Application of Ibipion toxin in preparation of weight-reducing medicine
By inhibiting the Kcnma1 target, scorpion toxin can be prepared into various dosage forms of weight loss drugs, solving the side effects of existing weight loss drugs and achieving safe and effective weight loss effects.
Patent Information
- Application Number
- CN202511018469.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-23
- Publication Date
- 2025-09-26
AI Technical Summary
Existing weight loss drugs such as semaglutide have significant gastrointestinal side effects and muscle mass loss during use. There is an urgent need to develop a new weight loss drug that can reduce side effects while ensuring weight loss effects.
Using ibirinus scorpion toxin as the active ingredient, by inhibiting the Kcnma1 target, it is prepared into weight loss drugs in various dosage forms such as tablets and capsules, which are used to reduce weight, lower serum triglyceride and total cholesterol levels, and improve glucose tolerance and insulin resistance.
Ibiribiris scorpion toxin significantly reduces weight, lowers blood lipids, and improves metabolism without obvious toxic side effects, providing a safe and effective option for new weight loss drugs.
Smart Images
Figure CN120695160A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the fields of biomedicine technology and food, and more specifically, relates to the application of scorpion toxin in the preparation of weight-loss drugs. Background Art
[0002] Obesity is a disease caused by abnormal energy metabolism, leading to excessive fat accumulation. Obesity can lead to complications such as type II diabetes, cardiovascular disease, bone and joint diseases, cancer, and can even cause death. Over the past 30 years, the number of overweight and obese adults (aged 25 and over) worldwide has increased from 731 million in 1990 to 2.11 billion in 2021. Obesity has become a global public health issue of the 21st century.
[0003] As the global prevalence of obesity continues to rise, exploring safe and effective treatment options has become an urgent need in the field of medical research. In recent years, the development of new drugs based on biological targets has opened up a new path for obesity intervention. In 2021, the glucagon-like peptide-1 receptor agonist Semaglutide was approved by the U.S. Food and Drug Administration (FDA), becoming the first drug for long-term weight management, marking a new stage in the drug treatment of obesity. Clinical trials have shown that the drug can reduce the average weight of obese patients by 15% through subcutaneous injection once a week, and its efficacy is significantly better than previous weight loss drugs, providing a new treatment option for overweight / obese groups. However, the therapy still has limitations. About 60% of Semaglutide users reported gastrointestinal side effects such as nausea and constipation, and some patients experienced a decrease in muscle mass, especially when eating. How to reduce side effects on the body while ensuring the weight loss effect has become a key scientific issue that urgently needs to be broken through in the field of obesity treatment. Summary of the Invention
[0004] In response to the above-mentioned defects or improvement needs of the prior art, the purpose of the present invention is to provide a use of ibiricid scorpion toxin in the preparation of weight loss drugs. ibiricid scorpion toxin can reduce the body weight of an organism, lower the levels of triglycerides and total cholesterol in serum, effectively alleviate obesity, and improve metabolic conditions such as glucose tolerance and insulin resistance. It provides a new idea for the prevention and treatment of obesity and its metabolic complications, and has broad clinical application prospects.
[0005] To achieve the above objectives, according to one aspect of the present invention, there is provided the use of Ibiricola venom in the preparation of weight loss drugs.
[0006] According to another aspect of the present invention, the present invention provides the use of Ibirusa venom in the preparation of a product for controlling fat accumulation in an organism.
[0007] According to another aspect of the present invention, the present invention provides a use of ibiricid venom in preparing functional foods for weight management.
[0008] According to another aspect of the present invention, the present invention provides the use of Ibirusa venom in the preparation of a product for reducing the body weight of an organism.
[0009] As a further preferred embodiment of the present invention, the weight loss drug or the product is a pharmaceutically acceptable carrier and excipient.
[0010] As a further preferred embodiment of the present invention, the ibiric scorpion toxin is used as an active ingredient to prepare any dosage form of tablets, capsules, powders, mixtures, pills, sprays, granules, capsules, oral liquids, and injections;
[0011] Preferably, the amount of the active ingredient of ibirostris toxin administered is 500 μg of ibirostris toxin per kg body weight of the organism per day.
[0012] As a further preferred embodiment of the present invention, the scorpion toxin can reduce the levels of triglycerides and total cholesterol in serum.
[0013] As a further preferred embodiment of the present invention, the scorpion toxin can improve glucose tolerance metabolism and insulin resistance metabolism of an organism.
[0014] Through the above technical solutions conceived by the present invention, compared with the existing technology, the present invention reveals for the first time that Iberiotoxin has significant weight loss effects. Iberiotoxin can significantly reduce the body weight of organisms (as illustrated in the examples below, it can significantly reduce the body weight of obese mice induced by a high-fat diet), reduce serum triglyceride and total cholesterol levels, effectively alleviate obesity, and improve metabolic conditions such as glucose tolerance and insulin resistance. It can be used as a weight loss nutritional supplement or medicine, providing a new option for the development of new weight loss drugs or weight management functional foods.
[0015] The present invention creatively applies ibirin toxin to weight loss, providing a new approach for the preparation of weight loss drugs and overcoming the side effects of semaglutide. In terms of basic research, the existing applications of ibirin toxin are mainly focused on treating respiratory, cardiovascular, and nervous system diseases. However, during the research and development process of the present invention, by identifying Kcnma1 as a new weight loss target, the known inhibitor ibirin toxin was then made into a weight loss drug and its significant weight loss function was verified. The present invention expands the application value of ibirin toxin and has good application prospects in the development of food-derived or bio-derived weight loss nutritional products and drugs. With the addition of pharmaceutically acceptable additives and / or excipients and / or carriers, it can be made into pharmaceutical preparations for the prevention and treatment of obesity, such as tablets, granules, and liquid preparations.
[0016] The ibirim scorpion toxin of the present invention achieves the purpose of weight loss by reducing body weight and lowering blood lipids without obvious toxic side effects. The present invention provides a new idea for the development of food-derived weight loss nutritional products or medicines and the clinical application of ibirim scorpion toxin. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 The changes in body weight and food intake of mice in Example 1, wherein: Figure 1 A in the figure represents the weight change of mice, where -56 to 0 days is the modeling period, and 0 to 32 days is the experimental period; Figure 1 B in the figure is the weight change rate curve of mice; Figure 1 C in is the weight change rate of mice; Figure 1 D in the table is the daily food intake of mice; Figure 1 E is the amount of food consumed per unit body weight of mice; Figure 1 F in the figure represents the daily water intake of mice; * in the figure indicates significant difference compared with the HFD group, * represents p<0.05, ** represents p<0.01, and *** represents p<0.001.
[0018] Figure 2 The body morphology, liver and fat tissue changes of the mice after 32 days of experiment in Example 1, wherein: Figure 2 A in the figure represents the morphology and weight of mice; Figure 2 B in the figure is the morphology and wet weight of inguinal white adipose tissue (iWAT) of mice; Figure 2 C in the figure represents the morphology and wet weight of mouse brown adipose tissue (BAT); Figure 2 D in the figure represents the morphology and wet weight of mouse liver tissue (Liver); * in the figure indicates significant difference compared with the HFD group, * represents p<0.05, ** represents p<0.01, and *** represents p<0.001; "Liraglutide" marked in the actual photos in the figure means "HFD+Liraglutide", and "Iberiotoxin" means "HFD+Iberiotoxin".
[0019] Figure 3 The glucose tolerance and insulin sensitivity of the mice after 32 days of the experiment in Example 1, wherein: Figure 3 A and B are the glucose tolerance curve and area under the curve of mice, respectively; Figure 3 C and D are the insulin tolerance curves and areas under the curves of mice, respectively; * in the figure indicates significant difference compared with the HFD group, * represents p < 0.05, ** represents p < 0.01, and *** represents p < 0.001.
[0020] Figure 4 The serum biochemical results of the mice after 32 days of experimental period in Example 1, wherein: Figure 4A in the figure corresponds to mouse serum alanine aminotransferase (ALT); Figure 4 B in the figure corresponds to mouse serum aspartate aminotransferase (AST); Figure 4 C in the figure corresponds to mouse serum glucose (GLU); Figure 4 D in the figure corresponds to mouse serum triglyceride (TG); Figure 4 E in the table corresponds to total cholesterol (TC) in mouse serum; Figure 4 F in the figure corresponds to mouse serum high-density lipoprotein cholesterol (HDL-C); Figure 4 The G in the figure corresponds to the serum low-density lipoprotein cholesterol (LDL-C) of mice; * in the figure indicates significant difference compared with the HFD group, * represents p < 0.05, ** represents p < 0.01, and *** represents p < 0.001.
[0021] Figure 5 The fecal biochemical and ELISA results of the mice after 32 days of experiment in Example 1 are as follows: Figure 5 A in the figure corresponds to glucose (GLU) in mouse feces; Figure 5 B in the figure corresponds to mouse fecal triglyceride (TG); Figure 5 The C in the table corresponds to the total cholesterol (TC) in mouse feces; Figure 5 The D in the table corresponds to high-density lipoprotein cholesterol (HDL-C) in mouse feces; Figure 5 E in the column corresponds to low-density lipoprotein cholesterol (LDL-C) in mouse feces; Figure 5 F in the figure corresponds to interleukin-6 (IL-6) in mouse feces; Figure 5 The G in the column corresponds to mouse fecal tumor necrosis factor α (TNF-α); Figure 5 The H in the column corresponds to leptin in mouse feces; Figure 5 The I in the table corresponds to mouse fecal glucagon-like peptide-1 (GLP-1); Figure 5 J in the figure corresponds to mouse fecal neuropeptide Y (PYY); Figure 5 The K in the figure corresponds to the total bile acid (TBA) in mouse feces; * in the figure indicates significant difference compared with the HFD group, * represents p < 0.05, ** represents p < 0.01, and *** represents p < 0.001.
[0022] Figure 6 The pathological sections of Liver, iWAT and BAT tissues of mice after 32 days of experiment in Example 1 are shown. Figure 6 A in the figure is HE staining of mouse Liver, iWAT, and BAT tissues; Figure 6 B in the figure corresponds to the area of mouse iWAT cells; Figure 6 C in the figure corresponds to the lipid droplet area of mouse liver tissue; Figure 6 D in the figure is the Oil Red O staining of mouse liver tissue; Figure 6E in the figure is Masson staining of mouse liver tissue; * in the figure indicates significant difference compared with the HFD group, * represents p < 0.05, ** represents p < 0.01, and *** represents p < 0.001.
[0023] Figure 7 The behavioral test results of mice after 32 days of experimental period in Example 1, wherein: Figure 7 A in the figure corresponds to the open field test of mice; Figure 7 B in the figure corresponds to the elevated plusmaze test for mice; Figure 7 C in the figure corresponds to the tail suspension test. Figure 7 The D in the figure corresponds to the forced swimming test in mice. Figure 7 E in the figure corresponds to the sucrose preference test in mice; * in the figure indicates significant difference compared with the HFD group, * represents p<0.05, ** represents p<0.01, and *** represents p<0.001. DETAILED DESCRIPTION
[0024] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely for the purpose of explaining the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
[0025] Example 1
[0026] This example relates to an in vivo experiment on reducing weight and lowering blood sugar and blood lipids using Ibiricola toxin, while using liraglutide as a comparison.
[0027] The Iberiotoxin used was purchased from Selleck (catalog number: E0015, purity: 99.42%), and its amino acid sequence is {Glp}-Phe-Thr-Asp-Val-Asp-Cys-Ser-Val-Ser-Lys-Glu-Cys-Trp-Ser-Val-Cys-Lys-Asp-Leu-Phe-Gly-Val-Asp-Arg-Gly-Lys-Cys-Met-Gly-Lys-Lys-Cys-Arg-Cys-Tyr-Gln (Disulfide bridge: Cys7-Cys28, Cys13-Cys33, Cys17-Cys35). That is to say, the amino acid sequence of Ibimotoxin can be regarded as the amino acid sequence shown in SEQ ID No. 1 connected to {Glp} (Glp represents pyroglutamic acid); and, with {Glp} as the first position, the Cys at the 7th position of the overall sequence is connected to the Cys at the 28th position through a disulfide bond (Disulfide bridge), the Cys at the 13th position is connected to the Cys at the 33rd position through a disulfide bond, and the Cys at the 17th position is connected to the Cys at the 35th position through a disulfide bond.
[0028] Liraglutide was purchased from MCE (Catalog No. HY-P0014, purity: 99.85%), and its amino acid sequence is His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-{Lys-N6-[N-(1-oxohexadecyl)-Lg-glutamyl]}-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly. In other words, the amino acid sequence of liraglutide can be considered to be obtained by modifying Lys at position 20 of the amino acid sequence shown in SEQ ID No. 2 with N6-[N-(1-oxohexadecyl)-Lg-glutamyl].
[0029] Specifically:
[0030] 1. Effect of Ibimotoxin on the Body Weight of Obese Mice Induced by a High-Fat Diet
[0031] Male C57BL / 6JGpt mice were obtained from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. All animals were housed in a specific pathogen-free (SPF) environment at a temperature of 22 ± 2°C and a 12-h light / dark cycle.
[0032] The experiment was divided into four groups, and each group underwent a 57-day modeling period (corresponding to "Days of injection" from -56 to 0, unit: day, e.g. Figure 1 ) and a 32-day experimental period (corresponding to "Days of injection" from 0 to 32, unit: day, as shown in Figure 1 shown).
[0033] Normal chow diet (NCD): Control mice were fed a normal diet during the modeling and experimental periods (the feed was purchased from Wuhan Wanqian Jiaxing Biotechnology Co., Ltd.).
[0034] High-fat diet (HFD): DIO obese mouse model induced by high-fat diet (high-fat feed purchased from Jiangsu Collaborative Pharmaceutical Bioengineering Co., Ltd., catalog number: XTHF60) was fed with a high-fat diet containing 60% fat (both during the modeling and experimental periods).
[0035] HFD+Liraglutide: High-fat diet-induced DIO obese mouse model + liraglutide, fed with a high-fat diet containing 60% fat during the modeling period, and fed with a high-fat diet containing 60% fat during the experimental period and simultaneously injected with liraglutide (100 μg / kg / d; i.e., 100 μg per kg body weight of the mouse per day) intraperitoneally, serving as the positive control group.
[0036] HFD+Iberiotoxin: DIO obese mouse model induced by high-fat diet + Iberiotoxin. The mice were fed with a high-fat diet containing 60% fat during the modeling period, and a high-fat diet containing 60% fat during the experimental period and were injected intraperitoneally with Iberiotoxin (500 μg / kg / d).
[0037] During this period, the body weight of mice was measured every two days. Figure 1 As shown in A, -56 to 0 days were the high-fat diet modeling period, and 0 to 32 days were the experimental period. During the experimental period, the body weight of the mice in the HFD+Iberiotoxin group was significantly reduced compared with that in the HFD group. This result indicates that Iberiotoxin can reduce the weight gain caused by a high-fat diet. Figure 1 Figures B and C show that compared with the HFD group, the body weight of mice in the HFD+Iberiotoxin group decreased by 27.2%, and the body weight of mice in the HFD+Liraglutide group decreased by 39.1%. At the same time, injection of Liraglutide and Iberiotoxin significantly reduced the mice's food intake and food intake per unit body weight ( Figure 1 C, D in the figure), but did not affect the water intake of mice ( Figure 1 E).
[0038] Figure 2Figure A shows that compared with the HFD group, the weight and body size of mice in the HFD+Iberiotoxin group were significantly reduced. At the same time, the morphology of liver tissue (Liver), inguinal white adipose tissue (iWAT), and brown adipose tissue (BAT) in the HFD+Iberiotoxin group were significantly reduced, and the wet weight was significantly reduced ( Figure 2 BD in ).
[0039] Effects of Ibimoto's venom on blood glucose regulation, serum, and feces in high-fat diet-induced obese mice
[0040] After the experimental period, the mice were tested for their ability to regulate blood sugar. Figure 3 Figures A and B show that compared with the HFD group, Iberiotoxin significantly enhanced the glucose tolerance of DIO mice; at the same time, the insulin sensitivity of mice was also significantly improved ( Figure 3 C, D in the above figure). Figure 3 The Time in is 0, which refers to the starting point of the glucose tolerance test and insulin tolerance test.
[0041] Serum samples of mice were collected to test liver function, blood glucose, and blood lipid levels, such as Figure 4 As shown in Figure AG, Iberiotoxin significantly reduced the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels of DIO mice, and significantly improved the liver function, blood glucose, and dyslipidemia of DIO mice.
[0042] Mouse fecal samples were collected to detect relevant biochemical and ELISA indicators, such as Figure 5 As shown in Figure AK, compared with the HFD group, there were no significant differences in fecal glucose (GLU), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), leptin (Leptin), glucagon-like peptide-1 (GLP-1), neuropeptide Y (PYY), and total bile acid (TBA) levels in the HFD+Iberiotoxin group. This suggests that Iberiotoxin primarily improves metabolic processes in the body, rather than intestinal absorption or intestinal flora activity, nor does it achieve weight loss by improving inflammation and hormone levels. During the experimental period, no gastrointestinal side effects such as nausea, constipation, or diarrhea were observed in any of the mice.
