CN116999434A - Application of HDAC5 activator Gbox in preparation of medicine for promoting skin wound healing - Google Patents
Application of HDAC5 activator Gbox in preparation of medicine for promoting skin wound healing Download PDFInfo
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- CN116999434A CN116999434A CN202311017211.1A CN202311017211A CN116999434A CN 116999434 A CN116999434 A CN 116999434A CN 202311017211 A CN202311017211 A CN 202311017211A CN 116999434 A CN116999434 A CN 116999434A
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- skin wound
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- healing
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- 206010072170 Skin wound Diseases 0.000 title claims abstract description 33
- 230000029663 wound healing Effects 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 title claims abstract description 25
- 102100021453 Histone deacetylase 5 Human genes 0.000 title claims abstract description 24
- 101000899255 Homo sapiens Histone deacetylase 5 Proteins 0.000 title claims abstract description 24
- 230000001737 promoting effect Effects 0.000 title claims abstract description 13
- 239000012190 activator Substances 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims description 11
- 230000000694 effects Effects 0.000 claims abstract description 16
- 230000035876 healing Effects 0.000 claims abstract description 11
- 150000003384 small molecules Chemical class 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 230000008685 targeting Effects 0.000 claims abstract description 5
- 238000002347 injection Methods 0.000 claims description 13
- 239000007924 injection Substances 0.000 claims description 13
- UBWVTCCKVGOTBG-VYZBTARASA-M [(1R,2S,5R)-5-methyl-2-propan-2-ylcyclohexyl] 2-(2-ethyl-3-methylbenzimidazol-3-ium-1-yl)acetate chloride Chemical compound [Cl-].CCc1n(CC(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)c2ccccc2[n+]1C UBWVTCCKVGOTBG-VYZBTARASA-M 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 102000003964 Histone deacetylase Human genes 0.000 claims description 3
- 108090000353 Histone deacetylase Proteins 0.000 claims description 3
- 230000004913 activation Effects 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000003213 activating effect Effects 0.000 abstract 1
- 206010052428 Wound Diseases 0.000 description 23
- 208000027418 Wounds and injury Diseases 0.000 description 23
- 238000000034 method Methods 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 9
- 230000007547 defect Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 208000002847 Surgical Wound Diseases 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000001952 enzyme assay Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- -1 small molecule compound Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000009168 stem cell therapy Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 210000001126 granulation tissue Anatomy 0.000 description 1
- 230000036074 healthy skin Effects 0.000 description 1
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- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
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- 238000013508 migration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000002660 stem cell treatment Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
Abstract
The invention discloses an application of an HDAC5 activator Gbox in preparing a medicament for promoting skin wound healing, wherein the Gbox has a chemical formula C 22 H 33 ClN 2 O 2 The chemical structural formula is shown in formula 1. The invention provides a medicine which can be used as HDAC5 activator to promote skin wound healing, in particular to a small molecule medicine which takes the Gbox as an active ingredient. The invention achieves the effect of promoting the healing of the skin wound surface by targeting and activating the HDAC5 through the Gbox, has high safety and stable medicine, can treat the skin wound surface with large area, has low synthesis cost, provides a new way for clinically treating the skin wound surface healing, and has important clinical application value.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to application of an HDAC5 activator Gbox in preparation of a medicine for promoting skin wound healing.
Background
Trauma, the first disease of global morbidity and teratogenicity, accounts for 12% of all diseases. Among the lesions caused by wounds, skin wounds are the most common, with new cases over ten million per year. When the skin defect is too large, the wound infection is serious or the basic condition of the patient is poor, the wound is difficult to heal, and the living quality of the individual patient and the national medical expense are greatly influenced. In the united states alone, refractory wounds require approximately $ 500 million healthcare costs per year, with surgical incisions and wounds resulting in refractory wounds of approximately $ 120 hundred million and burns resulting in refractory wounds of approximately $ 75.
At present, various methods for promoting the healing of skin wound surfaces exist, but the methods have obvious limitations, and the main methods are as follows: 1. wound surface covering wet dressing: only provides a closed wet environment for the wound surface, is beneficial to wound surface healing, but cannot directly activate the proliferation, migration and other capacities of wound surface cells to accelerate the healing process, and has limited effect. 2. Negative pressure sealing drainage: the method indirectly provides good environment for wound healing, but does not directly promote wound growth, has limited clinical curative effect and inaccurate treatment target spot. 3. Growth factors/cytokines: can promote granulation tissue proliferation to a certain extent, thereby accelerating wound healing, but the growth factors/cytokines belong to biological products, are easy to generate safety problems such as allergy and the like, have unstable activity, are easy to inactivate and limit clinical application. 4. Surgical treatment: skin grafting/skin flap grafting is carried out by cutting off the wound surface, and cutting healthy skin from other parts of the patient to cover the wound surface, so that the treatment process of the method is very painful, can cause damage to the skin supply area and leave large-area scars, and cannot be suitable for patients with large-area skin wound surfaces. 5. Stem cell treatment: is an emerging treatment technology, but has the risk of generating tumors and poor safety. In conclusion, the common methods such as wet dressing and negative pressure closed drainage all indirectly promote the healing by providing good environment for the wound healing, but can not directly promote the wound growth, and the growth factors, cytokines, stem cell therapies and the like are all biological products, have poor safety and stability, have higher preparation cost and limit the clinical application of the biological products. Thus, there is currently a lack of convenient and effective methods for promoting healing of skin wounds.
