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WO2018171279A1 - Application du composé ss-31 pour la préparation d'un médicament pour le traitement de l'athérosclérose et de maladies associées - Google Patents

Application du composé ss-31 pour la préparation d'un médicament pour le traitement de l'athérosclérose et de maladies associées Download PDF

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WO2018171279A1
WO2018171279A1 PCT/CN2017/118835 CN2017118835W WO2018171279A1 WO 2018171279 A1 WO2018171279 A1 WO 2018171279A1 CN 2017118835 W CN2017118835 W CN 2017118835W WO 2018171279 A1 WO2018171279 A1 WO 2018171279A1
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preparation
compound
aortic
development
medicament
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PCT/CN2017/118835
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Chinese (zh)
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李宽钰
乔彤
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南京大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides

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  • the invention belongs to the field of chemical medicine and relates to the application of a compound Szeto-Schiller-31 (SS-31) for preparing a medicament for treating atherosclerotic diseases.
  • Atherosclerosis is the pathological basis of cardiovascular disease, including carotid stenosis, lower extremity arteriosclerosis obliterans and coronary heart disease.
  • the clinical manifestations and pathological features of these diseases are not the same, but they have the common characteristics: the slow development of the lesions, the narrowing of the lumen of the affected arteries, and the lack of blood supply to the distal tissues. So far, there is no ideal preventive drug, which has become a worldwide cause. The most important cause of human death. At present, the pathogenesis of these diseases is still controversial. Genetic, inflammatory, high-fat diet, aging and other complex factors are the common pathogenic factors of these diseases.
  • the pathological mechanisms include vascular endothelial injury and monocyte adhesion migration.
  • Atherosclerotic diseases are a serious hazard to human health, which brings great psychological and economic burden to patients, their families and society.
  • the development of drugs for the prevention and treatment of atherosclerosis has received much attention.
  • AS Arterial endothelial injury is the initial step of AS, and damaged endothelial cells secrete adhesion molecules and cytokines to recruit white blood cells.
  • the persistence of inflammation upregulates the expression of macrophage scavenger receptors, increases ox-LDL uptake, and promotes foam cell formation.
  • Foam cells are the most prominent inflammatory cells in AS plaques.
  • adhesion molecules such as intracellular adhesion molecules, vascular cell adhesion molecules and monocyte chemotactic factors are highly expressed in AS plaques. After adhering to endothelial cells via adhesion molecules, leukocytes are mediated by chemokines and penetrate into the intima of the blood vessels.
  • CD36 and LOX-1 are oxidative low-density lipoprotein (ox-LDL) receptors, which are lipoproteins on the surface of macrophages; ABCA1 and ABCG1 are lipoproteins on the surface of macrophages, and cholesterol is excreted and receptor HDL Or apolipoprotein A-I binding.
  • Szeto-Schiller-31 (SS-31) is a novel mitochondrial-targeting compound synthesized by Szeto in 2005. It can act on mitochondrial inner membrane cardiolipin to protect mitochondrial integrity in an animal model of renal ischemia. Reduce or inhibit the production of mitochondria-derived reactive oxygen species (ROS), increase the level of adenosine triphosphate (ATP), and reduce oxidative stress. Obviously these findings are not directly related to anti-atherosclerosis. At present, SS-31 has been applied to many human disease models and has shown certain effects.
  • ROS mitochondria-derived reactive oxygen species
  • ATP adenosine triphosphate
  • SS-31 has a protective effect on heart failure and hypertensive cardiomyopathy, although heart failure and hypertensive myocardium
  • the disease and the atherosclerotic disease involved in this application are completely different from the pathogenesis of the disease, the pathophysiological basis, the corresponding therapeutic drugs, therapeutic targets and treatment strategies, and it is impossible to give guidance and enlightenment, but we still want to Boldly try to see if SS-31 has a protective effect on atherosclerotic disease.
  • the object of the present invention is to discover a new medical use of SS-31 in the preparation of atherosclerosis and related diseases through a disease model associated with atherosclerotic diseases.
  • SS-31 is used in an animal model of atherosclerotic disease, and the results show that subcutaneous injection of SS-31 delays the development of mouse AS, blocks the formation of plaque, and stabilizes vulnerable plaque on the other hand.
  • SS-31 can reduce the level of aortic ROS in mice, reduce oxidative damage, increase ATP levels, improve systemic inflammation in mice, and decrease the expression of lipid uptake proteins (CD36 and LOX-1) in mouse aortic plaques. These results indicate that SS-31 can be used clinically as a therapeutic drug for AS or related diseases.
  • SS-31 itself or its main component is used in the treatment of atherosclerotic diseases including carotid stenosis, lower extremity arteriosclerosis obliterans and coronary heart disease.
  • SS-31 itself or its use as a main component in the preparation of the following drugs:
  • the present invention is the first to apply the novel mitochondrial-targeting compound SS-31 for the treatment of atherosclerosis and related diseases, and can be used as a new application for preparing drugs for treating atherosclerosis and related diseases, and has a huge market. Value and social benefits.
  • the present invention provides the use of SS-31 as a main component of a drug in atherosclerotic diseases.
  • SS-31 delays the development of atherosclerotic disease in mice, reduces the formation of plaques, and stabilizes vulnerable plaques.
  • FIG. 6 Effect of SS-31 on aortic reactive oxygen species (ROS) in ApoE -/- mice.
  • ROS reactive oxygen species
  • ApoE -/- mice Male 8-week-old ApoE -/- mice (genetic background: C57BL/6) were purchased from the Institute of Model Animals of Nanjing University. ApoE -/- mice were housed in SPF-class animal rooms and fed a high-fat diet. High-fat diet formula: 0.2% cholesterol and 20% fat mixed with conventional feed. ApoE -/- mice were randomly divided into control group (P), low-dose drug group (M1, 1 mg/kg/d) and high-dose drug group (M3, 3 mg/kg/d), with 30 rats in each group.
  • P control group
  • M1, 1 mg/kg/d low-dose drug group
  • M3, 3 mg/kg/d high-dose drug group
  • Group P was injected subcutaneously with 5 mL ⁇ kg -1 ⁇ d -1 saline, and M1 group was injected subcutaneously with SS-31 5 mL ⁇ kg -1 ⁇ d -1 (SS-31 powder was dissolved in physiological saline at a concentration of 0.2 mg ⁇ mL -1 , Shanghai Qiang Yao Biotechnology Co., Ltd. synthesis, dose reference), M3 group subcutaneous injection of SS-31 5mL ⁇ kg -1 ⁇ d -1 (concentration 0.6mg ⁇ mL -1 ).
  • mice were anesthetized by intraperitoneal injection of pentobarbital (40 mg ⁇ kg -1 ), blood was taken through the inferior vena cava, the anesthetic dose (80 mg ⁇ kg -1 ) was added, and the neck dislocation was sacrificed, and the heart and aorta were collected.
  • Cardiac specimens were fixed in 4% paraformaldehyde for 24 hours, embedded in OCT or embedded in paraffin, and 10 slices of 6 ⁇ m thick paraffin or frozen sections were continuously cut in the microtome. The aortic sinus paraffin sections were stored at room temperature for use.
  • TG serum triglyceride
  • TC total cholesterol
  • Enzyme-linked immunosorbent assay (ELISA) kit detects intracellular adhesion molecule-1 (ICAM-1) and monocyte chemotaxis Factor-1 (Monocyte chemoattractant protein, MCP-1), interleukin (IL-6) and C-reactive protein (CRP) levels.
  • ICM-1 intracellular adhesion molecule-1
  • MCP-1 monocyte chemotaxis Factor-1
  • IL-6 interleukin
  • CRP C-reactive protein
  • the aorta was embedded in OCT immediately after excision. After cryopreservation, a 6 ⁇ m thick slice was sliced on a glass slide. The fluorescent probe (Dihydroethidium, DHE, 10 ⁇ M, Sigma-Aldrich, USA) was incubated at 37 ° C for 30 min in the dark. Focusing microscope (ZEISS HB050, ZEISS, Germany) observed fluorescence, and fluorescence strongly reacted with ROS levels. Immediately after the aorta was isolated, the ATP level and total SOD activity were measured using the ATP test kit (Shanghai Biyuntian Biotechnology Co., Ltd.) and the SOD test kit (Nanjing Institute of Bioengineering).
  • aorta was lysed by lysate (Thermo Fisher Scientific, UK), the protein concentration determined by BCA method, 35 ⁇ g of total protein extract was electrophoresed on a 12% SDS-PAGE gel, and transferred to a nitrocellulose transfer membrane (Nitrocellulose).
  • tissue sections of the mice were dewaxed, hematoxylin staining for 4 min, Masson's modified trichrome dyeing for 8 min, bright green staining for 8 min, 0.2% ammonium acetate wash to no dye shedding, dehydration, transparency, sealing, observation under light microscope And take pictures.
  • Image J software was used to analyze the amount of collagen (blue) in the plaque.
  • mice Tissue sections of mice were dewaxed, antigen-repaired, 3% H 2 O 2 inhibited endogenous peroxidase, primary antibody (1:200 dilution) was incubated for 1.5 h at room temperature, and secondary antibody (1:200 dilution) was incubated for 30 min at room temperature. DAB coloration, hematoxylin counterstaining. After the staining was completed, it was observed under an optical microscope and photographed.
  • CD68 macrophage molecular marker
  • ⁇ -SMA smooth muscle cell molecular marker
  • CD36 antibody was purchased from Proteintech Group, USA
  • LOX-1 antibody was purchased from Santa Cruz Biotech, USA
  • ABCA1 antibody was purchased from US Signalway Antibody LLC
  • secondary antibody goat anti-rabbit or oxygen anti-mouse
  • the P group ApoE -/- mice were similar in weight to the administration group (M1 and M3) at 8 and 20 weeks, and the serum TC and TG in the administration group were similar to the P group at 20 weeks, as shown in Table 1.
  • Gross aortic red staining of the aorta revealed a significant reduction in plaque area in the ApoE -/- mice of the M1 and M3 groups, as shown in Figure 1, and quantified on the right. Oil red staining of the frozen section of the aortic sinus area showed that the plaque size of the ApoE -/- mice in the M1 and M3 groups was significantly reduced, as shown in Fig. 2, and the quantified map below.
  • the plaque composition changes were studied by CD68, ⁇ -SMA immunohistochemistry and Masson special staining. As shown in Fig. 3, the immunohistochemical positive areas of CD68 in M1 and M3 groups were significantly reduced, and the quantitative map was below; Fig. 4 is ⁇ -SMA. Immunohistochemistry showed a significant increase in smooth muscle cells at the plaques of ApoE -/- mice in the M1 and M3 groups, with quantified maps below; Figure 5 is a special staining of Masson, blue area is quantified below, and ApoE -/- is small in M1 and M3 groups. Collagen increased significantly at the plaque of the mouse. The above results indicate that the plaque area of the SS-31 group is significantly reduced and the plaque is more early and more stable. Therefore, SS-31 can be used to block the formation of atherosclerotic plaque and delay the development of AS.
  • 2.2SS-31 reduces aortic oxidative stress levels in ApoE -/- mice and increases aortic ATP synthesis
  • FIG. 6 is a DHE staining of aortic frozen sections.
  • the red positive areas of ApoE -/- mice in the M1 and M3 groups were significantly reduced, indicating a decrease in ROS levels and a decrease in oxidative stress in ApoE -/- mice.
  • Aortic ATP results showed a significant increase in aortic ATP levels in the M1 and M3 groups, as shown in Figure 7.
  • SOD is the main protein for ROS clearance in cells, including SOD1 in cells and SOD2 in mitochondria.
  • SOD2 plays a major role.
  • Aortic Western blotting showed no change in SOD2 protein levels, as shown in Figure 8, below which is a quantitative map; but the total aortic SOD activity was significantly increased, as shown in Figure 9.
  • Increased ROS levels impair DNA, and 8-OHDG immunohistochemistry was used to detect arterial DNA damage.
  • the results showed that the 8-OHDG-positive area of mice in M1 and M3 groups was significantly reduced, as shown in Figure 10, and the upper part was 8-OHDG immunized.
  • Histochemical image below is a quantitative map of positive areas. The above results indicate that SS-31 reduces the level of arterial oxidative stress and can therefore be used to reduce aortic oxidative damage and further expansion of atheromatous plaques.
  • ICAM-1 and MCP-1 are the major inflammatory factors in AS, promoting the adhesion of monocytes/macrophages to endothelial cells and migration to the inner membrane.
  • the serum levels of ICAM-1 and MCP-1 in the M1 and M3 mice were significantly reduced (see Table 1).
  • Macrophages that migrate to the endothelium secrete pro-inflammatory factors, including IL-6, IL-1 ⁇ and Tumor necrosis factor alfa (TNF- ⁇ ). These inflammatory factors mediate systemic inflammatory responses, such as activation of acute phase proteins encoded by the liver gene, including CRP and serum amyloid A (SAA).
  • Serum IL-6 was significantly decreased in the ApoE -/- mice of the M1 and M3 groups, and CRP was slightly decreased, as shown in Table 1.
  • the above results indicate that SS-31 can improve the systemic inflammation level of ApoE -/- mice, which is beneficial to delay the further development of atheroma.
  • 2.4SS-31 reduces the expression of aortic lipid uptake protein in ApoE -/- mice
  • Foam cell formation is the key to the emergence of early plaques in AS. Excessive intake of Oxidized low-density lipoprotein (ox-LDL), excessive cholesterol esterification, and impaired cholesterol release lead to accumulation of cholesterol esters, formation of lipid droplets, and the cells gradually transform into foam cells.
  • CD36 Cluster of differentiation 36
  • LOX-1 Lectin-like ox-LDL receptor-1
  • ABCA1 ATP-binding cassette A1 is a lipid.
  • Excrete protein is a lipid.
  • Table 1 mouse body weight and serum lipid index.

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Abstract

L'invention concerne une application du composé Szeto-Schiller (SS-31) pour la préparation d'un médicament pour le traitement de l'athérosclérose et de maladies associées, telles que la sténose carotidienne, l'artériopathie oblitérante des membres inférieurs et la coronaropathie. Le composé SS-31 découvert permet de soulager le processus de l'athérosclérose de la manière suivante : réduction sensible du niveau de ROS dans les artères de souris, réduction du stress oxydant, augmentation du niveau d'ATP; réduction sensible de la teneur en macrophages à l'emplacement de la plaque athéromateuse fibreuse, augmentation sensible de la teneur en cellules musculaires lisses et de la teneur en collagène à l'emplacement de la plaque athéromateuse fibreuse et stabilisation de cette dernière; modification senseible du degré d'inflammation; et réduction sensible de l'expression d'une protéine d'absorption de lipide à l'emplacement de la plaque athémorateuse fibreuse. Les résultats ont montré que le SS-31 a une action thérapeutique contre l'athérosclérose et les maladies associées.
PCT/CN2017/118835 2017-03-24 2017-12-27 Application du composé ss-31 pour la préparation d'un médicament pour le traitement de l'athérosclérose et de maladies associées WO2018171279A1 (fr)

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CN107041946A (zh) * 2017-03-24 2017-08-15 南京大学 化合物ss‑31在制备治疗动脉粥样硬化及相关疾病药物或制剂上的应用
EP3771467A1 (fr) * 2019-07-30 2021-02-03 Fundacio Institut de Recerca de l'Hospital de la Santa Creu i sant Pau Ss-31 pour la prévention et/ou le traitement de l'anévrisme
CN113143922B (zh) * 2021-05-07 2022-12-20 广州医科大学 Dhc在制备动脉粥样硬化治疗制剂中的应用
CN115400201A (zh) * 2021-05-26 2022-11-29 四川大学华西医院 Ss-31在制备预防和/或治疗香烟诱导的气道炎症及慢性阻塞性肺疾病的药物中的用途
CN113476587B (zh) * 2021-07-19 2022-07-12 河南大学 一种脑靶向的神经保护剂ss31-ha-rt及其制备方法和应用
CN113975402B (zh) * 2021-07-19 2023-05-16 河南大学 靶向脑缺血区线粒体的神经保护药物ss31-ha-qt及其荧光探针和应用
CN116602952A (zh) * 2023-03-28 2023-08-18 浙江大学 脂肪代谢因子lipoxinB4在制备动脉粥样硬化治疗药物中的应用

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