Holý A. Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice. Antimicrob Agents Chemother. 1991 Apr;35(4):701–706. doi: 10.1128/aac.35.4.701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. De Clercq E., Holý A., Rosenberg I. Efficacy of phosphonylmethoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infections in vivo. Antimicrob Agents Chemother. 1989 Feb;33(2):185–191. doi: 10.1128/aac.33.2.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. De Clercq E., Holý A., Rosenberg I., Sakuma T., Balzarini J., Maudgal P. C. A novel selective broad-spectrum anti-DNA virus agent. Nature. 1986 Oct 2;323(6087):464–467. doi: 10.1038/323464a0. [DOI] [PubMed] [Google Scholar]
  60. De Clercq E. S-adenosylhomocysteine hydrolase inhibitors as broad-spectrum antiviral agents. Biochem Pharmacol. 1987 Aug 15;36(16):2567–2575. doi: 10.1016/0006-2952(87)90533-8. [DOI] [PubMed] [Google Scholar]
  61. De Clercq E., Sakuma T., Baba M., Pauwels R., Balzarini J., Rosenberg I., Holý A. Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res. 1987 Dec;8(5-6):261–272. doi: 10.1016/s0166-3542(87)80004-9. [DOI] [PubMed] [Google Scholar]
  62. De Clercq E. The antiviral spectrum of (E)-5-(2-bromovinyl)-2'-deoxyuridine. J Antimicrob Chemother. 1984 Aug;14 (Suppl A):85–95. doi: 10.1093/jac/14.suppl_a.85. [DOI] [PubMed] [Google Scholar]
  63. De Clercq E. Toward improved anti-HIV chemotherapy: therapeutic strategies for intervention with HIV infections. J Med Chem. 1995 Jul 7;38(14):2491–2517. doi: 10.1021/jm00014a001. [DOI] [PubMed] [Google Scholar]
  64. De Wit S., Hermans P., Sommereijns B., O'Doherty E., Westenborghs R., van de Velde V., Cauwenbergh G. F., Clumeck N. Pharmacokinetics of R 82913 in AIDS patients: a phase I dose-finding study of oral administration compared with intravenous infusion. Antimicrob Agents Chemother. 1992 Dec;36(12):2661–2663. doi: 10.1128/aac.36.12.2661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Debyser Z., Pauwels R., Andries K., Desmyter J., Kukla M., Janssen P. A., De Clercq E. An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk] [1,4]benzodiazepin-2 (1H)-one and -thione derivatives. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1451–1455. doi: 10.1073/pnas.88.4.1451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Descamps J., De Clercq E. Specific phosphorylation of E-5-(2-iodovinyl)-2'-deoxyuridine by herpes simplex virus-infected cells. J Biol Chem. 1981 Jun 25;256(12):5973–5976. [PubMed] [Google Scholar]
  67. Ding J., Das K., Moereels H., Koymans L., Andries K., Janssen P. A., Hughes S. H., Arnold E. Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Nat Struct Biol. 1995 May;2(5):407–415. doi: 10.1038/nsb0595-407. [DOI] [PubMed] [Google Scholar]
  68. Ding J., Das K., Tantillo C., Zhang W., Clark A. D., Jr, Jessen S., Lu X., Hsiou Y., Jacobo-Molina A., Andries K. Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor alpha-APA R 95845 at 2.8 A resolution. Structure. 1995 Apr 15;3(4):365–379. doi: 10.1016/s0969-2126(01)00168-x. [DOI] [PubMed] [Google Scholar]
  69. Dueweke T. J., Poppe S. M., Romero D. L., Swaney S. M., So A. G., Downey K. M., Althaus I. W., Reusser F., Busso M., Resnick L. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother. 1993 May;37(5):1127–1131. doi: 10.1128/aac.37.5.1127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Egberink H., Borst M., Niphuis H., Balzarini J., Neu H., Schellekens H., De Clercq E., Horzinek M., Koolen M. Suppression of feline immunodeficiency virus infection in vivo by 9-(2-phosphonomethoxyethyl)adenine. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3087–3091. doi: 10.1073/pnas.87.8.3087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Elion G. B., Furman P. A., Fyfe J. A., de Miranda P., Beauchamp L., Schaeffer H. J. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5716–5720. doi: 10.1073/pnas.74.12.5716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Faulds D., Brogden R. N. Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs. 1992 Jul;44(1):94–116. doi: 10.2165/00003495-199244010-00008. [DOI] [PubMed] [Google Scholar]
