CN116514909A - Antitumor active polypeptide and preparation method and application thereof - Google Patents

Antitumor active polypeptide and preparation method and application thereof Download PDF

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CN116514909A
CN116514909A CN202210983615.5A CN202210983615A CN116514909A CN 116514909 A CN116514909 A CN 116514909A CN 202210983615 A CN202210983615 A CN 202210983615A CN 116514909 A CN116514909 A CN 116514909A
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polypeptide
amino acid
dmf
side chain
protecting group
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CN116514909B (en
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陈晓杰
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Henan University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to an anti-tumor active polypeptide and a preparation method and application thereof, belonging to the technical field of polypeptide medicaments, in particular to an anti-tumor active polypeptide and a preparation method and application thereof. The polypeptide has the structure shown in the following formula (I):

Description

Antitumor active polypeptide and preparation method and application thereof
Technical Field
The invention relates to the technical field of polypeptide medicaments, in particular to an anti-tumor active polypeptide, a preparation method and application thereof.
Background
Polypeptides are a class of compounds formed by the linkage of multiple amino acids through peptide bonds, typically consisting of less than 100 amino acid molecules, in the same manner as proteins, with a relative molecular mass of less than 10000. Polypeptides are ubiquitous in organisms, and up to tens of thousands of polypeptides have been found in organisms to date, which are widely involved in and regulate the functional activities of various systems, organs, tissues and cells in the organism, playing an important role in life activities. Currently, glutathione, octreotide, thymopentin, oxytocin and the like are all polypeptide hormone drugs used clinically. The polypeptide has the characteristics of small molecular weight, low immunogenicity, low toxicity, strong targeting property, good biocompatibility and the like, so that the application prospect is wide.
Tumorigenesis is a complex, dynamic biological process involving genetic and epigenetic changes in multiple steps, and both abnormal expression of non-coding RNAs and changes in the expression profile of coding genes can lead to tumorigenesis and progression. The combination of these factors that are spatially unstable in the genome makes progress in the prevention, diagnosis and treatment of tumors slow. Recent studies have shown that the high expression of peptide receptors on the surface of tumor cells has led to the discovery that some small molecule polypeptides can be used as targeting agents for targeting drug delivery systems by means of ligand and receptor specific binding. The present polypeptide has excellent performance in a mediated targeting drug delivery system, and is widely paid attention to and studied. For example, bombesin (gastrin releasing peptide), the compound AN-215 of bombesin and the tourmaline doxorubicin can be combined with GRP receptors on renal cancer cell membranes, and the inhibition effect on the renal cancer cells is obviously higher than that of free tourmaline doxorubicin. Luteinizing hormone releasing hormone (1 uteinizing hormone-releasing hormone, LH-RH) is used as a ligand, and the linked pyrroline doxorubicin is used for targeting tumor cells expressing LH-RH receptors, such as breast cancer cells, ovarian cancer cells, endometrial cancer cells, prostate cancer cells and the like, so that the effect of remarkably inhibiting proliferation of the tumor cells is achieved. In addition, polypeptide complexes targeting lung cancer cells, colon cancer cells and gastric cancer cells have been reported. These complexes have made great research progress in peptide receptor-mediated drug delivery. Opens up a new way for diagnosing and treating tumors. However, the research in this field is still internationally under the initial stage, and there are some restriction factors in the development of the patent drug, such as the uncertainty of post-translational modification of polypeptide and cleavage site of precursor peptide, and the complexity of screening and purification. In addition, tumor cell surface receptor expression has complexity and diversity, which are also responsible for restricting the development of polypeptides in drug delivery systems; adequate in vivo data and in-depth research on the action mechanism of polypeptide drugs are the development direction of the field, and novel high-activity polypeptides are searched and discovered through in-vivo research and mechanism research.
Esophageal Squamous Cell Carcinoma (ESCC) is the major cancer type in developing countries, and lack of effective targeted therapy is one of the reasons for low 5-year survival. All polypeptide guides currently studied have little effect on esophageal cancer, mainly because there is no effective targeting of specifically expressed receptors on the esophageal cancer cell membrane, and no effective drug concentration can be produced in esophageal cancer cells.
