Use of hdac5 activator gboxin in the preparation of a medicament for promoting skin wound healing

Abstract

This invention discloses the use of the HDAC5 activator Gboxin in the preparation of drugs that promote skin wound healing. The chemical formula of Gboxin is C... 22 H 33 ClN2O2, with the chemical structure shown in Formula 1. This invention proposes that Gboxin can be used as an HDAC5 activator to prepare drugs that promote skin wound healing, especially small molecule drugs with Gboxin as the active ingredient. This invention achieves the effect of promoting skin wound healing by targeting and activating HDAC5 with Gboxin. It has high safety, drug stability, can treat large-area skin wounds, and has low synthesis cost, providing a new approach for clinical treatment of skin wound healing and has important clinical application value.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, and specifically relates to the use of the HDAC5 activator Gboxin in the preparation of drugs that promote skin wound healing. Background Technology

[0002] Trauma is the leading cause of disease incidence and disability worldwide, accounting for 12% of all diseases. Among trauma-related injuries, skin wounds are the most common, with over ten million new cases each year. When skin defects are excessive, wound infections are severe, or the patient's underlying condition is poor, wounds often fail to heal, significantly impacting individual patients' quality of life and national healthcare expenditures. In the United States alone, intractable wounds cost approximately $50 billion annually in healthcare, with surgical incisions and traumatic injuries accounting for nearly $12 billion and burns accounting for nearly $7.5 billion.

[0003] Currently, there are various methods to promote skin wound healing, but all have significant limitations. The main methods include: 1. Covering the wound with moist dressings: This only provides a closed, moist environment to the wound, which is beneficial for wound healing, but it cannot directly activate the proliferation and migration of wound cells to accelerate the healing process, thus its effect is limited. 2. Negative pressure wound therapy: This method uses intermittent or continuous negative pressure suction to drain liquefied necrotic tissue from the wound, achieving the purpose of removing necrotic tissue and accelerating wound healing. This method indirectly provides a good environment for wound healing, but it does not directly promote wound growth, resulting in limited clinical efficacy, and the treatment target is not precise. 3. Growth factors / cytokines: These can promote granulation tissue proliferation to a certain extent, thereby accelerating wound healing. However, growth factors / cytokines are biological products, which can easily cause safety issues such as allergies, and their activity is unstable and easily inactivated, limiting their clinical application. 4. Surgical Treatment: Skin grafting / flap transplantation involves excising the wound and harvesting healthy skin from other areas of the patient to cover it. This method is extremely painful and can cause damage to the donor site and leave large areas of scarring. It is also unsuitable for patients with large skin wounds. 5. Stem Cell Therapy: This is an emerging treatment technology, but it carries the risk of tumor formation and has a poor safety profile. In summary, commonly used methods such as moist dressings and negative pressure wound therapy indirectly promote healing by providing a favorable environment for wound healing, but they do not directly promote wound growth. Growth factors, cytokines, and stem cell therapies are all biological products with poor safety and stability, and high production costs, limiting their clinical application. Therefore, there is currently a lack of convenient and effective methods to promote skin wound healing.

[0004] Histone deacetylase 5 (HDAC5) plays a crucial role in skin wound healing. Decreased HDAC5 activity can hinder wound healing and delay its progression. Finding effective drugs to target and activate HDAC5 could potentially provide a precise and effective new clinical treatment for promoting skin wound healing. Gboxin is a small molecule compound with the chemical formula C0. 22 H 33 ClN2O2, with a molecular weight of 392.97 and a structural formula as shown in Formula 1, is a lipophilic molecule with low solubility in water. Gboxin is an inhibitor of oxidative phosphorylation in cancer cells, which can inhibit the activity of F0F1 ATP synthase. It can specifically inhibit the growth of primary mouse and human glioblastoma cells without affecting mouse embryonic fibroblasts or neonatal astrocytes. Currently, there are no reports on the role of Gboxin in promoting skin wound healing. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the purpose of this invention is to provide the use of the HDAC5 activator Gboxin in the preparation of drugs that promote skin wound healing. Studies have found that Gboxin can activate HDAC5 activity, thereby promoting skin wound healing.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] This invention provides the use of the HDAC5 activator Gboxin in the preparation of a drug that promotes skin wound healing. The chemical formula of Gboxin is C0. 22 H 33 ClN2O2, chemical structural formula is

[0008] Preferably, the drug includes a targeted drug that targets HDAC5.

[0009] As a preferred option, Gboxin, as an HDAC5 activator, promotes skin wound healing by targeting and activating HDAC5 activity.

[0010] Preferably, the dosage form of the drug includes tablets, powders, granules, capsules, oral liquids, injections, or sustained-release formulations.

[0011] Preferably, promoting skin wound healing means that the skin wound formed by the treatment is completely healed or the area of ​​the skin wound is reduced.

[0012] The present invention also provides a small molecule injectable formulation with Gboxin as the active ingredient at a concentration of 1-100 μM.

[0013] Preferably, the small molecule injectable formulation uses Gboxin as the sole active ingredient and also includes pharmaceutically acceptable excipients or auxiliary ingredients, wherein the concentration of Gboxin is 1-100 μM.

[0014] This invention proposes that Gboxin can be used as an HDAC5 activator in the preparation of drugs that promote skin wound healing, particularly small molecule drugs with Gboxin as the active ingredient. Compared with the prior art, the advantages of this invention are:

[0015] (1) By targeting and activating HDAC5 through Gboxin, the skin wound healing effect is promoted.