  73. Flores-Aguilar M., Huang J. S., Wiley C. A., De Clercq E., Vuong C., Bergeron-Lynn G., Chandler B., Munguia D., Freeman W. R. Long-acting therapy of viral retinitis with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. J Infect Dis. 1994 Mar;169(3):642–647. doi: 10.1093/infdis/169.3.642. [DOI] [PubMed] [Google Scholar]
  74. Fyfe J. A. Differential phosphorylation of (E)-5-(2-bromovinyl)-2'-deoxyuridine monophosphate by thymidylate kinases from herpes simplex viruses types 1 and 2 and varicella zoster virus. Mol Pharmacol. 1982 Mar;21(2):432–437. [PubMed] [Google Scholar]
  75. Fyfe J. A., Keller P. M., Furman P. A., Miller R. L., Elion G. B. Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl)guanine. J Biol Chem. 1978 Dec 25;253(24):8721–8727. [PubMed] [Google Scholar]
  76. Goldman M. E., Nunberg J. H., O'Brien J. A., Quintero J. C., Schleif W. A., Freund K. F., Gaul S. L., Saari W. S., Wai J. S., Hoffman J. M. Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6863–6867. doi: 10.1073/pnas.88.15.6863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. HAMRE D., BROWNLEE K. A., DONOVICK R. Studies on the chemotherapy of vaccinia virus. II. The activity of some thiosemicarbazones. J Immunol. 1951 Oct;67(4):305–312. [PubMed] [Google Scholar]
  78. Havlir D., Cheeseman S. H., McLaughlin M., Murphy R., Erice A., Spector S. A., Greenough T. C., Sullivan J. L., Hall D., Myers M. High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J Infect Dis. 1995 Mar;171(3):537–545. doi: 10.1093/infdis/171.3.537. [DOI] [PubMed] [Google Scholar]
  79. Heijtink R. A., De Wilde G. A., Kruining J., Berk L., Balzarini J., De Clercq E., Holy A., Schalm S. W. Inhibitory effect of 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) on human and duck hepatitis B virus infection. Antiviral Res. 1993 Jun;21(2):141–153. doi: 10.1016/0166-3542(93)90050-s. [DOI] [PubMed] [Google Scholar]
  80. Heijtink R. A., Kruining J., de Wilde G. A., Balzarini J., de Clercq E., Schalm S. W. Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture. Antimicrob Agents Chemother. 1994 Sep;38(9):2180–2182. doi: 10.1128/aac.38.9.2180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Herdewijn P., De Clercq E., Balzarini J., Vanderhaeghe H. Synthesis and antiviral activity of the carbocyclic analogues of (E)-5-(2-halovinyl)-2'-deoxyuridines and (E)-5-(2-halovinyl)-2'-deoxycytidines. J Med Chem. 1985 May;28(5):550–555. doi: 10.1021/jm50001a003. [DOI] [PubMed] [Google Scholar]
  82. Ho D. D., Neumann A. U., Perelson A. S., Chen W., Leonard J. M., Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. doi: 10.1038/373123a0. [DOI] [PubMed] [Google Scholar]
  83. Ho D. D. Viral counts count in HIV infection. Science. 1996 May 24;272(5265):1124–1125. doi: 10.1126/science.272.5265.1124. [DOI] [PubMed] [Google Scholar]
  84. Ho H. T., Woods K. L., Bronson J. J., De Boeck H., Martin J. C., Hitchcock M. J. Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. Mol Pharmacol. 1992 Jan;41(1):197–202. [PubMed] [Google Scholar]
  85. KAUFMAN H. E. Clinical cure of herpes simplex keratitis by 5-iodo-2-deoxyuridine. Proc Soc Exp Biol Med. 1962 Feb;109:251–252. doi: 10.3181/00379727-109-27169. [DOI] [PubMed] [Google Scholar]
  86. KAUFMAN H. E., HEIDELBERGER C. THERAPEUTIC ANTIVIRAL ACTION OF 5-TRIFLUOROMETHYL-2'-DEOXYURIDINE IN HERPES SIMPLEX KERATITIS. Science. 1964 Aug 7;145(3632):585–586. doi: 10.1126/science.145.3632.585. [DOI] [PubMed] [Google Scholar]
