CN112851757B

CN112851757B - Hexapeptide and application and pharmaceutical composition thereof

Info

Publication number: CN112851757B
Application number: CN202110067517.2A
Authority: CN
Inventors: 张桂荣; 张词嘉; 时亚男; 胡美娜
Original assignee: Jilin University
Current assignee: Jilin University
Priority date: 2021-01-19
Filing date: 2021-01-19
Publication date: 2022-06-03
Anticipated expiration: 2041-01-19
Also published as: CN112851757A

Abstract

The invention provides a hexapeptide, and application and a pharmaceutical composition thereof, and belongs to the technical field of biological medicines. The hexapeptide provided by the invention has an adjusting effect on energy metabolism of HT22 cells, has a migration effect on HaCaT cells, can inhibit escherichia coli, staphylococcus aureus and pseudomonas aeruginosa, and has a promoting effect on healing of skin trauma.

Description

Hexapeptide and application and pharmaceutical composition thereof

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to hexapeptide, application thereof and a pharmaceutical composition.

Background

Energy metabolism of an organism is closely related to mitochondria, which are a site where many biochemical reactions generate energy, and changes in mitochondrial membrane potential are closely related to energy metabolism of cells. AMP-activated protein kinase (AMPK) is a major effective sensor of the energy state of all eukaryotic cells, and is highly conserved across all eukaryotic species. AMPK is closely related to blood circulation dysfunction, for example, in ischemia of body, due to ischemia and hypoxia at the end of blocked or obstructed blood vessels, the expression of adenosine triphosphate synthase delta subunit (ATP5D) in mitochondria of cells is reduced, so that the synthesis of Adenosine Triphosphate (ATP) is reduced, and ATP is consumed in blood vessels and tissues around the blood vessels, so that ATP in blood vessels at the end of ischemia and tissues around the blood vessels is seriously deficient. The activity of AMPK is regulated by multiple upstream signals, making AMPK a central node for cellular energy utilization, coordinating cellular metabolism with specific energy requirements. Therefore, drugs that regulate energy metabolism by targeting AMPK are useful for the treatment of various metabolic diseases, especially diabetes, inflammation, cancer and obesity.

At present, the deproteinized calf blood extract for injection (DECB) is clinically used for treating the problems of cerebral blood circulation dysfunction, nutrition disorder (ischemic injury, craniocerebral injury), peripheral blood circulation disorder and related diseases (angiopathy and leg ulcer), skin transplantation of burn and chemical burn, wound healing and the like. The research has proved that the effective components in the calf serum deproteinized injection can improve the uptake of oxygen and glucose by brain tissue cells, thereby promoting the recovery of damaged nerve cells. The sales of the Cannel pharmaceutical industry of Jilin alone in 2017 was 1.7 hundred million. However, since DECB is a multi-component biochemical drug, the effective components and the action mechanism of the drug are unclear, the clinical application range of the DECB is limited, and the sales volume is 0.93 hundred million in 2019, which is in a descending trend. Therefore, the search for the medicine for replacing DECB, the effective ingredients and the action mechanism of the medicine are clear, and the medicine for regulating the energy metabolism of cells and the skin trauma has very important significance.

Disclosure of Invention

In view of the above, the present invention aims to provide a hexapeptide, and applications and pharmaceutical compositions thereof, wherein the hexapeptide provided by the present invention has effects of regulating cellular energy metabolism and promoting skin wound healing, achieves an effect superior to that of DECB, and is expected to replace DECB in clinical applications.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a hexapeptide which is composed of more than any three amino acids of serine, valine, proline, isoleucine and asparagine.

Preferably, the amino acid sequence of the hexapeptide is SVVPIN.

Preferably, the amino acid sequence of the hexapeptide is SPVVIN or SVPVIV.

Preferably, the amino acid sequence of the hexapeptide is PINVSV or PVINVI.

Preferably, the amino acid sequence of the hexapeptide is PVVPVI.

The invention also provides application of the hexapeptide in preparing a medicament for regulating energy metabolism of HT22 cells.

The invention also provides application of the hexapeptide in preparation of a drug for promoting HaCaT cell migration.

The invention also provides application of the hexapeptide in preparing a medicament for promoting skin trauma healing.

The invention also provides application of the hexapeptide in inhibiting microorganisms, wherein the microorganisms comprise one or more of escherichia coli, staphylococcus aureus and pseudomonas aeruginosa.

The invention also provides a pharmaceutical composition, which comprises the hexapeptide and pharmaceutically acceptable auxiliary materials.

The results of the embodiments of the present invention show that: the hexapeptide provided by the invention has an adjusting effect on energy metabolism of HT22 cells, has a migration effect on HaCaT cells, can inhibit escherichia coli, staphylococcus aureus and pseudomonas aeruginosa, and has a promoting effect on healing of skin trauma.

Drawings

FIG. 1 is a graph of the effect of DECB-6P on guinea pig respiratory activity;

FIG. 2 shows the effect of DECB-6P on mitochondrial membrane potential of HT22 cells;

FIG. 3-A is a graph showing the effect of DECB-6P on ATP content of HT22 cells;

FIG. 3-B is the effect of DECB-6P on the ATP content of HT22 cells after addition of Compound C;

FIG. 4 is a graph of the migration effect of DECB-6P on HaCaT cells, where A is the effect of varying concentrations of hexapeptide on the scratch width of HaCaT cells and B is the effect of varying concentrations of hexapeptide on the pro-migration rate of HaCaT cells;

FIG. 5 is a graph of the effect of DECB-6P on wound healing in mice;

FIG. 6-A shows the Escherichia coli inhibitory activity of DECB-6P;

FIG. 6-B shows DECB-6P inhibiting Staphylococcus aureus;

FIG. 6-C shows DECB-6P inhibiting Pseudomonas aeruginosa.

Detailed Description

In the present invention, the amino acid sequence of the hexapeptide is preferably SVVPIN (SEQ ID No. 1). In the present invention, the amino acid sequence of the hexapeptide is preferably SPVVIN (SEQ ID No.2) or SVPVIV (SEQ ID No. 3). In the present invention, the amino acid sequence of the hexapeptide is preferably PINVV (SEQ ID No.4) or PVINVI (SEQ ID No. 5). In the present invention, the amino acid sequence of the hexapeptide is preferably PVVPVI (SEQ ID No. 6).

The invention also provides application of the hexapeptide in the technical scheme in preparing a medicament for regulating energy metabolism of HT22 cells. In the invention, the hexapeptide enhances the aerobic metabolism level of cells, increases the ATP content in the cells, maintains the energy homeostasis of the cells, reduces the apoptosis degree of HT22 cells and regulates the energy metabolism of HT22 cells. The dosage form of the medicine is not particularly limited, the dosage form of the hexapeptide which is acceptable in medicine can be adopted, and the content of the hexapeptide in the medicine is not particularly limited according to the content of active medicine in the conventional dosage form. In the invention, the dosage form is preferably injection, tablet, aqua, ointment or external gel.

The invention also provides application of the hexapeptide in the technical scheme in preparation of a medicine for promoting HaCaT cell migration. The dosage form of the medicine is not particularly limited, the dosage form of the hexapeptide which is acceptable in medicine can be adopted, and the content of the hexapeptide in the medicine is not particularly limited according to the content of active medicine in the conventional dosage form. In the invention, the dosage form is preferably injection, tablet, aqua, ointment or external gel.

The invention also provides application of the hexapeptide in the technical scheme in preparation of a medicine for promoting skin trauma healing. The dosage form of the medicine is not particularly limited, the dosage form of the hexapeptide which is acceptable in medicine can be adopted, and the content of the hexapeptide in the medicine is not particularly limited according to the content of active medicine in the conventional dosage form. In the invention, the dosage form is preferably injection, tablet, aqua, ointment or external gel. When the wound healing is promoted, the proliferation period, migration, angiogenesis and collagen deposition of related cells and the formation of related factors are promoted, and finally, the wound healing is promoted.

The invention also provides application of the hexapeptide in inhibiting microorganisms, wherein the microorganisms preferably comprise one or more of escherichia coli, staphylococcus aureus and pseudomonas aeruginosa.

The invention also provides a pharmaceutical composition, which comprises the hexapeptide and pharmaceutically acceptable auxiliary materials. In the present invention, the dosage form of the pharmaceutical composition preferably includes injections, tablets, aqueous solutions, ointments or topical gels. The preparation method of the pharmaceutical composition into the corresponding dosage form is not particularly limited, and the pharmaceutical composition can be prepared by the conventional technology by the skilled in the art. In the present invention, the adjuvant may be selected from carbomer, glycerol (glycerin), triethanolamine, etc.

The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.

Example 1

Effect of hexapeptides on respiratory Activity

The specific method comprises the following steps:

a respiratory activity determination method of 2015 version Chinese pharmacopoeia is adopted:

1. guinea pig breeding and preparation of liver homogenate

The SPF male guinea pig is raised in an SPF animal room at 23 ℃ +/-3 ℃ with air humidity of 50% +/-5% and airflow value of 0.13-0.18 m³And/s, the number of air changes is 10-20 times/hour. When the weight of the guinea pig reaches 250-300 g, a respiratory activity determination experiment can be performed.

2. Respiratory activity assay after fasting for 24h, the guinea pigs were sacrificed by cervical tapping, the carotid artery was immediately cut off for bleeding, dissected and the liver was removed. Washed 2 times in Soerensen buffer. 5.5g of liver were divided into 7 equal sized pieces, immediately placed in Soerensen buffer and placed on an ice water bath. The liver tissue mass was homogenized on ice by placing 7mL of Soerensen buffer until no macroscopic tissue mass was present in the homogenate.

Respiratory activity was measured using a Bulbo respirator, and using deproteinized calf blood extract for injection (DECB, available from the Jilin Cornell pharmaceutical industry) as a drug positive control, a pressure measuring liquid was first filled in a pressure measuring tube, and the liquid level height of the pressure measuring liquid was maintained at 150 mm. 1.1mL of Soerensen buffer was added to the reaction flask, 0.2mL of DECB solution and DECB-6P (hexapeptide, SEQ ID No.1) solution of different concentrations were added to the sample tube, 0.2mL of Soerensen buffer was added to the blank control tube, and finally 1mL of liver homogenate was added, and 2.5mL of Soerensen buffer was added to the blank tube. The reaction flask and the manometer were connected and placed in a 37 ℃ water bath. The pressure tube right side level was adjusted to 150mm and a reading a of the left side level was recorded. The piston was closed and the reaction was allowed to proceed for 30 min. The right side level reading was adjusted to 150mm and the left side level reading was recorded as B. And opening the three-way piston, adjusting the right liquid level to 150mm, recording the left liquid level reading as C, reacting for 30min, adjusting the right liquid level to 150mm, and recording the left liquid level reading as D. 2mL of liver homogenate were dry weighed and the weight difference Δ W (mg) was calculated.

Respiratory activity calculation formula: qo2 ═ [ (A-B + C-D) x K1- Δ C × K2 ]/GxI

Calculation formula of constant K: k { [ (Rv + Mv) × 1000-

Qo2 in the equation represents respiratory activity. K1 represents the flask constant for the control or sample tube, and K2 represents the flask constant for the blank tube. G denotes the dry weight per ml of liver homogenate in mg, G ═ Δ W/2-9.3, 9.3 is the dry weight of Soerensen buffer. I is reaction time in hours. Rv represents the reaction flask volume and Mv represents the manometer volume.

Stimulation Index (SI) ═ Qo2 (sample tube)/Qo 2 (control tube)

The experimental result should satisfy the following conditions, otherwise, the medicine is regarded as invalid:

(1) qo2 (sample tube) is not less than4.0μLO₂V (mg. h) and SI.gtoreq.2.5

(2) Qo2 (control tube) is more than or equal to 1.0 mu LO₂/(mg·h)

3. Derivatized polypeptide respiratory activity assay

The results showed that 20mg/mL of DECB-group guinea pig hepatocytes exhibited a respiratory activity Qo2 of 5.45. mu.LO₂/(mg. h), 125. mu.g/mL of the respiratory activity Qo2 of DECB-6P group guinea pig hepatocytes was 10.2345. mu.LO₂/(mg. h). The respiratory activity of the drug positive controls DECB and DECB-6P on guinea pig liver cells is remarkably improved, and the respiratory activity of the DECB-6P is about 320 times that of the DECB, and the specific table is shown in Table 1.

