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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

VOTRUBA, I ; BERNAERTS, R ; SAKUMA, T ; DE CLERCQ, E ; MERTA, A ; ROSENBERG, I ; HOLY, A

Molecular pharmacology, 1987-10, Vol.32 (4), p.524-529 [Periódico revisado por pares]

Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics

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Título:
Intracellular phosphorylation of broad-spectrum anti-DNA virus agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and inhibition of viral DNA synthesis
Autor: VOTRUBA, I ; BERNAERTS, R ; SAKUMA, T ; DE CLERCQ, E ; MERTA, A ; ROSENBERG, I ; HOLY, A
Assuntos: Action of physical and chemical agents ; Adenine - analogs & derivatives ; Adenine - metabolism ; Animals ; Antiviral Agents - metabolism ; Biological and medical sciences ; DNA, Viral - biosynthesis ; Fundamental and applied biological sciences. Psychology ; Herpes Simplex - drug therapy ; Herpes Simplex - metabolism ; Leukemia L1210 ; Microbiology ; Organophosphonates ; Organophosphorus Compounds ; Phosphorylation ; Simplexvirus - genetics ; Simplexvirus - growth & development ; Tumor Cells, Cultured ; Virology ; Virus Replication - drug effects
É parte de: Molecular pharmacology, 1987-10, Vol.32 (4), p.524-529
Notas: ObjectType-Article-2
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Descrição: 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.
Editor: Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics
Idioma: Inglês

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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

VOTRUBA, I ; BERNAERTS, R ; SAKUMA, T ; DE CLERCQ, E ; MERTA, A ; ROSENBERG, I ; HOLY, A

Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics

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