Disclosure of Invention
In order to solve the above-mentioned shortcomings of the prior art, the present invention provides an antitumor active polypeptide, and a preparation method and application thereof, so as to solve the above-mentioned technical problems.
In a first aspect, the present invention provides a polypeptide having the structure of formula (I):
Met-Val-Glu-Glu-Glu-Arg-Pro-Ser-Arg
I。
in a second aspect, the present invention provides a process for the preparation of a compound of formula (I) as defined above, comprising the steps of:
(1) The synthesis sequence is as follows: from the C-terminal to the N-terminal.
(2) Putting the resin into a reactor, adding dichloromethane to swell for half an hour, then pumping out the dichloromethane, adding the first amino acid Met-Fmoc, DIEA, DMF in the sequence and the dichloromethane, and performing a nitrogen bubbling reaction for 60 minutes; then adding methanol, reacting for half an hour, pumping out the reaction liquid, and cleaning with DMF and methanol;
(3) Adding piperidine to remove Fmoc protecting groups, cleaning, and detecting ninhydrin;
(4) The second amino acids Val, HBTU and DIEA in the sequence were added to the reactor and reacted for half an hour with nitrogen bubbling, the liquid was withdrawn, washed with DMF and methanol, and ninhydrin was detected.
(5) Sequentially adding amino acids in the sequence according to the modes of the steps (3) and (4), pumping out liquid, washing with DMF, and detecting ninhydrin, wherein the Glu side chain has a protecting group OtBu; arg side chain has a protecting group Pbf, and Ser side chain has a protecting group tBu;
(6) Drying the resin with nitrogen, taking down from the reaction column, weighing, pouring into a flask, adding 95% TFA cutting fluid into the flask, vibrating for reacting for 2h, cracking the polypeptide from the resin carrier, and removing the side chain protecting group of the amino acid;
(7) Filtering out the resin to obtain filtrate, adding diethyl ether into the filtrate to separate out crude product, centrifuging, and cleaning to obtain crude polypeptide;
(8) Purifying the crude polypeptide through a preparation liquid phase, and concentrating in a freeze dryer to obtain the compound of the formula (I).
Preferably, in the step (2), the molar ratio of the amino acid to DIEA is 1:2.
Preferably, in the step (4), the molar ratio of the second amino acid to the first amino acid to the HBTU is 2:1:2.
In a third aspect, the invention provides the use of a compound of formula (I) in the manufacture of a medicament for inhibiting tumor cells.
Preferably, the tumor cells are esophageal squamous carcinoma cells KYSE30, KYSE150 and KYSE450.
The beneficial effects of the invention are as follows:
the polypeptide prepared by the invention can freely enter and exit esophageal squamous carcinoma cells and plays a certain role in inhibiting proliferation. The specific polypeptide guide of the invention makes up for the defect of polypeptide compounds in the field of esophageal cancer. The polypeptide prepared by the invention can be used for preparing lead compounds for treating esophageal cancer.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the description of the embodiments or the prior art will be briefly described below, and it will be obvious to those skilled in the art that other drawings can be obtained from these drawings without inventive effort.
FIG. 1 is an HPLC chart of the product of example 1 of the present invention.
FIG. 2 is an MS spectrum of the product of example 1 of the present invention.
FIG. 3 is a graph showing the results of cytotoxicity test on KYSE30 of the product of example 1.
FIG. 4 is a graph showing the results of cytotoxicity test on KYSE150 of the product of example 1.
FIG. 5 is a graph showing the results of cytotoxicity test on KYSE450 of the product of example 1.
FIG. 6 is a graph showing the results of the membrane permeation test in example 2 of the present invention.
FIG. 7 is a graph showing apoptosis results of KYSE150 and KYSE450 in example 2 according to the invention.
FIG. 8 is a graph showing the mass change of mouse tumors in example 2 of the present invention.
FIG. 9 is a graph showing the volume change of mouse tumor in example 2 of the present invention.
FIG. 10 is a graph showing the result of immunohistochemistry of mouse model tumor tissue in example 2 of the present invention (in the figure, 1 is a compound of formula (I), 2 is a polypeptide MERRVPEES of a scrambling sequence, and 3 is physiological saline).
