Characterization and biological activity of 8-substituted analogues of 2',5'-oligoadenylates.
Analogues of the 2',5'-linked adenylate trimer 5'-monophosphates (p5'A2'p5'A2'p5'A) containing 8-hydroxyadenosine and 8-mercaptoadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. The ability of p5'ASH2'p5'ASH2'p5'ASH (pASH3) (1c) to bind 2-5A dependent endonuclease was markedly decreased. On the other hand, an analogue of the 2',5'-linked adenylate trimer monophosphate substituted by 8-hydroxyadenosine in the first, second, and third nucleotide positions bound almost as well as parent 2-5A [pppA(2'p5'A)2] (p3A3) (1d) to RNase L. The 8-substituted analogues of 2-5A were more resistant to the degradation by the (2',5') phosphodiesterase. Of particular interest is monophosphate, pASH3 (1c) which possessed higher anti-HIV activity than pA3 (1a) or pAOH3 (1b).
Nagai
K
K
Department of Industrial Chemistry, Chiba Institute of Technology, Japan.
Kanbara
K
K
Nakashima
H
H
Yamamoto
N
N
Suhadolnik
R J
RJ
Takaku
H
H
D000227:Adenine Nucleotides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002942:Circular Dichroism; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D015497:HIV-1 / Q000187:drug effects; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects; D006801:Humans; D007739:L Cells; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009843:Oligoribonucleotides / Q000737:chemistry* / Q000494:pharmacology
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D009843:Oligoribonucleotides; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease