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Polypeptide CM4-R and application thereof

A CM4-R, application technology, applied in the field of polypeptide CM4-R and its application, can solve problems such as unsatisfactory male effect, and achieve the effect of QT interval prolongation correction and arrhythmia correction

Active Publication Date: 2020-11-03
中国医科大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have confirmed that β-blockers have different clinical effects on different LQTS subtypes. β-blockers can effectively reduce the risk of LQT1 and LQT2; Body blockers can only reduce the risk of disease in women, and the effect on men is not ideal. The above shows that there are differences and deficiencies in the treatment of different LQTS subtypes by β-blockers

Method used

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  • Polypeptide CM4-R and application thereof
  • Polypeptide CM4-R and application thereof
  • Polypeptide CM4-R and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Polypeptide CM4-R was synthesized by solid phase synthesis.

[0035] Peptide CM4-R (Gill Biochemical (Shanghai) Co., Ltd., Lot No: P171026-CQ616455).

[0036] The amino acid sequence of a polypeptide for treating QT prolongation caused by CaM mutation is as follows: CM4-R: GRKKRRQRRRGEVDEMIREADIDGDGQVNYEEFVQMM, MW: 4426.93. The purity of the peptide was detected by HPLC as figure 1 As shown in Table 1, it can be seen from the spectrum that the purity of the polypeptide CM4 is (6937832 / 7675371)×100%=90.39%.

[0037] Table 1. CM4-R HPLC detection related parameters.

[0038]

Embodiment 2

[0039] Embodiment 2 Langendorff perfusion experiment.

[0040] Guinea pigs were injected with heparin (150U / kg / ip) and anesthetized with sodium pentobarbital (40mg / kg / ip). The trachea is connected to an artificial respirator. The aorta was cannulated in situ under artificial respiration. The heart is quickly removed and mounted on a perfusion set. Coronary arteries were retrogradely perfused with Krebs-Henseleit (K-H) solution (5.4mM glucose, 116.0mM NaCl, 3.6mM KCl, 23.0mM NaHCO 3 , 1.16mM KH 2 PO 4 , 1.2mM CaCl 2 , 0.58mM MgSO 4 , 0.3mM pyruvate, and 2.8U·L - 1 insulin), and the heart was kept in a constant temperature room at 37°C. Coronary perfusion pressure was monitored during aortic cannulation and adjusted to a range of approximately 60-70 mmHg. Place the negative pole of the electrode in the right atrium, and the positive pole in the left ventricle (apex), and record the electrocardiogram (QT interval) using a biological experiment system. In this experimen...

Embodiment 3

[0055] Embodiment 3 Whole animal experiment.

[0056] The mice were randomly divided into four groups: (1) Control group: 0.9% NaCl; (2) CM4 group: 21mg / kg CM4; (3) CM4-R group: 21mg / kg CM4-R; (4) CM4+CM4 -R group: 21mg / kg CM4+42mg / kg CM4-R, administered for 3 weeks.

[0057] After 3 weeks, mice in each group were anesthetized with isoflurane (3%, inhalation). In order to determine the effect of CM4 on the QT interval of mice, we first used the biological experiment system (Chengdu Taimeng Software Co., Ltd., Chengdu, China) to detect the ECG, such as Figure 6-7 shown. The two ECG electrodes are placed in the standard lead II direction. Calculate the QT interval. The calculation formula of QTc is: QTc=QT / RR 1 / 2 , see Table 4.

[0058] Table 4 Effects of CM4 and CM4-R on ECG parameters of mouse heart.

[0059]

[0060] Abbreviations: N, number of animals; BW, body weight; HR, heart rate; PR, time from P wave onset to QRS or RS wave onset; QRS, time from Q wave to S w...

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Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to polypeptide CM4-R and an application thereof. The amino acid sequence of the polypeptide CM4R- is SEQID No.1, the N terminal of the polypeptide is connected with a leading cell-penetrating-peptide of 11 amino acids, the amino acid sequence is shown in SEQ ID No.2, the polypeptide CM4-R can carry thefollowing 26 amino acids to penetrate through a cell membrane, the following 26 amino acid sequences are shown in SEQ ID No.3 and are main bodies playing a role, and the polypeptide is derived from wild type CaM. The invention also discloses an application of the CaM mutant to preparation of medicines for treating diseases caused by the CaM mutant. The cell-film-penetrating peptide in the polypeptide provided by the invention can carry biomolecules to enter myocardial cells, the CM4-R and myocardial CaV1.2 calcium channels are combined to compensate for the reduction of the combination amountof CaM and CaV1.2 calcium channels caused by CaM mutation, the function recovery of the calcium channels is regulated, and the effects of treating arrhythmia and / or QT interval extension caused by CaM-E141G mutants are achieved. The polypeptide and the derivative thereof provided by the invention do not influence the cardiac function, and have a certain correction effect on QT interval extension and arrhythmia.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a polypeptide CM4-R and its application. Background technique [0002] Cardiac arrhythmias are an important condition in cardiovascular diseases with high morbidity and mortality. Arrhythmia not only occurs in heart disease patients with myocardial ischemia, chronic heart failure, myocardial hypertrophy and other organic diseases, but also in heart disease patients without obvious heart disease. Arrhythmia can be clinically divided into two categories: tachyarrhythmia and bradyarrhythmia according to the speed of the heart rate when it occurs. The chronic type has a lower incidence. The incidence, severity, and difficulty of treatment of tachyarrhythmia are far greater than those of slow arrhythmia. Severe tachyarrhythmias such as ventricular tachycardia and ventricular fibrillation are the leading cause of death, accounting for approximately 50% of cardiovascul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/47C07K19/00C12N15/12C12N15/62A61K38/17A61K47/64A61P9/06
CPCC07K14/4728A61K47/64A61P9/06C07K2319/10A61K38/00
Inventor 郝丽英苏敬阳
Owner 中国医科大学
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