FIG. 11 is a graph showing the comparison of liver, spleen and kidney weights after injection of different substances (in the graph, 1 is a compound of formula (I; 2 is a polypeptide MERRVPEES of a scrambling sequence; 3 is normal saline) in different treatment groups according to example 2 of the present invention.
FIG. 12 is a graph showing the weight comparison of tumors after injection of different substances (in the figure, 1 is a compound of formula (I); 2 is a polypeptide MERRVPEES of a scrambling sequence; 3 is physiological saline) in the different treatment groups according to example 2 of the present invention.
FIG. 13 is a graph showing the HE staining of the liver, spleen and kidney of mice in example 2 of the present invention.
Detailed Description
In order to make the technical solution of the present invention better understood by those skilled in the art, the technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
Example 1
Preparation of Compounds of formula (I)
(1) The synthesis sequence is as follows: from the C-terminal to the N-terminal.
(2) Placing a proper amount of resin into a reactor, adding dichloromethane to swell for half an hour, then pumping out the dichloromethane, adding 3 times excess of first amino acid Fmoc-Arg (pbf) -OH, 10 times excess of DIEA, DMF (10 ml/g) and dichloromethane (10 ml/g), and carrying out a bubbling reaction for 60 minutes by using nitrogen; then methanol (10 ml/g) was added thereto and reacted for half an hour, and the reaction mixture was removed and washed with DMF and methanol;
(3) Adding piperidine (15 ml/g) to remove Fmoc protecting groups, washing, and detecting ninhydrin;
(4) The reactor was charged with 3-fold excess of the second amino acid Fmoc-Ser (tBu) -OH, 3-fold excess of HBTU and 10-fold excess of DIEA, the liquid was withdrawn, washed with DMF and methanol and assayed by ninhydrin bubbling for half an hour.
(5) Sequentially adding amino acids in the sequence according to the modes of the steps (3) and (4), wherein the addition amount of each amino acid is 3 times of the excess, pumping out liquid, washing with DMF, and detecting ninhydrin, wherein the Glu side chain is provided with a protecting group OtBu; arg side chain has a protecting group Pbf, and Ser side chain has a protecting group tBu;
(6) Drying the resin with nitrogen, taking down from the reaction column, weighing, pouring into a flask, adding 95% TFA cutting fluid (10 ml/g) into the flask, vibrating and reacting for 2h, and cleaving the polypeptide from the resin carrier and removing the side chain protecting group of the amino acid;
(7) Filtering out the resin to obtain filtrate, adding diethyl ether into the filtrate to separate out crude product, centrifuging, and cleaning to obtain crude polypeptide;
(8) Purifying the crude polypeptide through a preparation liquid phase, and concentrating in a freeze dryer to obtain the compound of the formula (I).
The prepared product was tested and the results were as follows:
HPLC：97.27％；
MS：[M+3H] 3+ :546.19；[M+2H] 2+ :818.77。
example 2
Cytotoxicity test
1. Cell selection and resuscitation.
Esophageal squamous carcinoma cells KYSE30, KYSE150 and KYSE450 are selected in the experiment;
2. film penetration experiment
(1) FITC fluorescent markers are added to the N end of the polypeptide, and 10ug of the polypeptide with FITC is synthesized.
(2) KYSE450 cells were passaged and incubated with confocal dedicated 24-well plates, after 24h the FITC-carrying polypeptide was added at a concentration of 200 uM/L.
(3) Live cells were photographed during the culture. Photographs were taken 6h, 12h, 24h and 48h, respectively, after addition of the FITC-bearing polypeptide. FITC signal distribution and aggregation in esophageal cancer cells were observed under a confocal microscope, and the specific results are shown in FIG. 6.
MTT cytotoxicity assay.
(1) Inoculating 100 μl of cell suspension into 96-well plate, pre-placing at 37deg.C, 5% CO 2 Culturing in a saturated humidity incubator.
(2) Adding polypeptide into 6-well plate at 0, 12.5, 25, 50, 100, 200, 400 μm/L, repeating three wells for each group, and adding 5% CO at 37deg.C 2 Culturing in a saturated humidity incubator for 48 hours.
(3) 10. Mu.L of MTT reagent was added to each well.
(4) The culture plate is placed in an incubator for 1-4 hours.
