CN113845598B - Protein targeting chimera degradation MDM2/MDMX protein staple peptide conjugate and application thereof - Google Patents

Protein targeting chimera degradation MDM2/MDMX protein staple peptide conjugate and application thereof Download PDF

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CN113845598B
CN113845598B CN202111096791.9A CN202111096791A CN113845598B CN 113845598 B CN113845598 B CN 113845598B CN 202111096791 A CN202111096791 A CN 202111096791A CN 113845598 B CN113845598 B CN 113845598B
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peptide
mdm2
protein
peptide conjugate
resin
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CN113845598A (en
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李翔
陆五元
胡宏岗
耿晨晨
陈思
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Second Military Medical University SMMU
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • 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

Abstract

The invention relates to the field of polypeptide medicaments, in particular to a protein targeting chimera (PROTACTs) degradation MDM2/MDMX protein staple peptide conjugate, a preparation method and application thereof. The staple peptide conjugate consists of three parts: a first peptide fragment adapted to bind to MDM2/MDMX proteins; a second peptide fragment adapted to bind to E3 ubiquitin ligase VHL; and the connecting arm is used for connecting the first peptide segment and the second peptide segment. The E3 ubiquitin ligase VHL can perform ubiquitination modification on MDM2/MDMX proteins so that the protein is used for degrading the ubiquitinated MDM2/MDMX proteins, thereby activating the P53 factor to play a role in killing cancer cells and inhibiting the tumorigenic capacity, and has potential application value.

Description

Protein targeting chimera degradation MDM2/MDMX protein staple peptide conjugate and application thereof
Technical Field
The invention relates to the field of polypeptide medicaments, in particular to a protein targeting chimera (PROTACTs) degradation MDM2/MDMX protein staple peptide conjugate, a preparation method and application thereof.
Background
Tumors have become one of the major diseases that are increasingly common and severely threatening human life and quality of life. The treatment method of the tumor can be selected according to the type of the tumor and the maturity of the current technology, or the tumor can be treated by combining a plurality of treatment means. Current methods of treating tumors include surgical, radiation, and hormonal treatments, which produce side effects to varying degrees. In contrast, drug molecule targeted therapies are preferred. Targeting the interaction of p53 with two key negative regulatory factors MDM2 and MDMX for tumor treatment has become a research hotspot as p53 is the most important tumor suppressor. Thus, inhibition of tumor by specific degradation of MDM2/MDMX proteins to activate P53 factor against tumor is considered as the most direct and effective anticancer strategy.
In the past, inhibitors targeting the p53-MDM2/MDMX protein are almost all chemical small molecules, and the small molecule inhibitors have difficulty in thoroughly inhibiting the functions of MDM2/MDMX because the binding interfaces of MDM2/MDMX and other proteins are large, and the types of the binding proteins are multiple and complex. However, linear polypeptides have problems such as low stability and poor permeabilities. The stapled peptides are better able to overcome this problem, exhibiting better proteolytic stability and higher helicity than the linear peptides.
Disclosure of Invention
The invention aims at providing a protein dissolution targeting chimeric degradation MDM2/MDMX protein staple peptide conjugate, a preparation method and application thereof
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a protein targeting chimera (PROTACTs) in a staple peptide conjugate for degrading MDM2/MDMX protein and activating P53 factor to resist tumor, a preparation method and application thereof. Protein targeting chimera (protacs) consisting of an intracellular target protein and E3 ubiquitin ligase, the stapled peptide conjugate of the invention contains two peptide fragments that recognize and bind MDM2/MDMX protein and E3 ubiquitin ligase VHL, respectively, ubiquitinating MDM2/MDMX protein by E3 ubiquitin ligase VHL, allowing it to be degraded by proteases.
The staple peptide conjugate consists of three parts: a first peptide fragment prepared by using a TSFAEYWALLS sequence linear peptide as a template and S at a specific position on the basis of retaining a key amino acid residue 5 And R is 8 Instead of the original amino acid, the target stapling peptide is obtained through olefin metathesis reaction, has higher helicity and stability compared with the linear peptide, and is suitable for being combined with MDM2/MDMX protein; a second peptide fragment which is a VHL ligand consisting of hydroxyproline and homoleucine and has the sequence LA-Hyp-Y-Hle-P, and is suitable for being combined with E3 ubiquitin ligase VHL; and the connecting arms respectively adopt PEG1, PEG2 and PEG3 as the connecting arms of the first peptide fragment and the second peptide fragment. E3 ubiquitin ligase VHL can perform ubiquitination modification on MDM2/MDMX protein so that protease degrades ubiquitinated MDM2/MDMX protein, thereby activating P53 factor to play roles in killing cancer cells and inhibiting tumorigenic capacity, and has potential applicationThe application value.