Egg groupThe white deacetylase 5 (HDAC 5) plays an important role in the skin wound healing process, the reduction of the activity of the HDAC5 can cause the blockage of the wound healing process and the delay of wound healing, and if an effective drug can be found to target and activate the HDAC5, a new accurate and effective clinical treatment method can be possibly provided for promoting the skin wound healing. Gbox is a small molecule compound of formula C 22 H 33 ClN 2 O 2 The molecular weight 392.97 is shown in the formula 1, is a lipophilic molecule and has low solubility in water. Gbox is an oxidative phosphorylation inhibitor in cancer cells, can inhibit the activity of F0F1 ATP synthase, can specifically inhibit the growth of primary mice and human glioblastoma cells, but does not affect mouse embryo fibroblasts or neonatal astrocytes, and has not been reported about the effect of Gbox on promoting the healing of skin wound surfaces at present.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide the application of the HDAC5 activator Gbox in preparing the medicine for promoting the healing of the skin wound, and researches show that the Gbox can activate the HDAC5 activity so as to promote the healing of the skin wound.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides an application of an HDAC5 activator Gbox in preparing a medicament for promoting skin wound healing, wherein the chemical formula of the Gbox is C 22 H 33 ClN 2 O 2 The chemical structural formula is
Preferably, the agent comprises a targeting agent that targets HDAC 5.
Preferably, gboxin acts as an HDAC5 activator to promote skin wound healing by targeted activation of HDAC5 activity.
Preferably, the dosage form of the medicine comprises tablets, powder, granules, capsules, oral liquid, injection or sustained release agent.
Preferably, the promotion of skin wound healing means that the skin wound formed by treatment is completely healed or the area of the skin wound is reduced.
The invention also provides a small molecule injection preparation, which takes the Gbox as an active ingredient, and the concentration of the Gbox is 1-100 mu M.
Preferably, the small molecule injection preparation takes the Gbox as the only active ingredient and also comprises pharmaceutically acceptable auxiliary materials or auxiliary ingredients, wherein the concentration of the Gbox is 1-100 mu M.
The invention provides a medicine which can be used as HDAC5 activator to promote skin wound healing, in particular to a small molecule medicine which takes the Gbox as an active ingredient. Compared with the prior art, the invention has the beneficial effects that:
(1) HDAC5 is activated through Gbox targeting, so that the effect of promoting skin wound healing is achieved.
(2) Compared with stem cell therapy, the medicine provided by the invention has the advantages of definite therapeutic target, high safety, stable medicine and the like, and effectively avoids the defects of poor safety, possibility of tumor generation and the like.
(3) Compared with the operation treatment, the medicine can treat a large-area skin wound surface, and effectively avoids the defects of small treatment range, damage to the skin supply area, large-area scar left and the like.
(4) Compared with the wound surface covered wet dressing and negative pressure closed drainage, the medicine provided by the invention effectively avoids the defects of no definite treatment target, low efficiency, poor effectiveness and the like.
(5) Compared with growth factors/cytokines, the invention can overcome the defects of easy allergy generation, poor safety of biological products, unstable activity, easy inactivation and the like.
(6) Compared with the existing medicines, the preparation has obvious advantages in cost, low synthesis cost, provides a new potential way for clinically treating skin wound healing, and has important clinical application value.
Drawings
FIG. 1 shows the results of in vitro enzyme activity assays for the activation of HDAC5 deacetylase by Gbox in the examples.
Fig. 2 is a graph showing wound healing of different groups of mice recorded on days 0, 3, 7, 10 and 14 after the establishment of the wound healing model in the example.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present invention fall within the protection scope of the present invention.
Example 1
1. Experimental materials
Gbox (CAS 2101315-36-8) is available from Shanghai Sieve Jie biomedical Co.
Gbox is a small molecule compound with a chemical formula of C 22 H 33 ClN 2 O 2 Molecular weight is 392.97, and structural formula isAfter being injected into wound surface edge tissues, the hydrophilic tissue is not easy to absorb and diffuse into capillaries to enter body circulation due to good fat solubility, so that the effect of local action can be achieved, and the hydrophilic tissue can not act on other tissues and organs except skin wound surface tissues.
