Application of TRPML1 specific small-molecule inhibitor ML-SI3

Abstract

The invention provides an application of a TRPML1 specific small-molecule inhibitor ML-SI3 in preparation of a medicine for treating or preventing nephritis. The TRPML1 specific small-molecule inhibitor ML-SI3 disclosed by the invention has the beneficial effects that the TRPML1 specific small-molecule inhibitor ML-SI3 disclosed by the invention can be used for remarkably reducing the titer level of an anti-dsDNA antibody in serum of an MRL / lpr lupus mouse; the urinary albumin / creatinine ratio level is reduced; the serum urea nitrogen level is reduced; the swelling degree of spleen and axillary lymph nodes is relieved; the kidney pathological change is improved; the compound has a comprehensive protection effect on nephritis of MRL / lpr lupus mice; the invention provides the application of the TRPML1 specific small-molecule inhibitor ML-SI3 in preparation of the medicine for treating or preventing nephritis, provides a new medicine for treating lupus nephritis, and has good market value and clinical application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to an application of a TRPML1 specific small molecule inhibitor ML-SI3. Background Art

[0002] Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple systems. Among them, the kidney is one of the most commonly affected organs. Due to advances in treatment, the 5-year survival rate of SLE patients has reached 94%, and the 10-year survival rate has reached 89%, but kidney inflammation caused by SLE is still one of the main causes of death in patients. After active treatment with glucocorticoids, hydroxychloroquine and immunosuppressants, nephritis is relieved and renal function is restored, but a considerable number of patients with lupus nephritis eventually develop end-stage renal disease and die. Therefore, it is still necessary to actively find other effective drugs for lupus nephritis. Summary of the invention

[0003] The present application provides an application of a TRPML1-specific small molecule inhibitor ML-SI3, which aims to solve the problem of kidney inflammation caused by lupus erythematosus in the prior art.

[0004] The present application provides an application of a TRPML1-specific small molecule inhibitor ML-SI3 in the preparation of a drug for treating or preventing nephritis.

[0005] According to some embodiments of the use described in the present application, the nephritis is lupus nephritis.

[0006] According to some embodiments of the application described in this application, the structural formula of the TRPML1-specific small molecule inhibitor ML-SI3 is as shown below:

[0007]

[0008] According to some embodiments of the application described in the present application, in the preparation of drugs for treating or preventing nephritis, the effective dose of the TRPML1-specific small molecule inhibitor ML-SI3 is 2-5 mg / kg, for example, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, etc.

[0009] According to some embodiments of the application described in the present application, in the preparation of a drug for treating or preventing nephritis, the effective dose of the TRPML1-specific small molecule inhibitor ML-SI3 is 3 mg / kg.

[0010] In a second aspect of the present application, a drug for treating lupus nephritis is provided, comprising a pharmaceutically active ingredient and a pharmaceutically acceptable excipient, wherein the pharmaceutically active ingredient comprises a TRPML1-specific small molecule inhibitor ML-SI3.

[0011] According to some embodiments of the drug for treating lupus nephritis described in the present application, the content of the active ingredient in the drug is 2-5 mg / kg, for example, 2 mg / kg, 2.8 mg / kg, 3.2 mg / kg, 3.5 mg / kg, 4.1 mg / kg, 4.6 mg / kg, 5.0 mg / kg, etc.

[0012] According to some embodiments of the drug for treating lupus nephritis described in the present application, the content of the active ingredient in the drug is 3 mg / kg.

[0013] According to some embodiments of the drug for treating lupus nephritis described in the present application, the dosage form of the drug includes injection, tablet, capsule, granule, aerosol or oral liquid.

[0014] The beneficial effects of this application include:

[0015] The TRPML1-specific small molecule inhibitor ML-SI3 described in the present application can significantly reduce the serum anti-dsDNA antibody titer level of MRL / lpr lupus mice; reduce the urine albumin / creatinine ratio level; reduce the serum urea nitrogen level; reduce the swelling of the spleen and axillary lymph nodes; improve kidney pathological changes; and has a comprehensive protective effect on nephritis in MRL / lpr lupus mice.

[0016] The present application provides an application of a TRPML1-specific small molecule inhibitor ML-SI3 in the preparation of a drug for treating or preventing nephritis, providing a new drug for the treatment of lupus nephritis, and having good market value and clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The figure shows the preparation and administration time pattern of MRL / lpr lupus nephritis model mice;

[0018] Figure 2 This is an analysis diagram of the effect of ML-SI3 administration on the serum anti-dsDNA antibody titer level of MRL / lpr lupus mice;

[0019] Figure 3 This is an analysis diagram of the effect of ML-SI3 administration on the urine albumin / creatinine ratio level of MRL / lpr lupus mice;

[0020] Figure 4 This is a diagram analyzing the effect of ML-SI3 administration on serum urea nitrogen levels in MRL / lpr lupus mice;

[0021] Figure 5 This is an analysis of the effect of ML-SI3 administration on the swelling of spleen and axillary lymph nodes in MRL / lpr lupus mice;

[0022] Figure 6 This is the result of H&E and PAS staining to evaluate the pathological changes in mouse kidneys. DETAILED DESCRIPTION

[0023] Embodiments of the present invention are described in detail below, and examples of the embodiments are shown in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to be used to explain the present invention, but should not be understood as limiting the present invention.

[0024] In the present invention, the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0025] The present application provides a new use of a TRPML1-specific small molecule inhibitor ML-SI3, which is used to prepare a drug for treating lupus nephritis. Specifically, when the inhibitor is used to prepare an application for treating lupus nephritis, the inhibitor can significantly reduce the titer level of serum anti-dsDNA antibodies in MRL / lpr lupus mice; reduce urine protein levels; reduce serum urea nitrogen levels; reduce the degree of spleen and lymph node swelling; improve kidney pathological changes, and has a comprehensive protective effect on lupus nephritis in MRL / lpr mice.

[0026] When treating lupus nephritis, the effective dose of the TRPML1 specific small molecule inhibitor ML-SI3 is 2-5 mg / kg, preferably 3 mg / kg.

[0027] Studies have shown that the lysosomal cation channel TRPML1 is a target for regulating the release of cations within lysosomes. The expression of TRPML1 in the kidney tissue of MRL / lpr lupus mice is significantly upregulated, and the expressed TRPML1 channel participates in the pathological process of lupus nephritis by releasing cations in lysosomes. Reducing the activity of the TRPML1 channel by using TRPML1 inhibitors can relieve the fusion barrier between lysosomes and autophagosomes in renal podocytes, thereby relieving the podocyte autophagy barrier and restoring the normal autophagic activity of podocytes. The restored podocyte autophagic activity can improve the podocyte function of the kidneys of MRL / lpr mice, thereby reducing the degree of kidney damage in lupus mice and having a protective effect on lupus nephritis in MRL / lpr mice. The following is a specific small molecule inhibitor of TRPML1 in this application (see its chemical structure). Figure 1 ) Experimental verification of the therapeutic effect of MRL / lpr mice on lupus nephritis.

[0028] 1. Test methods

[0029] Adult female MRL / lpr mice were used as experimental animals. Sixteen 8-10-week-old female lupus-susceptible MRL / lpr mice were selected and divided equally into two groups: ML-SI3 group and Vehicle group. Eight 8-10-week-old adult female MRL / Mpj mice were selected as the normal control group and raised under normal conditions. The weight of the mice was recorded weekly starting from 11 weeks of age. At 12 weeks of age, mice in the ML-SI3 group were intraperitoneally injected with ML-SI3 (0.1 ml per 10 grams of animal body weight, 0.3 mg / ml of ML-SI3), and mice in the Vehicle group were injected with normal saline (0.1 ml per 10 grams of animal body weight) for 6 consecutive weeks. At 18 weeks of age, samples were collected to analyze the effects of ML-SI3 on ​​LN mice - serum anti-dsDNA antibody titer levels were analyzed; urine albumin / creatinine ratio was detected; serum urea nitrogen levels were detected; the length of the mouse axillary lymph nodes and spleen was measured, and the degree of renal lesions was evaluated by PAS or H&E staining of kidney sections. Nephritis in MRL / lpr mice was confirmed by pathology, and MRL / Mpj mice were normal control mice (no nephritis phenotype, raised under normal conditions). Figure 1 As shown:

[0030] Vehicle group: MRL / lpr mice were intraperitoneally injected with normal saline;

[0031] ML-SI3 group: MRL / lpr mice were intraperitoneally administered with ML-SI3.

[0032] MRL / Mpj group: normal control group mice, without nephritis phenotype.

