CN102977215A - Caspase-1 inhibitor targeting liver and application thereof - Google Patents
Caspase-1 inhibitor targeting liver and application thereof Download PDFInfo
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- CN102977215A CN102977215A CN2012105030771A CN201210503077A CN102977215A CN 102977215 A CN102977215 A CN 102977215A CN 2012105030771 A CN2012105030771 A CN 2012105030771A CN 201210503077 A CN201210503077 A CN 201210503077A CN 102977215 A CN102977215 A CN 102977215A
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Abstract
The invention discloses a caspase-1 inhibitor targeting liver. The caspase-1 inhibitor is formed by connection of human hepatitis B virus Pre-S1 peptide and caspase-1 inhibitor through a flexible connector, wherein the Pre-S1 peptide consists of amino acids from first to fiftieth of the Pre-S1 protein; and the caspase-1 inhibitor is formed by connection of trimolecular polymer of YVAD tetrapeptide and trimolecular polymer of VAD tripeptide. According to the inhibitor, the caspase-1 inhibitor is specifically targeted to a liver cell by utilizing the carrier Pre-S1 peptide which specifically targets liver, so that intrahepatic persistent chronic inflammation caused by endogenous danger signals released by injured liver cells can be blocked by terminating caspase-1 activation in the liver cell, sequential spinal cord injury of the liver cell can be blocked, body adverse response which is possibly caused by spread inhibition of caspase-1 can be reduced, and the liver cell can be specifically and effectively protected. The caspase-1 inhibitor can be used for preparing a medicament for treating intrahepatic chronic inflammation caused by endogenous danger signals released by injured liver cells.
Description
Technical field
The invention belongs to biomedicine field, relate to a kind of enzyme inhibitors and the purposes in field of medicaments thereof.
Background technology
The chronic hepatic injury that causes take chronic hepatitis as major cause is the great health problem of China, also is human mainly one of Death causes that the our times health organization is announced.Chronic inflammation further causes the generation of liver cirrhosis, liver failure, liver cancer in case startup is difficult to stop, and is called " chronic hepatopathy trilogy "; And hepatocellular damage also is difficult to stop, and is called " the never wound of healing ".
Previously research is thought, the activity of virus in liver is the major reason of inflammation sustainable existence in the liver, so antiviral therapy is to treat at present the mode of normal employing of chronic viral hepatitis B.But research finds, even establishment virus replication, also be difficult to stop the pernicious course of disease that chronic viral hepatitis B proceeds to liver cirrhosis/liver failure, and this main harm of chronic viral hepatitis B exactly.Present clinical effective therapeutic strategy and the medicine that to block the chronic hepatitis malignant progression that there is no.
Inflammation body (inflammasome) has vital role in inflammatory response and immunoregulation; by the various endogenous of perception and ectogenic danger signal; activation is take caspase-1 as main kinases; promote the secretion of IL-1 β; start inflammatory response, under the physiological situation, remove and infect and dead cell; keep the organismic internal environment stable state, also have the abnormal activation of report caspase-1 relevant with various autoimmune disease or self diseases associated with inflammation.
Summary of the invention
According to contriver and other researchists' current research result, the inflammation body comprises that with chronic hepatic injury the relevant chronic hepatitis of chronic hbv-infection is closely related.Contriver's result of study shows: the inflammation of chronic viral hepatitis B continues the activity that reason not merely comprises hepatitis B virus, also can by the damage liver cell particularly the endogenous danger signal that discharges of apoptosis liver cell cause; The ATP that these endogenous danger signals discharge take the damage liver cell by activation inflammation body, causes chronic inflammatory diseases and chronic injury in the liver as representative.Simultaneously, the research of contriver in the histocytes such as liver cell is also found, the acknowledgement mechanism that also has caspase-1 in the liver cell (a kind of nonimmune cell), in the liver in the microenvironment common endogenous danger signal (such as HMGB1, uric acid, ATP etc.) can the effectively start liver cell in the activation of caspase-1, and then promote inflammatory response.Therefore, the activation of caspase-1 might be blocked chronic inflammatory diseases in the liver that is caused by the endogenous danger signal of damaging liver cell release in the blocking-up liver cell, and then blocks the malignant progression of hepatocellular secondary lesion and chronic hepatitis.
In view of this, one of purpose of the present invention is to develop a kind of caspase-1 inhibitor of target liver, and investigate it and whether can activate to block chronic inflammatory diseases in the liver that the endogenous danger signal that discharged by the damage liver cell causes by stopping caspase-1 in the liver cell, and then block hepatocellular secondary lesion, the Body adverse reaction of avoiding simultaneously the extensive inhibition of caspase-1 to cause is finally realized the special effective protection of liver cell; Two of purpose is to provide the purposes of caspase-1 inhibitor in pharmacy field of described target liver.
Through research, the invention provides following technical scheme:
1. the caspase-1 inhibitor of target liver, be formed by connecting by flexible joint and caspase-1 inhibitor by viruses of human hepatitis B Pre-S1 peptide, described Pre-S1 peptide is comprised of the 1-50 amino acids of Pre-S1 albumen, and described caspase-1 inhibitor is by YVAD(Tyr-Val-Ala-Asp) three Molecularly Imprinted Polymers of tetrapeptide are that Tyr-Val-Ala-Asp-Tyr-Val-Ala-Asp-Tyr-Val-Ala-Asp is by flexible joint and VAD(Val-Ala-Asp) three Molecularly Imprinted Polymers of tripeptides are that Val-Ala-Asp-Val-Ala-Asp-Val-Ala-Asp is formed by connecting.
Further, the caspase-1 inhibitor of described target liver is comprised of the aminoacid sequence shown in the SEQ ID No.1, i.e. flexible joint between flexible joint between described Pre-S1 peptide and the caspase-1 inhibitor and YVAD peptide three Molecularly Imprinted Polymers and VAD peptide three Molecularly Imprinted Polymers forms by 3 glycine.
2. the purposes in the medicine of the caspase-1 inhibitor of described target liver chronic inflammatory diseases in the liver that the endogenous danger signal that preparation is discharged by the damage liver cell causes.
Beneficial effect of the present invention is: the present invention utilizes the carrier Pre-S1 peptide of selectively targeted liver to be connected with the caspase-1 inhibitor, has made a kind of caspase-1 inhibitor of target liver, and its pharmacologically active has been carried out experimental study.Result of study shows, the caspase-1 inhibitor of this target liver can specially be absorbed by primary hepatocyte effectively, the activation of caspase-1 in the primary hepatocyte that can establishment be started by endogenous danger signal ATP, reduce the generation of pro-inflammatory cytokine IL-1 β, and can effectively block the death of the primary hepatocyte that is started by endogenous danger signal ATP, thereby tentative confirmation can block persistence chronic inflammatory diseases in the liver that the endogenous danger signal that discharged by the damage liver cell causes by the activation of caspase-1 in the blocking-up liver cell, and then block hepatocellular secondary lesion, this is a kind of novelty strategy for the treatment of chronic hepatitis, may block the malignant progression of chronic hepatitis, will be important and necessary the replenishing of present routine clinical therapeutic modality.With the selectively targeted liver of caspase-1 inhibitor; the caspase-1 that not only is conducive to stop in the liver cell activates; and be conducive to reduce the systematic caspase-1 of whole body and suppress the untoward reactions such as the serious interior environment disturbance that may cause and immune deficiency, thereby realize the special effective protection of liver cell.Therefore, the caspase-1 inhibitor of target liver of the present invention can be used for preparing the medicine of chronic inflammatory diseases in the liver that the endogenous danger signal that discharged by the damage liver cell causes, and is stopping comprising to have potential, good application prospect aspect the various chronic hepatitis course advancements of chronic viral hepatitis B.
Description of drawings
In order to make the purpose, technical solutions and advantages of the present invention clearer, the invention will be further described below in conjunction with accompanying drawing, wherein:
Fig. 1 is that flow cytometer detects primary hepatocyte to the picked-up ratio of the caspase-1 inhibitor of target liver, wherein a represents negative control (fluorescently-labeled irrelevant seven peptides), b represents the caspase-1 inhibitor of fluorescently-labeled target liver, and c represents fluorescently-labeled caspase-1 inhibitor.
Fig. 2 is that protein immunoblot detects the caspase-1 inhibitor of target liver to the impact of caspase-1 activation in the primary hepatocyte of endogenous danger signal ATP startup, wherein 1 represents the not normal liver cell of intervention, show the p10 subunit that produces after a large amount of caspase-1 activation, 2,3,4 represent respectively caspase-1 inhibitor 5 μ M, 20 μ M, the 40 μ M treatment group of target liver.
Fig. 3 is that the ELISA experiment detects the caspase-1 inhibitor of target liver to the impact of the rear IL-1 of generation of Caspase-1 activation β ability in the endogenous danger signal ATP startup primary hepatocyte.
Fig. 4 is that the serum lactic dehydrogenase release experiment detects the caspase-1 inhibitor of target liver to the impact of the primary hepatocyte death of endogenous danger signal ATP startup.
The caspase-1 inhibitor of " block " expression target liver among Fig. 3 and Fig. 4.
Embodiment
Hereinafter with reference to accompanying drawing, the preferred embodiments of the present invention are described in detail.The experimental technique of unreceipted actual conditions in the preferred embodiment, usually according to normal condition, or the condition of advising according to manufacturer.
One, the preparation of the caspase-1 inhibitor of target liver
The caspase-1 inhibitor of design and the target liver of student on commission worker's biotechnology (Shanghai) limited-liability company synthetic amino acid array shown in SEQ ID No.1.In sequence shown in the SEQ ID No.1, the 1-50 amino acids is the 1-50 amino acids sequence that derives from the Pre-S1 albumen of the FMC#97 of MS-2, the 51-53 amino acids is flexible joint, the 54-65 amino acids is YVAD(Tyr-Val-Ala-Asp) three Molecularly Imprinted Polymers of tetrapeptide, the 66-68 amino acids is flexible joint, and the 69-77 amino acids is VAD(Val-Ala-Asp) three Molecularly Imprinted Polymers of tripeptides.
