CN116870133A - Application of cyclohexapeptide compound in preparation of anti-inflammatory drugs - Google Patents

Application of cyclohexapeptide compound in preparation of anti-inflammatory drugs Download PDF

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Publication number
CN116870133A
CN116870133A CN202310838569.4A CN202310838569A CN116870133A CN 116870133 A CN116870133 A CN 116870133A CN 202310838569 A CN202310838569 A CN 202310838569A CN 116870133 A CN116870133 A CN 116870133A
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China
Prior art keywords
compound
aspergillus
use according
scleroramide
culture medium
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CN202310838569.4A
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Chinese (zh)
Inventor
杨斌
周雪峰
陶华明
刘永宏
庞小艳
王俊锋
廖升荣
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South China Sea Institute of Oceanology of CAS
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South China Sea Institute of Oceanology of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • C12R2001/66—Aspergillus

Abstract

The invention discloses application of a cyclohexapeptide compound in preparation of anti-inflammatory drugs. The invention separates the cyclohexapeptide compound scleroramide shown in the formula (I) from fermentation culture of Aspergillus sp.BH6-7. The invention proves that the compound screaramide can inhibit NO release, down regulate IL-6, TNF-alpha, MCP-1, up regulate cytokines such as IL-4, IL-10 and the like, effectively inhibit inflammatory expression, obviously up regulate the expression of M2 type macrophage mark Arg1, promote M2 polarization and have NO cytotoxicity. At the same concentration, no cytotoxic activity on RAW264.7 cells indicates that the compound scThe leramide can be used as a lead compound for developing anti-inflammatory drugs, and has important significance for developing and utilizing marine microorganism drug resources in China.