[0033] Figure 1 Figure 1: Diagram of the ML-SI3 intervention model in MRL / lpr lupus mice.

[0034] 2. Effect of ML-SI3 administration on serum anti-dsDNA antibody titer levels in MRL / lpr lupus mice

[0035] 2.1 Measurement method:

[0036] The mice were sampled at 18 weeks of age. The mice were anesthetized, and the whiskers on both sides were trimmed with ophthalmic scissors. The mouse's head was turned downward, and the neck was gently pressed to make the eyeball protrude. The eyeball was removed with curved forceps to obtain venous blood. After blood collection, the blood was immediately placed in a 1.5 mL centrifuge tube and allowed to stand at room temperature (25°C) for 30 minutes. The blood sample was centrifuged at a relative centrifugal force of 14000g for 15 minutes, and the serum was separated by a pipette and transferred to a clean centrifuge tube. The serum sample can be centrifuged at 14000g for another 2 minutes to separate any remaining red blood cells. The separated serum was transferred to a clean centrifuge tube and the level of anti-dsDNA antibodies in the serum was analyzed. All data were statistically analyzed and statistical graphs were made using Graphpad 7.0 software.

[0037] The specific process is as follows: All steps are carried out at room temperature (25°C). Before adding each reagent and starting incubation, the plate should be gently tapped to mix the contents in the well.

[0038] (a) Sample addition: Dilute the mouse serum sample at a ratio of 1:10000. Then add 100ul of the sample diluent (blank control), standard, and diluted sample provided by the mouse anti-double-stranded DNA IgG ELISA kit to the designated wells, tap the plate gently to mix the liquid, and incubate at room temperature (25°C) for 60 minutes. Aspirate the liquid in the well, add 200ul / well of working washing solution, let it stand at room temperature at 25°C for 30 seconds, then discard it, and repeat the washing three times.

[0039] (b) Antibody incubation: Add 100 ul of diluted HRP anti-mouse IgG to each reaction well, incubate at room temperature (25°C) for 30 min, and repeat the above washing steps for 5 times.

[0040] (c) Add substrate for color development: Add 100ul TMB substrate to each reaction well. The liquid in the well will begin to turn blue. Incubate at room temperature (25°C) in the dark for 15 minutes.

[0041] (d) Termination reaction: Add 100ul of termination reaction solution to each reaction well and tap to mix. The enzyme reaction will stop and the liquid in the well will turn yellow.

[0042] (e) Absorbance reading: Within 30 minutes after adding the stop reaction solution, read the OD value of each well at a single wavelength of 450nm and 630nm on an ELISA reader, draw a standard curve, and calculate the sample concentration. The results are as follows: Figure 2 shown.

[0043] from Figure 2 It can be seen that ML-SI3 administration can significantly reduce the serum anti-dsDNA antibody titer level of MRL / lpr lupus mice. The serum anti-dsDNA antibody titer level of MRL / Mpj mice is the normal control mouse.

[0044] 3. Effect of ML-SI3 administration on the urine albumin / creatinine ratio level in MRL / lpr lupus mice

[0045] 3.1 Measurement method

[0046] Sixteen 8-10-week-old female lupus-prone MRL / lpr mice were selected as experimental animals and divided equally into two groups: ML-SI3 group and Vehicle group. Eight 8-10-week-old adult female MRL / Mpj mice were selected as the normal control group and raised under normal conditions. The weight of the mice was recorded weekly for 7 weeks starting at 11 weeks of age. At 12 weeks of age, the ML-SI3 group mice were intraperitoneally injected with ML-SI3 (injected at 0.1 ml per 10 grams of animal body weight, with a concentration of 0.3 mg / ml ML-SI3), and the Vehicle group mice were intraperitoneally injected with normal saline (injected at 0.1 ml per 10 grams of animal body weight) for 6 consecutive weeks. At 18 weeks of age, 12-hour urine of the mice was collected in metabolic cages to detect the urine albumin / creatinine ratio. All data were statistically analyzed and statistical graphs were made using Graphpad 7.0 software.

[0047] The method for measuring urine albumin is as follows (urine albumin kit):

[0048] a. Reagent Preparation

[0049] b. Sample preparation: Add 25 μL of mouse urine sample to the desired wells of a 96-well white plate. Adjust the volume to 50 μL / well with albumin diluent.