TABLE 1 measurement of respiratory Activity of derivatized Polypeptides

Sample (I)	Sequence of	Sequence of	Qo2	Amount of sample
					Blank control
	0		2.15O₂/(mg·h)	0
					Drug positive control	DECB		5.45μLO₂/(mg·h)	20mg/mL
Hexapeptide (hereinafter referred to as DECB-6P)	SVVPIN	SEQIDNo.1	6.16μLO₂/(mg·h)	0.5mg/mL
					Hexapeptides	SPVVIV	SEQIDNo.2	9.58μLO₂/(mg·h)	0.2mg/mL
Hexapeptides	SVPVIV	SEQIDNo.3	8.29μLO₂/(mg·h)	1mg/mL
					Hexapeptides	PINVSV	SEQIDNo.4	6.75μLO₂/(mg·h)	3mg/mL
Hexapeptides	PVINVI	SEQIDNo.5	7.60μLO₂/(mg·h)	5mg/mL
					Hexapeptides	PVVPVI	SEQIDNo.6	5.75μLO₂/(mg·h)	5mg/mL
Hexapeptide (hereinafter DECB-6P)	SVVPIN	SEQIDNo.1	10.23μLO₂/(mg·h	0.125mg/mL

4. Effect of different concentrations of DECB-6P on respiratory Activity

A respiratory activity determination method of 2015 version Chinese pharmacopoeia is adopted: the specific procedure is shown in example 1, and the results are shown in FIG. 1 and Table 2. The respiratory activity detection results of the positive drug control DECB and DECB-6P show that: the effect of DECB and DECB-6P on the respiratory activity of guinea pig hepatocytes, the improvement of the respiratory activity of 125. mu.g/mL DECB-6P on guinea pig hepatocytes was significantly better than that of 20mg/mL DECB, the DECB-6P was administered at a concentration of 1/160 of DECB, and the respiratory activity was about 1.88 times that of DECB.

TABLE 2 Effect of different concentrations of DECB-6P on respiratory Activity

Example 2

Effect of DECB-6P on energy metabolism of HT22 cells

1. Effect of DECBI-6P on the mitochondrial Membrane potential of HT22 cells

Mitochondria are power plants, many biochemical reactions, sites for energy production, and changes in mitochondrial membrane potential are closely related to cellular energy metabolism. JC-1 is an ideal lipophilic fluorescent probe for detecting mitochondrial membrane potential. When the mitochondrial membrane potential is higher, JC-1 exists in a polymer form in mitochondria and generates red fluorescence; when the mitochondrial membrane potential is low, it exists as a monomer to generate green fluorescence. The level of mitochondrial membrane potential can therefore be reflected by the ratio of mitochondrial red fluorescence and green fluorescence. The HT22 cell line is a mouse hippocampal neuronal cell line that grows adherently under normal conditions, a good cell model for studying glutamate toxicity in vitro, and has been widely used in a number of neurodegenerative diseases, such as Alzheimer's Disease (AD) and Parkinson's Disease (PD).

The specific implementation is as follows: HT22 cells with good growth state were plated in 6-well plates at a cell density of 1X 10⁶2mL of cell suspension per well, incubated at 37 ℃ in a 5% carbon dioxide incubator for 24 h. Modeling by using 20mML-Glu to act on HT22 cells for 24 h; HT22 cells were incubated with 25, 50, 100. mu.g/mL DECB-6P and L-Glu, respectively, for 24 h. The treated cells were washed 3 times with PBS, and 1mL of DMEM high-glucose minimal medium and 1mL of JC-1 working solution were sequentially added to the wells and incubated at 37 ℃ for 20 min. The wells were discarded and washed 2 times with 1 XJC-1 buffer for 5min each time and observed under a fluorescent microscope. JC-1 experimental result shows that the cells in the control group show strong red fluorescence indicating that the cells are healthy cells, and the cells in the model group after 20mM L-Glu is incubated for 24h show green fluorescence indicating that mitochondria are apoptotic. After the DECB-6P and the L-Glu are incubated together, the ratio of red fluorescence to green fluorescence is obviously enhanced, which shows that the mitochondrial membrane potential is recovered, the mitochondrial permeability is weakened, the effect of the DEBC-6P on HT22 cells is related to the change of the mitochondrial membrane potential and mitochondrial apoptosis, and the specific result is shown in figure 2.

As can be seen from FIG. 2, hexapeptide has the function of repairing mitochondrial membrane potential damage, which can cause Parkinson's disease, diabetes, tumor and Alzheimer's disease, and can possibly treat the diseases.

2. Effect of DECBI-6P on ATP content and cellular energy metabolism

ATP is biological energy, and ATP content results are obtained by utilizing the method of the ATP content measuring kit. The ATP content results after the DECB-6P treatment of HT22 cells show that compared with a control group, the ATP content in the cells of the model group is reduced by 37.98%, compared with the control group, the ATP content of the DECB treatment of 8mg/mL of a drug positive control group and the ATP content of the DECB-6P treatment of 25, 50 and 100 mu g/mL of the drug positive control group are obviously increased, wherein the ATP content of the DECB-6P group of 50 mu g/mL is the highest and is 99.05% of that of the control group, the level is almost recovered to the level before injury, the effect is better than that of the positive control group, and the optimal concentration of the DECB-6P is only 1/160 of the DECB, and particularly shown in FIG. 3-A and Table 3.

TABLE 3 Effect of DECBI-6P on ATP content

Control	--	8mg/mL	25mg/mL	50mg/mL	100mg/mL
						2.52	1.67	2.53	2.58	2.79	2.67
2.68	1.72	2.29	2.28	2.53	2.09
						2.67	1.49	2.35	2.43	2.47	2.37

AMPK is an evolutionary conserved energy sensor, and AMPK signals can be activated by insufficient cell energy, so that catabolic processes are stimulated, and energy homeostasis is maintained. Compound C is an AMPK inhibitor and, in order to explore the mechanism of action of DECB-6P, it was added to co-treat HT22 cells and then measure ATP levels. The results of the experiments show that there was no significant change in ATP levels in each group after co-treatment of cells with Compound C, but the ATP levels were reduced compared to the results without Compound C, as shown in FIG. 3-B and Table 4. The DECB-6P is proved to increase ATP production of HT22 cells and participate in energy metabolism, and the DECB-6P enhances aerobic metabolism level of the cells, maintains energy homeostasis of the cells and reduces apoptosis degree of HT22 cells, and the effect is related to an AMPK action mechanism.

TABLE 4 Effect of DECBI-6P on ATP content after addition of Compound C

Control	Model	8mg/mL	25mg/mL	50mg/mL	100mg/mL
						1.66	1.51	1.65	1.39	1.53	1.52
1.49	1.49	1.58	1.53	1.54	1.53
						1.69	1.57	1.65	1.45	1.62	1.62

Example 3

Migration of DECB-6P on HaCaT cells

And uniformly marking transverse lines at the back of the 6-hole plate by using a marker pen, and crossing the through holes approximately every 0.5-1 cm. Each hole passes through 5 lines. Approximately 5X 10 of complete medium (DMEM high-sugar minimal medium, 100kU/L penicillin, 100mg/L streptomycin, 100mL/L heat-inactivated fetal bovine serum) was added to a 6-well plate⁶One HaCaT cell, full overnight. Scratching with yellow tip perpendicular to the transverse line of the back with respect to the ruler in the next day, washing the cells with PBS 3 times, removing the scratched cells, adding serum-free culture medium and DECB-6P to the final concentration of 25, 50, 100200, 400. mu.g/mL at 37 ℃ in 5% CO₂Culturing in an incubator, sampling for 24h, and calculating the mobility. The results of fig. 4 and table 5 show that hexapeptide can promote the migration of HaCaT cells by virtue of the migration rate of the hexapeptide HaCaT cells at different concentrations, wherein the promotion effect of 200 μ g/mL hexapeptide is most obvious and reaches 87.13%.