  87. KAUFMAN H., MARTOLA E. L., DOHLMAN C. Use of 5-iodo-2'-deoxyuridine (IDU) in treatment of herpes simplex keratitis. Arch Ophthalmol. 1962 Aug;68:235–239. doi: 10.1001/archopht.1962.00960030239015. [DOI] [PubMed] [Google Scholar]
  88. Kirsch L. S., Arevalo J. F., Chavez de la Paz E., Munguia D., de Clercq E., Freeman W. R. Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology. 1995 Apr;102(4):533–543. doi: 10.1016/s0161-6420(95)30985-2. [DOI] [PubMed] [Google Scholar]
  89. Kirsch L. S., Arevalo J. F., De Clercq E., Chavez de la Paz E., Munguia D., Garcia R., Freeman W. R. Phase I/II study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol. 1995 Apr;119(4):466–476. doi: 10.1016/s0002-9394(14)71233-4. [DOI] [PubMed] [Google Scholar]
  90. Kit S., Ichimura H., De Clercq E. Differential metabolism of (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU) by equine herpesvirus type 1- and herpes simplex virus-infected cells. Antiviral Res. 1987 Aug;8(1):41–51. doi: 10.1016/0166-3542(87)90086-6. [DOI] [PubMed] [Google Scholar]
  91. Kleim J. P., Bender R., Billhardt U. M., Meichsner C., Riess G., Rösner M., Winkler I., Paessens A. Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication. Antimicrob Agents Chemother. 1993 Aug;37(8):1659–1664. doi: 10.1128/aac.37.8.1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Kramata P., Votruba I., Otová B., Holý A. Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases alpha, delta and epsilon. Mol Pharmacol. 1996 Jun;49(6):1005–1011. [PubMed] [Google Scholar]
  93. Kroeger Smith M. B., Rouzer C. A., Taneyhill L. A., Smith N. A., Hughes S. H., Boyer P. L., Janssen P. A., Moereels H., Koymans L., Arnold E. Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors: total energy of complexation as a predictor of drug placement and activity. Protein Sci. 1995 Oct;4(10):2203–2222. doi: 10.1002/pro.5560041026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Lalezari J. P., Drew W. L., Glutzer E., James C., Miner D., Flaherty J., Fisher P. E., Cundy K., Hannigan J., Martin J. C. (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (cidofovir): results of a phase I/II study of a novel antiviral nucleotide analogue. J Infect Dis. 1995 Apr;171(4):788–796. doi: 10.1093/infdis/171.4.788. [DOI] [PubMed] [Google Scholar]
  95. Lalezari J. P., Drew W. L., Glutzer E., Miner D., Safrin S., Owen W. F., Jr, Davidson J. M., Fisher P. E., Jaffe H. S. Treatment with intravenous (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS. J Infect Dis. 1994 Sep;170(3):570–572. doi: 10.1093/infdis/170.3.570. [DOI] [PubMed] [Google Scholar]
  96. Lalezari J. P., Stagg R. J., Kuppermann B. D., Holland G. N., Kramer F., Ives D. V., Youle M., Robinson M. R., Drew W. L., Jaffe H. S. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med. 1997 Feb 15;126(4):257–263. doi: 10.7326/0003-4819-126-4-199702150-00001. [DOI] [PubMed] [Google Scholar]
  97. Langtry H. D., Campoli-Richards D. M. Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs. 1989 Apr;37(4):408–450. doi: 10.2165/00003495-198937040-00003. [DOI] [PubMed] [Google Scholar]
  98. Larin N. M. Cardinal problems in search for antiviral drugs. Chemotherapy. 1967;12(4):201–214. doi: 10.1159/000220502. [DOI] [PubMed] [Google Scholar]
  99. Lin J. C., Smith M. C., Cheng Y. C., Pagano J. S. Epstein-Barr virus: inhibition of replication by three new drugs. Science. 1983 Aug 5;221(4610):578–579. doi: 10.1126/science.6306771. [DOI] [PubMed] [Google Scholar]