[0050] c. Dilution preparation of standards: Dilute 2 mg / mL BSA Standard II / BSA Standard to 0.5 mg / mL by adding 25 μl of BSA Standard II / BSA Standard provided by the Albumin Creatinine Ratio Kit to 75 μL of Albumin Diluent. Add 0 μL, 2 μL, 4 μL, 6 μL, 8 μL, and 10 μL of 0.5 mg / mL BSA Standard II / BSA Standard to the wells of a 96-well plate. Adjust the total volume of each well to 50 μL with Albumin Diluent to generate 0 μg, 1 μg, 2 μg, 3 μg, 4 μg, and 5 μg of BSA Standard II / BSA Standard per well.

[0051] d. Albumin Assay Procedure: For each well, prepare a total of 50 μL of mixture. Prepare and mix enough reagents to prepare the reaction mixture. The reaction mixture includes 46 μL of Albumin Assay Buffer II and 4 μL of Albumin Probe; the background mixture is only 50 μL of Albumin Assay Buffer II. Mix well before use. Add 50 μL of reaction mixture to each well containing BSA Standard II / BSA Standard (sample); add 50 μL of background mixture to the well containing sample background control.

[0052] e. Assay: Incubate at 25°C for 30 minutes in the dark. Measure fluorescence in endpoint mode (excitation / emission = 600 / 630 nm).

[0053] The method for measuring urine creatinine is as follows (urine creatinine kit):

[0054] a. Reagent Preparation

[0055] b. Sample preparation: Add 25ul of mouse urine sample to the desired wells of a 96-well transparent plate. Adjust the volume to 50μL / well with Assay Buffer XXXIV / Creatine Assay Buffer. Dilution of standard: Dilute 10μg / mL creatinine standard to 0.1μg / μL and add 990μL of ddHO. 2 Add 10 μL of standard to each well. Add 0 ul, 2 ul, 4 ul, 6 ul, 8 ul, and 10 ul of 0.1 μg / μL creatinine standard to the wells of a 96-well plate. Adjust the total volume of each well to 50 μL with Assay Buffer XXXIV / Creatine Assay Buffer to generate 0 μg, 0.2 μg, 0.4 μg, 0.6 μg, 0.8 μg, and 1 μg of creatinine standard per well.

[0056] c. Creatinine Assay Procedure: Prepare and mix enough reagents to prepare the reaction mixture. For each well, prepare a total of 50 μL of mixture. The reaction mixture includes 42 μL of assay buffer XXXIV / creatinine assay buffer, 2 μL of creatinase, 2 μL of creatinine enzyme, 2 μL of sarcosinase mixture / creatinase mixture, and 2 μL of OxiRed probe / creatinine probe. The background mixture includes 44 μL of assay buffer XXXIV / creatinine assay buffer, 2 μL of creatinase, 2 μL of sarcosinase mixture / creatinase mixture, and 2 μL of OxiRed probe / creatinine probe, mixed thoroughly before use. Add 50 μL of reaction mixture to each well containing creatinine standard (sample); add 50 μL of background mixture to the well containing sample background control.

[0057] e. Urine creatinine determination: Incubate the plate at 37°C for 60 minutes, away from light. Measure the absorbance (OD570nm) in endpoint mode. The results are as follows: Figure 3 shown.

[0058] from Figure 3 It can be seen that compared with the control group (Vehicle), ML-SI3 administration can significantly reduce the urine albumin / creatinine level of MRL / lpr lupus mice. The urine albumin / creatinine ratio level of MRL / Mpj mice is the normal control mouse.

[0059] 4. Effect of ML-SI3 administration on serum urea nitrogen levels in MRL / lpr lupus mice

