Synthesis and properties of 5′-triphosphoryl 2′-5′ oligoadenylates (2-5A), and a general method for synthesis of 3′, 5′-bisphosphorylated oligonucleotides

Ikehara, Morio; Oshie, Kazuyuki; Hasegawa, Akira; Ohtsuka, Eiko

doi:10.1093/nar/9.8.2003

Cited by 12 publications

(1 citation statement)

References 15 publications

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“…The various isoforms are induced differentially with a given IFN subtype. In Hs294t melanoma cells, after 48 hr of Ikehara et al, 1979Ikehara et al, , 1981 POCL, in PO(OEt), Ikehara et al. 1981 Mesitylene sulfonyl triazolide Shimidzu et al, 1984Hayakawa et al, 1985a,b Chattopadhyaya, 1980Jones and Reese, 1979Charubala and Pfleiderer, 1980aCharubala and Pfleiderer, 1982Engels and Krahmer, 1979Gioeli et al, 1981 Tris-( imidazol-1-yl) phosphine.…”

Section: Inductionmentioning

confidence: 99%

The 2–5 A system: Modulation of viral and cellular processes through acceleration of RNA degradation

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Torrence

1998

Pharmacology & Therapeutics

245

195

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The 2-5A system is an RNA degradation pathway that can be induced by the interferons (IFNs). Treatment of cells with IFN activates genes encoding several double-stranded RNA (dsRNA)-dependent synthetases. These enzymes generate 5'-triphosphorylated, 2',5'-phosphodiester-linked oligoadenylates (2-5A) from ATP. The effects of 2-5A in cells are transient since 2-5A is unstable in cells due to the activities of phosphodiesterase and phosphatase. 2-5A activates the endoribonuclease 2-5A-dependent RNase L, causing degradation of single-stranded RNA with moderate specificity. The human 2-5A-dependent RNase is an 83.5 kDa polypeptide that has little, if any, RNase activity, unless 2-5A is present. 2-5A binding to RNase L switches the enzyme from its off-state to its on-state. At least three 2',5'-linked oligoadenylates and a single 5'-phosphoryl group are required for maximal activation of the RNase. Even though the constitutive presence of 2-5A-dependent RNase is observed in nearly all mammalian cell types, cellular amounts of 2-5A-dependent mRNA and activity can increase after IFN treatment. One well-established role of the 2-5A system is as a host defense against some types of viruses. Since virus infection of cells results in the production and secretion of IFNs, and since dsRNA is both a frequent product of virus infection and an activator of 2-5A synthesis, the replication of encephalomyocarditis virus, which produces dsRNA during its life cycle, is greatly suppressed in IFN-treated cells as a direct result of RNA decay by the activated 2-5A-dependent RNase. This review covers the organic chemistry, enzymology, and molecular biology of 2-5A and its associated enzymes. Additional possible biological roles of the 2-5A system, such as in cell growth and differentiation, human immunodeficiency virus replication, heat shock, atherosclerotic plaque, pathogenesis of Type I diabetes, and apoptosis, are presented.

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Section: Inductionmentioning

confidence: 99%

The 2–5 A system: Modulation of viral and cellular processes through acceleration of RNA degradation

Player

Torrence

1998

Pharmacology & Therapeutics

245

195

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Mesitylsulfonyl-1H-1,2,4-triazole

Vaillancourt

Cudahy

2001

Encyclopedia of Reagents for Organic Synthesis

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Nucleotide, XVI. Synthese und Eigenschaften von Adenylyl‐adenylyl‐adenosinen

1981

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Mit Hilfe der Phosphotriester-Methode werden auf zwei verschiedenen Wegen unter Verwendung des o-Chlorphenyl-bzw. p-Nitrophenylethyl-Restes als Phosphat-Schutzgruppe die beiden vollgeschutzten Adenylyl(2',5')adenylyl(2',5')adenosine 21 und 22 in praparativen Mengen dargestellt .Bei den Schutzgruppenabspaltungen zeigt das (p-Nitrophenylethy1)phosphat 22 sinheitlichere Reaktionen und liefert das trimere A2'p5'A2'pS'A (23) auch in hoherer Ausbeute. Die beiden isomeren unterschiedlich verkniipften trirneren Adenosine A2'p5'A3'p?'A (30) und A3'pSrA2'p5'A (31) werden auf analogen Wegen synthetisiert und verschiedene physikalische Eigenschaften dieser Trinucfeosid-diphosphate verglichen. Nucleotides, XVI1). -Synthesis and Properties of Adenylyl-adenylyl-adenosinesThe completely protected adenylyl(2',5')adenylyl(2',5')adenosines 21 and 22 have been synthesized in preparative scale by the phosphotriester approach applying the o-chlorophenyl and p-nitrophenylethyl group, respectively, as phosphate protective groups. Deprotecting experiments showed more homogeneous reactions with the p-nitrophenylethyl phosphate 22 and gave higher yields of the trimeric A2'p5'A2'pSA (23). The two isomeric differently linked adenosine trimers A2'pSA3'pSA (30) and A3'p5'A2'pSA (31) have been prepared analogously. Various physical properties of these trinucleoside diphosphates have been determined and compared.Unter den niedermolekularen Oligonucleotiden mit der natiirlichen 3'+5'-Internucleotid-Bindung finden sich bislang keine Vertreter mit auffallender physiologischer oder biochemischer Aktivitat. Groljes Interesse hat daher in jiingster Zeit ein Befund2-I2) ausgelost, der einen sehr effektiven Inhibitor der zellfreien Proteinsynthese im subnanomolaren Konzentrationsbereich beschreibt und fur dessen Entstehung Extrakte Interferon-behandelter Zellen mit doppelstrangiger RNA und ATP erforderlich sind. Das auf diese Weise aktivierte Synthetase-Enzym katalysiert die Bildungneben wenig homologer Produkte -eines ungewohnlichen Trinucleosidpentaphosphates, das auf Grund seiner spektroskopischen, elektrophoretischen und chromatographischen Eigenschaften sowie chemischen und enzymatischen Hydrolyse-Studien als das 5'-O-Triphosphonoadenylyl(2'-.5')adenyly~(2'-*5')adenosin (pppA2'pSfA2'p5'A) identifiziert wurde. Diese interessante chemische Struktur und die Feststellung, dalj auch das am 5'-Ende dephosphorylierte trimere Analogon A2'p5'A2'pStA (23) eine nur wenig verminderte Inhibitor-Wirkung in vivo 13) zeigt, veranlaljte mehrere Arbeitskreise diese beiden Molekiile auf verschiedenen, rein chemischen Synthesewegen darzustellen 14-24).

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Synthesis and properties of 5′-triphosphoryl 2′-5′ oligoadenylates (2-5A), and a general method for synthesis of 3′, 5′-bisphosphorylated oligonucleotides

Cited by 12 publications

References 15 publications

The 2–5 A system: Modulation of viral and cellular processes through acceleration of RNA degradation

The 2–5 A system: Modulation of viral and cellular processes through acceleration of RNA degradation

Mesitylsulfonyl-1H-1,2,4-triazole

Nucleotide, XVI. Synthese und Eigenschaften von Adenylyl‐adenylyl‐adenosinen

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