Specific inhibition of the synthesis of influenza virus late proteins and stimulation of early, M2, and NS2 protein synthesis by 3-deazaadenosine.
3-Deazaaristeromycin and 3-deazaadenosine (3DA-Ado) both interfere with the methylation of RNA, but only 3DA-Ado is metabolized to the corresponding homocysteine derivative. In contrast to 3-deazaaristeromycin, 3DA-Ado inhibits the synthesis of late influenza A virus proteins in chicken embryo cells (CEC), while it causes an overproduction of early proteins and of the nonstructural proteins NS2 and M2. Only the former effect of 3DA-Ado can be reversed by concomitant addition of adenosine, but not by guanosine. 3DA-Ado acts only early in the infectious cycle and, after removal of the drug, its effect on the yield of infectious virus is reversible. It can be significantly enhanced by homocysteine thiolactone. Except for the M gene, synthesis of viral mRNA is not significantly affected by 3DA-Ado. We conclude that 3DA-Ado acts via its homocysteine derivative by interfering with a specific post-transcriptional modification of viral mRNA and on splicing of specifically the M mRNA. In L-cells influenza viral protein synthesis is comparable to that in CEC in the presence of 3DA-Ado in that there is only little HA and M1 synthesized, and a severe overproduction of NS2 is observed. Under the experimental conditions 3DA-Ado has no inhibiting effect on the replication of other RNA viruses like Newcastle disease virus, Semliki Forest virus, or West Nile virus whose RNA is not methylated, since they do not have a nuclear phase during replication.
Fischer
A A
AA
Institut für Virologie, Justus-Liebig-Universität Giessen, Federal Republic of Germany.
Müller
K
K
Scholtissek
C
C
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002213:Capsid / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D007536:Isomerism; D007700:Kinetics; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D012367:RNA, Viral / Q000096:biosynthesis; D014372:Tubercidin / Q000494:pharmacology*; D014758:Viral Core Proteins / Q000096:biosynthesis; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins / Q000096:biosynthesis* / Q000302:isolation & purification; D014779:Virus Replication
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D012367:RNA, Viral; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C018258:3-deazaadenosine; C034583:3-deazaaristeromycin; D000241:Adenosine; D014372:Tubercidin