CN114272379A - Novel small molecule inhibitor targeting Ero1 alpha/PDI electron transfer system - Google Patents
Novel small molecule inhibitor targeting Ero1 alpha/PDI electron transfer system Download PDFInfo
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- CN114272379A CN114272379A CN202111425684.6A CN202111425684A CN114272379A CN 114272379 A CN114272379 A CN 114272379A CN 202111425684 A CN202111425684 A CN 202111425684A CN 114272379 A CN114272379 A CN 114272379A
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- pdi
- ero1
- rutin
- alpha
- platelet aggregation
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Abstract
The invention provides a small molecule inhibitor of a targeted Ero1 alpha/PDI electron transfer system, wherein the inhibitor is rutin. The invention provides a new target for the research and development of anti-platelet aggregation drugs and lays a foundation for the research and development of more anti-platelet aggregation drugs.
Description
Technical Field
The invention belongs to the field of small molecule inhibitors, and particularly relates to a small molecule inhibitor targeting an Ero1 alpha/PDI electron transfer system.
Background
The types of anti-platelet aggregation drugs mainly include the following:
1. inhibitors of thromboxane A2(TXA2)
TAX2 is a potent agonist of platelet activation and vasoconstriction, and by binding to G-protein coupled receptors, causes phospholipase c (plc) β activation, an increase in intracellular calcium ions, and subsequent platelet activation. Aspirin is the antiplatelet drug which is most widely researched and applied in antiplatelet treatment at present, and mainly inhibits arachidonic acid epoxidase (COX) to irreversibly acetylate Ser-529 and Ser-516, so that the synthesis of TXA2 is blocked, and the antiplatelet aggregation effect is exerted. However, aspirin is often associated with gastrointestinal discomfort and gastrointestinal bleeding, but a few of aspirin also have allergic reactions, mainly manifested as asthma and urticaria.
2. Adenosine Diphosphate (ADP) P2Y12 receptor antagonists
After the ADP receptor antagonist is combined with an ADP receptor on the surface of a platelet membrane, the binding site of GPIIb/IIIa receptor coupled with the ADP receptor is prevented from being exposed, so that ligand can not be combined, and the aggregation of platelets is inhibited. Currently there are 3 thienopyridine derivatives blocking P2Y12 used clinically: ticlopidine, clopidogrel and prasugrel. But all present a risk of bleeding.
3. Thrombin receptor antagonists
Protease Activated Receptors (PARs) for the thrombin receptor belong to the family of G protein coupled receptors, which have 4 subtypes, of which PAR-1 and PAR-4 are expressed in human platelets. The current PAR-1 receptor antagonist is Vorapaxar. Adverse reactions are bleeding, including life-threatening and fatal bleeding, and are the most commonly reported adverse reactions.
4.5-hydroxytryptamine (5-HT) receptor antagonists
5-HT is a neurotransmitter and vasoactive substance, and more than 90% of 5-HT in humans is stored in platelets. A common 5-HT receptor antagonist is sarpogrelate.
5. Platelet glycoprotein IIb/IIIa receptor inhibitors, such as tirofiban. The preparation is mainly used for coronary artery angioplasty or coronary artery plaque excision and other diseases of patients with coronary artery ischemia syndrome in clinic. The medicine can be only injected intravenously, and the common adverse reaction is bleeding.
6. Phosphodiesterase inhibitors, such as dipyridamole. The main adverse reaction is gastrointestinal reaction, and long-term use of the traditional Chinese medicine in large quantities can cause bleeding tendency.
Although a large number of anti-platelet aggregation drugs are researched or put into clinical application, a novel anti-platelet drug with small toxic and side effects, strong drug effect and good selectivity is still required to be developed and utilized, and the research on the anti-platelet aggregation action mechanism can enable the drug development to achieve the effect which is twice the result with half the effort.
Based on this, the inventor proposes the technical scheme of the invention.
