Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1993 Dec;37(12):2540–2544. doi: 10.1128/aac.37.12.2540

Inhibition of visna virus replication by 2',3'-dideoxynucleosides and acyclic nucleoside phosphonate analogs.

H Thormar 1, J Balzarini 1, A Holy 1, J Jindrich 1, I Rosenberg 1, Z Debyser 1, J Desmyter 1, E De Clercq 1
PMCID: PMC192732  PMID: 7509142

Abstract

A series of acyclic nucleoside phosphonate (ANP) and 2',3'-dideoxynucleoside (ddN) derivatives were evaluated for their inhibitory effects on visna virus replication and maedi/visna virus-induced syncytium formation in sheep choroid plexus cells. Most ANP derivatives inhibited virus replication and syncytium formation within a concentration range of 0.2 to 1.8 microM. Among the most active ANP derivatives ranked (R)-9-(2-phosphonomethoxypropyl)adenine, (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine, and (S)-9-(3-fluoro-2-phosphonomethoxypropyl)adenine. Of the ddN derivatives, 2',3'-dideoxycytidine (ddCyd) proved to be the most inhibitory to visna virus-induced syncytium formation (50% effective concentration, 0.02 microM). The purine ddN analogs (i.e., 2',3'-dideoxyinosine, 2',3'-dideoxyadenosine, 2',3'-dideoxyguanosine, and 2,6-diaminopurine-2',3'-dideoxyribosine) were 10- to 30-fold less effective, and the thymidine derivatives 2',3'-didehydro-2',3'-dideoxythymidine (D4T) and 3'-azido-2',3'-dideoxythymidine (AZT) were more than 500-fold less inhibitory to visna virus than ddCyd. The 5'-triphosphate forms of AZT and D4T were 100- to 600-fold more inhibitory to visna virus particle-derived reverse transcriptase than was the 5'-triphosphate of ddCyd. The apparent discrepancy between the inhibitory effects of these ddN derivatives on virus replication and viral reverse transcriptase activity most likely reflects differences in the metabolic conversion of ddCyd versus D4T and AZT in sheep choroid plexus cells.

Full text

PDF
2540

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Balzarini J., Herdewijn P., De Clercq E. Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. J Biol Chem. 1989 Apr 15;264(11):6127–6133. [PubMed] [Google Scholar]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. Dahlberg J. E., Mitsuya H., Blam S. B., Broder S., Aaronson S. A. Broad spectrum antiretroviral activity of 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2469–2473. doi: 10.1073/pnas.84.8.2469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. De Clercq E. New acquisitions in the development of anti-HIV agents. Antiviral Res. 1989 Aug;12(1):1–19. doi: 10.1016/0166-3542(89)90064-8. [DOI] [PubMed] [Google Scholar]
  8. Debyser Z., Vandamme A. M., Pauwels R., Baba M., Desmyter J., De Clercq E. Kinetics of inhibition of endogenous human immunodeficiency virus type 1 reverse transcription by 2',3'-dideoxynucleoside 5'-triphosphate, tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thion e, and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives. J Biol Chem. 1992 Jun 15;267(17):11769–11776. [PubMed] [Google Scholar]
  9. 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]
  10. Frank K. B., McKernan P. A., Smith R. A., Smee D. F. Visna virus as an in vitro model for human immunodeficiency virus and inhibition by ribavirin, phosphonoformate, and 2',3'-dideoxynucleosides. Antimicrob Agents Chemother. 1987 Sep;31(9):1369–1374. doi: 10.1128/aac.31.9.1369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hartmann K., Donath A., Beer B., Egberink H. F., Horzinek M. C., Lutz H., Hoffmann-Fezer G., Thum I., Thefeld S. Use of two virustatica (AZT, PMEA) in the treatment of FIV and of FeLV seropositive cats with clinical symptoms. Vet Immunol Immunopathol. 1992 Dec;35(1-2):167–175. doi: 10.1016/0165-2427(92)90129-e. [DOI] [PubMed] [Google Scholar]
  12. Holý A., Votruba I., Merta A., Cerný J., Veselý J., Vlach J., Sedivá K., Rosenberg I., Otmar M., Hrebabecký H. Acyclic nucleotide analogues: synthesis, antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro. Antiviral Res. 1990 Jun;13(6):295–311. doi: 10.1016/0166-3542(90)90014-x. [DOI] [PubMed] [Google Scholar]
  13. Lin F. H., Thormar H. Ribonucleic acid-dependent deoxyribonucleic acid polymerase in visna virus. J Virol. 1970 Nov;6(5):702–704. doi: 10.1128/jvi.6.5.702-704.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. North T. W., North G. L., Pedersen N. C. Feline immunodeficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune deficiency syndrome. Antimicrob Agents Chemother. 1989 Jun;33(6):915–919. doi: 10.1128/aac.33.6.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Pauwels R., Balzarini J., Schols D., Baba M., Desmyter J., Rosenberg I., Holy A., De Clercq E. Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents. Antimicrob Agents Chemother. 1988 Jul;32(7):1025–1030. doi: 10.1128/aac.32.7.1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sundquist B., Larner E. Phosphonoformate inhibition of visna virus replication. J Virol. 1979 Jun;30(3):847–851. doi: 10.1128/jvi.30.3.847-851.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES