Application of USP9X as target spot in preparation of medicine for treating psoriasis

Abstract

The invention discloses application of USP9X serving as a target spot in preparation of a medicine for treating psoriasis, relates to the field of biological medicine, and particularly relates to application of a USP9X inhibitor in preparation of a medicine for treating psoriasis, back inflammation of IMQ-induced psoriasis-like mice treated by the USP9X inhibitor WP1130 is obviously relieved, erythema, scale and skin thickness are reduced, and the psoriasis-like mice are obviously prevented from suffering from psoriasis caused by the IMQ-induced psoriasis-like mice treated by the USP9X inhibitor WP1130. The PASI score is obviously reduced, and a foundation can be laid for research and development of psoriasis targeted therapeutic drugs in future.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to the use of USP9X as a target in the preparation of drugs for treating psoriasis. Background Art

[0002] Psoriasis is a common chronic inflammatory skin disease in dermatology. It is a chronic, recurrent, inflammatory, systemic immune-mediated disease driven by both genetic and environmental factors. The pathogenesis of psoriasis is primarily related to abnormal T cell-mediated immune responses, particularly Th17 cells and the cytokines they secrete (such as IL-17 and IL-23), which play a central role in the pathogenesis of psoriasis.

[0003] Specifically, the pathogenesis of psoriasis is mainly related to abnormal T cell-mediated immune responses, especially Th17 cells and the cytokines they secrete (such as IL-17, IL-23, etc.), which play a core role in the pathogenesis of psoriasis. Current treatments mainly include topical treatments (such as glucocorticoids, vitamin D3 analogs, etc.) and systemic treatments (such as biological agents, immunosuppressants, etc.). However, these treatments have certain limitations, such as the limited effect of local treatments and the possible serious side effects of systemic treatments. Although there is a certain understanding of the immune pathogenesis of psoriasis, it involves the interaction of multiple immune cells and cytokines, and the specific molecular mechanisms have not been fully elucidated. In addition, existing treatments still have certain limitations in controlling the disease and alleviating symptoms, and cannot achieve the desired therapeutic effect. Therefore, research needs to focus on in-depth analysis of the disease mechanism and the development of more accurate and safer treatment strategies to improve treatment efficacy and improve the quality of life of patients. Summary of the Invention

[0004] In response to the above problems, the present invention provides a new target and drug for treating psoriasis to alleviate the inflammatory manifestations of psoriasis.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention discloses the use of USP9X as a target in the development, screening and / or preparation of drugs for treating psoriasis.

[0007] On this basis, the present invention discloses the use of USP9X inhibitors in the preparation of drugs for treating psoriasis.

[0008] Furthermore, the USP9X inhibitor is at least one of a monoclonal antibody, a small molecule compound or a nucleic acid inhibitor that specifically inhibits the activity of USP9X.

[0009] Furthermore, the USP9X inhibitor is WP1130.

[0010] Furthermore, the drug also includes pharmaceutically acceptable excipients.

[0011] Furthermore, the drug can be prepared into any one of injection, patch, powder, tablet, capsule, gel or ointment.

[0012] Beneficial effects:

[0013] The deubiquitinating enzyme USP9X can be used as a therapeutic target for psoriasis. After inhibition by WP1130, an inhibitor that can inhibit the activity of the deubiquitinating enzyme USP9X, the inflammation on the back of mice was significantly alleviated, manifested as a reduction in erythema, scales and skin thickness, and a significant decrease in the PASI score. This shows that the WP1130 inhibitor has positive therapeutic significance for psoriasis and can lay the foundation for the future development of targeted psoriasis treatment drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 : PASI score and back images of IMQ mice after WP1130 treatment;

[0015] Figure 2 : qRT-PCR detection of downstream inflammatory factors after WP1130 treatment in IMQ mice. DETAILED DESCRIPTION

[0016] The present invention will be described in detail below with reference to specific embodiments and accompanying drawings:

[0017] Example 1: Therapeutic effect of WP1130 on psoriasis

[0018] 1. Drug preparation:

[0019] WP1130 was purchased from MCE (HY-13264) and dissolved in 10% DMSO + 90% corn oil to prepare a drug solution with a WP1130 concentration of 20 mg / mL.

