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    Relationship between Intracellular Concentration of S-Adenosylhomocysteine and Inhibition of Vaccinia Virus Replication and Inhibition of Murine L-929 Cell Growth

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    BorchardtR_AAC_33(6)828.pdf (1.318Mb)
    Issue Date
    1989-06
    Author
    Hasobe, Masahide
    McKee, James G.
    Borchardt, Ronald T.
    Publisher
    The American Society for Microbiology
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
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    Abstract
    9-(trans-2',trans-3'-Dihydroxycyclopent-4'-enyl)-adenine (compound 1) and -3-deazaadenine (compound 2), which are specific inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were reported earlier by our laboratory (M. Hasobe, J. G. McKee, D. R. Borcherding, and R. T. Borchardt, Antimicrob. Agents Chemother. 31:1849-1851, 1987) to have anti-vaccinia virus activity with reduced murine L-929 cell toxicity compared with the prototype compound neplanocin A. In this study, we showed that the antiviral and cytotoxic effects of compounds 1 and 2 can be related to intracellular concentrations of AdoHey, which are elevated in cells treated with these inhibitors of AdoHcy hydrolase. For example, concentrations of analogs 1 and 2 that produce 50% inhibition of vaccinia virus replication caused only slight elevations in intracellular levels of AdoHcy (from 50 [controls] to 100 to 125 [drug-treated cells] pmol/mg of protein) and elevations in the ratios of AdoHcy/S-adenosylmethionine (from 0.05 to 0.1 [controls] to 0.15 to 0.19 [drug-treated cells]). In contrast to the extreme susceptibility of virus replication to slight elevations in intracellular AdoHcy, cell viability was quite tolerant to higher levels of this metabolite. For example, concentrations of analogs 1 and 2 that produced 50% inhibition of L-929 cell replication caused significant increases in intracellular levels of AdoHcy (to 825 to 950 pmol/mg of protein) and elevations in AdoHcy/S-adenosylmethionine ratios (approximately 1.3). These data make it possible to assign a therapeutic index of 7 to 8 to these compounds on the basis of the comparison of intracellular levels of AdoHcy that caused 50% inhibition of vaccinia virus replication with those that caused 50% inhibition of L-929 cell replication.
    URI
    http://hdl.handle.net/1808/17658
    DOI
    https://doi.org/10.1128/AAC.33.6.828
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    • Pharmaceutical Chemistry Scholarly Works [327]
    Citation
    Haasobe, Masahide, James G. McKee, and Ronald T. Borchardt. "Relationship between Intracellular Concentration of S-Adenosylhomocysteine and Inhibition of Vaccinia Virus Replication and Inhibition of Murine L-929 Cell Growth." Antimicrob. Agents Chemother. June 1989 vol. 33 no. 6 828-834. http://dx.doi.org/10.1128/AAC.33.6.828

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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