(5) The MTT method uses 100. Mu.L of DMSO per well to dissolve and then determines the absorbance at 490nm, and the CCK-8 method directly determines the absorbance at 450 nm. The detection results are shown in detail in figures 3-5.
4. Apoptosis detection
(1) Cells were made into cell suspensions and diluted.
(2) The cell suspension was dripped into a special counting plate and placed into a BECKMAN cell technology instrument for counting. The cell concentration was adjusted to 30000/ml.
(3) Inoculating 1ml of cell suspension into 6-well plate, pre-placing at 37deg.C, 5% CO 2 The cells were incubated overnight in a saturated humidity incubator.
(4) 200. Mu.M/L of the compound of formula (I) (in PBS, control group in PBS of equal volume) was added to 6-well plates, three wells were repeated for each group at 37℃and 5% CO 2 Culturing in a saturated humidity incubator for 48 hours.
(5) Cells were collected after 48 hours;
(6) Cell culture medium was collected, cells were washed once with PBS, cells were digested and collected:
(7) Centrifuging at 4000rpm, collecting cells in 5min, adjusting the cell concentration to lxl06/ml, and adding 250uL of Annex v Buffer;
(8) Adding 5 mu Annex v for incubation for 10min;
(9) Adding 5 mu L of PI for dyeing and mixing uniformly, and keeping out of light for 15min at 4 ℃;
(10) And (5) detecting on the machine. The detection result is shown in FIG. 7.
5. Mouse experiment
Patient-derived xenograft (PDX) mouse models, 6-8 week old non-obese diabetic/severe combined immunodeficiency (NOD SCID) female mice (Vital River Labs, beijing, china) were used for animal experiments. Tumor tissue fragments of ESCC patients were collected and subcutaneously implanted into mice. Passaging the tumor for 3 generations; subsequent studies employed P3-P6 tumors. When the tumor volume reaches about 200mm 3 At this time, mice were divided into 3 treatment groups: (1) physiological saline; (2) 50mg/kg of polypeptide randomly scrambled (MERRVPEES); (3) 50mg/kg of the compound of formula (I). The polypeptide (dissolved in physiological saline) was administered daily by intraperitoneal injection. Tumor volume was calculated as length x width x height x 0.5. Tumor size and mouse weight were measured 2-3 times per week when tumor volume reached about 1cm 3 The in vivo study was terminated and mice were subsequently euthanized, tumors, livers, spleens and kidneys were removed, weighed one by one, embedded and sectioned, and subjected to the following immunohistochemistry and HE staining. The weighing result of the tumor is detailed inFig. 8 to 9. The weighing results of liver, spleen and kidney are detailed in fig. 11. Wherein, the quality change of liver, spleen and kidney of the experimental group is not different from that of the control group, and the compound of the formula (I) has no obvious toxic or side effect on the body.
6. Immunohistochemical S-P method for detecting expression of compound of formula (I) and Ki-67 protein
(1) Placing the tissue slice at room temperature for 60min, and then soaking the tissue slice in xylene (I) and xylene (II) for 25min;
(2) Soaking with anhydrous alcohol 100% (I) and 100% (II) for 2min, and then soaking with 95%, 80%, and 70% alcohol for 2min;
(3) Washing with PBS for 2-3 times, each time for about 4min, and then incubating with 80% formaldehyde for 10min for inactivation;
(4) PBS is washed for 2 to 3 times, and each time is about 4 minutes;
(5) Adding goat serum, and incubating for 15min at room temperature to block nonspecific reaction;
(6) To this was added the compound antibody of formula (I) (1:150) and the Ki-67 antibody (1:200), and the mixture was allowed to warm overnight at 4℃for 45min at 37 ℃;
(7) Washing with PBS for 2-3 times, dripping biotin secondary antibody (streptavidin-peroxidase), and incubating for 30 min-1 h at room temperature;
(8) Washing for 2-3 times by using PBS, dropwise adding horseradish enzyme-labeled streptavidin working solution, and then developing for 5-10 min by using DAB;
(9) Counterstaining with hematoxylin, dehydrating with alcohol, sealing with gum, and performing microscopic examination;
(10) PBS was used as a negative control instead of primary antibody, the rest of the procedure being the same as described above;
(11) Positive staining of the compound of formula (I) is located in the nucleus and cytoplasm during microscopic examination, and positive cells are obtained when the cytoplasm is yellow, brown or brown. The Ki-67 positive staining is located in the nucleus, and the positive cells are obtained when the cytoplasm is yellow, brown or brown.