[0020] 2. Animal model construction

[0021] The experiments used C57BL / 6 mice, approximately 8 weeks old, purchased from the Experimental Animal Center of the Air Force Medical University and housed in an SPF-grade barrier environment. An imiquimod (IMQ)-induced psoriasis mouse model was established by applying 5% imiquimod cream to the back of the C57BL / 6 mice once daily in the morning for six consecutive days.

[0022] 3. Drug treatment

[0023] Experimental group: Starting from the first day of applying imiquimod ointment, imiquimod cream was applied in the morning and the inhibitor WP1130 was injected intraperitoneally in the afternoon. The mice were intraperitoneally injected with a drug dose of 20 mg / kg and the treatment lasted for 6 consecutive days.

[0024] Control group: Apply equal amount of 10% DMSO + 90% corn oil solution, with the same dosage and frequency as before.

[0025] Observation indicators: Photos were collected to observe the inflammatory phenotypes of mouse skin, such as erythema and scaling, and the degree of inflammation of IMQ-induced psoriasis-like mouse skin lesions was analyzed by psoriasis area and severity index (PASI score). The results were as follows: Figure 1 shown.

[0026] analyze Figure 1 The results show that:

[0027] After treatment with the USP9X inhibitor WP1130, the dandruff on the back of mice was reduced and the erythema was alleviated. According to the results of the PASI standard (Psoriasis Area and Severity Index), treatment with WP1130 can effectively improve the symptoms of psoriasis.

[0028] Example 2:

[0029] The skin lesions of the mice in each group in Example 1 were cut into pieces and lysed with TRIzol at -20°C. RNA was extracted from tissues and cells using the phenol-chloroform combined extraction method. RNA was quantified and reverse transcription kit PrimeScript was used. TM RTreagent Kit reversed into cDNA. According to the quantitative PCR kit TB Premix Ex Taq TM Instructions: Prepare the PCR reaction solution in a PCR tube and perform qRT-PCR experiment on CFX384 Real-Time PCR Detection System. Export the data and perform relative quantitative analysis (such as 2^-ΔΔCt method) using GraphPad Prism statistical software to evaluate the expression differences of key genes of proliferation and inflammation in the epidermis of mouse lesions. The results are as follows: Figure 2 shown.

[0030] analyze Figure 2 The results show that:

[0031] qRT-PCR results showed that the mRNA expressions of proliferation (K16, K17, PCNA), glycolysis (GLUT1, HIF-1a, HK2), inflammatory factors (IL-23a, IL-17, IL-1a), chemokines (CXCL1, CCL20) and antimicrobial peptides (S100A8, S100A9) molecules related to psoriasis were significantly decreased compared with those in IMQ-induced psoriasis-like mice ( Figure 2 A, B). This suggests that the WP1130 inhibitor, which inhibits the activity of the deubiquitinating enzyme USP9X, can significantly reduce the expression of inflammatory factors in psoriasis cell models, effectively alleviate skin inflammation in psoriasis-like mouse models, and inhibit epidermal hyperplasia, thereby improving the psoriasis-like phenotype. These findings suggest that the WP1130 inhibitor has positive therapeutic implications for psoriasis and could lay the foundation for the future development of targeted psoriasis treatments.

[0032] The above embodiments are intended only to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art will appreciate that the technical solutions of the present invention may be modified or replaced with equivalents without departing from the spirit and scope of the technical solutions of the present invention, and such modifications or equivalents shall be encompassed by the claims of the present invention. Any techniques, shapes, and structures not described in detail herein are well known.

Claims

1. Use of USP9X as a target in the development, screening and / or preparation of drugs for the treatment of psoriasis.

2. Application of USP9X inhibitors in the preparation of drugs for the treatment of psoriasis.

3. The use according to claim 2, characterized in that The USP9X inhibitor is at least one of a monoclonal antibody, a small molecule compound or a nucleic acid inhibitor that specifically inhibits the activity of USP9X.

4. The use according to claim 3, characterized in that The USP9X inhibitor is WP1130.

5. The use according to any one of claims 2 to 4, characterized in that: The drug also includes pharmaceutically acceptable excipients.

6. The use according to claim 5, characterized in that The medicine can be prepared into any one of injection, patch, powder, tablet, capsule, gel or ointment.

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