Mechanism of antiviral activity of (XyloA2'p)2XyloA.
(XyloA2'p)2xyloA, the xyloadenosine core analog of the interferon mediator 2-5A [ppp(A2'p)2A], was found to exhibit potent antiviral activity against herpes simplex viruses 1 and 2 (D. A. Eppstein, J. W. Barnett, Y. V. Marsh, G. Gosselin, and J. -L. Imbach (1983a) Nature (London) 302: 723-724). This xylo 2-5A core analog was over 100 times more stable to phosphodiester cleavage than was parent 2-5A core in cell-free extracts, which was originally thought to have contributed to its increased activity. However, we have now shown that the xylo 2-5A core does not activate the 2-5A-dependent endonuclease, and, additionally, that its mechanism of action is different from that of parent 2-5A core, even though it too does not activate the endonuclease. In fact, the mechanism of action of xylo 2-5A core apparently involves its degradation to monomer units, which then exert the antiviral effect. The enhanced antiviral activity of xylo 2-5A core (normalized to monomer-unit equivalents) as compared to that of xyloadenosine appears to be mediated through a slow release of xyloadenosine monomer units (i.e., xyloAMP). XyloAMP is resistant to inactivation by deamination, and thus intracellular xyloAMP should have increased antiviral activity compared to an equivalent concentration of xyloadenosine, which is subject to rapid inactivation by deamination.
D000227:Adenine Nucleotides / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D003641:Deamination; D004720:Endonucleases / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D009841:Oligonucleotides / Q000494:pharmacology*; D018139:Simplexvirus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D009841:Oligonucleotides; C037912:xylo 2-5A core; C033547:2'-5'-oligo(A)-dependent endonuclease; D004720:Endonucleases; D004722:Endoribonucleases