Disclosure of Invention
Endoplasmic reticulum oxidase Ero1 alpha (Endoplasmic reticulum oxidase 1 alpha) and protein disulfide isomerase PDI (protein disulfide isomerase) constitute one of the most important protein oxidation and folding pathways in Endoplasmic reticulum of eukaryotic cells. Ero1 α generates a disulfide bond with molecular oxygen as an electron acceptor through a prosthetic group FAD bound thereto. Disulfide bonds are transferred from their internal active centers via external active centers to their substrates PDI, which ultimately transfer the disulfide bonds to nascent peptide chains, which themselves are reduced. This oxidative folding system of Ero1 α and PDI ensures efficient and correct synthesis of disulfide bonds in protein synthesis. Research shows that the Ero1 alpha-PDI electron transport chain plays an important role in various pathophysiological processes, including the occurrence and development of cervical cancer. Therefore, the development of the inhibitor targeting the Ero1 alpha-PDI electron transfer chain has important clinical significance and social value for treating cancers and thrombotic diseases.
In order to solve the problems in the prior art, the invention provides the following technical scheme:
in one aspect, the invention provides the use of the Ero1 alpha/PDI electron transfer chain as a target in the preparation of anti-platelet aggregation drugs.
On one hand, the invention provides application of rutin, bisphenol A, bepristat, KFWWFS peptide fragment, isoquercetin or other quercetin derivatives as an Ero1 alpha/PDI electron transfer chain inhibitor or application in preparing the Ero1 alpha/PDI electron transfer chain inhibitor.
In some embodiments, wherein the anti-platelet aggregation drug is rutin.
In another aspect, the present invention provides an Ero1 α/PDI electron transport chain inhibitor, wherein the inhibitor is rutin.
On the other hand, the invention provides application of an Ero1 alpha/PDI electron transport chain inhibitor in preparation of an anti-platelet aggregation medicament, and is characterized in that the inhibitor is rutin.
In some embodiments, the anti-platelet aggregation drug inhibits binding of Ero1 α and PDI.
In some embodiments, the antiplatelet aggregation agent is used to treat a disease associated with platelet aggregation selected from the group consisting of myocardial infarction, stroke, and atherosclerosis.
In another aspect, the present invention provides a platelet aggregation inhibitor, which comprises an Ero1 α/PDI electron transport chain inhibitor as an active ingredient.
In some embodiments, the Ero1 α/PDI electron transport inhibitor is selected from rutin, bisphenol a, bepristat, KFWWFS peptide fragments, isoquercetin or other quercetin-based derivatives.
In some embodiments, the medicament further comprises a pharmaceutically acceptable carrier and/or adjuvant.
In some embodiments, the pharmaceutical composition is in a dosage form including, but not limited to, injection, oral liquid, tablet, granule, capsule, and pill.
In some embodiments, the pharmaceutical formulation includes injections, oral liquids, tablets, granules, capsules, and pills.
On the other hand, the invention provides the application of rutin in preparing a medicament for treating diseases related to Ero1 alpha/PDI electron transfer.
In another aspect, the present invention provides a method of treating platelet aggregation, comprising administering to a subject an effective amount of an inhibitor of the Ero1 α/PDI electron transport chain.
In some embodiments, the Ero1 α/PDI electron transport chain inhibitor is rutin.
Drawings
Fig. 1 shows that rutin inhibits the oxidation of PDI catalyzed by Ero1 α and its IC 50.
Fig. 2 shows that rutin blocks the physical binding of Ero1 α and PDI.
Fig. 3 shows that rutin blocks binding of Ero1 α and PDI in platelets.
FIG. 4 shows the oxygen consumption of platelets induced by the Ero1 α/PDI system inhibited by rutin.
Detailed Description
In order that the objects, technical solutions and advantages of the present invention will become more apparent, the present invention will be further described in detail with reference to the accompanying drawings in conjunction with the following specific embodiments.
The invention utilizes in vitro biochemical and cell biological experiments to identify that the rutin is a novel micromolecule inhibitor targeting an Ero1 alpha/PDI electron transfer system for the first time, measures the IC50 of the micromolecule inhibitor, and provides a new target of an antiplatelet medicament.
Firstly, an oxygen consumption experiment is used to find that rutin can inhibit the oxidation of PDI catalyzed by Ero1 alpha in a concentration-dependent mode, and the IC50 for inhibiting oxygen consumption is measured; GST-pildowny experiments show that rutin can block the interaction between GST-Ero1 alpha and PDI, and further show that rutin can block the combination of Ero1 alpha and PDI in platelets and reduce the consumption of oxygen in the activation process of the platelets.
