Peptide nucleic acid (PNA) strand invasion offers an attractive alternative to DNA oligonucleotide directed triplex formation as a potential tool for gene inhibition. Peptide nucleic acid has been shown to interact with duplex DNA in a process which involves strand invasion of the duplex and binding of one of the DNA strands with two PNA oligomers. By blocking the interaction of a transcription factor with 5' regulatory sequences, PNA might specifically down-regulate gene activity. Here we demonstrate that PNA is capable of specifically blocking interaction of the transcription factor NF-kappa B with the IL2-R alpha NF kappa-B binding site in vitro. We further demonstrate that this interaction is sufficient to prevent transcriptional transactivation both in vitro and when transfected into cells in culture.

The demonstrated utility of the nucleoside analog ribavirin in the treatment of certain viral diseases can be ascribed to its multiple distinct properties. These properties may vary in relative importance in differing viral disease conditions and include the direct inhibition of viral replication, the promotion of T-cell-mediated immune responses via an enhanced type 1 cytokine response, and a reduction of circulating alanine aminotransferase (ALT) levels associated with hepatic injury. Ribavirin also has certain known toxicities, including the induction of anemia upon chronic administration. To determine if all these properties are linked, we compared the D-nucleoside ribavirin to its L-enantiomer (ICN 17261) with regard to these properties. Strong similarities were seen for these two compounds with respect to induction of type 1 cytokine bias in vitro, enhancement of type 1 cytokine responses in vivo, and the reduction of serum ALT levels in a murine hepatitis model. In contrast, ICN 17261 had no in vitro antiviral activity against a panel of RNA and DNA viruses, while ribavirin exhibited its characteristic activity profile. Importantly, the preliminary in vivo toxicology profile of ICN 17261 is significantly more favorable than that of ribavirin. Administration of 180 mg of ICN 17261 per kg of body weight to rats by oral gavage for 4 weeks generated substantial serum levels of drug but no observable clinical pathology, whereas equivalent doses of ribavirin induced a significant anemia and leukopenia. Thus, structural modification of ribavirin can dissociate its immunomodulatory properties from its antiviral and toxicologic properties, resulting in a compound (ICN 17261) with interesting therapeutic potential.Ribavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nucleoside analog that has demonstrated efficacy in treating viral disease as monotherapy (respiratory syncytial virus [RSV] [15]) and in combination with alpha interferon (IFN-␣) (hepatitis C virus [HCV] [27,36]). Ribavirin has multiple biologic properties that are favorable for treating viral diseases. It can directly inhibit the replication of many DNA and RNA viruses (38). More recently, studies have shown that it can also act as an immunomodulator and thus promote T-cell-mediated immunity against viral infection (18,25,30,39,40). The central focus of this effect of ribavirin is the augmentation of antiviral type 1 cytokine expression (interleukin-2 [IL-2], gamma interferon [IFN-␥], and tumor necrosis factor alpha [TNF-␣]) and concomitant suppression of type 2 cytokine levels by activated T cells in both human and murine systems. Finally, ribavirin, alone or in combination with IFN-␣, can lower serum alanine aminotransferase (ALT) levels during the course of treatment of HCV infection (11). Elevated serum ALT levels are a marker for liver damage and progressive hepatitis, and hence the ribavirin-mediated lowering of ALT levels is a distinct liver-specific effect of this nucleoside analog.The therapeutic use of ribavirin is restric...

No abstract

Nucleic acids U 0700Cyclic Monophosphate Prodrugs of Base-Modified 2'-C-Methyl Ribonucleosides as Potent Inhibitors of Hepatitis C Virus RNA Replication. -The novel nucleoside (I) belongs to the class of 2'-methyl ribonucleosides possessing a relatively good safety profile is tested for its anti-HCV replicon activity. It exhibits weak effects but no cytotoxicity. Monophosphate (II) shows better activity against the HCV replicon despite diminished cell penetration capabilities. The polarity of the compounds is reduced by synthesizing the cyclic monophosphate (III) and the potency against the HCV replicon is further enhanced. A prodrug strategy enhances the cell permeability characteristics of the series resulting in the synthesis of (V), a prodrug that shows strong potency without significant cytotoxicity. -(GUNIC*, E.; GIRARDET, J.-L.; RAMASAMY, K.; STOISAVLJEVIC-PETKOV, V.; CHOW, S.; YEH, L.-T.; HAMATAKE, R. K.; RANEY, A.; HONG, Z.; Bioorg. Med. Chem. Lett. 17 (2007) 9, 2452-2455; Valeant Res. Dev., Costa Mesa, CA 92626, USA; Eng.) -H. Hoennerscheid 36-193

No abstract