The invention utilizes colon cancer cells to detect the antitumor effect of the stapler peptide conjugate outside the cells. The anti-tumor effect of the staple peptide conjugate in vivo was tested using a nude mouse tumor-engrafting model.
In a first aspect of the invention there is provided a staple peptide conjugate selected from one of the following:
a) Ac-TSFAEYWALLS-PEG-LA-Hyp-Y-Hle-P-NH 2 Is a peptide chain template, 4 of which A And 11 (V) S Are respectively R 8 And S is 5 Replacing and cyclization;
b) Ac-TSFAEYWALLS-PEG2-LA-Hyp-Y-Hle-P-NH 2 Is a peptide chain template, 4 of which A And 11 (V) S Are respectively R 8 And S is 5 Replacing and cyclization;
c) Ac-TSFAEYWALLS-PEG3-LA-Hyp-Y-Hle-P-NH 2 Is a peptide chain template, 4 of which A And 11 (V) S Are respectively R 8 And S is 5 And (5) replacing and cyclization.
Further, the structural schematic diagram of the staple peptide conjugate is shown in fig. 1; the structural formula is shown as follows:
Figure BDA0003269323130000031
further, the staple peptide conjugate consists of three parts:
a first peptide fragment using a TSFAEYWALLS linear peptide as a template, 4 of which A And 11 (V) S Are respectively R 8 And S is 5 The replacement and cyclization, the first peptide fragment being adapted to bind to MDM2/MDMX proteins;
a second peptide fragment which is a VHL ligand consisting of hydroxyproline and homoleucine and has the sequence LA-Hyp-Y-Hle-P and is suitable for being combined with E3 ubiquitin ligase VHL;
and a connecting arm selected from any one of PEG, PEG2 or PEG3, wherein the first peptide segment and the second peptide segment are connected through the connecting arm.
In a second aspect of the invention, there is provided a method of preparing a stapled peptide conjugate as described above, comprising the steps of:
(1) An amount of amino resin was weighed and swollen for 20min with 4ml of DCM solution;
(2) Fmoc protecting groups were removed using 20% piperidine/DMF solution/0.1 mol/L Oxime for 5min and repeated twice;
(3) The resin was washed 5 times with 5ml DMF, 5 times with 5ml DCM, and finally 5 times with 5ml DMF.
(4) The reaction solution of natural amino acid condensation is used for composing Fmoc-AA-OH 4 times of equivalent, oxo 4 times of equivalent, DIC 4 times of equivalent to carry out condensation reaction at 60 ℃ for 20min. For Fmoc-S 5 /R 8 -OH 2 equivalents, oxime 2 equivalents, DIC 2 equivalents, 60 ℃ for 2h;
(5) Repeating the operations (2) - (4), and sequentially coupling according to the amino acid sequence; wherein, partial cyclization sites are respectively represented by R 8 And S is 5 Respectively substituting amino acids at positions i and i+7;
(6) Pyridine was used: acetylation of the N-terminally deprotected amino acid with acetic anhydride=1:1 solution;
(7) Treating the resin with a dichloroethane solution of Grubbs first generation catalyst to carry out a cyclization reaction;
(8) Using cleavage reagents (TFA/TIPS/H 2 O=95/2.5, v/v/v) cleaves the peptide chain from the resin.
(9) Iced diethyl ether (40 mL) was added to the crude peptide, centrifuged at 3500r/min for 3min, and the procedure was repeated 5 times.
(10) The crude peptide, which naturally volatilizes after centrifugation, was purified using RP-HPLC.
Further, the purification method adopted in the step (10) is reverse high performance liquid chromatography under the following conditions: chromatographic column: YMC-Pack ODS-AQ column; mobile phase: mobile phase a was 0.1% tfa/water and mobile phase B was 0.1% tfa/acetonitrile; gradient elution procedure: eluting with 35% B for 0-5 min, and eluting with 35% B-65% B for 5-60 min; the flow rate was 20ml/min, the sample injection amount was 1ml, and the detection wavelengths were 214nm and 254nm.
