Use of plitidepsin in the preparation of a medicament for the treatment of obesity and improvement of glucose metabolism
By using Plitidepsin to inhibit eEF1A2 and regulate skeletal muscle energy metabolism, obesity and glucose metabolism problems were resolved, resulting in significant weight and fat reduction as well as improved glucose tolerance, without causing liver, kidney or heart side effects.
Patent Information
- Application Number
- CN202510628203.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-15
- Publication Date
- 2025-12-09
- Estimated Expiration
- 2045-05-15
AI Technical Summary
Current technologies lack effective ways to control obesity and improve glucose metabolism, especially targeting the risk of obesity and diabetes caused by skeletal muscle energy metabolism imbalance. eEF1A2 is a potential therapeutic target, but the role of its inhibitor Plitidepsin has not been fully explored.
Plitidepsin was used as an eEF1A2 inhibitor to regulate skeletal muscle energy metabolism, reduce fat content, enhance insulin sensitivity, and improve glucose metabolism by inhibiting eEF1A2.
Plitidepsin significantly reduced body weight and fat content, particularly in the white adipose tissue around the groin and epididymis, and improved glucose tolerance and insulin sensitivity without causing significant liver or kidney damage or cardiac dysfunction.
Smart Images
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of new applications of targeted drugs, in particular to the application of Plitidepsin in the preparation of a medicament for treating obesity and improving glucose metabolism. BACKGROUND
[0002] In recent years, due to the improvement of living standards, the continuous increase of high-energy food intake and the lack of physical activity, the incidence of obesity has continued to increase globally, and obesity has become the most serious public health problem faced by countries around the world. The 2023 world obesity map shows that the number of obese people in the world has exceeded 1 billion, and the number of overweight people has exceeded 2.6 billion. Statistical data shows that BMI is highly positively correlated with mortality, and in people over the age of forty, the life expectancy of obese people is shortened by about 4 years.
[0003] Obesity is closely related to the occurrence and development of many diseases, especially greatly increasing the incidence of cardiovascular diseases, type 2 diabetes and its accompanying diseases. Obesity is at the top of the risk factors for hypertension and diabetes, and weight control is the first recommended way to prevent and treat diabetes. Obesity prevention and treatment is extremely necessary, but there is currently a lack of effective ways to control obesity other than changing diet and increasing exercise, so it is urgently necessary to identify the mechanism of obesity development and find good therapeutic targets.
[0004] Obesity is a disease caused by energy metabolism imbalance. Skeletal muscle, as the largest energy metabolism organ in the human body, plays a crucial role in maintaining energy metabolism balance. Skeletal muscle can regulate whole-body metabolism through muscle fiber remodeling and myokine secretion. Skeletal muscle can also act as an endocrine organ, secreting various factors to regulate whole-body metabolic function. For example, GDF15, IL-6, connexin, FGF21, Irisin, myostatin, Apelin, BDNF, and myomaker. Skeletal muscle maintains energy metabolism homeostasis through muscle fiber remodeling and myokine secretion, which is crucial for controlling obesity.
[0005] In previous studies on the pathogenesis of diabetic hamsters, the differentially expressed gene eEF1A2 in diabetic skeletal muscle was screened and verified by suppression subtractive hybridization technology. Using diabetic long-tailed hamsters, db / db mice animal models and palmitate-induced insulin-resistant myotube models, it was found that eEF1A2 exacerbated skeletal muscle insulin resistance through PKCβ and endoplasmic reticulum stress. eEF1A2 is a potential target for the treatment of diabetes.
[0006] Plitidepsin (aplidine) is a potent active molecule known to target eEF1A2, which was first discovered as a natural compound from Aplidium albicans. Previous studies have found that plitidepsin has strong antiviral activity against SARS-CoV-2 by targeting the host protein eEF1A. In addition, as a known eEF1A2 inhibitor, plitidepsin has shown therapeutic effects on various cancers in clinical trials and has been approved in Australia for the treatment of refractory multiple myeloma.
[0007] At present, the effect of eEF1A2 inhibitor plitidepsin on obesity and glucose metabolism has not been found. SUMMARY
[0008] The present application provides the use of plitidepsin in the preparation of a medicament for treating obesity and improving glucose metabolism. The present application aims to evaluate the effect of eEF1A2 inhibitor plitidepsin on obesity and glucose metabolism.
[0009] The present application provides the use of plitidepsin in the preparation of a medicament for treating obesity and improving glucose metabolism.
