Phosphorothioate and cordycepin analogues of 2',5'-oligoadenylate: inhibition of human immunodeficiency virus type 1 reverse transcriptase and infection in vitro.
Natural antiviral activity can be mediated by the interferon-induced synthesis of 2',5'-oligoadenylates (2-5As) and subsequent RNase L activation by these molecules. Analogues of 2-5A that are biologically active and metabolically stable were synthesized and analyzed for antiviral activity against the human immunodeficiency virus type 1 (HIV-1). Replacement of the 3' hydroxyl group of the adenosine moieties of 2-5A with hydrogen atoms (i.e., cordycepin analogues of 2-5A) converted authentic 2-5A trimer into anti-HIV-1 agents in vitro. These cordycepin analogues of 2-5A also inhibited partially purified HIV-1 reverse transcriptase. Introduction of chirality into the 2',5'-phosphodiester internucleotide linkages or 5'-phosphate moieties of the 2-5A molecule (i.e., phosphorothioate analogues of 2-5A) converted authentic 2-5A into more potent inhibitors of HIV-1 reverse transcriptase. However, these phosphorothioate 2-5As demonstrated little or no anti-HIV-1 activity in vitro. Thus, some analogues of 2-5A may form a class of anti-HIV-1 drugs with possible pleiotropic activities that include activation of latent RNase L and inhibition of reverse transcription.
Montefiori
D C
DC
Department of Pathology, Vanderbilt University, School of Medicine, Nashville, TN 37232.
Sobol
R W
RW
Li
S W
SW
Reichenbach
N L
NL
Suhadolnik
R J
RJ
Charubala
R
R
Pfleiderer
W
W
Modliszewski
A
A
Robinson
W E
WE
Mitchell
W M
WM
D000227:Adenine Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006801:Humans; D007700:Kinetics; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D013873:Thionucleotides / Q000138:chemical synthesis / Q000494:pharmacology*
C032558:2',5'-oligoadenylate cordycepin analog; D000227:Adenine Nucleotides; D000998:Antiviral Agents; D009838:Oligodeoxyribonucleotides; D009843:Oligoribonucleotides; D018894:Reverse Transcriptase Inhibitors; D013873:Thionucleotides; C023505:2',5'-oligoadenylate