  100. Machida H., Sakata S., Kuninaka A., Yoshino H. Antiherpesviral and anticellular effects of 1-beta-D-arabinofuranosyl-E-5-(2-halogenovinyl) uracils. Antimicrob Agents Chemother. 1981 Jul;20(1):47–52. doi: 10.1128/aac.20.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Mancini W. R., De Clercq E., Prusoff W. H. The relationship between incorporation of E-5-(2-Bromovinyl)-2'-deoxyuridine into herpes simplex virus type 1 DNA with virus infectivity and DNA integrity. J Biol Chem. 1983 Jan 25;258(2):792–795. [PubMed] [Google Scholar]
  102. Markham A., Faulds D. Ganciclovir. An update of its therapeutic use in cytomegalovirus infection. Drugs. 1994 Sep;48(3):455–484. doi: 10.2165/00003495-199448030-00009. [DOI] [PubMed] [Google Scholar]
  103. Maudgal P. C., De Clercq E. Bromovinyldeoxyuridine treatment of herpetic keratitis clinically resistant to other antiviral agents. Curr Eye Res. 1991;10 (Suppl):193–199. doi: 10.3109/02713689109020379. [DOI] [PubMed] [Google Scholar]
  104. Mayers D. L., Mikovits J. A., Joshi B., Hewlett I. K., Estrada J. S., Wolfe A. D., Garcia G. E., Doctor B. P., Burke D. S., Gordon R. K. Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: increased potency against 3'-azido-3'-deoxythymidine-resistant HIV-1 strains. Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):215–219. doi: 10.1073/pnas.92.1.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Mellors J. W., Rinaldo C. R., Jr, Gupta P., White R. M., Todd J. A., Kingsley L. A. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996 May 24;272(5265):1167–1170. doi: 10.1126/science.272.5265.1167. [DOI] [PubMed] [Google Scholar]
  106. Merluzzi V. J., Hargrave K. D., Labadia M., Grozinger K., Skoog M., Wu J. C., Shih C. K., Eckner K., Hattox S., Adams J. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science. 1990 Dec 7;250(4986):1411–1413. doi: 10.1126/science.1701568. [DOI] [PubMed] [Google Scholar]
  107. Merta A., Votruba I., Jindrich J., Holý A., Cihlár T., Rosenberg I., Otmar M., Herve T. Y. Phosphorylation of 9-(2-phosphonomethoxyethyl)adenine and 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine by AMP(dAMP) kinase from L1210 cells. Biochem Pharmacol. 1992 Nov 17;44(10):2067–2077. doi: 10.1016/0006-2952(92)90110-5. [DOI] [PubMed] [Google Scholar]
  108. Miyasaka T., Tanaka H., Baba M., Hayakawa H., Walker R. T., Balzarini J., De Clercq E. A novel lead for specific anti-HIV-1 agents: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J Med Chem. 1989 Dec;32(12):2507–2509. doi: 10.1021/jm00132a002. [DOI] [PubMed] [Google Scholar]
  109. Moyle G., Gazzard B. Current knowledge and future prospects for the use of HIV protease inhibitors. Drugs. 1996 May;51(5):701–712. doi: 10.2165/00003495-199651050-00001. [DOI] [PubMed] [Google Scholar]
  110. Naesens L., Balzarini J., Bischofberger N., De Clercq E. Antiretroviral activity and pharmacokinetics in mice of oral bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine, the bis(pivaloyloxymethyl) ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine. Antimicrob Agents Chemother. 1996 Jan;40(1):22–28. doi: 10.1128/aac.40.1.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Neyts J., Snoeck R., Schols D., Balzarini J., De Clercq E. 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). Virology. 1990 Nov;179(1):41–50. doi: 10.1016/0042-6822(90)90271-r. [DOI] [PubMed] [Google Scholar]
  112. Neyts J., Sobis H., Snoeck R., Vandeputte M., De Clercq E. 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. Eur J Clin Microbiol Infect Dis. 1993 Apr;12(4):269–279. doi: 10.1007/BF01967257. [DOI] [PubMed] [Google Scholar]
  113. O'Brien W. A., Hartigan P. M., Martin D., Esinhart J., Hill A., Benoit S., Rubin M., Simberkoff M. S., Hamilton J. D. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS. N Engl J Med. 1996 Feb 15;334(7):426–431. doi: 10.1056/NEJM199602153340703. [DOI] [PubMed] [Google Scholar]