In a third aspect of the invention there is provided the use of a staple peptide conjugate as described above in the manufacture of an anti-tumour medicament.
Further, the tumor is caused by excessive accumulation of MDM2 and MDMX in P53-MDM 2/MDMX.
Further, the tumor is colon cancer.
The abbreviations involved in the present invention are explained as follows:
DCM: dichloromethane (dichloromethane)
DMF: n, N-dimethylformamide
Oxime：Ethyl Cyanoglyoxylate-2-Oxime
Fmoc: fluorene methoxycarbonyl group
DIC: n, N-diisopropylcarbodiimide
Grubbs i: first generation of phenylmethylenebis (tricyclohexylphosphorus) dichloride
TFA: trifluoroacetic acid
Tigs: triisopropylsilane.
The invention has the advantages that:
1. the preparation is convenient: the staple peptide conjugate of the invention has shorter sequence length and can be prepared by a mature Fmoc solid-phase synthesis method;
2. high activity and high selectivity: compared with small molecules, the conjugate provided by the invention has a larger action surface;
3. penetrate directly into the cell membrane: the polypeptide provided by the invention basically maintains a natural alpha-helical structure and has positive charges under physiological conditions, so that the polypeptide is beneficial to penetrating cell membranes into cytoplasm and nucleus through endocytosis;
4. the serum stability is high: the conjugate is cyclic peptide, contains unnatural amino acid and is modified by N acetylation, so that the stability of the conjugate is improved.
Drawings
FIG. 1 is a schematic representation of a staple peptide conjugate of the invention.
FIG. 2 is a synthetic route diagram of the stapling peptide conjugate of example 1 of the invention.
FIG. 3 shows high performance liquid chromatography (A-F) of the target compounds of the present invention after purification.
FIG. 4 shows mass spectra (A-F) of the target compounds of the present invention after purification.
FIG. 5 shows the extracellular antitumor effect of the target compounds of the present invention.
FIG. 6 shows the antitumor effect (tumor size, volume change) of the objective compound of the present invention in vivo. Wherein P <0.05, there is a statistical difference; * P <0.01, with significant statistical differences; * P <0.001, with very significant statistical differences; * P <0.0001, there was a very significant statistical difference.
FIG. 7 shows the antitumor effect (change in body weight before and after administration of nude mice) of the objective compound of the present invention in vivo.
Detailed Description
The following provides a detailed description of embodiments of the present invention with reference to examples.
Example 1: preparation of protein dissolution targeting chimeric staple peptide conjugates
1. Synthesis of staple peptide (SPMI-HIF 2-1 for example)
The synthetic route is shown in fig. 2:
(1) Preparation of Compound 1
333mg of amino resin (sample loading of 0.30 mmol.g) -1 ) Adding the mixture into a solid phase synthesis reaction tube, soaking the mixture in DCM for 20min to fully swell the resin, and pumping the resin for later use.
A20% piperidine-DMF solution (0.1M Oxyme) was added until the resin was completely submerged, shaking was performed at 25℃for 5min X2 to remove Fmoc from the resin, and the resin was washed 5 times with DCM and DMF in sequence.
(2) Preparation of Compound 2
The first amino acid (1 mmol), oxyme (142 mg,1 mmol) and DIC (155.0. Mu.L, 1 mmol) in the sequence were mixed in 6ml NMP, the synthesis of PEG and amino acid was identical, added to the resin and shaken for 20min at 60℃ (R 8 /S 5 The latter amino acid was reacted for 2 h) and the resin was washed 5 times with DCM and DMF in sequence.
(3) Preparation of Compound 3
Repeating steps (1) and (2), sequentially mixing Fmoc amino acid (1 mmol), oxyme (142 mg) and DIC (155 μl) into 6ml NMP according to polypeptide sequence, adding into resin, oscillating at 60deg.C for 20min, and repeating deprotection, condensation and deprotection until all amino acids are connected. The resin was washed 5 times with DCM and DMF sequentially.
(4) Preparation of Compound 4
After deprotection of the last amino acid, 6ml of a pyridine/acetic anhydride (1:1) mixture was added and the resin was washed 5 times with DCM and DMF sequentially with shaking at 25℃for 20min.
(5) Preparation of Compound 5
After the resin was completely dried, a solution of Grubbs I (58 mg) in dichloroethane (6 ml) was added and the reaction was carried out with shaking twice at 25℃for 2h each, and after the completion of the reaction, the resin was washed with DCM, DMF and anhydrous diethyl ether 5 times each in sequence and the resin was dried by vacuum.
