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Use of oligonucleotides with modified bases as antiviral agents

An oligonucleotide and base technology, which can be used in antiviral agents, medical preparations containing active ingredients, gene therapy, etc., and can solve problems such as low efficiency

Inactive Publication Date: 2011-02-09
BALTIC TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Developing resistance to siRNAs is obviously quite easy, since the siRNA should have a 100% match to the target (microRNAs tolerate a few changes, but are much less efficient silencers)

Method used

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  • Use of oligonucleotides with modified bases as antiviral agents
  • Use of oligonucleotides with modified bases as antiviral agents
  • Use of oligonucleotides with modified bases as antiviral agents

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0148] 讲述了上述含磷连键的制备的代表性美国专利包括但不限于U.S.:3,687,808,4,469,863,4,476,301,5,023,243,5,177,196,5,188,897,5,264,423,5,276,019,5,278,302,5,286,717,5,321,131,5,399,676,5,405,939,5,453,496,5,455,233, 5,466,677,5,476,925,5,519,126,5,536,821,5,541,306,5,550,111,5,563,253,5,571,799,5,587,361,5,194,599,5,565,555,5,527,899,5,721,218,5,672,697和5,625,050,它们每个在此引为参考。

[0149] Contemplated modified oligonucleotide backbones containing no phosphorus atoms therein, having short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl internucleoside linkages, Or one or more short-chain heteroatoms or a backbone formed by linkages between heterocyclic nucleosides. They include backbones with morpholino linkages (partially formed from the sugar moieties of nucleosides); siloxane backbones; thioether, sulfoxide, and sulfone backbones; formyl and thioformyl backbones; methyleneformyl and Thioformyl skeleton; riboseacetyl skeleton; skeleton containing alkenes; sulfa...

Embodiment 1

[0247] Inhibition of Semliki Forest Virus Using Modified Oligonucleotides

[0248] To determine the effect of modified oligonucleotides on viral gene replication, antisense against Semliki Forest Virus (SFV - a rapid (acute) positive-sense RNA virus from the Togaviridae family Alphavirus genus was generated oligonucleotides, and the inhibition of viral genome replication was measured.

[0249] The list of oligonucleotides and targets within the SFV viral genome is shown in Table 1.

[0250] Table 1

[0251] the code

[0252] X-modified base, 8-oxo-dG

[0253] nsP4 - viral RNA polymerase - a conserved part of the coding region for nonstructural protein 4

[0254] BHK-21 (baby hamster kidney) cells were grown to confluence in 35 mm diameter dishes using lipofectamine RNAiMAX (Invitrogen) with modified oligonucleotides with or without metallonucleases (Eu). Acid-transfected cells. Transfection is performed at the time of infection or prior to infection. Cells we...

Embodiment 2

[0260] Inhibition of hepatitis C virus using modified oligonucleotides

[0261] To determine the effect of modified oligonucleotides on viral gene replication, antisense oligonucleotides were generated against hepatitis C virus (HCV), a slow (chronic) positive-strand RNA virus of the Flaviviridae genus Hepacivirus. nucleotides, and the inhibition of viral genome replication was measured.

[0262] The list of oligonucleotides and targets within the HCV viral genome is shown in Table 3.

[0263] table 3

[0264] the code

[0265] X-modified base, 8-oxo-dG; Y-modified base, 5-OH-dC

[0266] NS5B - viral RNA polymerase - a conserved portion of the coding region of nonstructural protein 5B

[0267] Analysis of HCV replication and the effect of inhibitors on this process was performed using HCV replicons containing the Luc-marker gene and delivered as RNA transcripts into Lunet cells. The analysis was performed using an HCV replicon (genotype 1b) without a selection ...

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Abstract

1The present invention relates to the use of oligonucleotides having modified nucleobases to inhibit gene expression and / or replication of viruses in a subject. The modified nucleobases may be mercapto-modified bases or hydroxy-modified nucleobases. It is contemplated that the oligonucleotides further comprise a nuclease complex which enhances anti-viral activity of the oligonucleotides.

Description

[0001] Cross references to related applications [0002] This application claims priority to US Provisional Application No. 61 / 057,685, filed May 30, 2008, and US Provisional Application No. 60 / 985,548, filed November 5, 2007, each of which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention relates to the use of oligonucleotide analogs containing specifically modified nucleotide bases to inhibit viral gene expression and / or replication. The oligonucleotide is optionally conjugated to a lanthanide organic complex with highly selective artificial nuclease activity. Background of the invention [0004] The use of oligonucleotides and modified oligonucleotides is of paramount importance in modern therapy and has been well documented (Uhlmann et al., Antisense oligonucleotides: A new therapeutic principle. (Antisense oligonucleotides: A new therapeutic principle. ) Chemical Reviews 1990, 90: 543-584; Crooke et al. "Antisense R...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/11C07H21/00A61K31/7115A61P31/00C12N15/113
CPCC12N15/1132C12N2310/3511C12N2310/14C12N2310/33C12N15/1131C12N15/111C12N2320/51C12N2310/11A61P31/00A61P31/12A61P31/14A61P31/16A61P31/18A61P31/20
Inventor 马特·萨尔玛安德烈斯·梅利茨马蒂·卡拉尔森
Owner BALTIC TECH DEV