  114. Oberg B. Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacol Ther. 1982;19(3):387–415. doi: 10.1016/0163-7258(82)90074-2. [DOI] [PubMed] [Google Scholar]
  115. Okamoto M., Makino M., Yamada K., Nakade K., Yuasa S., Baba M. Complete inhibition of viral breakthrough by combination of MKC-442 with AZT during a long-term culture of HIV-1 infected cells. Antiviral Res. 1996 Jun;31(1-2):69–77. doi: 10.1016/0166-3542(96)00946-1. [DOI] [PubMed] [Google Scholar]
  116. PRIVATDEGARILHE M., DE RUDDER J. EFFET DE DEUX NUCL'EOSIDES DE L'ARABINOSE SUR LA MULTIPLICATION DES VIRUS DE L'HERP'ES ET DE LA VACCINE EN CULTURE CELLULAIRE. C R Hebd Seances Acad Sci. 1964 Oct 19;259:2725–2728. [PubMed] [Google Scholar]
  117. PRUSOFF W. H. Synthesis and biological activities of iododeoxyuridine, an analog of thymidine. Biochim Biophys Acta. 1959 Mar;32(1):295–296. doi: 10.1016/0006-3002(59)90597-9. [DOI] [PubMed] [Google Scholar]
  118. Pantaleo G., Menzo S., Vaccarezza M., Graziosi C., Cohen O. J., Demarest J. F., Montefiori D., Orenstein J. M., Fox C., Schrager L. K. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med. 1995 Jan 26;332(4):209–216. doi: 10.1056/NEJM199501263320402. [DOI] [PubMed] [Google Scholar]
  119. Pauwels R., Andries K., Debyser Z., Kukla M. J., Schols D., Breslin H. J., Woestenborghs R., Desmyter J., Janssen M. A., De Clercq E. New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2',3'-dideoxynucleoside analogs. Antimicrob Agents Chemother. 1994 Dec;38(12):2863–2870. doi: 10.1128/aac.38.12.2863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Pauwels R., Andries K., Debyser Z., Van Daele P., Schols D., Stoffels P., De Vreese K., Woestenborghs R., Vandamme A. M., Janssen C. G. Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of alpha-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1711–1715. doi: 10.1073/pnas.90.5.1711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Pauwels R., Andries K., Desmyter J., Schols D., Kukla M. J., Breslin H. J., Raeymaeckers A., Van Gelder J., Woestenborghs R., Heykants J. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature. 1990 Feb 1;343(6257):470–474. doi: 10.1038/343470a0. [DOI] [PubMed] [Google Scholar]
  122. Perelson A. S., Neumann A. U., Markowitz M., Leonard J. M., Ho D. D. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996 Mar 15;271(5255):1582–1586. doi: 10.1126/science.271.5255.1582. [DOI] [PubMed] [Google Scholar]
  123. Ren J., Esnouf R., Garman E., Somers D., Ross C., Kirby I., Keeling J., Darby G., Jones Y., Stuart D. High resolution structures of HIV-1 RT from four RT-inhibitor complexes. Nat Struct Biol. 1995 Apr;2(4):293–302. doi: 10.1038/nsb0495-293. [DOI] [PubMed] [Google Scholar]
  124. Ren J., Esnouf R., Hopkins A., Ross C., Jones Y., Stammers D., Stuart D. The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design. Structure. 1995 Sep 15;3(9):915–926. doi: 10.1016/S0969-2126(01)00226-X. [DOI] [PubMed] [Google Scholar]
  125. Reymen D., Naesens L., Balzarini J., Holý A., Dvoráková H., De Clercq E. Antiviral activity of selected acyclic nucleoside analogues against human herpesvirus 6. Antiviral Res. 1995 Dec;28(4):343–357. doi: 10.1016/0166-3542(95)00058-5. [DOI] [PubMed] [Google Scholar]