Example 1 identification of rutin as an inhibitor of the Ero1 alpha/PDI electron transport system Using oxygen consumption
The method comprises the following steps:
1) rutin (-echeie (shanghai) chemical industry development limited, R0035) and 20 μ M recombinant PDI protein (Li S, et al.j Biol Chem 2006; 281:6581 and 6588) were mixed well and incubated at 37 ℃ for 20 minutes.
2) The incubated mixture of rutin and PDI was added to 100mM phosphate buffer containing 10mM reduced Glutathione (GST) (Sigma, catalog G4251), and loaded into an electrode reaction cup dedicated for oxygen consumption measurement (Hansatech Instruments, Oxygraph Clark-type), and the cup was capped.
3) To the electrode reaction cuvette was added 2 μ M Ero1 α protein (Wang L, et al.j Biol Chem 2009; 284: 199-.
And (3) identification result:
the results of the identification are shown in FIG. 1. Rutin inhibits the oxidation of PDI by Ero1 α in a concentration-dependent manner with an IC50 of about 4.9 μ M, i.e., the dose of rutin required to reduce oxygen consumption by 50% is 4.9 μ M. )
Example 2 identification of rutin blocking the binding of Ero1 alpha and PDI Using GST-pulldown assay
The method comprises the following steps:
1) 30 mu M rutin and 10 mu M recombinant PDI protein are mixed evenly and incubated for 20 minutes at 37 ℃.
2) The incubated PDI protein was mixed with 10. mu.M GST-Ero 1. alpha. protein in PBS, placed on a rotary mixer, and incubated at 4 ℃ for 2 hours.
3) Glutathione dextran resin particles (GE healthcare,17-5132-02) were added and incubation continued at 4 ℃ for 1 hour.
4) The mixture was centrifuged at 2000rpm for 5 minutes and the supernatant was discarded. Wash 5 times with PBS.
5) SDS loading buffer was added and the mixture was boiled at 100 ℃ for 10 minutes. Centrifuge and discard the bottom pellet.
6) The resulting supernatants were subjected to SDS-PAGE gel electrophoresis and binding of Ero1 α and PDI was detected using Coomassie blue staining. After PDI and Ero1 α are bound, glutathione dextran resin particles bound to Ero1 α are precipitated, and the extent of PDI binding to Ero1 α is determined based on the intensity of the coomassie blue-stained band of the precipitated PDI, thereby determining whether rutin treatment affects the binding of PDI to Ero1 α.
And (3) detection results:
the detection results are shown in FIG. 2. The band of PDI precipitated from the rutin-treated group was reduced compared to the DMSO group, and rutin blocked the binding of Ero1 α and PDI.
Example 3GST-pulldown experiments identify that rutin blocks the binding of Ero1 α to PDI in platelets
The method comprises the following steps:
1) mixing 30 μ M rutin and 100mg platelet lysate (obtained by extracting peripheral venous blood from healthy adult, centrifuging to obtain platelet, adding cell lysate (EMD Millipore, 20-188) and lysing), and incubating at 37 deg.C for 20 min.
2) 0.5mM GST-Ero1 α protein was added, placed on a rotary mixer, and incubated at 4 ℃ for 2 hours.
3) Glutathione dextran resin particles were added and incubation continued at 4 ℃ for 1 hour.
4) The mixture was centrifuged at 2000rpm for 5 minutes and the supernatant was discarded. Wash 5 times with PBS.
5) SDS loading buffer was added and the mixture was boiled at 100 ℃ for 10 minutes. Centrifuge and discard the bottom pellet.
6) The resulting supernatants were subjected to SDS-PAGE gel electrophoresis to detect binding of Ero1 α and PDI using anti-Ero 1 α (Abcam, ab177156) and anti-PDI antibody (Abcam, ab2792), respectively. After PDI and Ero1a are combined, glutathione dextran resin particles combined with Ero1a can be precipitated, and the degree of PDI combined with Ero1 alpha is judged according to the strength of PDI bands shown after antibody hybridization, so that whether rutin treatment affects the combination of PDI and Ero1 alpha in platelets is judged.
And (3) detection results:
the results of the identification are shown in FIG. 3. Rutin can block the binding of Ero1 alpha to platelet PDI.
Example 4 rutin inhibits oxygen consumption of platelets induced by the Ero1 alpha/PDI System
The method comprises the following steps:
1) taking human venous blood, centrifuging to prepare platelet suspension, adjusting the concentration of platelets to 2 × 109/ml。
2) Adding rutin, and incubating at 37 deg.C for 20 min.
3) And (4) placing the incubated platelet suspension into an electrode reaction cup special for oxygen consumption measurement, and covering a cup cover.
4) The oxygen concentration in the reaction cup was continuously monitored by adding 0.5. mu.M Ero 1. alpha. and the oxygen consumption curve was recorded.
And (3) detection results:
the results are shown in FIG. 4. The increase in oxygen consumption by the blue line (Ero1 α group) compared to the black line in the graph is about 10 μ M, indicating that the addition of Ero1 α induces platelets to consume oxygen; the amount of oxygen consumed by the red line (rutin group) was reduced by about 5 μ M compared to the blue line (DMSO group), indicating that rutin inhibits the Ero1 α -induced oxygen consumption of platelets.
Example 5 Oxidation of reduced Glutathione (GSH) in plasma by the rutin-inhibiting Ero1 alpha/PDI System
The method comprises the following steps:
1) venous blood from mice was collected, plasma was prepared by centrifugation, and 5-sulfosalicylic acid (Sigma, S2130) was added to remove proteins from the plasma.
2) To the plasma from which the protein was removed, 0.5. mu.M of recombinant PDI protein and 30. mu.M of rutin were added, and incubated at 37 ℃ for 20 minutes.
3) 0.5. mu.M Ero 1. alpha. was added and left at room temperature for 15 minutes.
4) The above sample was divided into two equal parts, absorbance at 412nm of DTNB was measured using a microplate reader (Perkinelmer) in the presence of glutathione reductase and NADPH, and the concentrations of total glutathione (GStotal) and oxidized glutathione (GSSG) were converted from a standard curve, and the ratio of GSH to GSSG was calculated and calculated according to the Nernst equation E' ═ E0′-RT/nF×ln([GSH]2/[GSSG]And calculating the reduction potential E' of the GSH, and evaluating the inhibition effect of the rutin.
And (3) detection results:
the results are shown in Table 1. Compared with the DMSO group, the rutin treated group E' is obviously reduced, which shows that rutin obviously inhibits the oxidation of GSH in plasma by an Ero1 alpha/PDI system. In this assay, Ero1 α oxidizes PDI, which reoxidizes GSH. Inhibition of GSH oxidation indicates inhibition of Ero1 α oxidation of PDI, blocking electron transfer from PDI to Ero1 α.
TABLE 1 rutin significantly inhibits the oxidation of plasma GSH by the Ero1 alpha/PDI system
*P<0.05
The data in table 1 illustrate that 1) the addition of Ero1 α and PDI proteins oxidized GSH and increased plasma E' compared to buffer in the DMSO group; 2) compared with DMSO, after rutin treatment, oxidation of GSH and increase of E' by Ero1 alpha and PDI proteins are blocked. The difference in rutin treated group (P <0.05) compared to DMSO group was statistically significant.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. Rutin, bisphenol A, bepristat, KFWWFS peptide fragment, isoquercetin or other quercetin derivatives are used as an Ero1 alpha/PDI electron transfer chain inhibitor or used for preparing the Ero1 alpha/PDI electron transfer chain inhibitor.
Use of an Ero1 alpha/PDI electron transport chain inhibitor selected from rutin, bisphenol A, bepristat, KFWWFS peptide fragment, isoquercetin or other quercetin derivatives, preferably rutin, in the preparation of an anti-platelet aggregation drug.
3. The use according to claim 2, wherein the antiplatelet aggregation agent is for the treatment of a disease associated with platelet aggregation selected from the group consisting of myocardial infarction, stroke and atherosclerosis.
4. The drug for resisting platelet aggregation is characterized in that the drug takes an Ero1 alpha/PDI electron transport chain inhibitor as an active ingredient.
5. The platelet aggregation reduction drug according to claim 4, wherein the inhibitor is selected from rutin, bisphenol A, bepristat, KFWWFS peptide fragment, isoquercetin or other quercetin derivatives, preferably rutin.
6. The drug for resisting platelet aggregation according to claim 4 or 5, further comprising a pharmaceutically acceptable carrier and/or adjuvant.
7. The platelet aggregation prevention medicament according to any one of claims 4 to 6, wherein the dosage form of the medicament includes injection, oral liquid, tablet, granule, capsule and pill.
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