CN115403664A - PTP1B polypeptide inhibitor BimBH3-12-R7A and application thereof - Google Patents
PTP1B polypeptide inhibitor BimBH3-12-R7A and application thereof Download PDFInfo
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- CN115403664A CN115403664A CN202210966082.XA CN202210966082A CN115403664A CN 115403664 A CN115403664 A CN 115403664A CN 202210966082 A CN202210966082 A CN 202210966082A CN 115403664 A CN115403664 A CN 115403664A
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- Prior art keywords
- ptp1b
- bimbh3
- polypeptide inhibitor
- dmf
- polypeptide
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Abstract
The invention discloses a PTP1B polypeptide inhibitor BimBH3-12-R7A, which has the following structural formula:
the mimic peptide compound is derived from a core 12 peptide of a BimBH3 structural domain, wherein Arg (R) at the 7 th position is replaced by Ala (A), the mimic peptide compound is prepared by a polypeptide solid phase synthesis method, and amino acids in the structure are all natural amino acids. The PTP1B polypeptide inhibitor BimBH3-12-R7A has remarkable PTP1B inhibition activity, and has potential application value in drug development of related diseases taking PTP1B as a target, such as diabetes, cancer, alzheimer's disease and the like.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a PTP1B polypeptide inhibitor BimBH3-12-R7A and application thereof.
Background
Protein tyrosine phosphatase 1B (ptp1b) is closely related to onset and development of type 2 diabetes and obesity, and is a key negative regulatory protein in the insulin signal transduction pathway. Abnormal overexpression of PTP1B can reduce insulin sensitivity and form insulin resistance. The PTP1B inhibitor can block tyrosine phosphorylation of an Insulin Receptor (IR) stimulated by insulin to further influence phosphorylation of an insulin receptor substrate (IRS-1), so that insulin-like and insulin sensitivity is enhanced, insulin resistance is effectively improved from the source, and blood sugar is reduced without low-blood-sugar adverse reactions of insulin-like medicines. Thus, PTP1B is also a popular target for the recent study of T2DM, and several candidate compounds have entered preclinical and phase I, II clinical trials. Recent research views in recent years show that: PTP1B can be used as a (potential) target for the development of anti-tumor and Alzheimer's disease drugs. Some researches find that the overexpression of PTP1B can obviously promote the generation and growth of tumors in mice, and the inhibition of the expression of PTP1B by an inhibitor can generate an anti-tumor effect; the mechanism research finds that PTP1B controls non-mitochondrial oxygen consumption of cells by regulating RNF213 genes, and further promotes the survival and growth of tumor cells under the anoxic condition. Thus, PTP1B is considered a target for anti-tumor drugs. In recent years, PTP1B has been also used as a regulatory action in physiological processes related to alzheimer's disease in the central nervous system, and a strategy for inhibiting PTP1B and further antagonizing harmful physiological processes related to alzheimer's disease regulated by PTP1B has been proposed to develop an anti-alzheimer's disease drug. Therefore, PTP1B becomes a potential hot target for development of medicaments for resisting diabetes, cancer and Alzheimer's disease, and the PTP1B inhibitor is expected to be applied to development of medicaments for resisting diabetes, cancer, alzheimer's disease and the like taking PTP1B as a target.
At present, inhibitors of PTP1B mainly comprise small inorganic molecule compounds, organic compounds and PTP1B inhibitors in natural products. But the selectivity of inorganic small molecule compounds is very low, and the compounds have stronger inhibition on all PTPs; most of organic compounds are screened by organic synthesis and combinatorial chemistry methods, a compound with PTP1B activity inhibition is screened firstly, then a substituent group of the compound is modified, and finally a better PTP1B inhibitor is obtained, wherein the inhibitor has the problems of poor stability, higher charge, overhigh lipophilic coefficient and the like which restrict the drug property; PTP1B inhibitors in natural products are obtained by high-throughput screening of natural products isolated and identified in nature, and although they have high selectivity and activity, the site of action is not well-defined. Therefore, it is necessary to overcome the defects of the existing PTP1B inhibitory molecules and develop novel PTP1B inhibitors with novel structures, strong selectivity, low toxicity and high efficiency so as to meet the urgent needs of domestic clinical application.