Description

Application of cyclohexapeptide compound in preparation of anti-inflammatory drugs
Technical Field
The invention belongs to the technical field of natural medicines, and particularly relates to application of a cyclohexapeptide compound in preparation of anti-inflammatory medicines.
Background
The microorganism has the characteristics of short growth cycle, easy regulation and control of metabolism, easy breeding of strains, realization of industrialization by large-scale fermentation and the like, has sustainable utilization of natural resources, is a main research object of medicine research, has the characteristics of far-beyond-land microorganism, ocean high pressure, high salt, low temperature, low illumination, oligonutrition and the like, enables the ocean microorganism to be generated in different defense systems and metabolic systems of land organisms, can generate metabolites with chemical specificity, novel structure and activity diversity, is an important source of ocean medicines, and is one of hot spots of research.
The peptide small molecule has the characteristics of multiple biological activities, strong specificity, easy absorption, strong targeting property, small side effect and the like, is one of hot spots in the research of biological medicines in recent years, and has wide clinical application. Marine microorganisms are also an important source of peptide small molecules, and in recent years, domestic and foreign scholars obtain a plurality of small molecular peptide compounds with development potential from the marine microorganisms, and part of the compounds enter clinical researches. Anti-inflammatory activity is an important research direction for peptide small molecule compounds.
Disclosure of Invention
The first object of the invention is to provide an application of a cyclohexapeptide compound, sceramide or a pharmaceutically acceptable salt thereof in preparing anti-inflammatory drugs, wherein the structural formula of the compound sceramide is shown as the formula (I):
further, the compound scleroramide is isolated from a fermentation culture of Aspergillus sp.BH6-7. The method comprises the following specific steps: preparing a fermentation culture of Aspergillus sp.BH6-7, extracting fermentation liquor with ethyl acetate, and concentrating the extract liquor to obtain ethyl acetate phase crude extract; the crude extract is purified by silica gel column chromatography and semi-preparative HPLC to obtain the compound scleroramide.
The fermentation culture is prepared by the following method: inoculating Aspergillus sp.BH6-7 into seed culture medium, shake culturing to obtain seed culture solution, inoculating into SWS oligotrophic culture medium, and static fermenting to obtain fermentation culture.
The formula of the seed culture medium is as follows: 15g of malt extract, 10g of sea salt, 1000mL of distilled water and pH of 7.4-7.8; the formula of the SWS oligotrophic culture medium is as follows: 10g of starch, 10g of sea salt and 1000mL of distilled water.
The second object of the present invention is to provide an anti-inflammatory agent comprising a compound of formula (i) scleramide or a pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable excipients or carriers.
Preferably, the dosage form of the medicament is an injection administration dosage form, a transdermal administration dosage form or an oral administration dosage form.
The invention has the following beneficial effects:
the invention separates a cyclohexapeptide compound scleramide from a fermentation culture of Aspergillus sp.BH6-7, which is a marine coral co-epiphyte in North bay, the compound scleramide can inhibit the release of NO, down regulate IL-6, TNF-alpha and MCP-1, up regulate cytokines such as IL-4, IL-10 and the like, effectively inhibit inflammatory expression, obviously up regulate the expression of M2 type macrophage marker Arg1, promote the polarization of M2, and have NO cytotoxicity. Under the same concentration, the compound has no cytotoxic activity to RAW264.7 cells, which indicates that the compound scleramide can be used as a lead compound for anti-inflammatory drug development, and has important significance for developing and utilizing marine microorganism drug resources in China.
Aspergillus sp.BH6-7 was deposited at the Guangdong province microbiological bacterial collection center (GDMCC) at 9/28 of 2020, address: building 5, guangzhou city, first, middle road 100, institute 59, guangdong province microbiological institute, post code: 510070, accession number: GDMCC No:61220.
drawings
FIG. 1 shows the X-ray structure of the compound scleroramide.
FIG. 2 shows the results of anti-inflammatory activity screening; a: nitric oxide release data results; b: anti-inflammatory gene expression downregulation factor results; c: up-regulation of anti-inflammatory gene expression factor results; d: inflammatory factor ELISA results. HTE7 in the figure represents the compound scleroramide.
Detailed Description
The following examples are further illustrative of the invention and are not intended to be limiting thereof.
Example 1 preparation and Structure identification of the Compound sceramide
1. Preparation of the compound sceramide
1. Microorganism culture conditions:
inoculating Aspergillus sp.BH6-7 into a triangular flask (100 mL) containing 10mL of seed culture medium, shake culturing at 25deg.C and 178rpm for 3d to obtain seed solution, transferring 10mL of seed solution into conical flask (1000 mL) containing SWS oligotrophic culture medium, and standing at 25deg.C under natural illumination for 3 months to perform co-fermentation for 60L to obtain Aspergillus sp.BH6-7 fermentation culture. The seed culture medium is MA culture medium, and the formula is as follows: 15g of malt extract, 10g of refined sea salt, 1000mL of distilled water and pH of 7.4-7.8, wherein the preparation steps are as follows: dissolving the above materials in water, stirring, regulating pH, and sterilizing. The formula of the SWS oligotrophic culture medium is as follows: 10g of starch, 10g of refined sea salt and 1000mL of distilled water, and the preparation steps are as follows: mixing the above materials with water, stirring, and sterilizing.
2. And (3) extracting and separating:
the strain BH6-7 is cultured in SWS oligotrophic culture medium for 3 months, and the metabolites are mainly target products through HPLC analysis. Extracting the fermentation liquor by using ethyl acetate with the same volume for 3 times, concentrating to obtain ethyl acetate phase crude extract, merging the ethyl acetate parts after concentrating to obtain total crude extract (15.6 g), separating the crude extract by using medium-pressure chromatography, mixing the crude extract with 100-200 meshes of silica gel, filling the normal phase column silica gel with 300-400 meshes, and filling the normal phase column silica gel with methylene dichloride as a mobile phase: methanol (V: v=99:1 to 0:100, flow rate 30ml·min -1 ) Gradient elution was performed and 6 fractions were identified by Thin Layer Chromatography (TLC). Wherein fr.2 (dichloromethane: methanol=19:1 to 9:1 elution fraction) is purified by reverse phase medium pressure chromatography (ODS) with mobile phase methanol: water (V: V=40:60 to 100:0, flow rate 15 mL. Min -1 ) Gradient elution, which is to take eluent according to the peak condition of the MPLC-ultraviolet detector at 210nm wavelength, to obtain 5 sub-fractions, sub-fraction Fr.2-4 (methanol: water=70:30 to 90:10 elution fraction) through semi-preparative column high performance liquid phase (V MeOH :V H2O Flow rate 3.0ml·min =70:30 -1 ) Further purification was carried out using YMC ODS semi-preparative column (YMC-Pack ODS-A, 250X 10mm I.D., S-5 μm,12 nm) at se:Sup>A column temperature of 27℃to give Compound 1 (34 mg, t) R ＝23min)