  126. Richman D. D., Havlir D., Corbeil J., Looney D., Ignacio C., Spector S. A., Sullivan J., Cheeseman S., Barringer K., Pauletti D. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol. 1994 Mar;68(3):1660–1666. doi: 10.1128/jvi.68.3.1660-1666.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Robbins B. L., Greenhaw J., Connelly M. C., Fridland A. Metabolic pathways for activation of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human lymphoid cells. Antimicrob Agents Chemother. 1995 Oct;39(10):2304–2308. doi: 10.1128/aac.39.10.2304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. Romero D. L., Busso M., Tan C. K., Reusser F., Palmer J. R., Poppe S. M., Aristoff P. A., Downey K. M., So A. G., Resnick L. Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8806–8810. doi: 10.1073/pnas.88.19.8806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Saag M. S., Emini E. A., Laskin O. L., Douglas J., Lapidus W. I., Schleif W. A., Whitley R. J., Hildebrand C., Byrnes V. W., Kappes J. C. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. L-697,661 Working Group. N Engl J Med. 1993 Oct 7;329(15):1065–1072. doi: 10.1056/NEJM199310073291502. [DOI] [PubMed] [Google Scholar]
  130. Schabel F. M., Jr The antiviral activity of 9-beta-D-arabinofuranosyladenine (ARA-A). Chemotherapy. 1968;13(6):321–338. doi: 10.1159/000220567. [DOI] [PubMed] [Google Scholar]
  131. Schaeffer H. J., Beauchamp L., de Miranda P., Elion G. B., Bauer D. J., Collins P. 9-(2-hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature. 1978 Apr 13;272(5654):583–585. doi: 10.1038/272583a0. [DOI] [PubMed] [Google Scholar]
  132. Shigeta S., Yokota T., Iwabuchi T., Baba M., Konno K., Ogata M., De Clercq E. Comparative efficacy of antiherpes drugs against various strains of varicella-zoster virus. J Infect Dis. 1983 Mar;147(3):576–584. doi: 10.1093/infdis/147.3.576. [DOI] [PubMed] [Google Scholar]
  133. Sidwell R. W., Huffman J. H., Khare G. P., Allen L. B., Witkowski J. T., Robins R. K. Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science. 1972 Aug 25;177(4050):705–706. doi: 10.1126/science.177.4050.705. [DOI] [PubMed] [Google Scholar]
  134. Snoeck R., Andrei G., De Clercq E., Gerard M., Clumeck N., Tricot G., Sadzot-Delvaux C. A new topical treatment for resistant herpes simplex infections. N Engl J Med. 1993 Sep 23;329(13):968–969. doi: 10.1056/NEJM199309233291317. [DOI] [PubMed] [Google Scholar]
  135. Snoeck R., Andrei G., Gérard M., Silverman A., Hedderman A., Balzarini J., Sadzot-Delvaux C., Tricot G., Clumeck N., De Clercq E. Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Clin Infect Dis. 1994 Apr;18(4):570–578. doi: 10.1093/clinids/18.4.570. [DOI] [PubMed] [Google Scholar]
  136. Snoeck R., Andrei G., Neyts J., Schols D., Cools M., Balzarini J., De Clercq E. Inhibitory activity of S-adenosylhomocysteine hydrolase inhibitors against human cytomegalovirus replication. Antiviral Res. 1993 Jul;21(3):197–216. doi: 10.1016/0166-3542(93)90028-h. [DOI] [PubMed] [Google Scholar]
  137. Snoeck R., Gérard M., Sadzot-Delvaux C., Andrei G., Balzarini J., Reymen D., Ahadi N., De Bruyn J. M., Piette J., Rentier B. Meningoradiculoneuritis due to acyclovir-resistant varicella zoster virus in an acquired immune deficiency syndrome patient. J Med Virol. 1994 Apr;42(4):338–347. doi: 10.1002/jmv.1890420404. [DOI] [PubMed] [Google Scholar]
  138. Snoeck R., Sakuma T., De Clercq E., Rosenberg I., Holy A. (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother. 1988 Dec;32(12):1839–1844. doi: 10.1128/aac.32.12.1839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  139. Snoeck R., Van Ranst M., Andrei G., De Clercq E., De Wit S., Poncin M., Clumeck N. Treatment of anogenital papillomavirus infections with an acyclic nucleoside phosphonate analogue. N Engl J Med. 1995 Oct 5;333(14):943–944. doi: 10.1056/NEJM199510053331418. [DOI] [PubMed] [Google Scholar]
  140. Soike K. F., Huang J. L., Zhang J. Y., Bohm R., Hitchcock M. J., Martin J. C. Evaluation of infrequent dosing regimens with (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine (S-HPMPC) on simian varicella infection in monkeys. Antiviral Res. 1991 Jul;16(1):17–28. doi: 10.1016/0166-3542(91)90055-v. [DOI] [PubMed] [Google Scholar]
