CN116808045A - Use of HDAC5 activator VLX600 in preparation of medicine for promoting skin wound healing - Google Patents
Use of HDAC5 activator VLX600 in preparation of medicine for promoting skin wound healing Download PDFInfo
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- CN116808045A CN116808045A CN202311017206.0A CN202311017206A CN116808045A CN 116808045 A CN116808045 A CN 116808045A CN 202311017206 A CN202311017206 A CN 202311017206A CN 116808045 A CN116808045 A CN 116808045A
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- UQOSBPRTQFFUOA-SRZZPIQSSA-N 6-methyl-n-[(e)-1-pyridin-2-ylethylideneamino]-5h-[1,2,4]triazino[5,6-b]indol-3-amine Chemical compound N=1N=C(C2=CC=CC(C)=C2N2)C2=NC=1N\N=C(/C)C1=CC=CC=N1 UQOSBPRTQFFUOA-SRZZPIQSSA-N 0.000 title claims abstract description 38
- 206010072170 Skin wound Diseases 0.000 title claims abstract description 34
- 230000029663 wound healing Effects 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 25
- 102100021453 Histone deacetylase 5 Human genes 0.000 title claims abstract description 21
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- UQOSBPRTQFFUOA-NHDPSOOVSA-N 6-methyl-n-[(z)-1-pyridin-2-ylethylideneamino]-5h-[1,2,4]triazino[5,6-b]indol-3-amine Chemical compound N=1N=C(C2=CC=CC(C)=C2N2)C2=NC=1N/N=C(/C)C1=CC=CC=N1 UQOSBPRTQFFUOA-NHDPSOOVSA-N 0.000 description 1
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Abstract
The invention discloses an application of an HDAC5 activator VLX600 in preparing a medicament for promoting skin wound healing, wherein the chemical formula of the VLX600 is C 17 H 15 N 7 The structural formula is shown in formula 1. The invention provides a medicine for promoting skin wound healing by taking VLX600 as an HDAC5 activator, in particular to a small molecule medicine taking VLX600 as an active ingredient. The invention achieves the effect of promoting the healing of the skin wound surface by activating the HDAC5 through the targeting of the VLX600, 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 an application of an HDAC5 activator VLX600 in preparing 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.
Histone deacetylase 5 (HDAC 5) inPlays an important role in the skin wound healing process, the reduction of the HDAC5 activity 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. VLX600 is a small molecule compound of formula C 17 H 15 N 7 The molecular weight 317.36 is shown in formula 1, and is a fat-soluble molecule and is insoluble in water. VLX600 is an iron chelate inhibitor of oxidative phosphorylation, can cause mitochondrial dysfunction in cells, exhibits selective cytotoxic activity against malignant cells, and has anticancer activity. However, no report has been made on the effect of VLX600 in promoting skin wound healing.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the application of the VLX600 serving as the HDAC5 activator in preparing medicaments for promoting the healing of skin wounds, and the VLX600 can activate the activity of the HDAC5, so that the healing of the skin wounds is promoted, the problems that the conventional wet dressing, negative pressure closed drainage and other methods can not directly promote the growth of the wounds, but biological products such as growth factors, cytokines, stem cell therapies and the like are poor in safety and stability are solved, and a novel way for promoting the healing of the skin wounds is provided.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides an application of VLX600 in preparing a medicament for promoting skin wound healing, wherein the chemical formula of VLX600 is C 17 H 15 N 7 The structural formula is
Preferably, the agent comprises a targeting agent that targets HDAC 5.
Preferably, VLX600 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 VLX600 as an active ingredient, and the concentration of the small molecule injection preparation is 1-100 mu M.
Preferably, the small molecule injection preparation takes VLX600 as the only active ingredient, and also comprises pharmaceutically acceptable auxiliary materials or auxiliary ingredients, wherein the concentration of the VLX600 is 1-100 mu M.
The invention provides a medicine for promoting skin wound healing by taking VLX600 as an HDAC5 activator, in particular to a small molecule medicine taking VLX600 as an active ingredient. Compared with the prior art, the invention has the beneficial effects that:
(1) HDAC5 is activated through VLX600 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 an in vitro enzyme activity assay for VLX600 activating HDAC5 deacetylase activity 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
VLX600 (CAS 327031-55-0) was purchased from Shanghai Sieve Jie biomedical Co., ltd. VLX600 is a small molecule compound of the formula C 17 H 15 N 7 Molecular weight is 317.36, and structural formula isAfter being injected into wound surface edge tissues, the hydrophilic tissue can not absorb and diffuse to 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 tissue organs except skin wound surface tissues.
2. Experimental method
2.1HDAC5 Activity assay
In each assay well, 5. Mu.L of HDAC5 substrate (20. Mu.M), 5. Mu.L of bovine serum albumin (1. Mu.g/mL), 30. Mu.L of LHDAC5 buffer were mixed. Add 5. Mu.L of diluted HDAC5 (0.6 ng/. Mu.L) and 5. Mu.L of VLX600 drug solution to VLX600 assay wells; the control wells were incubated with 10. Mu.L of buffer for 30 min at 37℃and 50. Mu.L of LHDAC5 developer 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.
2.3VLX600 injection
On the day when the establishment of the small wound healing model begins, the VLX600 injection is started and injected subcutaneously around the wound, and the mice are randomly divided into a control group (solvent group) and an experimental group (VLX 600 administration group), and 6 mice are in each group. Every other day, 8 points around each wound surface are injected, each point is injected with 10 mu L of medicine or control solvent, and is injected by connecting a 34-gauge needle (World Precision Instruments, saraota, FL) with a 10 mu L NanoFil micro-injector (World Precision Instruments) until the materials are obtained, and the concentration of VLX600 in the injection is 100 mu M.
3. Experimental results
3.1VLX600 can activate HDAC5 deacetylase Activity
In vitro enzyme activity assays showed that VLX600 significantly activated HDAC5 deacetylase activity (P < 0.001) (fig. 1).
3.2VLX600 it 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 area of the mice injected with VLX600 treatment groups on days 7, 10 and 14 is obviously reduced (P < 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)
- VLX600 in preparation promotionUse of VLX600 with chemical formula of C in medicine for healing skin wound 17 H 15 N 7 The 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 VLX600 as HDAC5 activator promotes 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 characterized in that VLX600 is used as an active ingredient, and the concentration of the small molecule injection preparation is 1-100 mu M.
- 7. The small molecule injection formulation of claim 6, wherein the small molecule injection formulation comprises VLX600 as the only active ingredient, and further comprises pharmaceutically acceptable excipients or auxiliary ingredients, wherein the concentration of VLX600 is 1-100 μm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311017206.0A CN116808045A (en) | 2023-08-14 | 2023-08-14 | Use of HDAC5 activator VLX600 in preparation of medicine for promoting skin wound healing |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311017206.0A CN116808045A (en) | 2023-08-14 | 2023-08-14 | Use of HDAC5 activator VLX600 in preparation of medicine for promoting skin wound healing |
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| Publication Number | Publication Date |
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| CN116808045A true CN116808045A (en) | 2023-09-29 |
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|---|---|---|---|
| CN202311017206.0A Pending CN116808045A (en) | 2023-08-14 | 2023-08-14 | Use of HDAC5 activator VLX600 in preparation of medicine for promoting skin wound healing |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116808045A (en) |
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2023
- 2023-08-14 CN CN202311017206.0A patent/CN116808045A/en active Pending
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