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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
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).
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).
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).
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).
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).
Rudolph, F.B., Baugher, B.W., and Beissner, R.S., Techniques in coupled enzyme assays, Meth. in Enzym. 63:22–42 (1979).
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).
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).
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).
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).
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).
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)
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1992 Springer Science+Business Media New York
About this chapter
Cite this chapter
Ho, HT., Woods, K.L., Konrad, S.A., De Boeck, H., Hitchcock, M.J.M. (1992). Cellular Metabolism and Enzymatic Phosphorylation of 9- (2-Phosphonylmethoxyethyl) Guanine (PMEG),a Potent Antiviral Agent. In: Block, T.M., Jungkind, D., Crowell, R.L., Denison, M., Walsh, L.R. (eds) Innovations in Antiviral Development and the Detection of Virus Infections. Advances in Experimental Medicine and Biology, vol 312. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3462-4_16
Download citation
DOI: https://doi.org/10.1007/978-1-4615-3462-4_16
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6533-4
Online ISBN: 978-1-4615-3462-4
eBook Packages: Springer Book Archive