Adenosine dialdehyde: a potent inhibitor of vaccinia virus multiplication in mouse L929 cells.
Adenosine dialdehyde (2'-O-[(R)-formyl(adenin-9-yl)methyl]-(R)-glyceraldehyde), formed by periodate oxidation of adenosine, is a potent inhibitor of S-adenosylhomocysteine hydrolase (EC 3.3.1.1.) in mouse L929 cells. Consequently, the dialdehyde produces an increase in intracellular levels of S-adenosylhomocysteine and subsequent inhibition of S-adenosylmethionine-dependent macromolecular methylations. In the present study we show that adenosine dialdehyde is also a potent inhibitor of vaccinia virus plaque formation in monolayer cultures of L cells. When added to the culture medium immediately following attachment of the virus, concentrations of the dialdehyde as low as 0.5 microM produce greater than 90% inhibition of plaque formation after 72 hr. The efficacy of the compound is greatest when added within 8 hr of virus attachment and gradually decreases in a time-dependent manner when added after this point. Treatment of L cells with 5 microM adenosine dialdehyde for 60 min prior to virus infection causes a transient, but virtually complete loss of S-adenosylhomocysteine hydrolase activity and subsequent 3-fold increase in the intracellular S-adenosylhomocysteine/S-adenosylmethionine ratio. Continuous exposure of infected cells to the dialdehyde results in prolonged inhibition of S-adenosylhomocysteine hydrolase accompanied by a 10-fold increase in the S-adenosylhomocysteine/S-adenosylmethionine ratio. Associated with these changes in the dialdehyde-treated, infected cells are an inhibition of early virus-specific protein synthesis and a 13% decrease in methylation of the cytoplasmic poly A+-mRNA. The antiviral action of this compound thus appears to be related to a decrease in viral mRNA methylation (e.g., the 5'-terminal cap structure) which results in suppressed translation of viral proteins essential for virus replication.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000998:Antiviral Agents; D006867:Hydrolases / Q000037:antagonists & inhibitors; D007739:L Cells; D008745:Methylation; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D014616:Vaccinia virus / Q000187:drug effects* / Q000254:growth & development; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins; C027579:periodate-oxidized adenosine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine