CN110294791B - Anti-atherosclerotic peptide analogue with cholesterol efflux activity and application thereof - Google Patents

Abstract

The invention discloses a novel structural anti-atherosclerosis peptide analogue with cholesterol outflow activity, and discloses application of the anti-atherosclerosis peptide analogue with cholesterol outflow activity in treating hyperlipidemia/atherosclerosis and other diseases caused by hypercholesterolemia. The invention relates to an anti-atherosclerosis peptide analogue with cholesterol outflow activity, which is characterized in that the sequence of a hydrophilic surface of a10 th section of amphipathic alpha-helix peptide segment (221-240 site) of human apolipoprotein A-I (ApoA-I) is replaced, the boundary of a hydrophilic surface and a hydrophobic surface is replaced by amino acid with positive charge, the middle site of the hydrophilic surface is replaced by amino acid with negative charge, then the sequence of the hydrophilic surface is fixed, and the hydrophobicity of the amino acid is gradually enhanced by replacing the hydrophobic surface, so as to obtain a series of new ApoA-I simulated peptides with gradually increased hydrophobicity.

Description

Anti-atherosclerotic peptide analogue with cholesterol efflux activity and application thereof

Technical Field

The invention belongs to the technical field of biochemistry, and particularly relates to an anti-atherosclerosis peptide analogue with cholesterol outflow activity and application thereof.

Background

In recent years, the Reverse Cholesterol Transport (RCT) theory is gradually mature, so that the development of a drug which can reversely Transport peripheral Cholesterol to the liver and discharge the peripheral Cholesterol out of the body to achieve the purposes of reducing blood fat and resisting atherosclerosis becomes a hot research goal. In the narrow sense, RCT generally refers to the extracellular transport of intracellular cholesterol (or cholesterol efflux). Apolipoprotein A-I (ApoA-I) synthesized and secreted from the liver is loaded with phospholipid to form primary HDL particles (pre beta-HDL), cholesterol ester is loaded into the pre beta-HDL to form mature HDL particles (alpha-HDL), and the alpha-HDL transfers cholesterol to the liver to form a complete RCT circulation, so that the RCT circulation can relieve the 'burden' of an artery and prevent excessive cholesterol from accumulating in the artery to induce a series of adverse cardiovascular events. The protein in HDL that functions primarily as RCT is apolipoprotein ApoA-I, which consists of 243 amino acids, comprises 10 linearly linked fragments of the alpha helix, all of which are amphiphilic and have some affinity for lipids. ApoA-I separated in vivo has good cholesterol lowering effect and anti-atherosclerosis effect, and is difficult to prepare due to high cost, large molecular weight and poor stability of in vivo separation or artificial synthesis, but the function of the ApoA-I separated in vivo can be simulated or enhanced by shorter apolipoprotein ApoA-I simulated peptide. Like ApoA-I, apoA-I mimetic peptides can specifically promote cholesterol efflux in peripheral cells through ABC transporters, can be combined with HDL to carry and transport cholesterol, can also be combined with alpha-HDL to reduce the negative of the alpha-HDL, strip and assist in transporting cholesterol, and can be used for 'remodeling' the alpha-HDL into pre beta-HDL, and the pre beta-HDL has stronger cholesterol carrying capacity relative to the alpha-HDL, so that the addition of the ApoA-I mimetic peptides enhances the cholesterol carrying and transporting efficiency of HDL in vivo.

The earliest 4F was modified by Fogelman et al, which first designed the apoA-I mimic peptide 18A consisting of 18 amino acids, whose all D-4F and all Reverse-sequence Reverse-4F both had better cholesterol efflux activity. However, D-4F only has obvious effect of improving the size of the thickened intima in an animal body, but has no obvious effect in a human body, and has intestinal targeting property and fails to pass clinical tests. The 18A dimer series also had good cholesterol efflux promoting effects, but the sequence was too long. There is a subject group of ApoA-I mimetic peptides ApoA-I designed by the characteristics of the 1 st to 10 th helices of ApoA-I _consensus A plurality of ApoA-I mimic peptides are derived, for example, ETC-642 is a classical ApoA-I mimic peptide which is modified by ETC-642 and has cholesterol efflux activity, and is clinically tested. In addition, the ApoA-I mimic peptide modified by using 10 th helix A10 of ApoA-I as a parent peptide, and FAMP5 modified by 196-219 sections of ApoA-I all have good cholesterol efflux promoting activityAnd (4) sex. The ELK series of two ApoA-I mimetic peptides linked in series by proline have further improved activity compared to the single peptide, but these are still under investigation. Interestingly, another subject group was also to obtain completely different ApoA-I mimetic peptides, which had very good cholesterol efflux activity, by using a polyproline triangular prism rigid helix structure as a scaffold, and connecting a benzene ring to the 4-position of the pyrrole ring at two edges to form a hydrophobic surface, and connecting a glycosyl group to the other edge to form a hydrophilic surface.

Disclosure of Invention

It is an object of the present invention to provide a novel class of structured anti-atherosclerotic peptides having cholesterol efflux activity.

In order to realize the purpose, the invention adopts the following technical scheme:

an anti-atherosclerotic peptide analog having cholesterol efflux activity, the amino acid sequence of which is represented by the general formula:

X ₁ X ₂ Y ₃ Z ₄ X ₅ Z ₆ Y ₇ X ₈ X ₉ Y ₁₀ Z ₁₁ X ₁₂ Z ₁₃ Y ₁₄ X ₁₅ X ₁₆ Z ₁₇ Z ₁₈ X ₁₉ X ₂₀ ，

wherein X is selected from hydrophobic amino acids, Y is selected from negatively charged amino acids or uncharged hydrophilic amino acids, Z is selected from positively charged amino acids or uncharged hydrophilic amino acids, and the number represents the sequence position of the amino acid from the N-terminus.

In the amino acid sequence general formula of the peptide, X is selected from one or more of alanine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, tyrosine or derivatives thereof, Y is selected from one or more of glutamic acid, aspartic acid, serine, threonine, glutamine, asparagine or derivatives thereof, and Z is selected from one or more of histidine, lysine, arginine, serine, threonine, glutamine, asparagine or derivatives thereof.

In the general formula of the amino acid sequence of the peptide, X is selected from one or more of leucine, valine and phenylalanine, Y is glutamic acid, and Z is selected from one or more of histidine, lysine and threonine.

The anti-atherosclerotic peptide analogue having cholesterol efflux activity is selected from one of the following compounds:

compound 1: VLEKLKELVVEHVKEVVTVL

Compound 2: VLEKLKELKELVTKVL

Compound 3: VLEKLKELLTKVL

Compound 4: FLEKLKELLEHLKELLTKLL.

The peptide analogue is heteropolypeptide formed by linking through a chemical chain.

It is another object of the present invention to provide the use of the above-described anti-atherosclerotic peptide analogues with cholesterol efflux activity for the manufacture of a medicament for the treatment of hyperlipidemia/atherosclerosis and other diseases caused by hypercholesterolemia.

The invention relates to an anti-atherosclerosis peptide analogue with cholesterol outflow activity, which is characterized in that the sequence of a hydrophilic surface of a10 th section of amphipathic alpha-helix peptide segment (221-240 site) of human apolipoprotein A-I (ApoA-I) is replaced, the boundary of a hydrophilic surface and a hydrophobic surface is replaced by amino acid with positive charge, the middle site of the hydrophilic surface is replaced by amino acid with negative charge, then the sequence of the hydrophilic surface is fixed, the hydrophobicity of the amino acid is gradually enhanced by replacing the hydrophobic surface, and a series of new ApoA-I simulated peptides with gradually increased hydrophobicity are obtained, wherein the sequence is X ₁ X ₂ Y ₃ Z ₄ X ₅ Z ₆ Y ₇ X ₈ X ₉ Y ₁₀ Z ₁₁ X ₁₂ Z ₁₃ Y ₁₄ X ₁₅ X ₁₆ Z ₁₇ Z ₁₈ X ₁₉ X ₂₀ Wherein X is selected from hydrophobic amino acids, Y is selected from negatively charged amino acids or uncharged hydrophilic amino acids, Z is selected from positively charged amino acids or uncharged hydrophilic amino acids, and the number represents the sequence position of the amino acid from the N-terminus.

Drawings

FIG. 1 mother peptide ApoA-I _221-240 Cholesterol efflux activity profile within 200. Mu. Mol/L of P1-P17, L-4F (12 h per concentration effect)

FIG. 2 mother peptide ApoA-I _221-240 DMPC vesicle dispersibility of P1-P17, L-4F (within 90 min)

FIG. 3 shows the measurement results of blood lipid and serum turbidity inflammatory factors. A-D are serum lipid determinations. E is the result of measurement of serum turbidity (OD) at 430 nm. F-I serum inflammation assay results. N represents a normal group; m represents a model group; L-4F represents the treatment group of L-4F (10 mg/kg); PP represents the parent peptide ApoA-I _221-240 (10 mg/kg) treatment group. P12-L and H represent the low dose group (10 mg/kg) and the high dose group (20 mg/kg) treatment groups. Data are expressed as mean ± SEM (N =10. N vs M: all the materials areP <0.01 andP <0.005. P12-L and H vs M: \82242424P < 0.05, ††P <0.01 and \8224 \\8224 \\8224242424andP < 0.005。P12-L vs L-4F: ‡P <0.05 and \8225P < 0.01. P12-L vs PP: §P <0.05, t-test significance error).

FIG. 4 shows the results of histopathological section (pathological section stained with HE). A is in apoE ^-/- Effect of arterial treatment in mice (HE staining, thickened parts marked with yellow line, total thickness marked with white line). B is apoE ^-/- Therapeutic effect of mouse liver (HE staining, lipid droplet vacuoles are indicated with single arrows). C is a statistic of the relative thickness of the arteries and the relative fat area of the liver. N represents a normal group; m represents a model group; L-4F represents the treatment group of L-4F (10 mg/kg); PP represents the parent peptide ApoA-I _221-240 (10 mg/kg) treatment group. P12-L and H represent the low dose group (10 mg/kg) and the high dose group (20 mg/kg) treatment groups. Data are expressed as mean ± SEM, data are expressed as mean ± SEM (N = 5N vs M: aP <0.005. P12-L and H vs M: \8224; \822424P< 0.005. P12-L vs L-4F: ‡P < 0.05. P12-L vs PP: §§P <0.05, t-test significance error).

Detailed Description

The present invention will be further described with reference to the following embodiments.

Example 1: determination of cholesterol efflux Activity of novel ApoA-I mimetic peptides P1-P17

TABLE 1 sequence of P1-P17 and its hydrophobicity

Using RAW264.7 cells, planting at a density of 4 ten thousand per well, planting in a 96-well plate, adding 22-NBD fluorescent cholesterol to mark the cells for 12h, adding P12 to induce the cells to flow out for 12h, finally measuring the fluorescence intensity of cell culture solution and cell lysis in each well, and calculating the cholesterol external flow rate, wherein the cholesterol external flow rate = the fluorescence intensity of the culture solution/(the fluorescence intensity of the culture solution + the fluorescence intensity of the cell lysis solution). L-4F was used as a control peptide.

As shown in figure 1, in the range of 0-200. Mu. Mol/L of the mimetic peptide, P1-P5 has little activity and no dose response, and as the hydrophobicity is increased, the mimetic peptide has concentration-dependent cholesterol efflux activity from P6, the hydrophobicity is further increased, cell membrane disruption toxicity occurs from P13, and cholesterol is suddenly released at higher concentration. When the hydrophobicity of the mimetic peptide is too low, no cholesterol efflux occurs, and when the hydrophobicity is too high, cytotoxicity occurs. Therefore, P6-P12 is the non-toxic ApoA-I mimic peptide with cholesterol efflux activity. L-4F was used as a control peptide.

Example 2: lipid affinity assay for novel ApoA-I mimetic peptides P1-P17

Lipid affinity is the basis for the ability of ApoA-I mimetic peptides to bind to cell membrane phospholipids, HDL phospholipids, cholesterol, and the like. Dimyristoyl phosphatidylcholine (DMPC) is common phospholipid on biological membranes, and is prepared into emulsion containing micron-sized vesicles by using phosphate buffer solution, and if ApoA-I mimic peptide has lipid affinity, the emulsion containing the micron-sized vesicles can be dispersed into transparent solution of the nano-sized vesicles. The lipid affinity of the emulsion can be assessed by measuring the change in absorbance of the emulsion over time.

As a result, as shown in FIG. 2, P1-P8 are too hydrophobic to clarify the DMPC vesicle solution, while P9-P11 can clarify it within 10min, and P12-P15 can clarify it slowly, e.g., P12 can also clarify it within 90 min. The rate at which P12-P17 clarifies it slowly decreases. The simulated peptide with too small hydrophobicity has no lipid affinity, and the simulated peptide with increased hydrophobicity has the lipid affinity; when the hydrophobicity is increased to a certain value, the affinity of the lipid is reduced with the increase of the hydrophobicity.

Example 3: in vivo anti-atherosclerosis effect of ApoA-I mimic peptide P12 was studied by way of example

(I) test materials and methods

1. Feeding grouping, modeling and administration conditions of mice

50 ApoE alone ^-/- The mice and 10 syngeneic control C57 male mice, each half male and female, with a body weight of about 20 + -10 g, were purchased from Beijing Wintonli laboratory animal technology Co., ltd (production certificate No.: scxk 2016-0006). Feeding under 12h day and night/cycle, at 23 + -1 deg.C and relative humidity of 55 + -5%. The mice were divided into 6 groups, each group was hermaphroditic, and each group was a normal control group (fed with basal feed and administered with intraperitoneal injection of normal saline), a model control group (fed with basal feed, with a feed formulation of 0.5% cholesterol, 10% fat, 89.5% basal feed and administered with intraperitoneal injection of normal saline), an L-4F treatment group (L-4F was administered with normal saline at a concentration of 1 mg/mL and administered with intraperitoneal injection of 10 mg/kg), apoA-I _221-240 Treatment group (ApoA-I) _221-240 1 mg/mL concentration is prepared by using normal saline, and 10 mg/kg dosage is used for intraperitoneal injection), a P12 treatment group (1 mg/mL and 2 mg/kg concentrations are prepared by using normal saline for P12, 10 and 20 mg/kg low and high dosage intraperitoneal injection) is used, the injection is carried out after 4 weeks of molding, 4 months of molding are totally carried out, the administration is carried out for 3 months, finally, after 12 hours of fasting without water prohibition, mice are anesthetized by ether, orbital venous blood is collected, cervical dislocation is killed, and liver and aortic tissues with heart are taken.

TABLE 2 Table of the feeding, grouping, modeling and administration of mice

2. Preparation of mouse serum and tissue samples

After anaesthetizing the mouse, venous blood is collected from the orbit without anticoagulation treatment, the mouse is stood for more than 30 min until the blood is coagulated, the mouse is centrifuged for 10min at 4 ℃ and 5000g, a liquid transfer gun collects serum, the serum is stored in batches at-20 ℃ according to the index to be measured, and the indexes are measured after the serum is slowly redissolved at 4 ℃. Killing mouse by dislocation of cervical vertebra, taking liver and artery tissue with heart, soaking part of liver and artery tissue in 4% paraformaldehyde solution, staining fixed tissue with paraffin section and eosin Hematoxylin (HE),

3. determination of serum turbidity

Serum from atherosclerotic mice turns into an emulsion after centrifugation due to the rise of blood lipids and lipoproteins as well as various inflammatory immune proteins, whereas normal groups are clear, colorless or pale yellow liquids. Therefore, the development process of the atherosclerosis of the mice is reflected by immediately measuring the serum turbidity at the wavelength of 430 nm by using a microplate reader.

4. Measurement of blood lipid, and serum inflammatory factor

Serum TC, TG, HDL-C, LDL-C, IL-6, MCP-1 and TNF- α were measured according to the kit instructions.

5. Examination of pathological sections

The arteries and liver of the mice were stained with HE, and changes in pathological structure were observed.

(II) results of the experiment

1. Serum turbidity and blood lipid measurement results

After 4 months of molding we measured serum turbidity and blood lipids, including TC, TG, LDL-C and HDL-C, in all mice. The serum turbidity is closely related to the blood fat and reflects the process of atherosclerosis, and as shown in figure 3, the serum turbidity is related to TC, TG and LDL-C to a certain extent, compared with the normal group, the ApoE after the model is made ^-/- The serum turbidity, TC, TG, LDL-C and HDL-C of the mouse are all obviously increased, and the blood turbidity can be obviously prevented after P12 treatment. Surprisingly, HDL-C was significantly elevated after modeling, which may be associated with ApoE gene knock-out. The drug treatment also has a tendency to raise HDL-C, and the high dosage of P12 can also raise HDL-C more obviously. Other indexes TC, TG and LDL-C are remarkably reduced by P12 treatment, especially for cholesterol and cholesterol in miceThe effect of reducing the acylglycerol is strong. It also has a better lowering effect on LDL-C, with the strongest lowering effect on triacylglycerols (as shown in Table 3).