Disclosure of Invention
The invention provides a PTP1B polypeptide inhibitor BimBH3-12-R7A and application thereof. The PTP1B polypeptide inhibitor BimBH3-12-R7A has remarkable PTP1B inhibition activity, and can be used for preparing drugs for preventing or treating related diseases taking PTP1B as a target.
In order to realize the purpose of the invention, the invention adopts the following technical scheme to realize:
the invention provides a novel BH3 mimetic peptide analogue for inhibiting PTP1B activity, and the structural formula of the novel BH3 mimetic peptide analogue is as follows:
wherein R1 is long-chain carboxylic acid, R2 is COOH, and R3 is carboxylic acid or polycarboxylic acid with different carbon chain lengths.
The invention provides a PTP1B polypeptide inhibitor BimBH3-12-R7A, wherein the PTP1B polypeptide inhibitor BimBH3-12-R7A has the following structural formula:
further, the preparation method of the PTP1B polypeptide inhibitor BimBH3-12-R7A comprises the following steps:
(1) Placing Fmoc-Phe-Wang resin in a manual polypeptide solid phase synthesizer at room temperature, and activating by using dichloromethane and dimethylformamide;
(2) Adding piperidine/dimethylformamide mixed solution to remove the Fmoc protecting group;
(3) Adding 3-4 times of resin molar weight of N-Fmoc protected amino acid or carboxylic acid, HOBT, HBTU and 5-6 times of resin molar weight of DIEA, and oscillating at room temperature for 2-4 h;
(4) Repeating steps (2) and (3) until the synthesis of the entire mimetic peptide sequence is completed;
(5) Adding the lysate into the product obtained in the step (4), stirring at room temperature, filtering, adding anhydrous ether to precipitate out a solid, washing, and drying in vacuum to obtain a crude mimic peptide analogue product;
(6) And purifying the crude product of the peptide analogue by using a reversed-phase preparative liquid chromatography, collecting a target peak mobile phase solution, removing acetonitrile, and freeze-drying to obtain a flocculent or powdery solid, thus obtaining a pure product of the PTP1B polypeptide inhibitor BimBH 3-12-R7A.
Further, the lysis solution comprises phenol, water, thioanisole and trifluoroacetic acid.
Further, blowing N after filtering in the step (5) 2 Excess trifluoroacetic acid is removed.
The invention also provides a medicament or a pharmaceutical composition taking the PTP1B polypeptide inhibitor BimBH3-12-R7A as an active ingredient, which comprises any one of the PTP1B polypeptide inhibitors BimBH3-12-R7A and one or more pharmaceutically acceptable carriers or excipients.
The invention also provides application of the PTP1B polypeptide inhibitor BimBH3-12-R7A in preparation of an inhibitor for inhibiting PTP1B activity.
The invention also provides application of the PTP1B polypeptide inhibitor BimBH3-12-R7A in preparation of a medicine for preventing or treating diseases taking PTP1B as a target.
Further, the diseases include diabetes, cancer and alzheimer's disease.
Furthermore, the administration mode of the medicament or the pharmaceutical composition taking the PTP1B polypeptide inhibitor BimBH3-12-R7A as an active ingredient is oral administration or injection.
Compared with the prior art, the invention has the advantages and the technical effects that: the PTP1B polypeptide inhibitor BimBH3-12-R7A is obtained by a polypeptide solid phase synthesis method, the mimic peptide compound is derived from a core 12 peptide of a BimBH3 structural domain, arg at the 7 th position is replaced by Ala, the mimic peptide compound is prepared by the polypeptide solid phase synthesis method, and amino acids in the structure are all natural amino acids. The novel BH3 mimetic peptide analogue has remarkable PTP1B inhibition activity, and has potential application value in drug development of related diseases taking PTP1B as a target, such as diabetes, cancer, alzheimer's disease and the like. Therefore, the PTP1B polypeptide inhibitor molecule BimBH3-12-R7A has potential application value and good development prospect.
