CN114539278B - IL-15 inhibitor Neoprzewaquinone A, screening method and application thereof - Google Patents
IL-15 inhibitor Neoprzewaquinone A, screening method and application thereof Download PDFInfo
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- 102000003812 Interleukin-15 Human genes 0.000 title claims abstract description 49
- SXQCYGZVSVUMEL-QGMBQPNBSA-N neoprzewaquinone a Chemical compound C1CCC(=C)C2=CC=C(C3=C(C(C)=CO3)C(=O)C3=O)C3=C2CC\C=C(/C)C(C=C2)=C1C(C(=O)C1=O)=C2C2=C1C(C)=CO2 SXQCYGZVSVUMEL-QGMBQPNBSA-N 0.000 title claims abstract description 33
- GSOOTZSZXIDGIP-UHFFFAOYSA-N Neo-przewaquinone A Natural products CC1=CCCc2c(ccc3c4occ(C)c4C(=O)C(=O)c23)C(=C)CCCc5cc1cc6c7occ(C)c7C(=O)C(=O)c56 GSOOTZSZXIDGIP-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 239000003112 inhibitor Substances 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title abstract description 8
- 238000012216 screening Methods 0.000 title abstract description 6
- 230000004663 cell proliferation Effects 0.000 claims description 5
- 230000000638 stimulation Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 9
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 238000009169 immunotherapy Methods 0.000 abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 5
- 210000002345 respiratory system Anatomy 0.000 abstract description 4
- 239000005557 antagonist Substances 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 abstract description 3
- 125000005842 heteroatom Chemical group 0.000 abstract description 3
- 102000004169 proteins and genes Human genes 0.000 abstract description 3
- 108090000623 proteins and genes Proteins 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 10
- 230000035755 proliferation Effects 0.000 description 6
- 239000012980 RPMI-1640 medium Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
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- 210000000653 nervous system Anatomy 0.000 description 4
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- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000003032 molecular docking Methods 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 208000025721 COVID-19 Diseases 0.000 description 2
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- 238000004458 analytical method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 108010057840 ALT-803 Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 102000018682 Interleukin Receptor Common gamma Subunit Human genes 0.000 description 1
- 108010066719 Interleukin Receptor Common gamma Subunit Proteins 0.000 description 1
- 102000004556 Interleukin-15 Receptors Human genes 0.000 description 1
- 108010017535 Interleukin-15 Receptors Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000011201 multiple comparisons test Methods 0.000 description 1
- 210000000581 natural killer T-cell Anatomy 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 238000003041 virtual screening Methods 0.000 description 1
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Abstract
The invention provides an IL-15 inhibitor Neoprzewaquinone A shown in a formula (1), and a screening method and application thereof. The screening method of the invention comprises the following steps: (1) Determining potential binding sites for the IL-15Rα antagonist based on the three-dimensional crystal structure of the IL-15/IL-15Rα complex; (2) IL-15Ra protein after removing all hetero atoms and water, adding hydrogen atoms, and combining all nonpolar hydrogens, and constructing by AutoDockToolsSetting a Grid center; (3) The energy minimization is performed after the alternative compounds are converted into 3D structures in Chem3D, the selected compounds are docked with IL-15Rα by using molecular docking software Autodock Vina, and the binding situation is scored, and the IL-15 inhibitor Neoprzewaquinone A is screened out. The IL-15 inhibitor Neoprzewaquinone A provided by the invention can be used for preparing tumor immunotherapy medicaments and medicaments for treating diseases related to respiratory systems.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an IL-15 inhibitor Neoprzewaquinone A, a screening method and application thereof.
Background
IL-15 contributes to proliferation and differentiation of B cells, T cells and NK cells. The cell signaling function is exerted by binding to a trimeric complex consisting of two common receptors, the common gamma chain (yc; CD 132) and the IL-2 receptor B chain (IL-2 Rbeta; CD 122), and the IL-15 receptor alpha (IL-15 Ralpha; CD 215). Are considered as potentially valuable therapeutic agents in oncology.
IL-15 is primarily presented as a membrane-bound heterodimeric complex with IL-15Rα on monocytes and dendritic cells by trans-presenting the IL-15/IL-15Rα complex to a medium affinity receptor complex (i.e., IL-2Rβ/γ complex) found, for example, on NK cells and CD8+ T cells.
IL-15/IL-15Rα as a classical immunocompetent molecule involved in regulating the survival, proliferation and function of a variety of immune cells, including NK cells, memory CD8 + T cells, NKT cells, and the like play an important role in the development and progression of autoimmune diseases, inflammatory diseases, tumors, and the like. IL-15 is thought to be a star molecule for immunotherapy in the therapeutic area of COVID-19. Current agonist and inhibitor drugs for IL-15 include SHR-1501, ALT-803, and BNZ-1, etc. for immunotherapy of tumors. However, there are no other commercially available inhibitors of IL-15 currently available for clinical use other than the reported Cef.
In addition, the regulation and control of immune molecules on the occurrence and development of neuropsychiatric diseases becomes a hot spot of research in recent years, and small-molecule drugs taking an IL-15/IL-15Rα system as a target point have little research in the treatment of nervous system related diseases and COVID-19.
Disclosure of Invention
In view of the above, to overcome the shortcomings of the prior art, the present invention provides an IL-15 inhibitor Neoprzewaquinone A, which is a small molecule compound Neoprzewaquinone A having a dose-dependent significant inhibitory effect on IL-15 stimulated MO7E cell proliferation.
The IL-15 inhibitor Neoprzewaquinone A provided by the invention has a structure shown in a formula (1):
the invention also provides a screening method of the IL-15 inhibitor Neoprzewaquinone A, which comprises the following steps:
1) Observing the binding site of IL-15 to IL-15Rα and determining the potential binding site of IL-15Rα antagonists based on the three-dimensional crystal structure of the IL-15/IL-15Rα complex;
2) Removing all hetero atoms and water from IL-15Ra protein, addingHydrogen atoms, and combining all nonpolar hydrogens, constructed by AutoDockToolsSetting a Grid center;
3) The energy minimization is performed after the alternative compounds are converted into 3D structures in Chem3D, the selected compounds are docked with IL-15Rα by using molecular docking software Autodock Vina, and the binding situation is scored, and the IL-15 inhibitor Neoprzewaquinone A is screened out.
The invention also provides application of the IL-15 inhibitor Neoprzewaquinone A in preparing tumor immunotherapy medicaments.
Further, the application dose is 1 μg/mL-3 μg/mL.
The invention also provides a tumor immunotherapy medicament, which comprises the following components: neoprzewaquinone A or a derivative thereof, and pharmaceutically acceptable auxiliary ingredients.
Further, the pharmaceutical dosage form is powder, granule, tablet, capsule, pill, solution, suspension or injection.
The invention also provides application of the IL-15 inhibitor Neoprzewaquinone A in preparing medicaments for treating diseases related to respiratory systems.
Further, the application dose is 0.3 μg/mL-3 μg/mL.
The invention also provides a medicament for treating diseases related to the respiratory system, which comprises the following components: neoprzewaquinone A or a derivative thereof, and pharmaceutically acceptable auxiliary ingredients.
The invention also provides application of the IL-15 inhibitor Neoprzewaquinone A in preparing medicaments for treating nervous system related diseases.
Further, the application dose is 0.3 μg/mL-3 μg/mL.
The invention also provides a medicament for treating the nervous system related diseases, which comprises the following components: neoprzewaquinone A or a derivative thereof, and pharmaceutically acceptable auxiliary ingredients.
Compared with the prior art, the invention has the beneficial technical effects that:
1. the invention demonstrates that small molecule compound Neoprzewaquinone A (0.3, 1 and 3 μg/mL) has a dose-dependent significant inhibitory effect on IL-15 stimulated MO7E cell proliferation. And Neoprzewaquinone A inhibited well above the positive control Cef (100 μg/mL) at 0.3, 1 and 3 μg/mL treatment conditions; there are no other commercially available inhibitors of IL-15 that are clinically useful, other than Neoprzewaquinone A and Cef that have been reported as IL-15 inhibitors.
2. The research of the invention shows that the IL-15 inhibitor Neoprzewaquinone A can be used for preparing tumor immunotherapy medicaments.
3. The research of the invention shows that the IL-15 inhibitor Neoprzewaquinone A has potential to be used for preparing medicaments for treating diseases related to the respiratory system.
4. The research of the invention shows that the IL-15 inhibitor Neoprzewaquinone A has potential to be used for preparing medicaments for treating the related diseases of the nervous system.
Drawings
FIG. 1 IL-15Rα and IL-15 binding sites; IL-15/IL-15Ra complex, right: IL-15; left: IL-15Rα,1b. IL-15 and IL-15Rα binding interface three regions specifically show: the bonding interface is divided into three regions: top, middle and bottom;
FIG. 2 is a structural formula of compound Neoprzewaquinone A;
FIG. 3 is a three-dimensional and two-dimensional plot of neo binding interactions with IL-15Rα; three-dimensional plot of neo-IL-15 ra binding interactions, two-dimensional plot of 3b.neo-IL-15 ra binding interactions;
fig. 4. MO7E cell proliferation curves for neo (0.1, 0.3, 1, 3 μg/mL) treatment versus IL-15 stimulation (n=8, mean±sem, # # p <0.0001, # p < 0.001);
note that: each group was plotted against the blank group 0h, with no Cef included in the significance analysis;
FIG. 5.Neo (0.1, 0.3, 1, 3 μg/mL) treatment vs. MO7E cell proliferation curve (N=8, mean+ -SEM, # # p <0.001, # # p < 0.01). And (3) injection: each group was plotted against the blank group 0 h.
