Drug for lowering blood lipid

A drug and blood lipid technology, applied in the field of medicine and biology, can solve the problems of expensive antibody preparations, interference with PCSK9 maturation and secretion, and inconvenience of long-term administration

Pending Publication Date: 2019-12-27
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 2. Interfering with the maturation and secretion of PCSK9
[0009] Macromolecular antibody drugs and interfering RNA need to be administered by injection. Since dyslipidemia is a chronic disease, it is inconvenient for long-term administration, and the current antibody preparations are expensive

Method used

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  • Drug for lowering blood lipid
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  • Drug for lowering blood lipid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0211] Embodiment 1, the construction of human PCSK9 gene expression modulator screening model

[0212] 1. Obtaining the upstream and downstream regulatory sequences of the human PCSK9 gene

[0213] Using human genomic DNA extracted from human HepG2 cells as a template, the target fragment was amplified by PCR method, that is, PCSK9 upstream promoter (-2112~-1bp, a total of 2112bp, with A of the transcription start site ATG as +1) and downstream 3'UTR region sequence (total 1269bp). The amplified product was detected by agarose gel electrophoresis, showing a uniform band with the same size as the expected fragment.

[0214] 2. Construction of reporter gene recombinant plasmid

[0215] The amplified PCR product was purified and recovered, cloned into the pEasy-Blunt Zero Cloning Vector vector to obtain recombinant plasmids pT-PCSK9-P and pT-PCSK9-3'UTR, transformed into Trans-T1 competent cells, and picked transformants . After the plasmids were extracted from the transform...

Embodiment 2

[0254] Embodiment 2, the high-throughput screening of PCSK9 gene expression modulator

[0255] 1. Obtain primary screening and re-screening results for different screening models

[0256] Using the high-throughput drug screening model at the transcriptional level and post-transcriptional level of the human PCSK9 gene established in this study, 7 series of samples 7001B to 7065B in the National New Drug (Microbial) Screening Compound Library, a total of 5,200 samples of compounds to filter. A single compound was dissolved in 100% DMSO at a concentration of 10 mg / ml, and the final concentration for screening was 25 μg / ml. Down 50% as a positive screening. Through primary screening, secondary screening and verification, For the pGL4-PCSK9-P model, we Obtained 20 positive compounds (typical compounds are shown in Table 1.5 below) , The screening positive rate was 0.38%. against pGL4- PCSK9-3'UTR model, finally obtained 7 positive compounds (typical compounds are shown in...

Embodiment 3

[0276] Example 3, the impact of positive compounds on the expression level and function of PCSK9 and LDLR in HepG2 cells

[0277] 1. The effect of 7030B-C5 on the expression level and function of PCSK9 and LDLR in HepG2 cells

[0278] (1) Effect of 7030B-C5 on PCSK9 and LDLR mRNA levels in HepG2 cells

[0279] Through the study on the dose-effect relationship of the compound on the PCSK9 gene expression regulator screening model, it was shown that within a certain range, the effect of 7030B-C5 on the expression activity of luciferase in cells was negatively correlated, which explained the transcriptional inhibition of the compound on the target gene at the molecular level effect.

[0280] In order to further examine the biological activity of 7030B-C5, we used Real-Time PCR to study the effect of positive compounds on PCSK9mRNA in HepG2 cells. We added 2.5 μM, 5 μM, 12.5 μM, and 25 μM 7030B-C5 to HepG2 for 24 hours, then extracted the total cellular RNA and reverse-transcrib...

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PUM

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Abstract

The invention relates to a drug for lowering blood lipid. A structure of the drug is shown as a formula (1) to a formula (4) (please see the specification for the formula (1) to the formula (4)). Theinvention further relates to following application of a compound shown in the formula (1) to the formula (4) to: (1) preparation of drugs for treating atherosclerotic cardiovascular diseases; (2) preparation of drugs for adjusting blood glucose metabolism, wherein blood glucose metabolism adjusting refers to lowering of blood glucose, lowering of glycated serum protein, and lowering of glycated albumin; (3) preparation of drugs for reducing liver lipid accumulation and preventing fatty liver; and (4) preparation of preparations for inhibiting the expression of PCSK9 at the genetic level and improving the expression of LDLR.

Description

technical field [0001] The invention belongs to the technical field of medicine and biotechnology, and in particular relates to a medicine for lowering blood fat. Background technique [0002] Elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor for atherosclerosis [1] . Statins are first-line therapeutic drugs for the prevention and treatment of atherosclerotic cardiovascular diseases, mainly by reducing LDL-C levels [2,3] . However, clinically, there are still about 25% of patients with high risk of cardiovascular disease who have no obvious degree of lipid lowering after receiving sufficient statin therapy. [4] . Some patients are intolerant to statins and have adverse reactions such as myalgia and rhabdomyolysis [5] . As a result, a large number of trials have been exploring new targets and new treatments for lowering LDL-C. [0003] Proprotein convertase subtilisin 9 (PCSK9) is a newly discovered drug target for lowering LDL-C levels i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/522A61K31/4439A61K31/4184A61P3/06A61P9/10A61P3/10A61P1/16A61P9/00
CPCA61K31/522A61K31/4439A61K31/4184A61P3/06A61P9/10A61P3/10A61P1/16A61P9/00
Inventor 洪斌王丽陈晓芳王雪蕾杜郁杨梦夏张秀敏武彦彬李星星侍媛媛
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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