TABLE 5 Effect of DECB-6P on HaCaT cell migration

Concentration (μ g/mL)	Control	25	50	100	200	400
							Cell mobility (%)	44.54	55.82	61.62	67.09	87.13	60.71

Example 4

DECB-6P for promoting traumatic skin healing

Utilizing six-week-old KunmingMouse, animal wound model was constructed, with the same area of wound on the back of the mouse, and control (no drug, physiological saline, dose 200 μ L/cm, no drug administration) on the left²) On the right side, the drug administration group (drug final concentration 200. mu.g/mL) was administered daily, and the healing of the wound of the mouse was observed and recorded by photographing. The experimental results are shown in fig. 5, and on day 3 after the operation, the wound peripheries of the control group mice and the administration group mice are red and swollen, and both have exudates, and are subjected to inflammatory reaction; on the 5 th day after the operation, the exudate and red swelling of the administration group are reduced, the wound surface of the mouse in the high-concentration group is already scabbed, and the wound area is reduced; by day 7, the red and swollen degree of the control group is reduced, the wound area of the mouse begins to be reduced, the wound of the mouse in the low-concentration group hardly has exudate, and the wound area of the mouse in the high-concentration group is gradually reduced; on day 9, the wounds of the mice in the high-concentration group and the medium-concentration group were significantly reduced, while the wounds of the control group were not significantly reduced. The wound of the high-concentration group of mice on day 11 is covered by the new epidermis and is basically healed, the wound of the control group of mice still heals, and the wound of the control group of mice still becomes red and swollen. Animal wound experiment results show that DECB-6P with the concentration of 200 mug/mL can obviously accelerate the healing speed of the mouse wound and further promote the wound healing, and particularly, the results are shown in figure 5.

Example 5

DECB-6P bacteriostatic activity

Inoculating Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa into a test tube containing 10mL of liquid culture medium under sterile environment, and performing shake culture at 37 deg.C and 120r/min for activation. The activated strain was inoculated into agar plate medium to obtain a single colony. Single colonies were picked and inoculated into a conical flask containing 150mL of liquid medium, and cultured with shaking at 37 ℃ and 120 r/min.

Diluting the bacterial liquid in logarithmic phase by 100 times, adding 100 μ L of bacterial liquid into 96-well plate, adding minimal medium and hexapeptide (DECB-6P) with hexapeptide final concentration of 0.25, 0.5, 1.0mg/mL, and measuring absorbance value of bacterial liquid at 490 nm.

Experimental results show that DECB-6P has obvious antibacterial activity on Escherichia coli, wherein 1mg/mL hexapeptide has an average inhibition rate of 65% on Escherichia coli, 24% on Staphylococcus aureus and 16% on Pseudomonas aeruginosa, and the results are shown in FIG. 6-A, FIG. 6-B, FIG. 6-C and Table 6-8.

TABLE 6 bacteriostatic results for E.coli

TABLE 7 bacteriostatic results for Staphylococcus aureus

TABLE 8 bacteriostatic results for Pseudomonas aeruginosa

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Sequence listing

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Claims

1. A hexapeptide having the amino acid sequence SVVPIN.

2. Use of the hexapeptide of claim 1 for the preparation of a medicament for promoting energy metabolism of HT22 cells.

3. Use of the hexapeptide of claim 1 for the preparation of a medicament for promoting migration of HaCaT cells.

4. Use of the hexapeptide of claim 1 for the preparation of a medicament for promoting healing of skin wounds.

5. Use of the hexapeptide of claim 1 for the preparation of a medicament for inhibiting microorganisms selected from the group consisting of escherichia coli, staphylococcus aureus, and pseudomonas aeruginosa.

6. A pharmaceutical composition comprising the hexapeptide of claim 1 and a pharmaceutically acceptable excipient.