2. Structural identification of compounds
Compound 1 was a white solid which was used as a solid, 1 h and 13 the 32 carbon signals observed by C NMR data (Table 1) showed that compound 1 contained 7 amide carbons, 6 amide NH protons, 2N-methyl groups and 3 phenyl signals, assuming that compound 1 was a polyphenyl cyclic peptide. Compound 1 was identified as sleramide by comparison with literature (j.nat. Prod.2000,63, 1006-1009.)And finally the configuration and structure of compound 1 was determined by X-ray.
The X-ray structure of the compound scleroramide is shown in FIG. 1.
TABLE 1 compound scleroramide 1 H (500 MHz) and 13 c (125 MHz) NMR data (DMSO 3 -d 6 )
The structural formula of the compound scleramide is shown as the following formula (I):
example 2: detection of anti-inflammatory Activity of the Compound sceramide
1. Experimental procedure
Griess assay for detecting the effect of test compounds on RAW26.7 cell NO
RAW264.7 cells with good growth state in 96-well plates are collected, and 10 counts are obtained 6 Individual cells/mL, plated into six well plates. After the cells grew to 80% confluence, a blank group (control) was given an incomplete medium (DMEM medium), an LPS group was given an incomplete medium containing LPS (0.1. Mu.g/mL), an administration group was given an incomplete medium containing LPS (0.1. Mu.g/mL) and test compounds (10. Mu.mol/L, 5. Mu.mol/L, 1. Mu.mol/L), a control group was given an incomplete medium containing LPS (0.1. Mu.g/mL) and L-NMMA (100. Mu.mol/mL), and 8 duplicate wells were set per well, and the cells were cultured for 24 hours. After the end of the incubation, the NO content of the supernatant was measured according to the Griess kit instructions.
ELISA kit for detecting influence of test compound on RAW264.7 cell pro-inflammatory factor level
RAW264.7 cells with good growth state in 12-well plates were collected and counted for 10 6 Individual cells/mLInoculated into six well plates. After the cells grew to 80% confluence, a blank group (control) was given with an incomplete medium, an LPS group was given with an incomplete medium containing LPS (0.1. Mu.g/mL), the administration group was given with an incomplete medium containing LPS (0.1. Mu.g/mL) and the test compound (10. Mu. Mol/L), and 2 duplicate wells were placed per well for 24 hours, and the cells were cultured. After the completion of the culture, the supernatant was collected, diluted with an appropriate dilution, and the content of MCP-1, TNF-a and IL-6 in the supernatant was measured according to the ELISA kit.
RT-PCR detection of Gene expression level of macrophage M1/M2 polarization State correlator
RAW264.7 cells with good growth state were collected and counted 10 6 Individual cells/mL, plated into six well plates. After the cells grew to 80% confluence, a blank group (control) was given with an incomplete medium, an LPS group was given with an incomplete medium containing LPS (0.1. Mu.g/mL), the administration group was given with an incomplete medium containing LPS (0.1. Mu.g/mL) and the test compound (10. Mu. Mol/L), and 3 duplicate wells were set per well, and the cells were cultured for 24 hours. Cells were collected and total cellular RNA was extracted to detect mRNA transcript levels according to Trizol kit instructions.
3.1 Total RNA extraction
Chloroform-phenol extraction: 500. Mu.L of Trizol reagent was added to each well of the six-well plate, and the mixture was allowed to stand on ice for 5min. The cells were thoroughly lysed by blowing them up and collected in 1.5mL EP tubes, 100. Mu.L of chloroform was added to each tube, vortexed for 30s or more and incubated on ice for 10min. Centrifuge, 13000rpm,20min,4 ℃. At this point the liquid in the 1.5mL EP tube separated into three layers, the RNA being present in the upper colorless aqueous phase.
RNA precipitation: the upper colorless aqueous phase was collected in another clean 1.5mL EP tube, 250. Mu.L of isopropanol was added to each tube, and incubated at-20℃for 10min. Centrifuge, 13000rpm,20min,4 ℃. At this point RNA precipitated at the bottom of the tube.
And (3) RNA cleaning: the supernatant was discarded, and 200. Mu.L of 75% ethanol prepared by DEPC Water was added to each tube to wash RNA, and centrifuged at 7500rpm for 5min; repeating the process once; and airing for 5min at room temperature.
RNA dissolution: RNA was dissolved with 80. Mu.L DEPC Water.
Concentration measurement: mu.L of RNA was taken and assayed for RNA concentration (μg/. Mu.L) in a NANODROP2000 UV spectrophotometer. RNA concentrations of 1.8-2.0. Mu.g/. Mu.L indicate good RNA quality and can be used in the following experiments.
3.2 reverse transcription to cDNA
The reverse transcription kit is strictly operated. 20. Mu.L of reaction system (5 XAnmix PCR 4. Mu.L; RNA and DEPC Water total 16. Mu.L): according to the determined RNA concentration, adding corresponding volumes of RNA and DEPC Water to the octant tube to make the RNA quality in the range of 3-5 mug and total volume 16 mug, and adding 4 mug of 5 XAnmix PCR. The reaction conditions were (15 min at 42 ℃ C., 5s at 85 ℃ C.). 200. Mu.L ddH after completion 2 O dilutes the cDNA.
3.3Real-time PCR
Primer design:
TABLE 3RAW264.7 mRNA oligo sequence related to cholesterol efflux from macrophages
3.4Real-time PCR detection
The relative expression level of mRNA was determined by ABI 7500system, strictly following the kit instructions. 20.4. Mu.L of the reaction system (pre-primer 0.5. Mu.L; post-primer 0.5. Mu.L; 2x TransTop qPCRmix 10. Mu.L; dyeII 0.4. Mu.L; ddH) was used 2 O6. Mu.L; cDNA 3. Mu.L). Reaction conditions: pre-denaturation at 95℃for 30s, denaturation at 95℃for 5s, annealing at 64℃for 30s, 40 cycles total. The cycle baseline set point (Ct value) is the detector software default. The assay was repeated 3 times per sample.
2. Experimental results
The influence of the compound scrammide on the NO of the RAW264.7 cells is detected by adopting a Griess method, the influence of the compound scrammide on the level of the proinflammatory factor of the RAW264.7 cells is detected by adopting an ELISA kit, and the gene expression level of the compound scrammide on the macrophage polarization state related factor is detected by adopting RT-PCR. Experimental results show that the compound scremide can inhibit NO release (figure 2A), down-regulate IL-6, TNF-alpha and MCP-1 (figure 2B), up-regulate the level of cytokines such as IL-4, IL-10 and the like (figure 2C), effectively inhibit inflammatory expression, can obviously up-regulate the expression of M2 type macrophage marker Arg1, promote M2 polarization and have NO cytotoxicity (figure 2D). At the same concentration, there was no cytotoxic activity on RAW264.7 cells. The results show that the compound scleramide can be used as a lead compound for the development of anti-inflammatory drugs, and has important significance for developing and utilizing marine microorganism drug resources in China.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that the above-mentioned preferred embodiment should not be construed as limiting the invention, and the scope of the invention should be defined by the appended claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.