(6) Preparation of Compound 6
Cleaning resin, draining, adding TIPS H 2 O tfa=2.5:2.5:95 (V/V) 10mL, shaking for 4h at normal temperature, filtering, washing the resin with a little TFA, and collecting the filtrate. And (3) bubbling argon to blow off excessive TFA, pouring into glacial ethyl ether for precipitation and centrifugation, discarding supernatant, repeatedly washing and centrifuging with the glacial ethyl ether for 5 times, and drying by argon to obtain a crude product of the staple peptide conjugate.
2. Purification of target stapling peptides
The crude peptide was dissolved with acetonitrile and water and purified by preparative RP-HPLC. The separation conditions were as follows:
instrument: pre-HPLC SD-1VARIAN high performance liquid chromatograph;
chromatographic column: YMC-Pack ODS-AQ column;
mobile phase: mobile phase a was an aqueous solution with a volume fraction of 0.1% tfa, and mobile phase B was an acetonitrile solution with a volume fraction of 0.1% tfa;
the steps and parameters are as follows: eluting with 35% B for 0-5 min, and eluting with 35% B-65% B for 5-60 min; the flow rate was 20ml/min, the sample injection amount was 1ml, and the detection wavelengths were 214nm and 254nm.
Example 2: liquid phase and mass spectrum characterization of protein dissolution targeting chimeric stapled peptide conjugates
The product of example 1 was identified by HPLC and subjected to structural analysis by HR-Q-TOF-MS with acetonitrile and water as the mobile phase for chromatography. Mobile phase A is aqueous solution with volume fraction of 0.1% TFA, mobile phase B is acetonitrile solution with volume fraction of 0.1% TFA, gradient elution is carried out (0-5 min, mobile phase B:5%, 5-30min, mobile phase B:5% -80%); the flow rate is 1mL min < -1 >; the detection wavelengths are 214nm and 254nm, and the sample injection amount is 20 μl. The peak time was determined to be consistent with the main peak of the crude product, and the purity of the prepared staple peptide conjugates of the invention was >98% (fig. 3). The results of analysis by HR-Q-TOF-MS mass spectrometry are shown in FIG. 4.
Example 3: detection of extracellular antitumor effects of staple conjugates using colon cancer cells
Colon cancer cell line HCT 116-knockout of P53 colon cancer cell line HCT 116-/-culture with high sugar DMEM containing 10% fetal bovine serum, 100U/ml penicillin and 100mgL-1 streptomycin at 37℃on the basis of 5% CO 2 And (5) conventional culture passage in an incubator. The next day of the application of 1000 cells per well in 96-well plates, different concentrations (0,3.125,6.25, 12.5, 25, 50, 100 μm) of the polypeptides PMI-HIF-1, PMI-HIF-2, PMI-HIF-3 were added, respectively; SPMI2; SPMI-HIF2-1, SPMI-HIF2-2, SPMI-HIF2-3, 10. Mu.L of CCK8 reagent was added to each well after 72 hours, and incubated at 37℃for 1 hour. The absorbance (OD) of each well was measured at a wavelength of 450nm using a microplate reader (BioTek, vermont, USA) and cell viability at different concentrations was calculated from the OD values.
As shown in FIG. 5, after 72 hours of the PMI-HIF-1 series peptides, the activity of HCT 116-/-of the colon cancer cell line HCT116 and the colon cancer cell line HCT116 knocked out by P53 is not affected; following the action of SPMI-HIF2 series peptides, the viability of HCT116 was significantly inhibited with increasing polypeptide concentration, whereas the activity of the P53 knockout cell line HCT 116-/-was unaffected, wherein the activity of the HCT116 cells after the action of SPMI-HIF2-1, SPMI-HIF2-2, SPMI-HIF2-3 on the HCT116 cells at 25. Mu.M concentration was 20.31%,22.75%,25.11% and 29.36% of the control, respectively. This result shows that SPMI-HIF2 series polypeptide has high specific anti-tumor effect and obvious inhibiting effect.
