Analogs of (2'-5')oligo(A). Endonuclease activation and inhibition of protein synthesis in intact cells.
Synthetic analogs of (2'-5')oligo(A) were assayed for endonuclease activation in cell extracts and for inhibition of protein synthesis in intact cells. The analogs are triadenylates: (i) methylated in the terminal 3'-OH; (ii) methylated at all three 3'-OH groups; (iii) with different numbers of phosphate groups at the 5' terminus or with a methylene group between the beta- and gamma-phosphate. Only 5'-phosphorylated monomethylated analogs activate an endonuclease in cell extracts and are powerful inhibitors of protein synthesis in intact cells. The analogs with only one 5'-terminal phosphate may require addition of another phosphate for activity since the kinase inhibitor 2-aminopurine prevents endonuclease activation by this compound but not by the di- and triphosphate-terminated triadenylates. These results suggest that two terminal phosphates and one or two free 3'-OH are required for endonuclease activation and inhibition of protein synthesis. The monomethylated analogs are more active than (2'-5')pppA3 because of their resistance to degradation by cellular enzymes. Accordingly, the monomethylated analogs cause a prolonged inhibition of protein synthesis in human fibroblasts treated with nanomolar concentrations of these compounds.
D000227:Adenine Nucleotides / Q000494:pharmacology*; D002472:Cell Transformation, Viral; D004720:Endonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009841:Oligonucleotides / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D013329:Structure-Activity Relationship; D014721:Vesicular stomatitis Indiana virus / Q000378:metabolism
D000227:Adenine Nucleotides; D009841:Oligonucleotides; D009843:Oligoribonucleotides; D012333:RNA, Messenger; C023505:2',5'-oligoadenylate; D004720:Endonucleases