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Alkyl modified nucleic acid and modification method and application thereof

A nucleic acid and alkyl technology, applied in the field of nucleic acids, can solve the problems of limited improvement of siRNA stability, and achieve the effects of simple and easy reaction, chemical stability and blood retention time improvement, good lipophilicity and membrane permeability.

Active Publication Date: 2013-07-24
合肥欧创基因生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing modification methods have very limited improvement on the stability of siRNA

Method used

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  • Alkyl modified nucleic acid and modification method and application thereof
  • Alkyl modified nucleic acid and modification method and application thereof
  • Alkyl modified nucleic acid and modification method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Tumor cell telomerase RNA has 11 nucleotides, which is used as a template to design the antisense oligonucleotide sequence of this nucleotide:

[0066] Antisense sequence: 5`-GTT AGG GTT AGA CAA AAA AT-3`

[0067] (1) preparation is selected from the nucleoside monomer shown in general formula 5 and general formula 6:

[0068]

[0069] (2) Synthesizing oligonucleotide chains by conventional solid-phase synthesis methods, and doping nucleoside monomers into the oligonucleotide chains during the synthesis process;

[0070]

[0071] (3) Olefin ring-closing metathesis reaction occurs under the action of Grubbs catalyst, and side chain olefins are coupled into alkane chains.

[0072]

Embodiment 2

[0074] According to the gene U5 sample sequence of hepatitis B, design the antisense oligonucleotide sequence of this section nucleotide:

[0075] Antisense sequence: 5`-CAT GCC CCA AAG CCA C-3`

[0076] (1) preparation is selected from the nucleoside monomer shown in general formula 7 and general formula 8:

[0077]

[0078] (2) Synthesizing oligonucleotide chains by conventional solid-phase synthesis methods, and doping nucleoside monomers into the oligonucleotide chains during the synthesis process;

[0079]

[0080] (3) Olefin ring-closing metathesis reaction occurs under the action of Grubbs catalyst, and side chain olefins are coupled into alkane chains.

[0081]

Embodiment 3

[0082] Example 3 Application of the chemical modification method of the present invention in improving the stability of siRNA

[0083] (1) Select the target gene, determine the sequence of the sense strand and the antisense strand of the siRNA Select GAPDH (Genbank accession number is NC_000012) as the target gene, design siRNA, and its position corresponding to NC_000012 is 2700-2718bp;

[0084] Justice Chain: 5`-GUA UGA CAA CAG CCU CAA GTT-3`

[0085] Antisense strand: 5`-CUU GAG GCU GUU GUC AUA CTT-3`

[0086] (2) preparation is selected from the nucleoside monomer shown in general formula 5 and general formula 6

[0087]

[0088] (3) Solid-phase synthesis of sense and antisense strands of siRNA

[0089] Justice Chain:

[0090]

[0091] Antisense strand: 3`-TT CAU ACU GUU GUC GGA GUU C-5`

[0092] (4) Annealing and hybridization to form siRNA double strands

[0093]

[0094] (5) Olefin metathesis reaction occurs under the action of Grubbs catalyst to fix the c...

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Abstract

The invention relates to alkyl modified nucleic acid and a modification method and application thereof. The nucleic acid modified in the method has excellent lipophilicity and membrane permeability, and not only can tolerate hydrolysis of protease, peptidase, nuclease and the like in the body, but also can endure the oxidation, reduction, substitution, elimination, addition and the like in the physical environment and the environment with a wide range of pH. The invention also relates to application of the method for chemical modification of the nucleic acid in improvement of the stability ofantisense nucleic acid and siRNA. For the antisense nucleic acid and siRNA modified in the method of the invention, the chemical stability and blood accommodating time are both significantly improved.

Description

technical field [0001] The invention relates to a nucleic acid, in particular to a nucleic acid modified with an alkyl group and a chemical modification method thereof, as well as the application of the method in improving the stability of antisense nucleic acid and siRNA. Background technique [0002] Antisense nucleic acid refers to a piece of DNA or RNA that is complementary to the target DNA or RNA base and can bind to it. Antisense nucleic acid technology refers to the use of antisense nucleic acid to specifically inhibit the expression of certain genes. In 1978, Paul et al. used an antisense DNA oligonucleotide chain to successfully inhibit the replication of Rous sarcoma virus, which attracted great attention. In the 1980s, with the success of oligonucleotide artificial synthesis technology, the research on antisense nucleic acid developed rapidly, making antisense technology achieve certain achievements in anti-tumor, anti-virus, apoptosis mechanism, signal transmis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H21/02C07H1/00
CPCY02P20/55
Inventor 高源刘迎春
Owner 合肥欧创基因生物科技有限公司
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