TABLE 3 reduction of TC, TG, LDL-C and HDL-C elevation by P12

2. Serum inflammatory factor assay results

As can be seen from the results in FIG. 3, the apoE after molding was comparable to that of normal mice ^-/- The indexes of CRP, TNF-alpha, IL-6, MCP-1 and the like of the mice are obviously increased (P)<0.01 And the increase of the indexes (P) can be remarkably controlled after the ApoA-I mimic peptide P12 is administrated in the midway<0.01 Wherein the levels of TNF-alpha, IL-6 and MCP-1 approach normal, and the anti-inflammatory effects of L-4F are less than those of P12 and the parent peptide. From the measurement results of CRP, CRP is closely related to atherosclerosis, the CRP value of a normal group without atherosclerosis approaches to 0, and the CRP mean value of a model group is higher than 150 mg/L. This indicates that the mice in the model group had developed more severe inflammation, suggesting that the progression of atherosclerosis is higher than that in the other groups, and that P12 may significantly reduce CRP production.

Results of pathological changes in P12 in atherosclerotic mice

The therapeutic effect is shown in A of figure 4 by HE staining of pathological section of artery, the atherosclerosis characteristics are not seen in normal group mice, the atherosclerosis pathological characteristics are obvious in model group A of figure 4, and the successful establishment of the model can be obviously seen, and L-4F, the parent peptide ApoA-I _221-240 And P12, wherein the part marked by the yellow line is the thickened thickness of the intima of the artery, the white line is the total wall thickness of the artery, L-4F, the parent peptide treatment groups have atherosclerotic lesions with different degrees, the lesion degree is smaller than that of the model group, the P12 has better treatment effect, the atherosclerotic lesions can be greatly reduced by P12, the size of the plaque and the relative thickness of the intima are all obviousSmaller than model group, L-4F and parent peptide ApoA-I _221-240 In the group, the statistical analysis of relative intimal thickening in all the HE stained pathologic section fields of each specimen taken in conjunction with FIG. 4C revealed that P12 had a better therapeutic effect, but the dose-dependent effect was not significant, possibly the dose gradient was not large enough, or the 10 mg/kg dose had reached the maximum response dose.

From the results in B in FIG. 4, it can be seen that liver tissue is fattened in a large area after modeling, HE section can see obvious round fat vacuole, hepatic cell arrangement disorder, intercellular space increase, inflammatory cell infiltration, immune edema, hepatic cell content lack, cell nucleus large, liver red fat reduction after P12 treatment, hepatic cell arrangement compact and ordered, hepatic cell content full, cell size and cell nucleus size ratio are appropriate, and the cell size and cell nucleus size ratio approach to the normal group, compared with the normal group, P12 has better liver protection effect than L-4F and maternal peptide ApoA-I _221-240 。

As shown in fig. 4C, relative intimal thickness is data determined using arterial HE stained sections = thickness of abnormal intimal thickening of the artery/total thickness of arterial vessel wall. Relative organ fat area is data counted by using liver HE staining section, relative liver fat area = area of fat cavity/area of each graph, L-4F, maternal peptide, P12 low and high dose reduce degree of thickening of inner membrane of atherosclerosis mice 56.79%,11.68%,85.32% and 89.56% respectively. The reduction degree of fatty area of mouse liver by low and high doses of L-4F, the mother peptide and P12 is 60.36%,37.59%,65.87% and 68.04%, respectively, and P12 shows better effect on resisting atherosclerosis and fatty liver than L-4F and the mother peptide.

Sequence listing

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Claims (2)

1. An anti-atherosclerotic peptide analog having cholesterol efflux activity characterized by: the compound sequence of the anti-atherosclerotic peptide analog with cholesterol efflux activity is as follows:

FLEKLKELLEHLKELLTKLL。

2. use of an anti-atherosclerotic peptide analogue with cholesterol efflux activity as defined in claim 1 for the manufacture of a medicament for the treatment of hyperlipidemia/atherosclerosis and other diseases caused by hypercholesterolemia.

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