(Neo is an abbreviation of Neoprzewaquinone A)
Detailed Description
The present invention is described in detail below by way of specific examples, with the understanding that the examples below are merely illustrative and do not limit the scope of the present invention in any way. In the following embodiments, biochemical reagents not specifically described are all conventional in the art, and can be formulated according to conventional methods in the art or commercially available, and are of laboratory purity grade.
Neoprzewaquinone A CAS No.: 630057-39-5, trade name: neoprzewaquinone A from Presspush bio.
Examples: IL-15 inhibitor Activity of Neoprzewaquinone A
1. Molecular docking virtual screening:
the three-dimensional crystal structure of the IL-15/IL-15Rα complex (PDB: 2Z 3Q) was extracted from Protein Data Bank and potential binding sites for IL-15Rα antagonists were determined by observing the binding sites for IL-15 to IL-15Rα (FIG. 1). After removal of all heteroatoms and water of the IL-15Ra protein, all hydrogen atoms were added and all nonpolar hydrogens were combined, followed by AutoDockTools constructionGrid Box of (x, y, z= 52.489,6.812,16.214) is set. In addition, compounds that need to be screened are converted to 3D structures in Chem3D and energy minimized. And finally, utilizing molecular docking software Autodock Vina to dock more than 3000 compounds in the 48 traditional Chinese medicines with IL-15Rα, and scoring the combination condition.
Molecular docking results found that compound Neoprzewaquinone A (Neo, C36H28O6, molecular weight: 556.6, structural formula shown in FIG. 2) was more biased to bind to the middle and bottom of IL-15Rα in the IL-15Rα binding interface, and that amino acids that interacted with Neo also participated in the IL-15 and IL-15Rα binding process. The Affinity scored by Autodock Vina docking was-7.3. Thus, neo is presumed to exert an effect of agonizing IL-15Rα or inhibiting IL-15 from activating IL-15Rα by the binding means in FIG. 3.
2. Human cytomegaloleukemia cells (MO 7E) validation:
MO7E cells are useful in cell proliferation assays following IL-15 stimulation, have been described by R&The company D proved (https:// www.bio-techne.com/cn /). Taking MO7E cells in logarithmic growth phase, adjusting cell density to 2.15X10 with RPMI 1640 complete medium 5 Each mL of the cell suspension was inoculated into a 96-well culture plate with 100. Mu.L of each well, and placed at 37℃in 5% CO 2 Saturated humidity incubator; after 12h of cultivation, 100. Mu.L of RPMI 1640 complete culture solution containing Neo (purity not less than 95.0%; manufacturer: bosi biotechnology) with different concentrations is added, 8 compound wells are arranged for each concentration, 4 concentration gradients are respectively arranged, and the final concentrations are respectively 0.1, 0.3, 1 and 3. Mu.g/mL. The blank group is added with 100 mu L of RPMI 1640 complete culture solution; IL-15 treatment group: RPMI 1640 complete medium containing IL-15 (30 ng/mL), IL-15+Cefazolin (Cef, 100. Mu.g/mL) and IL-15+neo (0.1, 0.3, 1, 3. Mu.g/mL) was added respectively; neo treatment group alone: RPMI 1640 complete medium containing Neo (0.1, 0.3, 1, 3. Mu.g/mL) was added separately. The growth and proliferation of MO7E cells in 72h are continuously monitored in real time under an IncuCyte S3 living cell analysis system.
3. Statistical method
Experimental data were processed using Graphpad analysis software, metering data were expressed as mean±sem, data analysis was performed using the Two-way AVOVA method, tuney's multiple comparisons test compared between groups, and p <0.05 had significant differences.
4. The results of the study are as follows:
proliferation activity of MO7E cells (p < 0.0001) was significantly improved after il-15 (30 ng/mL) stimulation (fig. 4);
MO7E cells after IL-15 stimulation showed significant proliferation inhibition after neo (0.3, 1 and 3 μg/mL) treatment and a significant dose-dependent relationship (p <0.0001, p < 0.001), whereas no significant difference (p > 0.05) occurred after treatment with the positive drug Cef (100 μg/mL) (fig. 4);
3. MO7E cells were treated with Neo alone (0.1, 0.3, 1, 3 μg/mL) and proliferation of MO7E cells was found to be significantly reduced (72 h: 0.11-0.24, based on blank 0 h) following Neo treatment (1 and 3 μg/mL) (fig. 5).
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the present invention, which is intended to be covered by the claims of the present invention.
Claims (2)
1.Neoprzewaquinone A as an inhibitor of MO7E cell proliferation after IL-15 stimulation,
the inhibitor Neoprzewaquinone A is represented by formula (1)
Formula (1).
2. The use of Neoprzewaquinone A according to claim 1, wherein the applied dose is 0.3, 1 or 3 μg/mL.
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