Influence of S-adenosylhomocysteine hydrolase inhibitors on S-adenosylhomocysteine and S-adenosylmethionine pool levels in L929 cells.
S-Adenosylhomocysteine hydrolase has been recognized as the target enzyme for the antiviral activity of several carbocyclic and acyclic adenosine analogues. In a previous study [Cools M and De Clercq E, Biochem Pharmacol 38: 1061-1067, 1989], we found a close correlation between the antiviral activity of six adenosine analogues [S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA], (RS)-3-adenin-9-yl-2-hydroxypropanoic acid [(RS)-AHPA] (isobutyl ester), 3-deazaneplanocin A, carbocyclic 3-deazaadenosine (C-c3 Ado), adenosine dialdehyde and neplanocin A) against vaccinia virus and vesicular stomatitis virus and the inhibitory effect of these compounds on purified AdoHcy hydrolase isolated from murine L929 cells. We have now examined the effects of the different adenosine analogues on the intracellular pool levels of S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet). Treatment of vaccinia virus-infected L929 cells for 24 hr with the adenosine analogues at a dose that reduced vaccinia virus growth by 90% (ID90) increased the average AdoHcy pool levels from 0.027 nmol/mg protein to approximately 0.3 nmol/mg protein and the AdoHcy/AdoMet ratio from 0.038 to approximately 0.3. Moreover, the AdoHcy/AdoMet ratio correlated closely with the vaccinia virus yield reduction, both determined over the 24-hr post infection period (correlation coefficient of 0.972). These findings indicate that the activity of the AdoHcy hydrolase inhibitors against vaccinia virus may be related to the raise in intracellular AdoHcy pool levels and AdoHcy/AdoMet ratio.
Cools
M
M
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
De Clercq
E
E
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007739:L Cells / Q000187:drug effects; D051379:Mice; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000187:drug effects
D004791:Enzyme Inhibitors; C016391:9-(2,3-dihydroxypropyl)adenine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000225:Adenine