HE staining
(1) Removing paraffin from slice by xylene, passing through high concentration to low concentration alcohol, adding distilled water,
(2) Tissue sections after distilled water had been added were stained in hematoxylin aqueous solution for several minutes.
(3) The color was separated in acid water and aqueous ammonia for several seconds.
(4) After washing with running water for 1 hour, distilled water was added for a moment.
(5) Dehydrated in 70% and 90% alcohol for 10 minutes each.
(6) Adding alcohol eosin staining solution for 2-3 minutes.
(7) The dyed slice is dehydrated by pure alcohol and then transparent by dimethylbenzene.
(8) The clear sections were drip coated with Canadian gum and mounted on a cover slip.
As can be seen from the results of the examination in FIG. 10, the expression level of the compound of formula (I) in the experimental group 1 injected with the compound of formula (I) was significantly increased and the expression level of Ki-67 (an index reflecting the ability of cell proliferation) was significantly decreased, as compared with the control group 3 injected with physiological saline and the control group 2 injected with the polypeptide of scrambling sequence. From the results of the examination in FIG. 11, it can be seen that the three groups of mice have no change in the morphology of liver, spleen and kidney tissues, further indicating no significant hepatotoxicity, spleen and kidney toxicity.
Although the present invention has been described in detail by way of preferred embodiments with reference to the accompanying drawings, the present invention is not limited thereto. Various equivalent modifications and substitutions may be made in the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and it is intended that all such modifications and substitutions be within the scope of the present invention/be within the scope of the present invention as defined by the appended claims. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (6)

1. A polypeptide having the structure of formula (i):
2. a method of producing the polypeptide of claim 1, comprising the steps of:
(1) The synthesis sequence is as follows: from C end to N end;
(2) Putting the resin into a reactor, adding dichloromethane to swell for half an hour, then pumping out the dichloromethane, adding the first amino acid Met-Fmoc, DIEA, DMF in the sequence and the dichloromethane, and performing a nitrogen bubbling reaction for 60 minutes; then adding methanol, reacting for half an hour, pumping out the reaction liquid, and cleaning with DMF and methanol;
(3) Adding piperidine to remove Fmoc protecting groups, cleaning, and detecting ninhydrin;
(4) Adding the second amino acids Val, HBTU and DIEA in the sequence into a reactor, performing nitrogen bubbling reaction for half an hour, pumping out liquid, washing with DMF and methanol, and detecting ninhydrin;
(5) Sequentially adding amino acids in the sequence according to the modes of the steps (3) and (4), pumping out liquid, washing with DMF, and detecting ninhydrin, wherein the Glu side chain has a protecting group OtBu; arg side chain has a protecting group Pbf, and Ser side chain has a protecting group tBu;
(6) Drying the resin with nitrogen, taking down from the reaction column, weighing, pouring into a flask, adding 95% TFA cutting fluid into the flask, vibrating for reacting for 2h, cracking the polypeptide from the resin carrier, and removing the side chain protecting group of the amino acid;
(7) Filtering out the resin to obtain filtrate, adding diethyl ether into the filtrate to separate out crude product, centrifuging, and cleaning to obtain crude polypeptide;
(8) Purifying the crude polypeptide through a preparation liquid phase, and concentrating in a freeze dryer to obtain the compound of the formula (I).
3. The method of claim 2, wherein in step (2), the molar ratio of amino acid to DIEA is 1:2.
4. The process of claim 2, wherein in step (4), the molar ratio of the second amino acid to the first amino acid to HBTU is 2:1:2.
5. Use of the polypeptide of claim 1 for the preparation of a medicament for inhibiting tumor cells.
6. The use of claim 5, wherein the tumor cells are esophageal squamous carcinoma cells KYSE30, KYSE150 and KYSE450.
CN202210983615.5A 2022-08-16 2022-08-16 Antitumor active polypeptide and preparation method and application thereof Active CN116514909B (en)

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CN115490754B (en) * 2022-10-13 2024-04-26 河南科技大学 Anti-tumor active polypeptide derivative and preparation method and application thereof

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