Application of Plitidepsin in preparation of medicine for treating obesity and improving glucose metabolism

Abstract

The invention relates to the technical field of novel application of targeted drugs, in particular to application of Plitidepsin in preparation of drugs for treating obesity and improving glucose metabolism. It can be known through exploration that plitidepsin can reduce the weight and fat content of a treated object and the content of white adipose tissue around inguinal white fat and epididymis, and meanwhile, the sugar tolerance and insulin sensitivity of the treated object can be improved. Therefore, the plitidepsin can be used for preparing the medicine for treating obesity and improving glucose metabolism.

Description

Technical Field

[0001] The present application relates to the technical field of new applications of targeted drugs, and in particular to the use of Plitidepsin in the preparation of drugs for treating obesity and improving glucose metabolism. Background Art

[0002] In recent years, the global incidence of obesity has continued to rise due to improvements in living standards, a continued increase in the intake of high-energy foods, and a lack of physical activity. Obesity has become a serious public health issue facing countries around the world. The 2023 World Obesity Atlas shows that the number of obese people worldwide has exceeded 1 billion, and the number of overweight people has exceeded 2.6 billion. Statistics show that BMI is highly positively correlated with mortality, and that among people over 40 years old, obese people have a life expectancy reduction of approximately four years.

[0003] Obesity is closely linked to the development and progression of numerous diseases, particularly significantly increasing the incidence of cardiovascular disease, type 2 diabetes, and its associated conditions. Obesity tops the risk factor list for both hypertension and diabetes, and weight control is the primary diabetes prevention and treatment recommended by guidelines. The prevention and treatment of obesity are crucial, but effective methods for controlling obesity beyond dietary changes and increased exercise are currently lacking. Therefore, there is an urgent need to clarify the mechanisms underlying the development and progression of obesity and identify promising therapeutic targets.

[0004] Obesity is a disease caused by an imbalance in energy metabolism. As the body's largest energy metabolism organ, skeletal muscle plays a vital role in maintaining energy metabolic homeostasis. Skeletal muscle regulates systemic metabolism through myofiber remodeling and myokine secretion. Skeletal muscle also acts as an endocrine organ, secreting a variety of factors that regulate systemic metabolic function. These include GDF15, IL-6, myonectin, FGF21, irisin, myostatin, apelin, BDNF, and myosin. Skeletal muscle maintains energy metabolic homeostasis through myofiber remodeling and myokine secretion, playing a crucial role in controlling obesity.

[0005] In previous studies investigating the pathogenesis of diabetic gerbils, suppression subtractive hybridization was used to screen and validate the differentially expressed gene in diabetic skeletal muscle—the eukaryotic translation elongation factor eEF1A2. Using diabetic gerbils, db / db mice, and palmitate-induced insulin-resistant myotube models, the researchers found that eEF1A2 exacerbated skeletal muscle insulin resistance through PKCβ and endoplasmic reticulum stress. eEF1A2 is a potential target for diabetes treatment.

[0006] Plitidepsin (aplidine) is a known, potent active molecule targeting eEF1A2. It was originally discovered as a natural compound from the white sea squirt (Aplidium albicans). Studies have shown that plitidepsin exhibits potent antiviral activity against SARS-CoV-2 by targeting the host protein eEF1A. Furthermore, plitidepsin, a known eEF1A2 inhibitor, has demonstrated efficacy against various cancers in clinical trials and is approved in Australia for the treatment of refractory multiple myeloma.

[0007] Currently, the effects of the eEF1A2 inhibitor plitidepsin on obesity and glucose metabolism have not been found. Summary of the Invention

[0008] The present application provides a use of plitidepsin in the preparation of a medicament for treating obesity and improving glucose metabolism. The present application aims to evaluate the effects of the eEF1A2 inhibitor plitidepsin on obesity and glucose metabolism.

[0009] The present application provides a use of Plitidepsin in the preparation of a medicament for treating obesity and improving glucose metabolism.

[0010] Optionally, the plitidepsin reduces body weight in the subject.

[0011] Optionally, the plitidepsin reduces fat mass in the subject.

[0012] Optionally, the plitidepsin reduces the amount of inguinal white fat and peri-epididymal white adipose tissue in the treated subject.

[0013] Optionally, the plitidepsin improves glucose tolerance and insulin sensitivity in the subject.

[0014] In summary, this application includes at least one of the following beneficial technical effects:

[0015] The present application has determined that plitidepsin reduces body weight, fat content, and the amount of inguinal white fat and peri-epididymal white adipose tissue in treated subjects, while also improving glucose tolerance and insulin sensitivity. Therefore, plitidepsin can be used to prepare drugs for treating obesity and improving glucose metabolism. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The chemical structure of plitidepsin.

[0017] Figure 2 The curve of the change of mouse body weight over time (*P<0.05).

[0018] Figure 3 MRI images and body fat content of mice (***P<0.001).

[0019] Figure 4 The coefficients are mouse organ coefficients (*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 results of HE staining of mouse liver and kidney.

[0022] Figure 7 The results of biochemical index detection.

[0023] Figure 8 The results of HE staining and echocardiography of mouse hearts are shown.

[0024] Among them, the solvent group was the control group; the treatment group was the experimental group. DETAILED DESCRIPTION

[0025] Before describing the embodiments of the present application in detail, it should be understood that the terminology used herein is only for the purpose of describing particular embodiments. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the term belongs.

[0026] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of this application, unless otherwise specified, "plurality" means two or more.

[0027] The endpoints of the ranges and any values disclosed in this application are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered to be specifically disclosed herein.

[0028] In this application, the term "comprise" or "include" is an open expression, that is, it includes the content specified in this application, but does not exclude other aspects of the content.

[0029] To make the purpose, technical solutions, and advantages of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without making any creative work are within the scope of protection of this application. The embodiments described below are exemplary and are only used to explain this application, and should not be understood as limiting this application.

[0030] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. All reagents or instruments used without specifying the manufacturer are commercially available conventional products.

[0031] The present application is further described in detail below in conjunction with the examples and test results.

[0032] Example

[0033] This example demonstrates that the eEF1A2 inhibitor plitidepsin has the effects of reducing obesity, lowering fat content, and enhancing insulin sensitivity in db / db mice. Figure 1 shown.

[0034] The specific process is as follows:

[0035] 1. Experimental Animals

[0036] Ten 8-week-old male diabetic db / db mice were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd. and randomly divided into experimental and control groups, with 5 mice in each group.

[0037] 2. Experimental modeling method

[0038] The experimental group received daily intraperitoneal injections of 0.05 mg / kg plitidepsin for 5 consecutive days, followed by a 5-day drug-free period, and then received intraperitoneal injections of 0.025 mg / kg plitidepsin every two days for 15 days.

[0039] The control group received daily injections of a solvent (solvent: 2% cremophor (castor oil), 2% ethanol, 0.75% NaCl).

[0040] Mice were weighed weekly and tested for oral glucose tolerance (OGTT) every two weeks. Body fat content was measured using magnetic resonance imaging (MRI) and organ coefficients. Hematoxylin and eosin staining and serum biochemical markers were used to assess drug damage in tissues such as the liver, kidney, and heart.

[0041] 3. Experimental Results

[0042] (1) Mouse weight

[0043] The curve of mouse weight changes over time is as follows Figure 2 shown.

[0044] Depend on Figure 2 It can be seen that compared with the control group, the body weight of mice decreased significantly one week after treatment with the eEF1A2 inhibitor plitidepsin, and this difference persisted during the dosing period.

[0045] (2) Mouse fat

[0046] MRI images and body fat content Figure 3 shown.

[0047] Depend on Figure 3 It can be seen that magnetic resonance imaging measurement found that the fat content of db / db mice in the plitidepsin treatment group was significantly reduced (***P<0.001).

[0048] (3) Organ coefficient

[0049] Mouse organ coefficients Figure 4 shown.

[0050] Depend on Figure 4 Calculation of organ coefficients revealed no significant differences in the weights of major organs, including the liver, kidney, and pancreas, between the vehicle group (control group) and the plitidepsin-treated group (experimental group). Neither did the weights of the gastrocnemius and soleus muscles. However, the plitidepsin-treated group (experimental group) showed a significant decrease in the amount of inguinal white fat and perididymal white adipose tissue.

[0051] (4) Oral glucose tolerance test (OGTT) in mice

[0052] OGTT curve and area under the curve (AUC) Figure 5 As shown,

[0053] Depend on Figure 5 It can be seen that the oral glucose tolerance results of db / db mice after four weeks of drug treatment showed that there were significant differences in the oral glucose tolerance results and areas under the curve between the solvent group (control group) and the plitidepsin treatment group (experimental group), indicating that the glucose tolerance of db / db mice in the plitidepsin treatment group (experimental group) was significantly improved and the insulin sensitivity was enhanced.

[0054] (5) HE staining of liver and kidney

[0055] HE staining results of mouse liver and kidney Figure 6 shown.

[0056] Depend on Figure 6 It can be seen that HE staining of the liver and kidney tissues of db / db mice in the solvent group (control group) and the plitidepsin treatment group (experimental group) showed that the liver and kidney tissue structures were not affected by the drug, indicating that no obvious liver and kidney damage occurred after medication.

[0057] (6) Biochemical index detection

[0058] Biochemical index test results such as Figure 7 shown.

[0059] Depend on Figure 7 It can be seen that the serum biochemical index detection of db / db mice in the solvent group (control group) and the plitidepsin treatment group (experimental group) found that the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), creatine kinase (CK) and creatinine (CREA-S) did not show significant changes, indicating that no obvious liver and kidney function damage occurred after medication.

[0060] (7) Cardiac function test

[0061] Heart HE staining and echocardiography results Figure 8 shown.

[0062] Depend on Figure 8 Although eEF1A2 is expressed in the heart and clinical cases of eEF1A2 mutations leading to heart failure have been reported, HE staining of the hearts of db / db mice in the vehicle (control) and plitidepsin-treated (experimental) groups showed no structural changes in the heart. Echocardiography revealed no significant changes in left ventricular ejection fraction (EF), left ventricular fractional shortening (FS), left ventricular anterior wall thickness at end-systole (LVAW(s)), left ventricular anterior wall thickness at end-diastole (LVAW(d)), left ventricular internal diameter at end-diastole (LVID(d)), left ventricular internal diameter at end-systole (LVID(s)), left ventricular end-diastolic volume (LV Vol(d)), and left ventricular end-systolic volume (LV Vol(s)), indicating no significant cardiac impairment following drug administration.

[0063] In summary, the eEF1A2 inhibitor plitidepsin has the effects of reducing obesity, lowering fat content, and enhancing insulin sensitivity in db / db mice.

[0064] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" means 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 application. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of 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, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. Use of Plitidepsin in the preparation of a medicament for treating obesity and improving glucose metabolism.

2. The use according to claim 1, characterized in that The plitidepsin reduces body weight in treated subjects.

3. The use according to claim 1, characterized in that The plitidepsin reduces fat content in treated subjects.

4. The use according to claim 1, characterized in that The plitidepsin reduces the content of inguinal white fat and peri-epididymal white adipose tissue in treated subjects.

5. The use according to claim 1, characterized in that The plitidepsin improves glucose tolerance and insulin sensitivity in the treated subject.

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