[0043] Effects of Ibimotoxin on Pathological Sections of Liver, iWAT, and BAT Tissues in High-Fat Diet-Induced Obese Mice
[0044] Mouse liver tissue (Liver), inguinal white adipose tissue (iWAT), and brown adipose tissue (BAT) were collected for HE staining. Figure 6 As shown in A and B, injection of Liraglutide and Iberiotoxin can improve the size of iWAT adipocytes and reduce lipid droplet accumulation; BAT cell morphology is closer to normal, and lipid droplets become smaller; and liver lipid droplet vacuoles are significantly reduced, indicating that the drugs may improve tissue abnormalities induced by a high-fat diet.
[0045] Oil red O staining of mouse liver tissue was performed. Figure 6 As shown in Figures C and D, injection of Liraglutide and Iberiotoxin can significantly reduce liver fat deposition induced by a high-fat diet, significantly improve liver steatosis, and reduce the degree of fat accumulation in hepatocytes. In addition, Masson staining of mouse liver tissues was performed, as shown in Figure 4. Figure 6 As shown in E, the blue collagen fiber component of DIO mice increased, but to a lesser extent, and there were more fat vacuoles and disordered liver tissue structure. After injection of Liraglutide and Iberiotoxin, some blue fibers still existed, but the fat vacuoles were significantly reduced, and the liver cell structure was improved.
[0046] 4. Effects of Ibimotoxin on the Behavior of High-Fat Diet-Induced Obese Mice
[0047] After the four groups of mice were continuously injected with the drug for one month, they were monitored with a series of behavioral experiments to assess the safety of the drug.
[0048] The mice were subjected to open field test and elevated plus maze test to assess their anxiety level. Figure 7 As shown in Figures A and B, injection of Liraglutide and Iberiotoxin did not lead to differences in the anxiety levels of mice. However, it was noted that the total movement distance of the mice in the open field decreased, suggesting that the drugs did not cause weight loss by increasing the amount of exercise.
[0049] The mice were subjected to tail suspension test, forced swimming test and sucrose preference test to assess the degree of depression in the mice. Figure 7As shown in CE, no difference in the depressive phenotype mediated by the serotonin system was detected in mice injected with Liraglutide and Iberiotoxin in the tail suspension test and forced swimming test. In the sucrose preference test, the mice injected with Iberiotoxin rescued the decreased sucrose preference index of DIO mice, indicating that Iberiotoxin can alleviate the depressive phenotype of DIO mice by regulating the dopamine system.
[0050] It can be seen that the present invention found that ibiricid scorpion toxin has health benefits of positively regulating basal metabolism in the obese mouse model induced by a high-fat diet, mainly including weight loss, lowering body fat, improving glucose tolerance and insulin resistance, thereby effectively alleviating obesity.
[0051] The above embodiments are merely examples. When Iberiotoxin is used in the preparation of weight loss drugs, it can be one or more pharmaceutically acceptable carriers of the amino acid sequence of Iberiotoxin, and the resulting weight loss drugs or products are pharmaceutically acceptable carriers and excipients. In addition, with the Iberiotoxin as the active ingredient, it can be prepared into any dosage form such as tablets, capsules, powders, mixtures, pills, sprays, granules, capsules, oral liquids, and injections according to actual conditions.
[0052] It will be easily understood by those skilled in the art that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.
Claims
1. Application of Ibirostris venom in the preparation of weight loss drugs.
2. Application of Ibi scorpion toxin in the preparation of products for controlling fat accumulation in organisms.
3. Application of Ibimotoxin in the preparation of functional foods for weight management.
4. Application of Ibirostris scorpion toxin in the preparation of products for reducing the body weight of organisms.
5. The use according to any one of claims 1 to 4, characterized in that: The weight-loss drug or the product is a pharmaceutically acceptable carrier and excipient.
6. The use according to any one of claims 1 to 4, characterized in that: The ibirostris scorpion toxin is used as an active ingredient to prepare any dosage form of tablets, capsules, powders, mixtures, pills, sprays, granules, capsules, oral liquids, and injections; Preferably, the amount of the active ingredient of ibirostris toxin administered is 500 μg of ibirostris toxin per kg body weight of the organism per day.
7. The use according to any one of claims 1 to 4, characterized in that: Ibibens venom can lower serum triglyceride and total cholesterol levels.
8. The use according to any one of claims 1 to 4, characterized in that: Ibi scorpion toxin can improve the glucose tolerance metabolism and insulin resistance metabolism of the organism.