Advertisement

Cellular Metabolism and Enzymatic Phosphorylation of 9- (2-Phosphonylmethoxyethyl) Guanine (PMEG),a Potent Antiviral Agent

  • Hsu-Tso Ho
  • Kathleen L. Woods
  • Sherry A. Konrad
  • Hilde De Boeck
  • Michael J. M. Hitchcock
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 312)

Abstract

PMEG (9-(2-Phosphonylmethoxyethyl)guanine) is a potent, broad spectrum antiviral agent in the nucleoside phosphonate class (Figure 1). In vitro, PMEG is active against HSV-1, HSV-2, VZV, HCMV and Rauscher murine leukemia virus with IC50s (the concentrations of drug required to reduce the plaque formation by 50%) less than 1 ug/ml (1,2,3). Similar antiviral activity was demonstrated with TK-minus mutants of HSV-1. However, the toxic effect exerted by PMEG on CEM and Vero cells in culture (TC50 5-10 μg/ml, the concentrations of drug affecting the viability of uninfected cells by 50%) limits the utility of PMEG as an antiviral agent. On the other hand, PMEG has antitumor activity (4) against intraperitoneal P388 leukemia and subcutaneously implanted B16 melanoma in mice. PMEG, also supresses human condylomas from papillomavirus (HPV-11) infected human foreskin in transplanted mice (5). We have investigated the cellular metabolism of PMEG and the viral and cellular target enzymes involved in the mode of action to provide rationale for the low antiviral selectivity and to assist with future design of more selective analogs of PMEG.

Keywords

Vero Cell Pyruvate Kinase Antiviral Agent Nucleoside Diphosphate Kinase Guanylate Kinase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    De Clerq, E., Sakuma, T., Baba, M., Pauwels, R., Balzarini, J., Rosenberg, I., and Holy, A., Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidine, Antiviral Res. 8:261–272 (1987).CrossRefGoogle Scholar
  2. Bronson, J.J., Kim, C., Ghazzouli, I., Hitchcock, J.M., Kern, E.R., and Martin, J.C., Synthesis and antiviral activity of phosphonylmethoxyethyl derivatives of purine and pyrimidine bases, in: “Nucleotide Analogues as Antiviral Agents”, J.C. Martin, ed., ACS symposium series 401:72–87 (1989).CrossRefGoogle Scholar
  3. 3.
    Kim, C., Luh, B., Misco, P.F., Bronson, J.J., Hitchcock, M.J.M., Ghazzouli, I., and Martin, J.C., Synthesis and biological activities of phosphonylalkyl purine derivatives, Nucleosides & Nucleotides 8(5&6):927–932 (1989).Google Scholar
  4. 4.
    Rose, W.C., Crosswell, A.R., Bronson, J.J., and Martin, J.C., In vivo antitumor activity of 9-((2-phosphonylmethoxy)ethyl)-guanine and related phosphonate nucleotide analogues, J. Natl. Can. Inst. 82:50–52 (1990).CrossRefGoogle Scholar
  5. 5.
    Krieder, J.W., Balogh, K., Olson, R.O., and Martin, J.C., Treatment of latent rabbit and human papillomavirus infections with 9-(2-Phosphonylmethoxy) ethylguanine (PMEG), Antiviral Res. 14:51–58 (1990).CrossRefGoogle Scholar
  6. 6.
    Rudolph, F.B., Baugher, B.W., and Beissner, R.S., Techniques in coupled enzyme assays, Meth. in Enzym. 63:22–42 (1979).CrossRefGoogle Scholar
  7. 7.
    Agarwal, K.C., Miech, R.P., and Parks, Jr., R.E., Guanylate kinase from human erythrocytes, hog brain, and rat liver, Meth. in Enzym. LI:483–490 (1978).Google Scholar
  8. 8.
    Zimmerman, T.P., Mahony, W.B., and Prus, K.L., 3’-Azido-3’-deoxythymidine, an unusual nucleoside analogue that permeates the membrane of human erythrocytes and lymphocytes by nonfacilitated diffusion, J. Biol. Chem. 262:5748–5754 (1987).PubMedGoogle Scholar
  9. 9.
    Hitchcock, M.J.M., Woods, K.L., Bronson, J.J., Martin, J.C., and Ho, H.T., Intracellular metabolism of the anti-herpes agent, (S)-1-(3-hydroxy-2-Phosphonyl methoxypropyl) cytosine (HPMPC), 29th Interconference of Antiviral Agents and Chemotherapy, Abstract (1989).Google Scholar
  10. 10.
    Balzarini, J., Hao, Z., Herdewijn, P., Johns, D.G., and De Clerq, E., Intracellular metabolism and mechanism of anti-retrovirus action of 9-(phosphonylmethoxyethyl) adenine, a potent anti-human immunodeficiency virus compound, Proc. Natl. Acad. Sci. USA 88:1499–1503 (1991).CrossRefPubMedGoogle Scholar
  11. 11.
    Yang, H., Franco, C., Drain, R.P., and Datema, R., New anti-retroviral acyclic nucleotide analog: (R)-2’-me-PMEG ((R)-N9-(2-phosphonylmethoxypropyl) guanine), Symposium HIV Disease: Pathogenesis and Therpay, J. Acq. Imm Def. Syndromes,Abstract, 4:359 (1991).Google Scholar
  12. 12.
    Ho, H.T., De Boeck, H., Woods, K.L., Konrad, S.A., Hitchcock, M.J.M., and Datema, R., Structure and activity correlation-studies of anti-HIV acyclic guanine nucleotide analogs at enzyme level, Symposium HIV Disease: Pathogenesis and Therapy, J. Acq. Imm. Def. Syndromes,Abstract, 4:353 (1991)Google Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Hsu-Tso Ho
    • 1
  • Kathleen L. Woods
    • 1
  • Sherry A. Konrad
    • 1
  • Hilde De Boeck
    • 1
  • Michael J. M. Hitchcock
    • 1
  1. 1.Bristol Myers-Squibb Pharamaceutical Research InstituteWallingfordUSA

Personalised recommendations