Drawings
FIG. 1 is a dose-inhibitory effect curve of the PTP1B polypeptide inhibitor molecule BimBH3-12-R7A (i.e., scan-6) on the target protein PTP 1B.
Detailed Description
The technical solution of the present invention will be described in further detail with reference to specific examples. The methods in the following examples are conventional unless otherwise specified.
Example 1
The specific preparation process of the synthetic route taking scan-1 as an example is as follows:
(1) Resin activation: weighing corresponding amount of Fmoc-Phe-Wang (scan-11 is Fmoc-Ala-Wang) resin, placing the Fmoc-Phe-Wang resin in a manual polypeptide solid phase synthesizer, washing with DCM for 4 times, adding 5ml of DCM for swelling and activating for 3h, washing with DMF for 4 times, adding 20% piperidine DMF for removing Fmoc protecting groups twice (20min + 5min), washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(2) Ligation Phe (F): washing with DMF for 3 times, respectively adding Fmoc-Phe-OH, HBTU, HOBt and DIEA with the molar weight being 3 times that of the resin and 6 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(3) Linkage Glu (E): washing with DMF for 3 times, respectively adding Fmoc-Glu (OtBu) -OH, HBTU, HOBt and DIEA (6 times the molar weight of the resin) with 3 times of the molar weight of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(4) Attachment of Asp (D): washing with DMF for 3 times, respectively adding Fmoc-Asp (OtBu) -OH, HBTU, HOBt and DIEA with resin molar amount 3 times that of resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with DMF for 4 times with 5ml, washing with DCM for 4 times with 5ml, and detecting with Kaiser's reagent.
(5) Attachment of Gly (G): washing with DMF for 3 times, respectively adding Fmoc-Gly-OH, HBTU, HOBt and DIEA with the molar weight being 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(6) Ligation Ile (I): washing with DMF for 3 times, respectively adding Fmoc-Ile-OH, HBTU, HOBt and DIEA with the molar weight being 3 times that of the resin and 6 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(7) Arg (R) linker: washing with DMF for 3 times, respectively adding Fmoc-Arg (Mtr) -OH, HBTU, HOBt and DIEA with resin molar amount 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent. This step was repeated 1 time.
(8) Attachment of Arg (R): washing with DMF for 3 times, respectively adding Fmoc-Arg (Mtr) -OH, HBTU, HOBt and DIEA with resin molar amount 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent. This step was repeated 1 time.
(9) Attachment of Leu (L): washing with DMF for 3 times, respectively adding Fmoc-Leu-OH, HBTU, HOBt and DIEA (diethylene glycol ethyl acetate) with the molar weight being 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(10) Ligation Glu (E): washing with DMF for 3 times, respectively adding Fmoc-Glu (OtBu) -OH, HBTU, HOBt and DIEA (6 times the molar weight of the resin) with 3 times of the molar weight of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(11) Link Glu (Q): DMF is washed for 3 times, fmoc-Glu (OtBu) -OH, HBTU, HOBt with the molar weight of 3 times that of the resin and DIEA with the molar weight of 6 times that of the resin are respectively added and dissolved in 10ml DMF, the mixture is stirred for reaction at room temperature for 2h, DMF is washed for 4 times, 20% piperidine DMF is added for removing Fmoc protecting groups twice (20min + 5min), 5ml DMF is washed for 4 times, 5ml DCM is washed for 4 times, and Kaiser's reagent is used for detection.
(12) Connection to Ala (A): washing with DMF for 3 times, respectively adding Fmoc-Ala-OH, HBTU, HOBt and DIEA with resin molar weight being 3 times of that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(13) Attachment of Ala (A): washing with DMF for 3 times, respectively adding Fmoc-Ala-OH, HBTU, HOBt and DIEA with the resin molar weight being 3 times of that of the resin molar weight, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min + 5min), washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(14) Ligation palmitic acid (Pal): washing with DMF for 3 times, respectively adding palmitic acid, HBTU, HOBt and DIEA in an amount which is 6 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 4h, washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(15) Cleavage, side chain protecting group cleavage: adding 250mg phenol, 0.5ml water, 0.5ml thioanisole, 9.0ml trifluoroacetic acid into the product, stirring for 2.5h at room temperature, filtering, and N 2 Blowing off trifluoroacetic acid, adding 30ml cold anhydrous ether, centrifuging at 5000rpm for 5min to obtain white precipitate, washing with cold anhydrous ether for 3 times, and vacuum drying to obtain crude product.
