Oligoadenylates

The antiviral state induced by different types of IFNs is mediated by various IFN-induced proteins. The best-known antiviral effectors produced as a result of IFN cascade induction are shown in Table 2. They include 2 -5 oligoadenylate synthetase (2 -5 OAS), double-stranded RNA activated protein kinase (PKR), and myxovirus (Mx) proteins. Additional effectors include RNA-specific adenosine deaminase 1 (ADARl), the 20-kDa ISG product (ISG20), ISG54 and ISG56, and IFN-stimulated micro RNAs (Pedersen et al. 2007). 

OAS 2 -5 oligoadenylate synthetase Activate a latent endoribonuclease, RNAse L, which degrades viral and cellular mRNAs and rRNAs... 

Method a has been used to synthesize ATPs modified in the ribose portion and/or in the nucleobase[71H73] as well as 5 -triphosphates of 2, 5 -oligoadenylates [for example pppA(p5 A2 )n with n = and 2].[743,[75]... 

The molecular basis by which interferons promote their characteristic effects, in particular antiviral activity, is understood at least in part. Interferon stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These antiviral gene products are generally enzymes, the most important of which are 2 -5 oligoadenylate synthetase (2,5-A synthetase) and the eIF-2a protein kinase. 

Example 3 Antiviral Enzyme 2 5 "-Oligoadenylate Synthetase Gene (OASl) Splice Site SNP... 

Kajaste-Rudnitski, A., Mashimo, T., ErenMel, M. P., Guenet, J. L., Lucas, M., and Despres, P. (2006) The 2, 5"-oligoadenylate synthetase lb is a potent inhibitor of West Nile virus replication inside infected cells. J. Biol.Chem. 281, 4624-4637. 

Mashimo, T., Lucas, M., Simon-Chazottes, D., et al. (2002) A nonsense mutation in the gene encoding 2, 5 -oligoadenylate synthetase/Ll isoform is associated with West Nile virus susceptibility in laboratory mice. Proc. Natl. Acad. Sci. U. S. A. 99, 11311-11316. 

NADPH DEHYDROGENASE 2, 5 -OLIGOADENYLATE SYNTHETASE OLIGOMERIZATION OMEGA (ft or oj)... 

Merritt, J.A., L.A. Ball, K.M. Sielaff, D.M. Meltzer, and E.C. Borden, Modulation of 2, 5 -oligoadenylate synthetase in patients treated with alpha-interferon effects of dose, schedule, and route of administration. J Interferon Res, 1986. 6(3) 189-98. 

Pharmacokinetics The pharmacokinetic properties of Infergen have not been evaluated in patients with chronic hepatitis C. Pharmacokinetic profiles were evaluated in normal, healthy volunteer subjects after subcutaneous injection of interferon alfacon-1 at doses up to 9 j,g. Plasma levels of interferon alfacon-1 at any dose were too low to be detected. However, analysis of Infergen-induced cellular products— induction of 2 5 oligoadenylate synthetase and (beta)-2 microglobulin—after treatment in these subjects revealed a statistically significant, dose-related increase in the area under the curve (AUC). 

Eskildsen, S., Justesen, J., Schierup, M.H., and Hartmann, R., 2003, Characterization of the 2 -5 -oligoadenylate synthetase ubiquitin-like family. Nucleic Acids Res. 31 3166-3173. 

Although it is not possible to delineate the mechanisms by which interferon beta-lb exerts its activity in MS. it is known that the interferon binds to specific receptors on cell surfaces and induces the expression of a number of interferon-induced gene products, such as 2. 5 -oligoadenylate synthetase and protein kinase. Additionally, interferon beta-lb blocks the synthesis of INF-y. which is believed to be involved in MS attacks. 

Phosphorothioate analogues of 2, 5 -oligoadenylates have promising antiviral and anticancer properties and are able to elicit RNase L activation [61]. Short tri- and tetra-2, 5 -oligoadenylates were recently synthesized as a mixture of diastereomers and then separated into diastereomerically pure compounds [62]. For the purpose of their stereocontrolled synthesis, AT6-benzoyl-5 -0-DMT-3 -0-ferf-butyldimethylsilyl adenosine-2 -0-(2-thio-l,3,2-oxathiaphospholane) was synthesized and chromatographically separated into P-diastereomers [63]. The separated monomers were used for synthesis of 2, 5 -tri- and tetra-adenosine analogues, which were cleaved from the support, deprotected, and identified by physicochemical and enzymatic methods. The step-yields 94-95% were achieved for attachment of consecutive adenosine 2 -0-phosphorothioate moieties. 

A series of 2 -5 oligoadenylate analogues (48) containing intemucleoside and ribose modifications has been prepared by solid-phase methods as potential interferon mimetics. ... 

Interferons are generally stimulatory proteins that exert their activity through interactions with cell surface receptors, inducing cellular processes and enhancing specific gene translation (79). Interferons also regulate the expression of unique antiviral proteins such as MX protein, which alters microtubule formation and mitosis, and 2 -5 -oligoadenylate synthetase (2,5-0AS), which induces the destruction of viral RNA. 

The triphosphates of 2 -5 -oligoadenylate trimers are implicated in at least one of the mechanisms of the antiviral action of interferon and bind to and activate a RNaseL resulting in the cleavage of viral mRNA and the inhibition of viral replication. In order to study the cellular function of oligoadenylate, the ... 

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