Metabolism of arabinosyladenine in herpes simplex virus-infected and uninfected cells: Correlation with inhibition of DNA synthesis and role in antiviral selectivity |
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Authors: | Pauline M Schwartz Jean Novack Charles Shipman John C Drach |
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Institution: | School of Dentistry and Interdepartmental Graduate Program in Medicinal Chemistry, The University of Michigan, Ann Arbor, MI 48109, U.S.A. |
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Abstract: | The metabolism of 9-β-D-arabinofuranosyladenine (ara-A, vidarabine) and its effects on DNA synthesis were compared in uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells. In the absence of an inhibitor of adenosine deaminase, ara-A was deaminated to 9-β-D-arabinofuranosylhypoxanthine and phosphorylated to ara-A-5′-mono-, di- and triphosphates in both types of cells. When an inhibitor of adenosine deaminase (coformycin) was added to cell cultures, nucleotides were the only metabolites detected—primarily the 5′-triphosphate of ara-A (aATP). Detailed studies performed in the presence of coformycin established that the net rate and extent of aATP formation were the same in uninfected and HSV-1-infected cells. After a 12-hr exposure to 50 μM ara-A, intracellular concentrations of aATP were approximately 40 μM. Levels of aATP correlated directly with inhibition of total DNA synthesis. Approximately 0.7 μM aATP was required for 50% inhibition of total DNA synthesis in both uninfected and HSV-1-infected cells. Following removal of ara-A-containing culture medium, aATP levels in uninfected cells declined with a half-life of 3.2 hr. In marked contrast, the half-life in HSV-1-infected cells was 9.3 hr; this may explain why as little as a 3-hr exposure to ara-A resulted in a significant HSV-1 titer reduction. Taken together, the data show that when ara-A was removed from culture medium, levels of aATP persisted longer in HSV-1-infected cells thereby prolonging antiviral activity. This effect could be important in vivo where levels of ara-A oscillate with dosing schedule. |
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Keywords: | ara-A aAMP the 5′-mono- di- aADP the 5′-mono- di- aATP triphosphates of ara-A ara-H aHMP aHDP aHTP triphosphates of ara-H HSV-1 herpes simplex virus type-1 50% inhibitory concentration PEI polyethyleneimine and pfu plaque forming unit |
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