title: Chemistry and biochemistry of 2',5'-oligoadenylate-based antisense strategy.
abstract: 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.
authors.affiliation: Section on Biomedical Chemistry, Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Adah
authors.forename: S F
authors.initials: SF
authors.lastname: Bayly
authors.forename: H
authors.initials: H
authors.lastname: Cramer
authors.forename: R H
authors.initials: RH
authors.lastname: Silverman
authors.forename: P F
authors.initials: PF
authors.lastname: Torrence
mesh_terms: 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
chemical_list: 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