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Application of RNase L inhibitor

A technology of inhibitors and compounds, applied in the direction of resisting vector-borne diseases, medical preparations and instruments containing active ingredients, etc., can solve the problem of poor inhibition of cancer cells, etc. normal effect

Active Publication Date: 2020-01-03
PEKING UNIV SHENZHEN GRADUATE SCHOOL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, when using vesicular stomatitis virus (Vsicular Stomatitis Virus, VSV) to develop anti-cancer oncolytic virus therapy, researchers found that RNase L will attack the used VSV virus, resulting in poor inhibition of VSV virus on cancer cells

Method used

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  • Application of RNase L inhibitor
  • Application of RNase L inhibitor
  • Application of RNase L inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] 1 Experimental method

[0041] 1.1 Preparation of RNase L protein samples

[0042] The prokaryotic expression vector originally preserved by our laboratory and used to express RNase L is pGEX-FL-RNase L (constructed by inserting the nucleotide sequence fragment NM_001097512 of RNase L into the BamHI and XhoI multiple cloning sites of the vector pGEX-4-T1 obtained) and pGEX-N21732, which contains the wild-type RNase L gene sequence (used to resolve the full-length crystal structure of RNase L: including all domains, N-terminal and C-terminal excised a small number of fragments without secondary structure ). The relevant plasmids were transformed into prokaryotic expression E. coli strain BL-21. Single clones were picked and expanded for culture, and finally induced overnight by adding IPTG at low temperature. The obtained bacteria were crushed under high pressure and centrifuged at high speed to obtain the protein supernatant, the obtained supernatant was mixed with G...

Embodiment 2

[0065] Two 10G5 derivatives, 10G-1 and 10G-2, were used as two inhibitory fragments respectively, and the binding constant of the inhibitory fragments to RNase L was determined by microscale thermophoresis (MST). The result is as image 3 as shown, image 3 It is the measurement result of the binding constant of 10G5-1 and 10G5-2 according to another example of the present invention. A is a schematic diagram of molecular docking of 10G5 derivatives based on the co-crystal structure, B and C are the results of measuring the binding constants of derivatives 10G5-1 / 10G5-2 and RNaseL by MST method, respectively. It can be seen from the figure that the binding constants of 10G5-1 and 10G5-2 are 14 μM and 10 μM, respectively.

Embodiment 3

[0067] A kind of antitumor pharmaceutical composition, comprises encephalomyocarditis virus and

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Abstract

The invention discloses application of an RNase L inhibitor and a pharmaceutical composition. The application of the RNase L inhibitor comprises application of a specific compound in preparation of the RNase L inhibitor, an oncolytic virus anti-tumor synergist and an anti-tumor product, and the specific compound has targeted specificity for the RNase L. The prepared RNase L inhibitor can effectively inhibit the activity of the RNase L, degradation of oncolytic viruses is avoided, thus the oncolytic viruses can successfully replicate and kill tumor cells in host tumor cells, and the antitumor effect of the oncolytic viruses is effectively improved. On this basis, the RNase L inhibitor and specific oncolytic viruses can be combined into an anti-tumor product to ensure the normal function ofthe oncolytic viruses in killing the tumor cells.

Description

technical field [0001] The invention relates to the technical field of anti-cancer, in particular to the application of an RNase L inhibitor. Background technique [0002] RNase L is a class of protein molecules that play an important role in the process of resisting virus invasion and human innate immunity in higher animals. Higher animals will secrete interferon when they are invaded by viruses. Interferon induces the expression of 2-5A synthetase (Oligo-adenylate Synthetase, OAS), which is activated by the combination of 2-5A synthetase and viral double-stranded RNA, and then ATP is synthesized as 2'-5' linked oligoadenylate (2'-5'linked oligoadenylate, 2-5A). The chemical structure of 2-5A contains three linearly linked adenosine (A): px5'A(2'p5'A)n, where x=1–3, n≥2. The generated 2-5A binds to RNase L, activates the RNase L molecule, and enables it to degrade the virus and host single-stranded RNA, making the virus unable to replicate, thereby achieving the antiviral...

Claims

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Application Information

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IPC IPC(8): A61K35/768A61K31/4709A61K31/47A61K31/277A61P35/00G01N21/64
CPCA61K31/277A61K31/47A61K31/4709A61K35/768A61P35/00G01N21/6428G01N21/6486G01N2021/6432G01N2021/6439A61K2300/00Y02A50/30
Inventor 黄昊汤金乐刘志宏付子阳
Owner PEKING UNIV SHENZHEN GRADUATE SCHOOL