Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1993 Feb;37(2):332–338. doi: 10.1128/aac.37.2.332

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.

J Balzarini 1, A Holy 1, J Jindrich 1, L Naesens 1, R Snoeck 1, D Schols 1, E De Clercq 1
PMCID: PMC187663  PMID: 8452366

Abstract

The (S)- and (R)-enantiomers of acyclic purine nucleoside phosphonate analogs (i.e., 3-hydroxy-2-phosphonomethoxypropyl [HPMP] derivatives, 3-fluoro-2-phosphonomethoxypropyl [FPMP] derivatives, and 2-phosphonomethoxypropyl [PMP] derivatives of adenine [A], 2-aminopurine, 2,6-diaminopurine [DAP], and guanine [G]) have been synthesized and evaluated for antiviral activity. As a rule, the HPMP derivatives proved effective against DNA viruses but not RNA viruses or retroviruses. In particular, (S)-HPMPA, (S)-HPMPDAP, and (R)- and (S)-HPMPG were exquisitely inhibitory to herpes simplex virus type 1 (50% effective concentrations, 0.63, 0.22, 0.10, and 0.66 microM, respectively). The FPMP and PMP derivatives showed marked inhibitory activities against retroviruses but not DNA viruses. The (S)-enantiomer of FPMPA and the (R)-enantiomer of PMPA were approximately 30- to 100-fold more effective against human immunodeficiency virus and Moloney murine sarcoma virus (MSV) than their enantiomeric counterparts. In contrast, both (S)- and (R)-enantiomers of the DAP and G derivatives proved equally effective against retroviruses, except for (R)-PMPDAP, which was 15- to 40-fold more inhibitory than (S)-PMPDAP. (R)-PMPDAP emerged as the most potent and selective inhibitor of MSV-induced transformation of murine C3H/3T3 cells and human immunodeficiency virus-induced cytopathicity in MT-4 and CEM cells (50% effective concentration, approximately 0.1 to 0.6 microM). When administered intraperitoneally at a single dose as low as 2 mg/kg, (R)-PMPDAP efficiently decreased MSV-induced tumor formation in newborn NMRI mice and significantly increased the survival time of MSV-infected mice. In addition, upon oral administration to MSV-infected mice, (R)-PMPDAP showed marked antiretroviral efficacy.

Full text

PDF
333

Selected References

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

  1. Baba M., Konno K., Shigeta S., De Clercq E. In vitro activity of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine against newly isolated clinical varicella-zoster virus strains. Eur J Clin Microbiol. 1987 Apr;6(2):158–160. doi: 10.1007/BF02018198. [DOI] [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., Karlsson A., Pérez-Pérez M. J., Vrang L., Walbers J., Zhang H., Oberg B., Vandamme A. M., Camarasa M. J., De Clercq E. HIV-1-specific reverse transcriptase inhibitors show differential activity against HIV-1 mutant strains containing different amino acid substitutions in the reverse transcriptase. Virology. 1993 Jan;192(1):246–253. doi: 10.1006/viro.1993.1027. [DOI] [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. Balzarini J., Perno C. F., Schols D., De Clercq E. Activity of acyclic nucleoside phosphonate analogues against human immunodeficiency virus in monocyte/macrophages and peripheral blood lymphocytes. Biochem Biophys Res Commun. 1991 Jul 15;178(1):329–335. doi: 10.1016/0006-291x(91)91818-w. [DOI] [PubMed] [Google Scholar]
  7. Clavel F., Guétard D., Brun-Vézinet F., Chamaret S., Rey M. A., Santos-Ferreira M. O., Laurent A. G., Dauguet C., Katlama C., Rouzioux C. Isolation of a new human retrovirus from West African patients with AIDS. Science. 1986 Jul 18;233(4761):343–346. doi: 10.1126/science.2425430. [DOI] [PubMed] [Google Scholar]
  8. De Clercq E., Balzarini J., Torrence P. F., Mertes M. P., Schmidt C. L., Shugar D., Barr P. J., Jones A. S., Verhelst G., Walker R. T. Thymidylate synthetase as target enzyme for the inhibitory activity of 5-substituted 2'-deoxyuridines on mouse leukemia L1210 cell growth. Mol Pharmacol. 1981 Mar;19(2):321–330. [PubMed] [Google Scholar]
  9. 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]
  10. De Clercq E., Descamps J., Verhelst G., Walker R. T., Jones A. S., Torrence P. F., Shugar D. Comparative efficacy of antiherpes drugs against different strains of herpes simplex virus. J Infect Dis. 1980 May;141(5):563–574. doi: 10.1093/infdis/141.5.563. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. Naesens L., Balzarini J., Rosenberg I., Holý A., De Clercq E. 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. Eur J Clin Microbiol Infect Dis. 1989 Dec;8(12):1043–1047. doi: 10.1007/BF01975167. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
  19. 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]

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

RESOURCES