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Intracellular phosphorylation of broad-spectrum anti-DNA virus agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and inhibition of viral DNA synthesis

I Votruba, R Bernaerts, T Sakuma, E De Clercq, A Merta, I Rosenberg and A Holy

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

The acyclic nucleotide analogue (S)-9-(3-hydroxy-2-phosphonyl- methoxypropyl)-adenine [(S)-HPMPA], which contains a phosphonate- substituted aliphatic chain, is a potent and selective inhibitor of the replication of various DNA viruses, including herpes simplex virus type 1 (HSV-1). We have synthesized radiolabeled (S)-[U-14C-adenine]HPMPA and investigated its metabolism by HSV-1-infected and mock-infected cells. The drug is as such taken up by the cells and subsequently converted to its monophosphoryl [(S)-HPMPAp] and diphosphoryl [(S)- HPMPApp] derivatives by cellular enzymes. It is incorporated to a very low extent into DNA of both mock-infected and HSV-1-infected Vero cells. (S)-HPMPA inhibits HSV-1 DNA synthesis at a concentration that is several orders of magnitude lower than the concentration required for inhibition of cellular DNA synthesis. Thus the selectivity of (S)- HPMPA as an antiviral agent cannot be attributed to a differential phosphorylation by virus-infected or uninfected cells but resides in a specific inhibitory effect on viral DNA synthesis. The exact basis for the latter effect is under investigation.

Volume 32, Issue 4, pp. 524-529, 10/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1987 by the American Society for Pharmacology and Experimental Therapeutics