Intracellular phosphorylation of broad-spectrum anti-DNA virus agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and inhibition of viral DNA synthesis.
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.
Votruba
I
I
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Bernaerts
R
R
Sakuma
T
T
De Clercq
E
E
Merta
A
A
Rosenberg
I
I
Holý
A
A
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D004279:DNA, Viral / Q000096:biosynthesis*; D006561:Herpes Simplex / Q000188:drug therapy / Q000378:metabolism; D007939:Leukemia L1210; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D010766:Phosphorylation; D018139:Simplexvirus / Q000235:genetics / Q000254:growth & development; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine