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Application of Chinese herbal monomer in preparation of drugs capable of inhibiting PCSK9 targets

A drug and inhibitor technology, which is applied in the application field of preparing proprotein convertase subtilisin 9 target inhibitory drugs, can solve the problems of high research and development costs of monoclonal antibody drugs, high price, poor compliance of monoclonal antibody injections, etc.

Active Publication Date: 2019-01-04
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, PCSK9 monoclonal antibody inhibitors are all injections, and clinical adverse reactions are similar to swelling, pain and allergies, etc., and the use compliance is poor
The research and development costs of monoclonal antibody drugs are high and expensive. Alirocumab and Evolocumab need to pay high medical expenses of US$14,300 / year and US$14,523 / year respectively. Long-term use makes patients overwhelmed
In recent years, people have gradually focused on the development of small-molecule PCSK9 inhibitors to overcome the disadvantages of poor patient compliance and high price of monoclonal antibody injections. Currently, small-molecule PCSK9 inhibitors are all in preclinical research

Method used

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  • Application of Chinese herbal monomer in preparation of drugs capable of inhibiting PCSK9 targets
  • Application of Chinese herbal monomer in preparation of drugs capable of inhibiting PCSK9 targets
  • Application of Chinese herbal monomer in preparation of drugs capable of inhibiting PCSK9 targets

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Preparation and identification of embodiment 1, KCGR

[0023] KCGR is separated and purified in our laboratory, and the specific separation steps are carried out by referring to the literature [12] , see NMR spectrum figure 1 and figure 2 .

[0024] Compound KCGR: yellow solid powder, λ max 266, 314nm, suggesting flavonoids. 1 HNMR (600MHz, MeOD): δ1.05 (3H, d, J = 6.2Hz, Me rha), δ3.82 (1H, dd, J = 9.8, 3.5Hz, H-3rha), δ4.39 (1H, dd, J=3.5, 1.2Hz, H-2rha), δ4.48 (1H, d, J=8.0Hz, H-1glc), δ5.81 (1H, d, J=1.2Hz, H-1rha), δ5.99(1H,d,J=16Hz,H-8coum), δ6.16(2H,d,J=2.0Hz,H-6and H-8), δ6.68(2H,d,J=8.5Hz ,H-3coum and H-5coum), δ6.91(2H,d,J=8.8Hz,H-3',H-5'),δ7.20(2H,d,J=8.5Hz,H-2coum and H-6coum), δ7.41 (1H, d, J = 16Hz, H-7coum), δ7.67 (2H, d, J = 8.8Hz, H-2', H-6'). 13 C-NMR (151MHz, MeOD): δ158.33 (C-2), 136.77 (C-2), 179.52 (C-4), 163.32 (C-5), 100.03 (C-6), 165.66 (C- 7), 95.01(C-8), 158.37(C-9), 105.84(C-10), 122.62(C-1'), 131.93(C-2', C-6'), 116.62(C-3 ', C-5...

Embodiment 2

[0025] Embodiment 2, the influence of KCGR on TG, TC, HDL-C and LDL-C of hyperlipidemia mice

[0026] 1. Experimental animals

[0027] Healthy female ICR mice, clean grade, weighing 18-22 g, were provided by the Animal Center of Yangzhou University. The experimental animals were raised in an independent environment with 12h-12h alternation of day and night, the room temperature was maintained at 24±2°C, water and food were free to drink, and the experiment was carried out after 1 week of adaptation to the environment. All handling of animals followed the requirements of the Ethics Committee of the International Association for the Study of Pain.

[0028] 2. Experimental materials

[0029] KCGR was isolated in our laboratory. Basic feed and high-fat feed (containing 3% cholesterol). Triglyceride (TG) test kits, total cholesterol (TC) test kits, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) test kits were purchased from Nanjing ...

Embodiment 3

[0042] Embodiment 3, expression and purification of PCSK9 and EGF-A protein

[0043] PCSK9 mainly binds to the EGF-A domain of LDLR, leading to the degradation of LDLR, reducing the ability of cells to absorb LDL, and exerting its activity in regulating lipid metabolism. In order to facilitate purification and subsequent detection, the expression and purification of PCSK9 and EGF-A proteins were performed separately. A His tag was added to the N-terminal of PCSK9, and a GST tag was added to the N-terminal of EGF-A. His-PCSK9 [15] and GST-EGF-A [16] The expression and purification of protein were carried out according to literature. His-PCSK9 crude bacterial solution was adsorbed by Ni column, and imidazole was eluted sequentially to obtain His-PCSK9 protein ( image 3 ). The GST-EGF-A crude bacterial liquid is captured by the GST adsorption column, and glutathione is eluted to obtain the GST-EGF-A protein ( Figure 4 ).

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Abstract

The invention relates to the field of lipid reduction based on Kaempferol 3-O-2''-(6'''-p-coumaroyl) glucosylrhamnoside (KCGR) and discloses application of the KCGR in preparation of drugs capable ofinhibiting PCSK9 targets. It is discovered for the first time that the KCGR has the specificity of inhibiting the combination activity of PCSK9 and LDLR and can be compatibly combined in an active pocket area of a PCSK9 crystal structure and form stable hydrogen bonds with multiple amino acid residues, and therefore the KCGR is a novel micromolecular inhibitor for the PCSK9. The KCGR can lower thelevel of TC, TG and TDL-C in plasma of a hyperlipidaemia model mouse and raise the level of HDL-C, has the effect of alleviating lipid metabolism disorder caused by hyperlipidaemia and can be used for preventing or treating cardiovascular diseases and hyperlipidaemia.

Description

technical field [0001] The invention relates to a traditional Chinese medicine monomer component drug capable of specifically affecting the target point of proprotein convertase subtilisin 9 (PCSK9) to achieve lipid-lowering effect, and the drug is used in the preparation of proprotein convertase subtilisin 9 (PCSK9) target Application in Point Inhibitory Drugs. Background technique [0002] Dyslipidemia is one of the risk factors for cardiovascular disease. The 2013 guidelines of the American College of Cardiology and the American Heart Association pointed out that hypercholesterolemia, mainly elevated low-density lipoprotein cholesterol (LDL-C), is the most important cause of coronary heart disease, ischemic stroke, and peripheral arteriosclerosis. risk factor. At present, the common lipid-lowering drugs in clinical practice mainly include statins, fibrates, nicotinic acid, and cholesterol absorption inhibitors, among which statins are the drugs of choice for clinically ...

Claims

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Application Information

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IPC IPC(8): A61K31/7048A61P3/06A61P3/00A61P9/00
CPCA61K31/7048A61P3/00A61P3/06A61P9/00
Inventor 刘吉华刘秀峰李丽
Owner CHINA PHARM UNIV
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