[0016] (2) Compared with stem cell therapy, the drug of the present invention has a clear therapeutic target, high safety, stable drug, and effectively avoids the disadvantages of poor safety and possible tumor formation.

[0017] (3) Compared with surgical treatment, the drug of the present invention can treat large areas of skin wounds, effectively avoiding the defects such as small treatment range, damage to the donor site and large area of ​​scarring.

[0018] (4) Compared with wound covering with wet dressings and negative pressure closure drainage, the drug of the present invention effectively avoids the disadvantages of no clear treatment target, low efficiency and poor effectiveness.

[0019] (5) Compared with growth factors / cytokines, the present invention can overcome the disadvantages of easy allergic reactions, poor safety of biological products, and unstable activity that is easy to be inactivated.

[0020] (6) It has a significant cost advantage over existing drugs, with lower synthesis costs, providing a new potential approach for clinical treatment of skin wound healing and has important clinical application value. Attached Figure Description

[0021] Figure 1 The results of in vitro enzyme activity detection for Gboxin-activated HDAC5 deacetylase activity in the examples are shown.

[0022] Figure 2 The images show the wound healing status of different groups of mice on days 0, 3, 7, 10, and 14 after the wound healing model was established in this example. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the described embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] Example 1

[0025] 1. Experimental Materials

[0026] Gboxin (CAS2101315-36-8) was purchased from Shanghai Shaijie Biomedical Co., Ltd.

[0027] Gboxin is a small molecule compound with the chemical formula C0. 22 H 33 ClN2O2, with a molecular weight of 392.97, has the following structural formula: After being injected into the wound edge tissue, due to its good lipid solubility, it is not easily absorbed by hydrophilic tissues and diffuses into the capillaries to enter the systemic circulation, thus achieving a local effect without affecting other tissues and organs other than the skin wound tissue.

[0028] 2. Experimental Methods

[0029] 2.1 HDAC5 Activity Assay

[0030] In each well, mix 5 μL of HDAC5 substrate (20 μM), 5 μL of bovine serum albumin (1 μg / mL), and 30 μL of HDAC5 buffer. Add 5 μL of diluted HDAC5 (0.6 ng / μL) and 5 μL of Gboxin drug solution to each Gboxin well; add 10 μL of buffer to each control well to complete the reaction. Incubate at 37°C for 30 minutes. After incubation, add 50 μL of HDAC5 chromogenic reagent to each well and incubate at room temperature for 15 minutes. Measure fluorescence at an excitation wavelength of 360 nm and an emission wavelength of 450 nm.

[0031] 2.2 Establishment of a mouse wound healing model

[0032] The wound healing model was based on previous literature (The mouse excisional wound splinting model, including applications for stem cell transplantation. Nature Protocol. 2013; 8(2):302-9.). In short, 12-week-old C57 / BL6 mice were anesthetized, and their backs were prepared. An 8 mm diameter full-thickness skin excision wound was created along the midline of the back, and the dartos fascia was removed. A silicone ring splint was sutured and fixed to the skin around the wound using 4-0 silk sutures to prevent skin contraction and wound closure. Mice were photographed immediately after surgery and on days 3, 7, 10, and 14. The wound area was statistically analyzed using ImageJ.

[0033] 2.3Gboxin injection

[0034] On the day the small wound healing model was established, Gboxin injections were started, injected subcutaneously around the wound. Mice were randomly divided into a control group (solvent group) and an experimental group (Gboxin administration group), with 6 mice in each group. Injections were given every other day, at 8 points around each wound. 10 μL of the drug or control solvent was injected at each point. A 34-gauge needle (WorldPrecision Instruments, Sarasota, FL) was used to connect to a 10 μL NanoFil micro-injector (World Precision Instruments) for injection. Injections continued until tissue samples were collected. The concentration of Gboxin in the injection solution was 100 μM.

[0035] 3. Experimental Results

[0036] 3.1Gboxin can activate HDAC5 deacetylase activity.

[0037] In vitro enzyme activity assays showed that Gboxin significantly activated HDAC5 deacetylase activity (P < 0.001). Figure 1 ).

[0038] 3.2Gboxin can promote skin wound healing.

[0039] Wound healing in mice of different groups was recorded by photograph on days 0, 3, 7, 10, and 14 after the establishment of the wound healing model. The results showed that the wound area in the Gboxin-treated group was significantly smaller than that in the control group on days 7, 10, and 14 (P < 0.001). Figure 2 ).

[0040] The above description is merely a preferred embodiment of the present invention, but the present invention should not be limited to the content disclosed in this embodiment. Therefore, any equivalent or modified versions made without departing from the spirit of the present invention fall within the scope of protection of the present invention.

Claims

1. The use of Gboxin in the preparation of drugs that promote skin wound healing. The chemical formula of Gboxin is C0. 22 H 33 CIN2O2, chemical structural formula is .

2. The use according to claim 1, characterized in that, The drugs include targeted drugs that target HDAC5.

3. The use according to claim 2, characterized in that, Gboxin, as an HDAC5 activator, promotes skin wound healing by targeting and activating HDAC5 activity.

4. The use according to claim 1, characterized in that, The dosage forms of the drug include tablets, powders, granules, capsules, oral liquids, or injections.

5. The use according to claim 1, characterized in that, Promoting skin wound healing refers to the complete healing of skin wounds caused by disease treatment or the reduction of the area of ​​skin wounds.

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