[0010] Optionally, the plitidepsin reduces the body weight of the treatment subject.
[0011] Optionally, the plitidepsin reduces the fat content of the treatment subject.
[0012] Optionally, the plitidepsin reduces the content of inguinal white adipose tissue and periepididymal white adipose tissue of the treatment subject.
[0013] Optionally, the plitidepsin improves the glucose tolerance and insulin sensitivity of the treatment subject.
[0014] In summary, the present application includes at least one of the following beneficial technical effects:
[0015] The present application finds that plitidepsin reduces the body weight, fat content, and the content of inguinal white adipose tissue and periepididymal white adipose tissue of the treatment subject, and improves the glucose tolerance and insulin sensitivity of the treatment subject. Therefore, plitidepsin can be used in the preparation of a medicament for treating obesity and improving glucose metabolism. BRIEF DESCRIPTION OF DRAWINGS
[0016] Figure 1 The chemical structure of plitidepsin.
[0017] Figure 2 The change curve of the body weight of mice over time (*P<0.05).
[0018] Figure 3 The MRI image and the body fat content of mice (***P<0.001).
[0019] Figure 4 The organ coefficient of mice (*P<0.05, **P<0.01, ***P<0.001).
[0020] Figure 5 The OGTT curve and the area under the curve (AUC) (*P<0.05, **P<0.01).
[0021] Figure 6 The HE staining results of the liver and kidney of mice.
[0022] Figure 7 The biochemical index detection results.
[0023] Figure 8 The HE staining results and echocardiographic results of the heart of mice.
[0024] Among them, the solvent group is the control group; the treatment group is the test group. DETAILED DESCRIPTION
[0025] Before describing the embodiments of the present application in detail, it should be understood that the terms used herein are for the purpose of describing specific embodiments only. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the term belongs.
[0026] It should be noted that the terms "first", "second" are only for the purpose of description, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. Therefore, the features defined with "first", "second" can explicitly or implicitly include one or more of the features. Further, in the description of the present application, unless otherwise stated, the meaning of "multiple" is two or more.
[0027] In the present application, the endpoints of the ranges and any values disclosed are not limited to the precise range or value, and these ranges and values should be interpreted as including values proximate to the ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.
[0028] In the present application, the term "comprising" or "including" is an open expression, i.e. including what is indicated in the present application, but not excluding other aspects.
[0029] In order to make the purpose, technical solutions and advantages of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application. The embodiments described below are exemplary and are only used to explain the present application and cannot be understood as limitations of the present application.
[0030] Unless specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in the art or according to the product instructions are used. Unless the manufacturer of the reagent or instrument is specified, it is a conventional product that can be obtained by purchase on the market.
[0031] The present application will be further described in detail below in combination with the embodiments and test results.
[0032] Embodiments
[0033] This embodiment verifies that the eEF1A2 inhibitor plitidepsin has the effects of reducing obesity, reducing fat content and enhancing insulin sensitivity in db / db mice. The chemical structure of plitidepsin is as shown in Figure 1 .
[0034] The specific process is as follows:
[0035] I. Experimental animals
[0036] 10 eight-week-old male diabetic db / db mice were purchased from Spafas (Beijing) Biotechnology Co., Ltd. They were randomly divided into an experimental group and a control group, with 5 mice in each group.
[0037] II. Experimental modeling method
[0038] The experimental group was intraperitoneally injected with 0.05 mg / kg plitidepsin daily for 5 days, stopped for 5 days, and then intraperitoneally injected with 0.025 mg / kg plitidepsin every two days for 15 days.
[0039] The control group was injected with solvent (solvent: 2% cremophor (castor oil), 2% ethanol, 0.75% Nacl) every day.
[0040] The body weight of the mice was detected every week, and the oral glucose tolerance test (OGTT) of the mice was detected every two weeks. The body fat content of the mice was calculated by magnetic resonance imaging (MRI) and organ coefficient. Whether the drug damage occurred in the tissues such as liver, kidney and heart was detected by HE staining and serum biochemical indicators.
[0041] III. Experimental results
[0042] (1) Mouse weight
[0043] The curve of mouse weight change over time is shown in Figure 2 .
[0044] As can be seen from Figure 2 , the mouse weight began to decrease significantly one week after eEF1A2 inhibitor plitidepsin treatment compared with the control group, and this difference continued throughout the drug administration period.