Claims (9)

1. The application of the compound scleroramide shown as the formula (I) or the pharmaceutically acceptable salt thereof in preparing anti-inflammatory drugs;
2. the use according to claim 1, wherein said compound scleroramide is isolated from a fermentation culture of aspergillus sp.
3. The use according to claim 2, wherein the preparation of the compound sleramide comprises the following steps: preparing a fermentation culture of Aspergillus sp.BH6-7, extracting fermentation liquor with ethyl acetate, and concentrating the extract liquor to obtain ethyl acetate phase crude extract; the crude extract is purified by silica gel column chromatography and semi-preparative HPLC to obtain the compound scleroramide.
4. Use according to claim 3, characterized in that the fermentation culture is prepared by the following method: inoculating Aspergillus sp.BH6-7 into seed culture medium, shake culturing to obtain seed culture solution, inoculating into SWS oligotrophic culture medium, and static fermenting to obtain fermentation culture.
5. The use according to claim 4, wherein the seed culture medium is formulated as follows: 15g of malt extract, 10g of sea salt, 1000mL of distilled water and pH of 7.4-7.8; the formula of the SWS oligotrophic culture medium is as follows: 10g of starch, 10g of sea salt and 1000mL of distilled water.
6. The use according to claim 2, wherein the Aspergillus sp.bh6-7 deposit No. GDMCC No:61220.
7. an anti-inflammatory agent comprising, as an active ingredient, a compound of formula (i) sleramide or a pharmaceutically acceptable salt thereof;
8. the anti-inflammatory agent as in claim 7, further comprising a pharmaceutically acceptable adjuvant or carrier.
9. The anti-inflammatory agent as claimed in claim 7, wherein the dosage form of the agent is an injectable dosage form, a transdermal dosage form or an oral dosage form.
CN202310838569.4A 2023-07-10 2023-07-10 Application of cyclohexapeptide compound in preparation of anti-inflammatory drugs Pending CN116870133A (en)

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