(16) Purifying the crude product by using reverse phase preparative liquid chromatography (RP-HPLC), collecting a target peak mobile phase solution, removing acetonitrile, freezing and drying to obtain a flocculent or powdery solid, namely a pure BH3 mimetic peptide analogue product, and carrying out structure confirmation by mass spectrometry and high performance liquid chromatography analysis.
The mass spectral data and HPLC purity analysis data for the 27 BH3 mimetic peptide analogs obtained in the manner described above are shown in Table 1.
TABLE 1 Mass Spectrometry data and HPLC purity analysis data for BH3 mimetic peptide analogs
Example 2: determination of protein tyrosine phospholipase 1B (PTP 1B) inhibitory Activity
According to the invention, MES buffer solution is adopted as a reaction system, human protein tyrosine phosphatase 1B (PTP 1B) is utilized, sodium p-nitrophenylphosphate (pNPP) is adopted as a specific substrate, a lead compound SM-6 is selected as a positive control, DMSO is adopted as a negative control, a screening model with a 96-well microplate based on an enzyme reaction rate as a carrier is established, and a PTP1B inhibitor is searched by an enzymology method.
The specific implementation method comprises the following steps: mu.L of 10. Mu.L of pNPP (77 mM), 86. Mu.L of MES buffer, 4. Mu.L of compound (2 mM), and 100. Mu.L of PTP1B solution (50 nM) were added in sequence to a 96-well plate using MES buffer (25mM, pH 6.5) in a total reaction volume of 200. Mu.L. Each group of 3 replicates was shaken at 25 ℃ for 1min on a shaker with DMSO as a negative control and sodium orthovanadate (2 mM) as a positive control, read every 60s on a microplate reader, and dynamically measured for 5min for changes in OD 405 (OD/min). The reaction rate in the initial phase of each well is linearly related, and the slope of the linear part of the kinetic curve determines the reaction rate of PTP1B, and the rate indicates the enzyme activity. For the obtained data
Each set of data was analyzed using the t-test. The inhibition rate of the compound on PTP1B is calculated according to the formula:
inhibition ratio (%) = (v) DMSO -v Sample(s) )/v DMSO ×100％
Wherein v is DMSO 、v Sample(s) The initial average reaction rates of the negative control group and the test compound are expressed respectively
The invention performs primary screening on the PTP1B inhibition rate of the mimic peptide under the concentration of 10 mu mol/L, and performs IC (integrated Circuit) on the compound with the primary screening inhibition rate higher than 70 percent 50 The results of the assay and inhibition are shown in Table 2.
TABLE 2 results of inhibition of PTP1B activity by the tested peptidomimetic analogs
* : compounds with a preliminary screening inhibition of less than 50%To carry out IC 50 The measurement of (1).
Performing statistical processing by adopting GraphPad Prism software, drawing an inhibitor amount effect curve (shown in figure 1), and calculating to obtain PTP1B inhibition medium concentration IC of mimic peptide analogues of scan-2, scan-3, scan-4, scan-5, scan-6, scan-7, scan-8, scan-11, C13-SM6, C14-SM6, C16 diacid-SM6, C18 diacid-SM6, C20 diacid-SM6, C22 diacid-SM6 and Lila-SM6 50 91.6nmol/L, 703.0nmol/L, 580.9nmol/L, 1208.0nmol/L, 56.5nmol/L, 45.4nmol/L, 63.7nmol/L, 511.9nmol/L, 835.4nmol/L, 262.7nmol/L, 2875nmol/L, 120.2nmol/L, 384.6nmol/L, 3887nmol/L, 443.5nmol/L, 337.9nmol/L, 199.6nmol/L, 4345nmol/L, respectively.
