2’,5‘-oligoadenylate synthetase

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... 

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. 

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. 

Type I (IFN-a/P) and type II (IFN-y) IFNs are major lines of defense against viral infection. IFNs mediate direct antiviral effector mechanisms that inhibit multiple steps of viral replication (Samuel 1991 Vilcek and Sen 1996). For example, 2, 5 -oligoadenylate synthetase (2, 5 -OAS) activates ribonuclease L, which degrades mRNA and limits the accumulation of viral transcripts. Protein kinase R blocks translation of viral transcripts by phosphorylating translation initiation factor eIF-2. Mx proteins block influenza, vesicular stomatitis virus, and herpes simplex virus replication by an unknown mechanism. 

Yokosawa N, Kubota T, Fujii N (1998) Poor induction of interferon-induced 2, 5 -oligoadenylate synthetase (2-5 AS) in cells persistently infected with mumps virus is caused by decrease of STAT-la. Arch Virol 143 1985-1992... 

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