Comparison of the modes of antiviral action of 2'-nor-deoxyguanosine and its cyclic phosphate, 2'-nor-cyclic GMP.

The metabolisms of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (2'NDG) and its cyclic phosphate, 9-[(2-hydroxy-1,3,2-dioxophosphorinan-5-yl) oxymethyl]guanine P-oxide (2'-nor-cGMP), were compared in cultures of primary rabbit kidney cells infected with herpes simplex virus type 1 (HSV-1). 2&#...

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Main Authors: Germershausen, J, Bostedor, R, Liou, R, Field, A K, Wagner, A F, MacCoss, M, Tolman, R L, Karkas, J D
Formato: Artigo
Idioma:en
Publicado em: 1986
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Research Article
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC180495/
https://ncbi.nlm.nih.gov/pubmed/3015013
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spelling pubmed-1804952003-12-16 Comparison of the modes of antiviral action of 2'-nor-deoxyguanosine and its cyclic phosphate, 2'-nor-cyclic GMP. Germershausen, J Bostedor, R Liou, R Field, A K Wagner, A F MacCoss, M Tolman, R L Karkas, J D Antimicrob Agents Chemother Research Article The metabolisms of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (2'NDG) and its cyclic phosphate, 9-[(2-hydroxy-1,3,2-dioxophosphorinan-5-yl) oxymethyl]guanine P-oxide (2'-nor-cGMP), were compared in cultures of primary rabbit kidney cells infected with herpes simplex virus type 1 (HSV-1). 2'-Nor-cGMP was taken up by the cells essentially intact, after which it was opened to the acyclic monophosphate and phosphorylated further, ultimately to the triphosphate. Formation of the triphosphate was independent of HSV thymidine kinase expression, unlike what is observed with 2'NDG. In addition, there was a direct correlation between the antiviral activity of 2'NDG and the level of triphosphate formed in HSV-1-infected cells, whereas such a correlation was absent with 2'-nor-cGMP. In vivo experiments indicated that only a small percentage of free 2'NDG was formed in the bloodstream of mice after oral administration of 2'-nor-cGMP. Incubation of 2'-nor-cGMP with crude extracts of HSV-1-infected or uninfected HeLa cells resulted in the direct production of 2'NDG triphosphate. The possibility that the triphosphate of 2'NDG produced from 2'-nor-cGMP was the enantiomer of the triphosphate made from 2'NDG by viral and cellular kinases was investigated and disproved. Taken together, these data indicate that (i) 2'-nor-cGMP does not act simply as a prodrug of 2'NDG, (ii) 2'-nor-cGMP does not require viral thymidine kinase for its activity, and (iii) 2'-nor-cGMP may have an additional, triphosphate-independent mode of action. 1986-06 /pmc/articles/PMC180495/ /pubmed/3015013 Text en
institution US National Library of Medicine
collection PubMed Central
language en
format Article
topic Research Article
spellingShingle Research Article
Germershausen, J
Bostedor, R
Liou, R
Field, A K
Wagner, A F
MacCoss, M
Tolman, R L
Karkas, J D
Comparison of the modes of antiviral action of 2'-nor-deoxyguanosine and its cyclic phosphate, 2'-nor-cyclic GMP.
description The metabolisms of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (2'NDG) and its cyclic phosphate, 9-[(2-hydroxy-1,3,2-dioxophosphorinan-5-yl) oxymethyl]guanine P-oxide (2'-nor-cGMP), were compared in cultures of primary rabbit kidney cells infected with herpes simplex virus type 1 (HSV-1). 2'-Nor-cGMP was taken up by the cells essentially intact, after which it was opened to the acyclic monophosphate and phosphorylated further, ultimately to the triphosphate. Formation of the triphosphate was independent of HSV thymidine kinase expression, unlike what is observed with 2'NDG. In addition, there was a direct correlation between the antiviral activity of 2'NDG and the level of triphosphate formed in HSV-1-infected cells, whereas such a correlation was absent with 2'-nor-cGMP. In vivo experiments indicated that only a small percentage of free 2'NDG was formed in the bloodstream of mice after oral administration of 2'-nor-cGMP. Incubation of 2'-nor-cGMP with crude extracts of HSV-1-infected or uninfected HeLa cells resulted in the direct production of 2'NDG triphosphate. The possibility that the triphosphate of 2'NDG produced from 2'-nor-cGMP was the enantiomer of the triphosphate made from 2'NDG by viral and cellular kinases was investigated and disproved. Taken together, these data indicate that (i) 2'-nor-cGMP does not act simply as a prodrug of 2'NDG, (ii) 2'-nor-cGMP does not require viral thymidine kinase for its activity, and (iii) 2'-nor-cGMP may have an additional, triphosphate-independent mode of action.
author Germershausen, J
Bostedor, R
Liou, R
Field, A K
Wagner, A F
MacCoss, M
Tolman, R L
Karkas, J D
author_facet Germershausen, J
Bostedor, R
Liou, R
Field, A K
Wagner, A F
MacCoss, M
Tolman, R L
Karkas, J D
author_sort Germershausen, J
title Comparison of the modes of antiviral action of 2'-nor-deoxyguanosine and its cyclic phosphate, 2'-nor-cyclic GMP.
title_short Comparison of the modes of antiviral action of 2'-nor-deoxyguanosine and its cyclic phosphate, 2'-nor-cyclic GMP.
title_full Comparison of the modes of antiviral action of 2'-nor-deoxyguanosine and its cyclic phosphate, 2'-nor-cyclic GMP.
title_fullStr Comparison of the modes of antiviral action of 2'-nor-deoxyguanosine and its cyclic phosphate, 2'-nor-cyclic GMP.
title_full_unstemmed Comparison of the modes of antiviral action of 2'-nor-deoxyguanosine and its cyclic phosphate, 2'-nor-cyclic GMP.
title_sort comparison of the modes of antiviral action of 2'-nor-deoxyguanosine and its cyclic phosphate, 2'-nor-cyclic gmp.
publishDate 1986
url https://ncbi.nlm.nih.gov/pmc/articles/PMC180495/
https://ncbi.nlm.nih.gov/pubmed/3015013
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