Chemistry and biochemistry of 2',5'-oligoadenylate-based antisense strategy.
This review describes the application of a natural defense mechanism to develop effective agents for the post-transcriptional control of gene expression. 2-5A is a unique 2',5'-phosphodiester bond linked oligoadenylate, (pp)p5'A2'(p5'A)(n), that is elaborated in virus-infected interferon-treated cells. The 2-5A system is an RNA degradation pathway that is an important mechanistic component of interferon's action against certain viruses. It may also play a role in the anticellular effects of interferon and in general RNA decay. A major player in the 2-5A-system is the latent and constitutive 2-5A-dependent ribonuclease (RNase L) which upon activation by 2-5A, degrades RNA. This RNase L enzyme can be recruited for antisense therapeutics by linking it to an appropriate oligonucleotide targeted to a chosen RNA. Syntheses of 2-5A, its analogues, 2-5A-antisense, and its modifications are detailed herein. Applications of 2-5A-antisense to particular targets such as HIV, PKR, chronic myelogenous leukemia, telomerase, and respiratory syncytical virus are described.
Adah
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Section on Biomedical Chemistry, Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Bayly
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Cramer
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Silverman
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Torrence
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D000227:Adenine Nucleotides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004722:Endoribonucleases / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D009843:Oligoribonucleotides / Q000737:chemistry / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D012328:RNA Viruses / Q000187:drug effects*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects; D012689:Sequence Homology, Nucleic Acid; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002352:Carrier Proteins; D009843:Oligoribonucleotides; D020320:Oligoribonucleotides, Antisense; C023505:2',5'-oligoadenylate; D007372:Interferons; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease