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Spirocyclosporin X and application thereof to preparation of drug for treating influenza A

A type of influenza A virus and drug technology, applied in the field of medicine, can solve the problems of drug side effects, unscientific and comprehensive elaboration of antiviral mechanism, and increased drug resistance.

Active Publication Date: 2019-02-15
广州南方医大科技园有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, the anti-influenza drugs in global clinical application mainly include neuraminidase inhibitors and M2 ion channel inhibitors, but the development and application of these drugs have been plagued by the increase of drug resistance and drug side effects.
However, its antiviral mechanism has not been scientifically and comprehensively elucidated

Method used

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  • Spirocyclosporin X and application thereof to preparation of drug for treating influenza A
  • Spirocyclosporin X and application thereof to preparation of drug for treating influenza A
  • Spirocyclosporin X and application thereof to preparation of drug for treating influenza A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Isolation, preparation and structure identification of compound SSX

[0037] The fungus Cochliobolus lunatus SCSIO41401 is a symbiotic fungus of seaweed, collected from the waters near Yongxing Island in the South China Sea (Journal of Natural Products, Cytotoxic and Antibacterial Eremophilane Sesquiterpenes from the Marine-Derived Fungus Cochliobolus lunatus SCSIO41401, WEI Fang et al., 2018, 81, 1405-1410). The strain can be provided by the School of Pharmacy of Southern Medical University. The strain is stored in MB medium. The composition of MB medium is 15 g agar, 15 g malt extract powder, 24.4 g coarse sea salt, 1000 mL water, and pH 7.2-7.4.

[0038] Take a small amount of slant strains for seed fermentation culture (medium: 6.25g maltose, 6.25g malt extract powder, 1g yeast extract powder, 6.25g peptone, 1.25g potassium dihydrogen phosphate, 20g sea salt, 1000mL distilled water, pH 7.0), 500 One milliliter Erlenmeyer bottle is filled with 100 ml, and the cu...

Embodiment 2

[0046] Example 2 Cytotoxicity detection of compound SSX

[0047] The cytotoxicity of compound SSX was detected by MTT method. The specific method is as follows:

[0048] MDCK cells press 1×10 4 / Well inoculated in 96-well plate at 37℃, 5% CO 2 Incubate to a single layer in a constant temperature cell incubator, add gradient dilutions of compound SSX to a 96-well plate, 200 μl per well, and continue to incubate for 48 hours. Discard the culture supernatant, add 100μL of DMEM medium containing 0.5mg / ml MTT to each well, and incubate at 37°C for 4h. A multifunctional microplate reader (GeniosPro, Tecan, US) was used to detect the absorbance at 570nm. The cell survival rate was used as an indicator of the toxicity of compound SSX to MDCK cells.

[0049] Cell survival rate (%) = E / N×100

[0050] E is the absorbance of the drug group, and N is the absorbance of the cell control group.

[0051] Test result: the compound SSX is less cytotoxic, CC 50 Value is greater than 200μM, high biologi...

Embodiment 3

[0053] Example 3 Inhibitory activity of compound SSX against influenza viruses of multiple subtypes

[0054] The in vitro antiviral experiment of the present invention involves multiple subtypes of influenza A viruses, including A / Aichi / 2 / 68(H3N2), A / FM-1 / 1 / 47(H1N1), A / Puerto Rico / 8 / 34(H1N1), H274Y and A 690(H3), the specific methods are as follows:

[0055] MDCK cells press 2×10 4 / Well inoculated in 96-well plate at 37℃, 5% CO 2 Culture to a single layer in a constant temperature cell incubator. Use 100TCID 50 Infected cells with influenza A virus, 100μl per well, incubated at 37°C for 1h, discarded the virus solution, added DMEM (containing 1μg / ml TPCK) gradient dilution compound SSX, 200μl per well, and continued to culture for 48h. Combining MTT method and plaque experiment, the antiviral activity of compound SSX is determined by the protective effect of compound SSX on cells, including observation of compound SSX inhibiting virus-caused cell virus phenomenon (CPE) and detec...

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Abstract

The invention discloses application of spirocyclosporin X to the preparation of a drug for treating influenza A. Influenza viruses are influenza A viruses and are preferably selected from H1N1, H3N2,H5N1 or H7N9. An action mechanism of the spirocyclosporin X in the anti-influenza A viruses is to inhibit the ribonucleoprotein complex vRNP activity by binding to PB2cap proteins; and the drug for preventing and treating the influenza is prepared. Sites at which the spirocyclosporin X binding to the influenza virus PB2cap proteins are arginine 355 (Arg355), asparagine 429 (Asn429), lysine 339 (Lys 339), methionine 431 (Met431) and phenylalanine 325 (Phe325).

Description

Technical field [0001] The invention relates to the application of Spirosporin X in anti-influenza A virus drugs, and belongs to the technical field of medicine. Background technique [0002] Influenza virus infection is an infectious disease that seriously endangers human health. Prevention and treatment of influenza, especially drug treatment, is imminent. So far, there are mainly two types of anti-influenza drugs in clinical use around the world, neuraminidase inhibitors and M2 ion channel inhibitors, but the increase in drug resistance and drug side effects have been plagued by the development and application of these drugs. . For this reason, people are eager to find and develop new anti-influenza drugs. It is particularly important to find low-toxic and effective anti-influenza virus drugs from natural products. [0003] Studies have shown that the ocean is an important resource for finding drug-lead compounds. From a large number of marine natural products, not only som...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/54A61K31/403C12P17/10A61P31/16C12R1/645
CPCA61P31/16C07D209/54C12P17/10
Inventor 杨洁唐斓周雪峰刘叔文陈飞敏
Owner 广州南方医大科技园有限公司
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