CN108203465B - Polypeptide with stable properties and capable of inhibiting tumor cells and tumor blood vessels in dual-targeting manner - Google Patents
Polypeptide with stable properties and capable of inhibiting tumor cells and tumor blood vessels in dual-targeting manner Download PDFInfo
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- CN108203465B CN108203465B CN201611185320.4A CN201611185320A CN108203465B CN 108203465 B CN108203465 B CN 108203465B CN 201611185320 A CN201611185320 A CN 201611185320A CN 108203465 B CN108203465 B CN 108203465B
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Abstract
The invention relates to the field of protein polypeptide, in particular to a small molecular polypeptide ERCP which is designed and prepared by using chemical synthesis or genetic engineering and protein engineering technologies, and experimental research results show that the polypeptide not only has the effect of inhibiting tumors by other angiogenesis inhibitors, but also can induce tumor cells to apoptosis, and the small peptide is very stable and is possible to become a new anti-tumor medicament.
Description
Technical Field
The present invention relates to proteinsThe field of polypeptide, in particular to a target recognition alpha v β 3 And alpha 5 β 1 The small peptide ERCP is characterized in that omega-aminocaprylic acid is introduced into the amino end of the small peptide, the property is very stable, and the small peptide ERCP has the functions of inhibiting tumor cells and tumor neovascularization simultaneously.
Background
Malignant tumors are common and frequently encountered diseases that seriously threaten human health. Epidemiological statistics show that the cancer mortality rate of China is the first cause of death in ten years, and according to statistics, one person in every 6 minutes in China is diagnosed as cancer, 8550 people become cancer patients every day, one person in every seven to eight people dies of cancer, and the morbidity and mortality rate of Chinese cancer continue to rise in the next 10 years. The history and geographical coordinates of the onset of tumors in China from cancer county to cancer village are behind the high incidence of cancer due to decades of changes in social development and lifestyle. The ministry of health of the forepart of the defenders has announced that cancer is one of the biggest threats to the health of the world today, as published by the ministry of health at 2010, 8/18. The incidence of cancer has increased by 80% in china over the last 30 years. In the open captioning of the world anticancer conference held in Shenzhen in 2010, the Chenzhu Ming means that 260 ten thousand Chinese people are diagnosed with cancer each year, of which 180 thousand people are due to poor diet. Cancer has become the first leading cause of death from disease in 2009. The most common cancers are lung, liver, stomach, esophagus, colon and rectum. The incidence of breast cancer is also on an increasing trend. In fact, not only China currently suffers from cancer, but also some developed countries suffer from cancer, and data published by the international anti-cancer alliance show that the number of deaths caused by cancer is more than the sum of AIDS, malaria and tuberculosis in the world. If no effective measures are taken, 2600 ten thousand new cancer cases are expected to appear in 2030 every year, 1700 thousand cancer deaths are expected, and countries with low or medium income become "serious areas" of cancer abuse. Over the past 30 years, the cancer mortality rate in china has increased by 80%, with 180 million people who died each year.
The main hazards of malignant tumors are their unlimited proliferation capacity and strong migratory capacity. Although the development of medical science has greatly improved the ability to treat tumors clinically, tumor metastasis remains the most serious challenge to clinical treatment of tumors.
Angiogenesis in tumor tissue provides not only nutrients for tumor growth, but also a pathway for tumor cell metastasis. In the angiogenic phase, angiogenesis is formed by the expansion of the preexisting vascular buds, endothelial cells must adhere to each other and to the extracellular matrix to build and expand new microvessels, but both the tumorigenic basement membrane and the vascular endothelium are deficient, and tumor cells are highly susceptible to crossing their basement membrane barrier into the blood circulation, and thus metastasize and spread distally. The metastatic foci further induce neovascularisation to meet their excessive growth needs and, in certain cases, to metastasize again. As can be seen from the process of tumor metastasis, the establishment of self-vascular network and the induction of angiogenesis are the necessary conditions for tumor proliferation and metastasis. For some time, angiogenesis inhibition therapy is expected to become a new type of therapy with the greatest prospect, in addition to chemotherapy, radiotherapy and surgery.
Although the angiogenesis inhibition therapy shows great superiority in animal experiments, years of research finds that some factors limit the popularization and application of the angiogenesis inhibitor, for example, Angiostatin derived from snake venom is considered as the strongest angiogenesis inhibition factor at present, and the angiogenesis inhibition therapy has the advantages of high-efficiency inhibition of tumor angiogenesis, no drug resistance after repeated use and the like. However, the dosage required by clinical diagnosis and treatment is large, the cost is high, and in recent years, the snake venom is found to be derived from snake venom, and the immunogenicity is not negligible. Second, angiogenesis inhibitors typically only cause tumor cells to become dormant and do not directly kill them. Moreover, although anti-tumor vascular therapy can effectively reduce the volume of the tumor, some tumor cells are always left in the marginal area of the tumor, and the tumor cells can obtain nutrition from the blood vessels of normal tissues. Thus, the limitations of vascular simplex therapy are apparent.
Alpha to one of the Integrin (Integrin) family members v β 3 Plays an important role in the angiogenesis process. Alpha is alpha v β 3 When the blood vessel of a normal organism can not be detected and the endothelial cells are stimulated and activated, a large amount of expression is carried out, so that the information transmission and the endothelial cell activation of angiogenesis are initiated; in addition to expression on the surface of blood vessels, α v β 3 It is also expressed on the surface of many tumor cells such as colon cancer cells, osteosarcoma cells, melanoma cells, etc., and alpha is also expressed on the surface of these tumor cells 5 β 1 The receptor is abundantly expressed. These integrins are recognized and bound by the deltegrin (Disintegrin) -specific supersecondary structure RGD (Arg-Gly-Asp) motif, resulting in alpha v β 3 、α 5 β 1 Is competitively inhibited. Action of disintegrin on blood vessel surface alpha v β 3 Can inhibit tumor angiogenesis, and also can inhibit tumor surface alpha v β 3 The receptor, inhibiting tumor cell proliferation, causes apoptosis of tumor cells. Disintegrin is considered as a dual-functional effector molecule that not only inhibits tumor angiogenesis, but also inhibits and kills tumor cells. Therefore, the problem that the angiogenesis inhibitor can not kill tumor cells by being singly applied in the past can be solved. In recent years, researches show that the tumor treatment by the disintegrin has some problems, firstly, the integrin is mostly from snake venom and has larger immunogenicity; secondly, disintegrin can recognize a variety of different integrins, and thus its effect is broad but not specific. In recent years, the RGD membrane body and the C end of the disintegrin Echistatin are fused in the laboratory to obtain a new small peptide ERC (N) 5 ) Pharmacodynamic studies have confirmed ERC (N) 5 ) Targeting high efficiency and low toxicity, ERC (N) was found in pharmacokinetic studies 5 ) The molecular weight is small, the half-life period is short, the in vivo stability is very small, the degradation can occur in a short time, and the anti-tumor effect of the composition is influenced. To extend its half-life, we decided to treat ERC (N) 5 ) Modifying ERC (N) 5 ) Mutation of 5 th and 6 th amino acids into W and P, and connection of omega-aminocaprylic acid to amino terminal, and named ERCPThe design mode not only improves the activity of the tumor cell, but also greatly enhances the stability of the tumor cell in vivo, thereby fully playing the aim of the tumor cell and the tumor neovascularization in a targeted manner.
The invention aims to provide a polypeptide which has stable property and can target and recognize and inhibit tumor cells and tumor neovascularization, thereby overcoming the defects of weak specificity and single effect of the existing antitumor drugs, and also overcoming the problems of short half-life period and instability of small peptide drugs so as to play efficient and specific tumor inhibition and killing effects in clinical treatment.
Disclosure of Invention
The invention provides a brand-new small molecular polypeptide which consists of RGD (Arg-Gly-Asp) and a part of C-terminal sequence of Echistatin. The primary structure of the mutated protein is omega ARGD WP PRNPHKGPAT (bold and italic show the amino acid sequence after mutation), omega-amino caprylic acid is added at the N terminal of Echistatin, the small molecular polypeptide has certain soft space conformation through computer simulation, the distance between RGD motif and C terminal sequence is close to the distance between RGD and C terminal in the Echistatin structure, theoretically has similar biological activity of Echistatin and ERC (N5), and ERC (N5) is increased 5 ) Stability of (2).
The modified polypeptide is combined by partial C ends of RGD and Echistatin, the amino end is omega-aminocaprylic acid, the second one
Five amino acids are W, and the RGD structure is wider after the W is introduced, and is easier to react with alpha v β 3 、α 5 β 1 And (4) combining. The polypeptide is named ERCP in the invention. ERCP both retains ERC (N) 5 ) Specific recognition of alpha v β 3 、α 5 β 1 The method has the advantages of reducing immunogenicity with smaller molecular weight, and particularly solving the problem of poor stability of small peptides.
One of the key points of the invention is to provide a novel design and synthesis of small molecule polypeptide, and the amino acid sequence of the novel small molecule polypeptide is characterized in that: omega ARGDWPPRNPHKGPAT under the name ERCP.
The invention also provides the application of ERCP polypeptide in the clinical treatment of malignant tumor proliferation and metastasis.
Advantages of the invention：
The invention has the advantages and positive effects that a micromolecule polypeptide is designed and prepared by utilizing chemical synthesis or genetic engineering and protein engineering technology, the polypeptide not only has the tumor inhibition effect of other angiogenesis inhibitors, but also has the specific effect of killing tumor cells, has stable property, and is expected to become a novel polypeptide medicine for targeted therapy of malignant tumors.
Drawings：
FIG. 1-HepG 2 cell growth graph
FIG. 2-morphological observations of apoptosis in HepG2 cells
Wherein: a: HepG2 cells were cultured normally for 12 hours; b: ERCP action on HepG2 cells for 12 hours
FIG. 3-change in cell invasion of HepG2 cells after ERCP treatment
Wherein: a: a negative control group; and B, ERCP treatment group.
FIG. 4-morphological Observation of apoptosis of HUVEC
Wherein: a: a negative control group; ERCP treatment group
FIG. 5-AO/EB staining to detect morphological changes in apoptosis
Wherein: a: a negative control group; ERCP treatment group
FIG. 6-cell invasion changes of HUVEC cells after ERCP treatment
Wherein: a: a negative control group; ERCP treatment group
Detailed description of the preferred embodiments：
The following examples are only for the purpose of helping the skilled person to better understand the present invention, but do not limit the present invention in any way.
< example 1 >: chemical Synthesis of ERCP
1. Swelling of the resin
Rink Amide-MBHA resin and DCM (15ml/g) were added to the reaction tube and the mixture was shaken under nitrogen (20 min). DCM was then filtered off, 4-fold Fmoc-Arg (Pbf) -OH amino acid, HBTU, and 10-fold DIEA were added, and DMF was finally added for dissolution. Shaking with nitrogen at room temperature for 20 min. The DMF was filtered off, shaken with 20% piperidine DMF solution (15ml/g) for 10min, the piperidine was filtered off and the shaking with piperidine DMF was repeated once for 10 min. The piperidine is filtered off, the resin is filtered by ethanol, ninhydrin, KCN and phenol solution are added one drop at a time, and the color is changed to blue after heating for 10min at 105-110 ℃. Finally, the carrier resin in the reaction tube can be washed twice with DMF, methanol and DCM respectively. The residual piperidine on the carrier resin was washed away.
2. And (3) repeating the step (1) in the condensation reaction, and sequentially connecting the amino acids in the sequence from right to left. The resin was washed several times with DCM, vacuum dried, and 10ml/g of cleavage medium (TFA 94%; H) was slowly added to the polypeptide solid phase reactor containing the resin 2 O2.5 percent; 2.5 percent of EDT; TIS 1%). Shaking the shaking table at constant temperature for 3h, removing most of the solvent with nitrogen, and adding anhydrous ether into the residual liquid to obtain white precipitate. And centrifuging to remove impurities. Drying the cutting fluid with nitrogen as much as possible, rinsing with diethyl ether for multiple times, and volatilizing the solvent at normal temperature to obtain an ERCP crude product. Purifying by C18 high performance liquid chromatography to obtain ERCP pure product.
< example 2 >: ERCP inhibition experiment on human liver cancer HepG2 cells
1. Effect of different incubation times on HepG2 cell proliferation
The OD values decreased in both the negative and ERCP-treated groups as the culture time was extended. Negative group cells compared to experimental group
The change in OD value was small, see figure 1.
2. Morphological changes
Under the conventional culture conditions, the liver cancer HepG2 cells extend, are fusiform and are closely arranged. After the ERCP acts on the cells for 12 hours, the cells become round, the capsule is protruded, the gap is enlarged, and cell debris appears. See fig. 2. The ERCP is shown to inhibit the growth and development of cells and has an effect on HepG2 cells.
3. Invasion of HepG2 cells
Negative control group, i.e.cells without ERC (N) 5 ) After 48 hours of normal culture, the cells grow vigorously; HepG2 cell channel
After 48 hours of ERCP treatment, the cells disintegrated and ruptured, and the cells were significantly decreased, as shown in fig. 3.
< example 3> experiment of ERCP inhibiting human umbilical vein endothelial cells:
1. effect of HUVEC cell morphology
HUVEC cells are expanded, fusiform and tightly arranged under the conventional culture condition; after 24h of ERCP action, cells were rounded, the capsule was prominent, the space was enlarged, and cell debris appeared, which are typical characteristics of programmed cell death, as shown in fig. 4.
2. AO/EB staining detection of apoptosis
The apoptosis morphology of the cells after AO/EB staining was observed by fluorescence microscopy. HUVEC after 16 u mol/L ERCP treatment for 24h can see different cell morphology. FIG. 4A shows that the chromatin is all green and normal in structure is living cells, and FIG. 4B shows that the chromatin is colored green and is in the form of a solid condensed or beaded form, which is an early apoptotic cell; wherein the chromatin is orange-red and normal in structure and is a non-apoptotic dead cell; chromatin is orange red and is in a condensed or beaded form as a late apoptotic cell. The results show that the HUVEC cell apoptosis rate after ERCP treatment is 20.6%, and ERCP can induce significant apoptosis morphological change of HUVEC cells, and the results are shown in figure 5.
3. Transwell invasion test
By observing cells in the lower Transwell chamber after HUVEC cell invasion, FIG. 6A shows a negative control group, i.e., the state of cells after invasion without ERCP treatment after normal culture for 24 hours; FIG. 6B shows the state of the cells after 24 hours of ERCP treatment, after invasion. Although both groups of cells were able to cross the polycarbonate membrane, the number of the cells was significantly different, the number of the cells crossed by the negative control group was (144. + -. 5.5), the number of the cells crossed by the ERCP-treated group was (18.8. + -. 3.0), and the invasion inhibition rate was 87%. The differences were statistically significant (P < 0.05) in the ERCP-treated versus the negative groups.
SEQUENCE LISTING
<110> university of Shanxi medical science
<120> a polypeptide with stable properties for inhibiting tumor cells and tumor blood vessels in dual targeting manner
<160> 1
<170> SIPO Sequence Listing 1.0
<210> 1
<211> 16
<212> PRT
<400> 1
Ala Arg Gly Asp Trp Pro Pro Arg Asn Pro His Lys Gly Pro Ala Thr
5 10 15
Claims (3)
1. A small molecular polypeptide ERCP comprises a polypeptide with an amino acid sequence shown in SEQ ID NO.1, and is formed by connecting omega-amino octanoic acid at the N end of the polypeptide, and the structure of the ERCP is 8-amino octanoic acid-ARGDWPPRNPHKGPAT.
2. The method for preparing the polypeptide ERCP of claim 1, which comprises solid phase synthesis method and genetic engineering construction.
3. The use of the polypeptide ERCP of claim 1 in the preparation of a medicament for the treatment of malignant tumor proliferation and metastasis.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5747457A (en) * | 1993-10-28 | 1998-05-05 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Linear adhesion inhibitors |
| CN101280004A (en) * | 2008-05-28 | 2008-10-08 | 山西医科大学 | Polypeptide ERC(N5) for specific inhibition of tumor cell and tumor angiogenic blood vessel |
| CA2791058A1 (en) * | 2010-02-24 | 2011-09-01 | Ben Gurion University Of The Negev Research And Development Authority | Methods for inhibiting necrosis |
| CN107253986A (en) * | 2017-05-24 | 2017-10-17 | 上海大学 | Integrin intracellular peptide sequence is suppressing the application during new vessels is formed |
| CN111018952A (en) * | 2019-12-23 | 2020-04-17 | 哈尔滨医科大学 | Anti-tumor polypeptide with dual effects and application thereof |
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- 2016-12-20 CN CN201611185320.4A patent/CN108203465B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5747457A (en) * | 1993-10-28 | 1998-05-05 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Linear adhesion inhibitors |
| CN101280004A (en) * | 2008-05-28 | 2008-10-08 | 山西医科大学 | Polypeptide ERC(N5) for specific inhibition of tumor cell and tumor angiogenic blood vessel |
| CA2791058A1 (en) * | 2010-02-24 | 2011-09-01 | Ben Gurion University Of The Negev Research And Development Authority | Methods for inhibiting necrosis |
| CN107253986A (en) * | 2017-05-24 | 2017-10-17 | 上海大学 | Integrin intracellular peptide sequence is suppressing the application during new vessels is formed |
| CN111018952A (en) * | 2019-12-23 | 2020-04-17 | 哈尔滨医科大学 | Anti-tumor polypeptide with dual effects and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| AoGDW肽抑制血小板聚集的活性及特异性;王晓霞等;《中国生物制品学杂志》;20070620(第6期);432-434+438 * |
| Specificity of ERC (N 5) polypeptide in recognizing integrin α vβ 3and its effect on proliferation and apoptosis of HepG2 cells;H.-T. Liu等;《Chinese Journal of Biologicals》;20120731;第25卷(第7期);865-868+876 * |
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