A short peptide of py sequence and its application in inhibiting the degradation of Herg potassium channel

A potassium channel and short peptide technology, which is applied to the PY sequence short peptide and its application in inhibiting the degradation of hERG potassium channel, can solve the problems of proarrhythmia and enlargement

Active Publication Date: 2022-04-05
HEBEI MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The purpose of the present invention is to provide a short peptide of PY sequence and its application in inhibiting hERG potassium channel degradation, to solve the problem of existing K + Potential proarrhythmic risk of channel openers, in order to increase K + Current offers a new way

Method used

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  • A short peptide of py sequence and its application in inhibiting the degradation of Herg potassium channel
  • A short peptide of py sequence and its application in inhibiting the degradation of Herg potassium channel
  • A short peptide of py sequence and its application in inhibiting the degradation of Herg potassium channel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Cellular Level Experiment of Steadily Turning hERG Potassium Channel

[0025] (1) Observe the down-regulation effect of Nedd4-2 on hERG protein:

[0026] Three concentrations of Nedd4-2 plasmid were introduced into the stably transfected hERG-HEK293 cells, and the effects on hERG protein were observed. The result is as figure 1 As shown, transfection of Nedd4-2 plasmid (500 ng, 1000 ng, 2000 ng) significantly reduced the expression of mature hERG protein (155 kDa but not 135 kDa) on the membrane.

[0027] figure 1 It showed that, compared with the control group (CON), transfection of Nedd4-2 plasmid 500ng, 1000ng and 2000ng reduced the mature hERG protein (155kD) to 63.14%, 49.64% and 51.57% of the control level, respectively. The immature hERG protein (135kD) had no significant difference among the groups.

[0028] (2) Observe the effect of Nedd4-2 on hERG current:

[0029] Whole-cell patch clamp results figure 2 As shown, different concentrations of...

Embodiment 2

[0035] Embodiment 2 Whole animal level experiment

[0036] Angiotensin II (Ang II) is an endogenous hormone that binds to angiotensin receptors and has a strong vasoconstrictor function to increase the load on the heart. Chronic administration can be used to induce pathological cardiac hypertrophy. The previous experiments of our research group showed that in AngⅡ-induced pathological cardiac hypertrophy model, I Kr The current was significantly reduced, and the activation of Nedd4-2 led to increased ubiquitination and degradation of hERG channels was the main reason. In this example, Ang II was still used to prepare the model of pathological cardiac hypertrophy in guinea pigs. SPF grade adult male guinea pigs with a body weight of about 300 g (purchased from Beijing Weitong Lihua Animal Experiment Center) were randomly divided into control group (CON, n=4), cardiac hypertrophy model group (AngⅡ, n=7) and experimental group. (AngⅡ+PY short peptide, n=5). Among them, the mod...

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Abstract

The present invention provides a PY sequence short peptide and its application in inhibiting the degradation of hERG potassium channel. The sequence of the short peptide is shown in SEQ ID NO.1. The present invention also provides a derivative of the above-mentioned PY sequence short peptide, which is a chimeric peptide formed by linking the PY sequence short peptide with a cell-penetrating peptide. The cell-penetrating peptide is connected to the C-terminal or N-terminal of the short peptide of the PY sequence. The sequence of the cell penetrating peptide is shown in SEQ ID NO.2. An application of the above-mentioned PY sequence short peptide and its derivatives in inhibiting hERG potassium channel degradation. The PY sequence short peptide designed according to the binding site of Nedd4-2 and hERG channel in the present invention can significantly increase I at the level of cells and whole animals Kr This effect can significantly prevent the electrophysiological remodeling accompanied by cardiac hypertrophy, and is expected to be applied to combat arrhythmias caused by pathological cardiac hypertrophy.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to a PY sequence short peptide and its application in inhibiting hERG potassium channel degradation. Background technique [0002] Pathological myocardial hypertrophy is a common complication of many diseases such as hypertension, myocardial ischemia, and diabetic cardiomyopathy. It is a complex pathophysiological process mediated by various neurohumoral factors and involved by various cell signaling pathways. Histological hypertrophic remodeling (remodeling) can compensatory increase cardiac output in the early stage, but progressively can lead to systolic decompensation and eventually heart failure. Accompanied by hypertrophic remodeling is myocardial electrophysiological remodeling, which greatly increases the incidence of arrhythmia, and the resulting sudden cardiac death (Sudden cardiac death, SCD) accounts for about 50% of deaths in heart failure patients. However, most of the ex...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/08C07K19/00A61P9/06
CPCC07K7/08A61P9/06C07K2319/10
Inventor 许彦芳章华邹思豪傅天邱素华师晨霞
Owner HEBEI MEDICAL UNIVERSITY
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