[0060] 4.1 Measurement method

[0061] Sixteen 8-10 week old female lupus susceptible MRL / lpr mice were selected and evenly divided into two groups, ML-SI3 group and Vehicle group. Eight 8-10 week old female MRL / Mpj mice were selected as normal control group and raised under normal conditions. At 12 weeks old, mice in ML-SI3 group were injected intraperitoneally with ML-SI3 (injected at 0.1 ml per 10 g of animal body weight, with a concentration of 0.3 mg / ml ML-SI3), and mice in Vehicle group were injected intraperitoneally with normal saline (injected at 0.1 ml per 10 g of animal body weight) for 6 consecutive weeks. Mice were collected at 18 weeks old. The mice were anesthetized, and the whiskers on both sides were trimmed with ophthalmic scissors. The head of the mouse was turned down, and the neck was gently pressed to make the eyeball protrude. The eyeball was removed with curved forceps to collect venous blood. After blood collection, the blood was immediately placed in a 1.5 mL centrifuge tube and allowed to stand at room temperature of 25°C for 30 minutes. The blood samples were centrifuged at 14000g for 15 minutes, and the serum was separated by pipetting and transferred to a clean centrifuge tube. The serum samples were centrifuged at 14000g for another 3 minutes to separate any remaining red blood cells. The separated serum was transferred to a clean centrifuge tube and analyzed for the level of urea nitrogen in the serum. All data were statistically analyzed and plotted using Graphpad 7.0 software.

[0062] Urea nitrogen levels are measured as follows:

[0063] a. Balance the aluminum foil bag at room temperature (25°C) for 20 minutes, take out the required strips, seal the remaining strips in a ziplock bag, and store them in a dry place at 4°C.

[0064] b. Set up standard wells and sample wells, and add 50 μL of standard solution of different concentrations (0, 0.2, 0.4, 0.6, 0.8, 1, 3, 5, 10, 15, 20, 25 mmol / L) in the urea nitrogen (BUN) detection kit to each standard well.

[0065] c. First add 10μL of the sample solution to be tested to the test sample well, then add 40μL of sample diluent, and do not add sample to the blank well.

[0066] d. Except for the blank wells, add HRP-labeled detection antibody to the standard wells and the sample wells at a volume of 100 μL / well, then seal the reaction wells with a sealing film and incubate in a 37°C water bath or incubator for 1 hour.

[0067] e. Discard the liquid in the wells, drain the remaining liquid on absorbent paper, fill up the wells with washing buffer, let it stand for 1 minute, spin dry the washing buffer, drain on absorbent paper, and repeat washing 5 times.

[0068] f. Add 50 μL of substrate A and B in the kit to each well and incubate at 37°C in the dark for 15 minutes.

[0069] g. Add 50 μL of the stop solution in the kit to each well, set the detection wavelength of the microplate reader to 450 nm, and measure the OD value of each well within 15 minutes. The results are as follows: Figure 4 shown.

[0070] from Figure 4 It can be seen that compared with the control group (Vehicle), ML-SI3 administration can significantly reduce the urea nitrogen level of MRL / lpr lupus mice. The urea nitrogen level of MRL / Mpj mice is the normal control mouse.

[0071] 5. Effect of ML-SI3 administration on the swelling of spleen and axillary lymph nodes in MRL / lpr lupus mice

[0072] 5.1 Measurement method

[0073] Sixteen 8-10 week old female lupus susceptible MRL / lpr mice were selected and evenly divided into two groups, ML-SI3 group and Vehicle group. Eight 8-10 week old adult female MRL / Mpj mice were selected as the normal control group and raised under normal conditions. At 12 weeks of age, the ML-SI3 group mice were intraperitoneally injected with ML-SI3 (0.1 ml per 10 grams of animal body weight, 0.3 mg / ml of ML-SI3), and the Vehicle group mice were intraperitoneally injected with normal saline (0.1 ml per 10 grams of animal body weight) for 6 consecutive weeks. When the mice were 18 weeks old, they were anesthetized and PBS buffer was perfused by left ventricle puncture. The intact spleen and axillary lymph nodes were collected, and the sizes of the spleen and axillary lymph nodes of the control group and the ML-SI3 administration group were measured and compared. All data were statistically analyzed and statistical graphs were made using Graphpad7.0 software. The results are shown in the figure. Figure 5 shown.

[0074] from Figure 5 It can be seen that compared with the control group (Saline), ML-SI3 administration can significantly reduce the swelling of the spleen and axillary lymph nodes in MRL / lpr lupus mice. The sizes of the spleen and axillary lymph nodes in MRL / Mpj mice are normal control mice. The scale is in centimeters.