[0045] (2) Mouse fat
[0046] The MRI image and body fat content are shown in Figure 3 .
[0047] As can be seen from Figure 3 , magnetic resonance imaging found that the fat content of plitidepsin-treated db / db mice was significantly reduced (***P<0.001).
[0048] (3) Organ coefficient
[0049] The mouse organ coefficient is shown in Figure 4 .
[0050] As can be seen from Figure 4 , organ coefficient measurement found that there was no significant difference in the weights of major organs such as liver, kidney and pancreas between the solvent group (control group) and plitidepsin-treated group (experimental group) db / db mice, and there was also no significant difference in muscle weight such as gastrocnemius and soleus. However, it is particularly noteworthy that the content of inguinal white adipose tissue and periepididymal white adipose tissue in plitidepsin-treated group (experimental group) db / db mice was significantly reduced.
[0051] (4) Mouse oral glucose tolerance (OGTT)
[0052] The OGTT curve and area under the curve (AUC) are shown in Figure 5 ,
[0053] As can be seen from Figure 5 , the oral glucose tolerance results of db / db mice four weeks after drug treatment showed that there was a significant difference in the oral glucose tolerance results and area under the curve between the solvent group (control group) and plitidepsin-treated group (experimental group) db / db mice, indicating that the glucose tolerance of plitidepsin-treated group (experimental group) db / db mice was significantly increased, and the insulin sensitivity was enhanced.
[0054] (5) Liver and kidney HE staining
[0055] The results of mouse liver and kidney HE staining are shown in Figure 6 .
[0056] Depend on Figure 6 HE staining of liver and kidney tissues from db / db mice in the solvent group (control group) and the plitidepsin treatment group (experimental group) showed that the liver and kidney tissue structures did not develop lesions due to the drug, indicating that no significant liver and kidney damage occurred after drug administration.
[0057] (6) Biochemical index detection
[0058] Biochemical indicator test results as follows Figure 7 As shown.
[0059] Depend on Figure 7 It was found that serum biochemical indicators of db / db mice in the solvent group (control group) and the plitidepsin treatment group (experimental group) did not show significant changes in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG), creatine kinase (CK), and creatinine (CREA-S), indicating that no significant liver and kidney function damage occurred after drug administration.
[0060] (7) Cardiac function testing
[0061] Heart HE staining and echocardiography results as follows Figure 8 As shown.
[0062] Depend on Figure 8 It is known that although eEF1A2 is also expressed in the heart, and there are clinical cases of eEF1A2 mutation leading to heart failure, HE staining of the hearts of db / db mice in the solvent group (control group) and the plitidepsin treatment group (experimental group) showed that the cardiac structure of the db / db mice in the treatment group (experimental group) did not change due to the drug. Echocardiography results of db / db mice in the solvent group (control group) and the plitidepsin treatment group (experimental group) showed no significant changes in left ventricular ejection fraction (EF), left ventricular fractional shortening (FS), left ventricular end-systolic anterior wall thickness (LVAW(s)), left ventricular end-diastolic anterior wall thickness (LVAW(d)), left ventricular end-diastolic diameter (LVID(d)), left ventricular end-systolic diameter (LVID(s)), left ventricular end-diastolic volume (LVVol(d)), and left ventricular end-systolic volume (LVVol(s)), indicating that no significant cardiac function impairment occurred after drug administration.
[0063] In conclusion, the eEF1A2 inhibitor plitidepsin has the effect of reducing obesity, lowering fat content, and enhancing insulin sensitivity in db / db mice.
[0064] In the description of the specification, the description of the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are contained in at least one embodiment or example of the present application. In the description of the specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine the different embodiments or examples described in the specification and the features of the different embodiments or examples without contradiction.
[0065] Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present application, and not to limit them; although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solution deviate from the spirit and scope of the technical solutions of the embodiments of the present application.
Claims
1. Use of plitidepsin for the preparation of a medicament for the treatment of obesity and the improvement of glucose metabolism.
2. Use according to claim 1, characterized in that, Said plitidepsin reduces the body weight of the treated subject.
3. Use according to claim 1, characterized in that, Said plitidepsin reduces the fat content of the treated subject.
4. Use according to claim 1, characterized in that, Said plitidepsin reduces the inguinal and periepididymal white adipose tissue content of the treated subject.
5. The use according to claim 1, characterized in that, Said plitidepsin improves the glucose tolerance and the insulin sensitivity of the treated subject.