  141. Starrett J. E., Jr, Tortolani D. R., Russell J., Hitchcock M. J., Whiterock V., Martin J. C., Mansuri M. M. Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). J Med Chem. 1994 Jun 10;37(12):1857–1864. doi: 10.1021/jm00038a015. [DOI] [PubMed] [Google Scholar]
  142. Staszewski S., Massari F. E., Kober A., Göhler R., Durr S., Anderson K. W., Schneider C. L., Waterbury J. A., Bakshi K. K., Taylor V. I. Combination therapy with zidovudine prevents selection of human immunodeficiency virus type 1 variants expressing high-level resistance to L-697,661, a nonnucleoside reverse transcriptase inhibitor. J Infect Dis. 1995 May;171(5):1159–1165. doi: 10.1093/infdis/171.5.1159. [DOI] [PubMed] [Google Scholar]
  143. Staszewski S., Miller V., Kober A., Colebunders R., Vandercam B., Delescluse J., Clumeck N., Van Wanzeele F., De Brabander M., De Creé J. Evaluation of the efficacy and tolerance of R 018893, R 089439 (loviride) and placebo in asymptomatic HIV-1-infected patients. Loviride Collaborative Study Group. Antivir Ther. 1996 Jan;1(1):42–50. [PubMed] [Google Scholar]
  144. Staszewski S., Miller V., Rehmet S., Stark T., De Crée J., De Brabander M., Peeters M., Andries K., Moeremans M., De Raeymaeker M. Virological and immunological analysis of a triple combination pilot study with loviride, lamivudine and zidovudine in HIV-1-infected patients. AIDS. 1996 May;10(5):F1–F7. doi: 10.1097/00002030-199605000-00001. [DOI] [PubMed] [Google Scholar]
  145. Tantillo C., Ding J., Jacobo-Molina A., Nanni R. G., Boyer P. L., Hughes S. H., Pauwels R., Andries K., Janssen P. A., Arnold E. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. J Mol Biol. 1994 Oct 28;243(3):369–387. doi: 10.1006/jmbi.1994.1665. [DOI] [PubMed] [Google Scholar]
  146. Thormar H., Balzarini J., Holy A., Jindrich J., Rosenberg I., Debyser Z., Desmyter J., De Clercq E. Inhibition of visna virus replication by 2',3'-dideoxynucleosides and acyclic nucleoside phosphonate analogs. Antimicrob Agents Chemother. 1993 Dec;37(12):2540–2544. doi: 10.1128/aac.37.12.2540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  147. Thormar H., Georgsson G., Pálsson P. A., Balzarini J., Naesens L., Torsteinsdóttir S., De Clercq E. 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. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3283–3287. doi: 10.1073/pnas.92.8.3283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  148. Tricot G., De Clercq E., Boogaerts M. A., Verwilghen R. L. Oral bromovinyldeoxyuridine therapy for herpes simplex and varicella-zoster virus infections in severely immunosuppressed patients: a preliminary clinical trial. J Med Virol. 1986 Jan;18(1):11–20. doi: 10.1002/jmv.1890180103. [DOI] [PubMed] [Google Scholar]
  149. Tsai C. C., Follis K. E., Grant R., Sabo A., Nolte R., Bartz C., Bischofberger N., Benveniste R. Comparison of the efficacy of AZT and PMEA treatment against acute SIVmne infection in macaques. J Med Primatol. 1994 Feb-May;23(2-3):175–183. doi: 10.1111/j.1600-0684.1994.tb00119.x. [DOI] [PubMed] [Google Scholar]
  150. Tsai C. C., Follis K. E., Sabo A., Beck T. W., Grant R. F., Bischofberger N., Benveniste R. E., Black R. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. Science. 1995 Nov 17;270(5239):1197–1199. doi: 10.1126/science.270.5239.1197. [DOI] [PubMed] [Google Scholar]
  151. Tsai C. C., Follis K. E., Sabo A., Grant R. F., Bartz C., Nolte R. E., Benveniste R. E., Bischofberger N. Preexposure prophylaxis with 9-(2-phosphonylmethoxyethyl)adenine against simian immunodeficiency virus infection in macaques. J Infect Dis. 1994 Feb;169(2):260–266. doi: 10.1093/infdis/169.2.260. [DOI] [PubMed] [Google Scholar]