[0075] 6. Effects of ML-SI3 administration on renal pathological changes in MRL / lpr lupus mice

[0076] 6.1 Measurement method

[0077] Sixteen 8-10 week old female lupus susceptible MRL / lpr mice were selected and evenly divided into two groups: ML-SI3 group and Vehicle group. Eight 8-10 week old female MRL / Mpj mice were selected as the normal control group and raised under normal conditions. At 12 weeks of age, mice in the ML-SI3 group were intraperitoneally injected with ML-SI3 (0.1 ml per 10 g of animal body weight, 0.3 mg / ml of ML-SI3), and mice in the Vehicle group were intraperitoneally injected with saline (0.1 ml per 10 g of animal body weight) for 6 consecutive weeks. At 18 weeks of age, mice were anesthetized and perfused with PBS buffer by left ventricle puncture. The intact mouse kidneys were collected for HE and PAS staining.

[0078] HE staining: The renal tissue was fixed with 4% paraformaldehyde, embedded in paraffin, and paraffin sections were prepared from the renal cortex. The prepared paraffin sections were dewaxed with xylene, rehydrated with graded ethanol, stained with hematoxylin, differentiated with hydrochloric acid ethanol, stained with eosin solution, then dehydrated with graded ethanol, transparentized with xylene, and finally sealed with neutral gum. The changes in glomerular inflammatory cell infiltration, capillary lesions, and glomerular cell proliferation were observed under a light microscope to evaluate the degree of LN renal lesions.

[0079] PAS staining: paraffin sections of renal cortical tissue fixed with 4% paraformaldehyde were dewaxed with xylene and stained with PAS. PAS staining, also known as glycogen staining, is one of the conventional staining methods in pathology. This staining solution can not only show glycogen, but also neutral mucous substances, certain acidic substances, amyloid substances, basement membranes, etc. Under a light microscope, glomerular cell proliferation, basement membrane thickening, and changes in the mesangial area can be observed. It is also one of the methods for evaluating LN kidney pathological changes. The staining results are as follows: Figure 6 shown.

[0080] from Figure 6 It can be seen that compared with the control group, ML-SI3 administration can significantly reduce the renal pathological changes in MRL / lpr lupus mice. MRL / Mpj mice are normal control mice. HE and PAS staining results. The scale bar is 20 microns.

[0081] The TRPML1-specific small molecule inhibitor ML-SI3 described in the present application can significantly reduce the serum anti-dsDNA antibody titer level of MRL / lpr lupus mice; reduce the urine albumin / creatinine ratio level; reduce the urea nitrogen level; reduce the swelling of the spleen and axillary lymph nodes; improve kidney pathological changes; and has a comprehensive protective effect on lupus nephritis in MRL / lpr mice.

[0082] The above experimental results prove that the ML-SI3 small molecule inhibitor can comprehensively improve the progression of lupus nephritis model mice. The present invention provides a new drug for the treatment of lupus nephropathy, which has good market value and clinical application prospects.

[0083] Although the above embodiments have been shown and described, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. Changes, modifications, substitutions and variations of the above embodiments by those of ordinary skill in the art are all within the scope of protection of the present invention.

Claims

1. Use of a TRPML1-specific small molecule inhibitor ML-SI3 in the preparation of drugs for treating or preventing nephritis.

2. The use according to claim 1, characterized in that: The nephritis is lupus nephritis.

3. The use according to claim 1, characterized in that: The structural formula of the TRPML1 specific small molecule inhibitor ML-SI3 is shown below:

4. The use according to claim 1, characterized in that: In the preparation of drugs for treating or preventing nephritis, the effective dose of the TRPML1-specific small molecule inhibitor ML-SI3 is 2-5 mg / kg.

5. The use according to claim 1, characterized in that: In the preparation of drugs for treating or preventing nephritis, the effective dose of the TRPML1-specific small molecule inhibitor ML-SI3 is 3 mg / kg.

6. A drug for treating lupus nephritis, characterized in that: The invention comprises active pharmaceutical ingredients and pharmaceutically acceptable excipients, wherein the active pharmaceutical ingredients comprise TRPML1-specific small molecule inhibitor ML-SI3.

7. The drug for treating lupus nephritis according to claim 6, characterized in that: The content of the active pharmaceutical ingredient in the medicine is 2-5 mg / kg.

8. The drug for treating lupus nephritis according to claim 6, characterized in that: The content of the active pharmaceutical ingredient in the medicine is 3 mg / kg.

9. The drug for treating lupus nephritis according to claim 6, characterized in that: The dosage form of the drug includes injection, tablet, capsule, granule, aerosol or oral liquid.

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