The test result shows that: the mimic peptide analogue of the invention has obvious inhibition effect on protein tyrosine phosphatase 1B, can be used as an excellent PTP1B inhibitor, and is applied to the development of antidiabetic, antitumor and anti-Alzheimer's disease drugs taking PTP1B as a target, thereby having good development prospect.
The above examples are only intended to illustrate the technical solution of the present invention, and not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the technical solutions described in the foregoing embodiments, or some of the technical features may be substituted equally; such modifications and substitutions do not depart from the spirit and scope of the corresponding claims.
Claims (10)
1. A novel BH3 mimetic peptide analog for inhibiting PTP1B activity having the structural formula:
wherein R1 is long-chain carboxylic acid, R2 is COOH, and R3 is carboxylic acid or polycarboxylic acid with different carbon chain lengths.
2. A PTP1B polypeptide inhibitor BimBH3-12-R7A is characterized in that the PTP1B polypeptide inhibitor BimBH3-12-R7A has the following structural formula:
3. the PTP1B polypeptide inhibitor BimBH3-12-R7A, according to claim 2, wherein the preparation method of the PTP1B polypeptide inhibitor BimBH3-12-R7A comprises the following steps:
(1) Placing Fmoc-Phe-Wang resin in a manual polypeptide solid phase synthesizer at room temperature, and activating by using dichloromethane and dimethylformamide;
(2) Adding piperidine/dimethylformamide mixed solution to remove the Fmoc protecting group;
(3) Adding 3-4 times of resin molar weight of N-Fmoc protected amino acid or carboxylic acid, HOBT, HBTU and 5-6 times of resin molar weight of DIEA, and oscillating at room temperature for 2-4 h;
(4) Repeating steps (2) and (3) until the synthesis of the whole mimic peptide sequence is completed;
(5) Adding the lysate into the product obtained in the step (4), stirring at room temperature, filtering, adding anhydrous ether to precipitate a solid, washing, and drying in vacuum to obtain a crude mimic peptide analogue product;
(6) And purifying the crude peptide analogue product by using reversed-phase preparative liquid chromatography, collecting a target peak mobile phase solution, removing acetonitrile, and freeze-drying to obtain a flocculent or powdery solid, thus obtaining a pure product of the PTP1B polypeptide inhibitor BimBH 3-12-R7A.
4. The PTP1B polypeptide inhibitor BimBH3-12-R7A, according to claim 3, wherein the lysing solution comprises phenol, water, thioanisole, and trifluoroacetic acid.
5. The PTP1B polypeptide inhibitor BimBH3-12-R7A, according to claim 3, which isCharacterized in that N is blown after filtering in the step (5) 2 Excess trifluoroacetic acid is removed.
6. A medicament or pharmaceutical composition comprising as an active ingredient the PTP1B polypeptide inhibitor BimBH3-12-R7A according to any one of claims 2 to 5, wherein said medicament or pharmaceutical composition comprises any one of said PTP1B polypeptide inhibitor BimBH3-12-R7A and one or more pharmaceutically acceptable carriers or excipients.
7. Use of the PTP1B polypeptide inhibitor BimBH3-12-R7A of any one of claims 2-5 for the preparation of an inhibitor for inhibiting PTP1B activity.
8. Use of the PTP1B polypeptide inhibitor BimBH3-12-R7A of any one of claims 2-5 in the preparation of a medicament for preventing or treating diseases targeted at PTP 1B.
9. Use according to claim 8, characterized in that: the diseases include diabetes, cancer and alzheimer's disease.
10. Use according to claim 8, characterized in that: the medicament or the pharmaceutical composition taking the PTP1B polypeptide inhibitor BimBH3-12-R7A as an active ingredient is orally taken or injected.
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| ZA202203821B (en) | 2022-11-30 |
| CN112608375A (en) | 2021-04-06 |
| CN115403661A (en) | 2022-11-29 |
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