  152. Vahlenkamp T. W., De Ronde A., Balzarini J., Naesens L., De Clercq E., van Eijk M. J., Horzinek M. C., Egberink H. F. (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine is a potent inhibitor of feline immunodeficiency virus infection. Antimicrob Agents Chemother. 1995 Mar;39(3):746–749. doi: 10.1128/AAC.39.3.746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  153. Van Cutsem E., Snoeck R., Van Ranst M., Fiten P., Opdenakker G., Geboes K., Janssens J., Rutgeerts P., Vantrappen G., de Clercq E. Successful treatment of a squamous papilloma of the hypopharynx-esophagus by local injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. J Med Virol. 1995 Feb;45(2):230–235. doi: 10.1002/jmv.1890450221. [DOI] [PubMed] [Google Scholar]
  154. Vasudevachari M. B., Battista C., Lane H. C., Psallidopoulos M. C., Zhao B., Cook J., Palmer J. R., Romero D. L., Tarpley W. G., Salzman N. P. Prevention of the spread of HIV-1 infection with nonnucleoside reverse transcriptase inhibitors. Virology. 1992 Sep;190(1):269–277. doi: 10.1016/0042-6822(92)91213-e. [DOI] [PubMed] [Google Scholar]
  155. Wainberg M. A., Drosopoulos W. C., Salomon H., Hsu M., Borkow G., Parniak M., Gu Z., Song Q., Manne J., Islam S. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science. 1996 Mar 1;271(5253):1282–1285. doi: 10.1126/science.271.5253.1282. [DOI] [PubMed] [Google Scholar]
  156. Wei X., Ghosh S. K., Taylor M. E., Johnson V. A., Emini E. A., Deutsch P., Lifson J. D., Bonhoeffer S., Nowak M. A., Hahn B. H. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. doi: 10.1038/373117a0. [DOI] [PubMed] [Google Scholar]
  157. Whittington R., Brogden R. N. Zalcitabine. A review of its pharmacology and clinical potential in acquired immunodeficiency syndrome (AIDS). Drugs. 1992 Oct;44(4):656–683. doi: 10.2165/00003495-199244040-00009. [DOI] [PubMed] [Google Scholar]
  158. Wigerinck P., Pannecouque C., Snoeck R., Claes P., De Clercq E., Herdewijn P. 5-(5-Bromothien-2-yl)-2'-deoxyuridine and 5-(5-chlorothien-2-yl)-2'-deoxyuridine are equipotent to (E)-5-(2-bromovinyl)-2'-deoxyuridine in the inhibition of herpes simplex virus type I replication. J Med Chem. 1991 Aug;34(8):2383–2389. doi: 10.1021/jm00112a011. [DOI] [PubMed] [Google Scholar]
  159. Wildiers J., De Clercq E. Oral (E)-5-(2-bromovinyl)-2'-deoxyuridine treatment of severe herpes zoster in cancer patients. Eur J Cancer Clin Oncol. 1984 Apr;20(4):471–476. doi: 10.1016/0277-5379(84)90231-1. [DOI] [PubMed] [Google Scholar]
  160. Wutzler P., De Clercq E., Wutke K., Färber I. Oral brivudin vs. intravenous acyclovir in the treatment of herpes zoster in immunocompromised patients: a randomized double-blind trial. J Med Virol. 1995 Jul;46(3):252–257. doi: 10.1002/jmv.1890460315. [DOI] [PubMed] [Google Scholar]
  161. Xiong X., Smith J. L., Kim C., Huang E. S., Chen M. S. Kinetic analysis of the interaction of cidofovir diphosphate with human cytomegalovirus DNA polymerase. Biochem Pharmacol. 1996 Jun 14;51(11):1563–1567. doi: 10.1016/0006-2952(96)00100-1. [DOI] [PubMed] [Google Scholar]
  162. de Clercq E. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infections: strategies to overcome drug resistance development. Med Res Rev. 1996 Mar;16(2):125–157. doi: 10.1002/(SICI)1098-1128(199603)16:2<125::AID-MED1>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  163. de Clercq E. Topical treatment of cutaneous herpes simplex virus infection in hairless mice with (E)-5-(2-bromovinyl)-2'-deoxyuridine and related compounds. Antimicrob Agents Chemother. 1984 Aug;26(2):155–159. doi: 10.1128/aac.26.2.155. [DOI] [PMC free article] [PubMed] [Google Scholar]

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