Application of ALDH2 small molecule agonists in the preparation of drugs for treating cardiovascular diseases and metabolic diseases

Abstract

The present invention discloses the use of an ALDH2 small molecule agonist in the preparation of a drug for treating cardiovascular diseases and metabolic diseases thereof. The ALDH2 small molecule agonist is Tedizolid, and the drug is a targeted drug, with Tedizolid as an active ingredient and ALDH2 protein as a target. The present invention screened Tedizolid through a cardiovascular disease model to effectively promote the activity of ALDH2 to achieve the function of protecting the heart. At the same time, through a diabetic cardiomyopathy disease model, it was found that Tedizolid can reduce the toxic side effects of a high sugar environment on the heart, especially the toxic side effects of STZ diabetes on the heart, confirming that the ALDH2 small molecule agonist Tedizolid can be used to treat cardiovascular diseases and metabolic diseases thereof, and is expected to provide a new targeted drug for clinical treatment.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to the use of ALDH2 small molecule agonists in the preparation of drugs for treating cardiovascular diseases and metabolic diseases thereof. Background Art

[0002] Surgical correction is the main treatment for congenital heart disease. Deformity correction under direct surgical vision requires the assistance of extracorporeal circulation (CPB), and a certain period of aortic occlusion is required to obtain a clear surgical field. The resulting myocardial ischemia and ischemia-reperfusion (I / R) injury will be inevitable. Congenital heart disease surgery often requires a long aortic occlusion time. The current myocardial protective solution still cannot avoid I / R injury, and there is still a high incidence of postoperative low cardiac output syndrome. Therefore, it is necessary to improve the existing myocardial protection strategy to improve the efficacy of congenital heart disease surgery.

[0003] Aldehyde dehydrogenase 2 (ALDH2) is an important detoxification enzyme secreted by various cells in the human body. It is mainly located in the mitochondria and can protect the body from damage by endogenous and exogenous harmful substances. Previous studies have found that in various cardiovascular disease models such as diabetes, obesity and sepsis, overexpression of ALDH2 alleviates mitochondrial damage and endoplasmic reticulum stress response, inhibits the body's oxidative stress response, thereby protecting cells from damage in stress states and reducing organ damage caused by stress response. Oxidative stress is the most important mechanism of I / R injury. During the I / R process, a large amount of reactive oxygen species (ROS) will be produced. Under the attack of ROS, unsaturated lipids in cells are oxidized, among which acetaldehyde is the metabolite with the highest production and the strongest toxicity. Since acetaldehyde is much more stable than ROS, it will diffuse throughout the organs, amplifying the effect of oxidative damage. 4-HNE (4-hydroxynonenal) and MDA (malondialdehyde) are the main metabolites of acetaldehyde. With the accumulation of aldehydes in the heart, they will have a great toxic effect on myocardial cells. Studies have shown that acetaldehyde metabolites such as 4-HNE and MDA can affect glycolysis and change the activity of proteasomes. More importantly, they can directly inhibit the function of the mitochondrial respiratory chain, promote the opening of the mitochondrial permeability conversion channel, and directly lead to mitochondrial dysfunction. Therefore, aldehyde metabolites play an extremely important role in I / R injury.

[0004] In summary, ALDH2, as an enzyme that degrades aldehyde metabolites, plays a pivotal role in the cardiovascular system, but no agonists have been reported. Therefore, further identification of small molecule agonists of ALDH2 is expected to provide new strategies for the prevention and treatment of clinical cardiovascular diseases and congenital heart disease surgery. Summary of the invention

[0005] In view of the above-mentioned deficiencies in the prior art, the present invention provides the use of ALDH2 small molecule agonists in the preparation of drugs for the treatment of cardiovascular diseases and metabolic diseases thereof, which makes up for the defect that there are no ALDH2 agonists that can be used in vivo in current basic research. It is derived on the basis of basic experiments and is expected to provide new strategies for the prevention and treatment of clinical cardiovascular diseases.

[0006] To achieve the above object, the technical solution adopted by the present invention is:

[0007] The present invention provides an application of an ALDH2 small molecule agonist in the preparation of a drug for treating cardiovascular diseases and metabolic diseases thereof. The ALDH2 small molecule agonist is Tedizolid, and its structural formula is

[0008] Preferably, the cardiovascular disease and metabolic diseases thereof include diabetic cardiomyopathy.

[0009] Preferably, the drug is a targeted drug.

[0010] Preferably, the drug uses tedizolid as an active ingredient and uses ALDH2 protein as a target.

[0011] Preferably, the drug further comprises a pharmaceutically acceptable drug carrier or excipient, selected from one or a combination of two or more of a filler, a binder, a solubilizer, a disintegrant and a glidant.

[0012] Preferably, the filler is selected from one or a combination of two or more of lactose, microcrystalline cellulose, starch, dextrin, fructose, sucrose, mannitol, sorbitol, xylitol, and maltitol;

[0013] and / or the binder is selected from one or a combination of two or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, gum arabic, guar gum, xanthan gum, dextrin and starch;

[0014] and / or the solubilizing agent is selected from one or a combination of two or more of sodium lauryl sulfate, poloxamer, β-cyclodextrin, hydroxypropyl β-cyclodextrin, hydroxyethyl β-cyclodextrin, α-cyclodextrin, polysorbate, polyethylene glycol, and polyvinyl pyrrolidone;

[0015] and / or the disintegrant is selected from one or a combination of two or more of crospovidone, croscarmelose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and microcrystalline cellulose;

[0016] And / or the glidant is selected from one or a combination of two or more of magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, polyethylene glycol, and sodium octadecyl fumarate.

[0017] Preferably, the drug is prepared as a pharmaceutically acceptable drug preparation, and the dosage form is selected from one or a combination of two or more of tablets, capsules, pills, granules, suspensions, oral liquids, coatings, papules, sprays, powder injections and water injections.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The present invention is derived from basic experiments. By screening small molecule agonists targeting ALDH2 in various cardiovascular disease models, it was found that Tedizolid can effectively promote the activity of ALDH2 to protect the heart. At the same time, it was verified in animal models and cell models that Tedizolid intervention can improve myocardial hypertrophy, myocardial cell pyroptosis and other processes, but Tedizolid cannot play the above role in ALDH2-KO mice and cell models, which confirms that the ALDH2 small molecule agonist Tedizolid can be used to treat cardiovascular diseases and metabolic diseases, and is expected to provide new targeted drugs for clinical treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0021] Figure 1 The molecular structure of the ALDH2 small molecule agonist Tedizolid.

[0022] Figure 2 The results of screening small molecule compounds and verifying the activity of Tedizolid in promoting ALDH2 in the drug-induced myocardial injury model in the embodiment are as follows: NG: control group; HG: high glucose treatment group; NG-Tedizolid: drug alone group; HG-Tedizolid: high glucose injury treatment group; NG-Tedizolid-Daidzin: drug combination group; HG-Tedizolid-Daidzin: high glucose injury combination treatment group, wherein Daidzin is soybean glycoside with a molecular structure of

[0023] Figure 3The results of verifying that Tedizolid alleviates myocardial cell dysfunction caused by diabetes in the examples, wherein NG: control group; HG: high glucose treatment group; NG-Tedizolid: drug itself group; HG-Tedizolid: high glucose damage treatment group; PRKKO: mitochondrial autophagy protein parkin knockout group; A: cell contraction intensity; B: maximum cell contraction rate; C: maximum cell relaxation rate; D: cell relaxation time.

[0024] Figure 4 The results of verifying the effect of Torezolid in alleviating the toxic and side effects of STZ diabetes (streptozotocin-induced diabetes) on the heart in the examples, wherein Control: control group; DM: diabetes group (200 mg / kg, 4 weeks); Control-Tedizolid (10 mg / kg, 4 weeks): drug blank group; DM-Tedizolid: diabetes drug treatment group (200 mg / kg+10 mg / kg, 4 weeks); A: left ventricular end-diastolic size; B: left ventricular end-systolic size; C: short-axis contraction rate; D: ejection fraction; E: left ventricular mass; F: heart rate. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical solution and advantages of the embodiment of the present invention clearer, the technical solution of the embodiment of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the embodiment of the present invention. Obviously, the described embodiment is a part of the embodiment of the present invention, not all of the embodiments. Based on the described embodiment of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] The molecular structure of Tedizolid used in the following examples is as follows Figure 1 As shown, it can be synthesized by existing synthetic routes, or purchased from the current market, for example, from Welsman Bioengineering Company.

[0027] Example 1

[0028] In this example, a drug-induced myocardial injury model was constructed and small molecule compounds were screened. It was found that Tedizolid can effectively promote the activity of ALDH2 and protect the damaged heart. This ALDH2 activation effect can be reversed by the ALDH2-specific inhibitor Daidzin. At the same time, after high sugar treatment (mimicking diabetes), the decrease in ALDH2 activity can be rescued by Tedizolid, that is, Tedizolid can effectively upregulate ALDH2 activity and rescue the decrease in ALDH2 activity after high sugar treatment. In addition, through software models such as Autodock, it was found that Tedizolid forms hydrogen bonds with the GLU268, GLN349 and ASP346 amino acid residues of the ALDH2 protein, playing a key role in the binding of Tedizolid to ALDH2 ( Figure 2 ).

[0029] Example 2

[0030] Diabetic cardiomyopathy is an important complication of diabetes that can cause myocardial damage. In this example, a drug-induced myocardial cell dysfunction model was constructed and the effect of Tedizolid on alleviating myocardial cell dysfunction caused by diabetes was verified, wherein NG: control group; HG: high glucose treatment group; NG-Tedizolid: drug itself group; HG-Tedizolid: high glucose damage treatment group; PRKKO: mitochondrial autophagy protein parkin knockout group; A: cell contraction intensity; B: maximum cell contraction rate; C: maximum cell relaxation rate; D: cell relaxation time. The results are shown in Figure 2. Figure 3 As shown, Tedizolid can alleviate the toxic side effects of high-glucose environment on the heart, and this effect is achieved through mitochondrial autophagy.

[0031] Example 3

[0032] In this example, the streptozotocin-induced diabetes model was used to verify that Torezolid alleviates the toxic side effects of STZ diabetes on the heart, wherein Control: control group; DM: diabetes group (200 mg / kg, 4 weeks); Control-Tedizolid (10 mg / kg, 4 weeks): drug blank group; DM-Tedizolid: diabetes drug treatment group (200 mg / kg+10 mg / kg, 4 weeks); A: left ventricular end-diastolic size; B: left ventricular end-systolic size; C: short-axis contraction rate; D: ejection fraction; E: left ventricular mass; F: heart rate, the results are as follows Figure 4 As shown, Torezolid (10 mg / kg) can alleviate the side effects of STZ diabetes on the heart.

[0033] In summary, the present invention, on the one hand, screens small molecule agonists targeting ALDH2 in a variety of cardiovascular disease models and finds that Tedizolid can effectively promote the activity of ALDH2 to protect the heart. On the other hand, in vivo experiments also found that Tedizolid can mitigate the toxic side effects of high sugar environments on the heart, especially Torezolid (10 mg / kg) can mitigate the toxic side effects of STZ diabetes on the heart, confirming that the ALDH2 small molecule agonist Tedizolid can be used to treat cardiovascular diseases and metabolic diseases, and is expected to provide new targeted drugs for clinical treatment.

[0034] The above is only a preferred embodiment of the present invention, but the present invention should not be limited to the contents disclosed in the embodiment. Therefore, any equivalent or modification completed without departing from the spirit disclosed in the present invention shall fall within the scope of protection of the present invention.

Claims

1. Use of an ALDH2 small molecule agonist in the preparation of a drug for treating cardiovascular diseases and metabolic diseases, wherein the ALDH2 small molecule agonist is tedizolid, and its structural formula is The metabolic disease of the cardiovascular disease is diabetic cardiomyopathy.

2. The use according to claim 1, characterized in that: The drug is a targeted drug.

3. The use according to claim 2, characterized in that: The drug has tedizolid as an active ingredient and ALDH2 protein as a target; The drug also includes a pharmaceutically acceptable drug carrier selected from one or a combination of two or more of a filler, a binder, a solubilizer, a disintegrant and a glidant.

4. The use according to claim 3, characterized in that: The filler is selected from one or a combination of two or more of lactose, microcrystalline cellulose, starch, dextrin, fructose, sucrose, mannitol, sorbitol, xylitol, and maltitol; and / or the binder is selected from one or a combination of two or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, gum arabic, guar gum, xanthan gum, dextrin and starch; and / or the solubilizing agent is selected from one or a combination of two or more of sodium lauryl sulfate, poloxamer, β-cyclodextrin, hydroxypropyl β-cyclodextrin, hydroxyethyl β-cyclodextrin, α-cyclodextrin, polysorbate, polyethylene glycol, and polyvinyl pyrrolidone; and / or the disintegrant is selected from one or a combination of two or more of crospovidone, croscarmelose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and microcrystalline cellulose; And / or the glidant is selected from one or a combination of two or more of magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, polyethylene glycol, and sodium octadecyl fumarate.

5. The use according to any one of claims 1 to 4, characterized in that: The drug is prepared as a pharmaceutically acceptable drug preparation, and the dosage form is selected from one or a combination of two or more of tablets, capsules, pills, granules, suspensions, oral liquids, coatings, papules, sprays, powder injections and water injections.

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