Example 4: detection of in vivo anti-tumor effect of staple peptides by nude mice transplantation tumor model
36 nude mice of 20-25 g in weight and 4-6 weeks old were purchased and 1X 10 was used 7 The individual HCT116 cells were injected subcutaneously in the armpit of nude mice in a 100ul system;when the tumor size reaches 100mm 3 After that, nude mice were randomly divided into PBS group, PMI-HIF-1 group, SPMI2 group and SPMI-HIF2-1 group, and the tail vein injection administration was started at a dose of 50mg/kg in a 100. Mu.L system, once every other day, and 6 times in total.
FIG. 6 shows that the polypeptides SPMI2 and SPMI-HIF2-1 can inhibit the growth of tumor cells in vivo, and compared with the PMI-HIF1-1 group, the polypeptide SPMI-HIF2-1 group has significantly reduced tumor size and significantly reduced tumor size. The monitoring results of the weights of the nude mice in fig. 7 show that the weights of the nude mice in each group are not obviously different before and after administration, so that the series has no obvious toxic or side effect. This result shows that the polypeptide SPMI-HIF2-1 can specifically inhibit the growth of tumor cells in vivo and has no toxic or side effect on normal cells.
While the preferred embodiments of the present invention have been illustrated and described, the present invention is not limited to the embodiments, and various equivalent modifications and substitutions can be made by one skilled in the art without departing from the spirit of the present invention, and these equivalent modifications and substitutions are intended to be included in the scope of the present invention as defined in the appended claims.

Claims (4)

1. A staple peptide conjugate, wherein the staple peptide conjugate is selected from one of the following:
a) Ac-TSFAEYWALLS-PEG1-LA-Hyp-Y-Hle-P-NH 2 Is a peptide chain template, 4 of which A And 11 (V) S Are respectively R 8 And S is 5 Replacing and cyclization;
b) Ac-TSFAEYWALLS-PEG2-LA-Hyp-Y-Hle-P-NH 2 Is a peptide chain template, 4 of which A And 11 (V) S Are respectively R 8 And S is 5 Replacing and cyclization;
c) Ac-TSFAEYWALLS-PEG3-LA-Hyp-Y-Hle-P-NH 2 Is a peptide chain template, 4 of which A And 11 (V) S Are respectively R 8 And S is 5 And (5) replacing and cyclization.
2. Use of the stapled peptide conjugate of claim 1 for the preparation of an anti-tumor drug; the tumor is colon cancer.
3. A method of preparing the stapled peptide conjugate of claim 1, comprising the steps of:
(1) The amino resin was weighed and swollen in 4ml of DCM solution for 20min;
(2) Fmoc protecting groups were removed with 20% (v/v) piperidine-DMF solution containing 0.1mol/L Oxime for 5min and repeated twice;
(3) The resin was washed 5 times with 5ml DMF, 5 times with 5ml DCM, and finally 5 times with 5ml DMF;
(4) The reaction solution of natural amino acid condensation is used for composing Fmoc-AA-OH 4 times of equivalent, the oxidation is 4 times of equivalent, the DIC is 4 times of equivalent to carry out condensation reaction, and the temperature is 60 ℃ for 20min; fmoc-S 5 /R 8 -OH 2 equivalents, oxime 2 equivalents, DIC 2 equivalents, 60 ℃ for 2h;
(5) Repeating the operations (2) - (4), and sequentially coupling according to the amino acid sequence; wherein, partial cyclization sites are respectively represented by R 8 And S is 5 Respectively substituting amino acids at positions i and i+7;
(6) Pyridine was used: acetylation of the N-terminally deprotected amino acid with acetic anhydride=1:1 solution;
(7) Treating the resin with a dichloroethane solution of Grubbs first generation catalyst to carry out a cyclization reaction;
(8) Use of cleavage reagent TFA/TIPS/H 2 O=95/2.5/2.5 (v/v/v) cleavage of the peptide chain from the resin;
(9) Adding 40mL of glacial diethyl ether into the crude peptide, centrifuging at 3500r/min for 3min, and repeating the operation for 5 times;
(10) The crude peptide, which naturally volatilizes after centrifugation, was purified using RP-HPLC.
4. The method of claim 3, wherein the purification method used in step (10) is reverse-phase high performance liquid chromatography under the following conditions: chromatographic column: YMC-Pack ODS-AQ column; mobile phase: mobile phase a was 0.1% tfa/water and mobile phase B was 0.1% tfa/acetonitrile; gradient elution procedure: eluting with 35% B for 0-5 min, and eluting with 35% B-65% B for 5-60 min; the flow rate was 20ml/min, the sample injection amount was 1ml, and the detection wavelengths were 214nm and 254nm.
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