2. Experimental method
2.1HDAC5 Activity assay
In each assay well, 5 μl HDAC5 substrate (20 μΜ), 5 μl bovine serum albumin (1 μg/mL), 30 μl HDAC5 buffer are mixed. 5. Mu.L of diluted HDAC5 (0.6 ng/. Mu.L) and 5. Mu.L of a Gbox drug solution were added to the Gbox assay wells; the control wells were incubated with 10. Mu.L of buffer for 30 min at 37℃and 50. Mu.L of HDAC5 dye per well for 15 min at room temperature, and fluorescence with excitation wavelength of 360nm and emission wavelength of 450nm was measured.
2.2 establishment of wound healing model of mice
The wound healing model is described in the prior art (The mouse excisional wound splinting model, including applications for stem cell transformation. Nature protocol.2013;8 (2): 302-9.). Briefly, 12 week old C57/BL6 mice were anesthetized and dorsal skin prepared. A full-thickness excision wound surface of the skin with the diameter of 8 mm is manufactured at the midline position of the back, and a meat membrane is cut off. The ring-shaped clamping plates made of the silica gel material are fixed on the skin around the wound surface by ring-stitching through 4-0 silk threads, so that the wound surface is prevented from being closed due to skin shrinkage. Mice were photographed and recorded immediately after surgery, day 3, 7, 10, 14, and the wound area was counted using ImageJ.
2.3 Gbocin injection
On the day when the establishment of the small wound healing model begins, the injection of the Gbox injection is started and is injected subcutaneously around the wound, and the injection is randomly divided into two groups of mice, namely a control group (solvent group) and an experimental group (Gbox administration group), and 6 mice are in each group. Every other day, 8 points around each wound were injected, each point was injected with 10 μl of drug or control solvent, and 10 μl of NanoFil mini-syringe (World Precision Instruments) was connected with a 34 gauge needle (World Precision Instruments, saraota, FL) for injection until the material was obtained, and the concentration of Gboxin in the injection was 100 μm.
3. Experimental results
3.1Gbox activates HDAC5 deacetylase Activity
In vitro enzyme activity assays showed that Gboxin significantly activated HDAC5 deacetylase activity (P < 0.001) (fig. 1).
3.2Gbox can promote skin wound healing
The wound healing conditions of different groups of mice recorded by photographing on days 0, 3, 7, 10 and 14 after the wound healing model is established show that the wound areas of the mice injected with the Gbox treatment group on days 7, 10 and 14 are obviously reduced (P is less than 0.001) compared with the control group (figure 2).
The foregoing is illustrative of a preferred embodiment of the present invention, but the present invention should not be limited to the disclosure of this embodiment. So that equivalents and modifications will fall within the scope of the invention, all within the spirit and scope of the invention as disclosed.
Claims (7)
- Application of Gbox in preparation of medicine for promoting skin wound healingIn the way, the chemical formula of Gbox is C 22 H 33 ClN 2 O 2 The chemical structural formula is
- 2. The use according to claim 1, wherein the medicament comprises a targeting medicament targeting HDAC 5.
- 3. The use according to claim 2, wherein Gboxin acts as an HDAC5 activator to promote skin wound healing by targeted activation of HDAC5 activity.
- 4. The use according to claim 1, wherein the dosage form of the medicament comprises a tablet, powder, granule, capsule, oral liquid, injection or sustained release agent.
- 5. The use according to claim 1, wherein the promotion of skin wound healing means complete healing of skin wound formed by disease treatment or reduction of the area of skin wound.
- 6. A small molecule injection preparation is characterized in that Gbox is taken as an active ingredient, and the concentration of the Gbox is 1-100 mu M.
- 7. The small molecule injection preparation of claim 6, wherein the small molecule injection preparation uses Gboxin as the only active ingredient, and further comprises pharmaceutically acceptable auxiliary materials or auxiliary ingredients, wherein the concentration of the Gboxin is 1-100 μm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311017211.1A CN116999434A (en) | 2023-08-14 | 2023-08-14 | Application of HDAC5 activator Gbox in preparation of medicine for promoting skin wound healing |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311017211.1A CN116999434A (en) | 2023-08-14 | 2023-08-14 | Application of HDAC5 activator Gbox in preparation of medicine for promoting skin wound healing |
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| Publication Number | Publication Date |
|---|---|
| CN116999434A true CN116999434A (en) | 2023-11-07 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311017211.1A Pending CN116999434A (en) | 2023-08-14 | 2023-08-14 | Application of HDAC5 activator Gbox in preparation of medicine for promoting skin wound healing |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116999434A (en) |
-
2023
- 2023-08-14 CN CN202311017211.1A patent/CN116999434A/en active Pending
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