Simultaneously, the synthetic caspase-1 inhibitor that lacks targeting vector is namely removed the 1-53 amino acids in contrast from sequence shown in the SEQ ID No.1.
Two, the activity of the caspase-1 inhibitor of target liver detects
1, the cultivation of human primary hepatocyte
Get the relevant liver cancer patient surgical operation tumor resection of non-HBV without adjacent healthy tissues, press literature method (Methods for preparation of adult and fetal hepatocytes. Isolated and cultured hepatocytes. A.Guillouzo and C.Guguen-Guillouzo. Les E ' ditions INSERM Paris, John Libbey and Co., Ltd. 1986,1-12) separate primary hepatocyte, with containing 3.5 * 10
-6The H culture medium culturing of M hydrocortisone monomester succinate, 2% (v/v) dimethyl sulfoxide (DMSO), 5% (v/v) human serum and 5% (v/v) foetal calf serum.
2, flow cytometer detects primary hepatocyte to the uptake ratio of the caspase-1 inhibitor of target liver
Human primary hepatocyte is seeded in 12 orifice plates cultivates every hole about 10
6Individual cell, hatched altogether 60 minutes with the caspase-1 inhibitor of the target liver of FITC mark, discard culture supernatant, cell PBS rinsing 2 times, after fixing with 4% (v/v) paraformaldehyde solution, under flow cytometer 488nm exciting light, detect cell to the picked-up ratio of the caspase-1 inhibitor of target liver, with the caspase-1 inhibitor that lacks targeting vector of FITC mark in contrast.The result as shown in Figure 1, visible primary hepatocyte can specially absorb the caspase-1 inhibitor of target liver effectively, and very nearly the same to uptake ratio and the negative control of the caspase-1 inhibitor that lacks targeting vector.
3, protein immunoblot detects the caspase-1 inhibitor of target liver to the impact of caspase-1 activation in the primary hepatocyte of endogenous danger signal ATP startup
The Caspase-1 activation needs dual signal, a pre-energizing signal is arranged usually in order to raise pro-caspase-1 and the equimolecular expression of pro-IL-1 β, can be the toxicity molecule that the various pathogenic agent such as LPS, CpG are carried; Another signal is danger signal, directly activates the inflammation body (inflammasome) in cell, makes pro-caspase-1 be cut into activated caspase-1, cuts pro-IL-1 β again and produces activated IL-1 β.Under the normal physiological state, liver cell just is in the blood of the LPS that contains physiologically active concentration.Therefore, in protein immunoblot experiment and follow-up ELISA experiment and serum lactic dehydrogenase release experiment, all adopt LPS as the pre-energizing signal of caspase-1 activation, and employing ATP is as the endogenous danger signal.
Human primary hepatocyte is seeded in 12 orifice plates cultivates every hole about 10
6Individual cell, set up 4 groups separately: 1. group was hatched 24 hours altogether with 200ng/ml LPS, removed LPS, added 5 μ M ATP again and continued to stimulate 6 hours; 2. organize before adding LPS, use first the caspase-1 inhibitor pre-treatment 1 hour of 5 μ M target livers, all the other with 1. organize identical; 3. organize before adding LPS, use first the caspase-1 inhibitor pre-treatment 1 hour of 20 μ M target livers, all the other with 1. organize identical; 4. organize before adding LPS, use first the caspase-1 inhibitor pre-treatment 1 hour of 40 μ M target livers, all the other with 1. organize identical; Last collecting cell after the cracking of RIPA lysate, is collected total protein and is measured concentration.The total protein of collecting is carried out SDS-PAGE, the complete rear transferring film of electrophoresis, with the rinsing of WB washings, add again the WB confining liquid, room temperature sealing 60 minutes, remove confining liquid, the caspase-1 primary antibodie (Santa Cruze company) and the GAPDH antibody that add again by volume 1:200 dilution, 4 ℃ of night incubation are removed primary antibodie, with the rinsing of WB washings, add two again and resist, incubated at room 1 hour is removed two and is resisted, use again the rinsing of WB washings, adopt at last chemoluminescence method to detect caspase-1 activation fragment p10 subunit.The result as shown in Figure 2, the caspase-1 inhibitor of visible target liver has been blocked the activation of caspase-1 in the primary hepatocyte effectively.
4, the ELISA experiment detects the caspase-1 inhibitor of target liver to the impact of the rear IL-1 of generation of endogenous danger signal ATP startup primary hepatocyte caspase-1 activation β ability
Human primary hepatocyte is seeded in 12 orifice plates cultivates every hole about 10
6Individual cell, set up 5 groups separately: 1. group does not add any reagent; 2. group was hatched 12 hours or 24 hours altogether with 200ng/ml LPS, removed LPS, added 5 μ M ATP again and continued to stimulate 6 hours; 3. organize before adding LPS, use first the caspase-1 inhibitor pre-treatment 1 hour of 5 μ M target livers, all the other with 2. organize identical; 4. organize before adding LPS, use first the caspase-1 inhibitor pre-treatment 1 hour of 20 μ M target livers, all the other with 2. organize identical; 5. organize before adding LPS, use first the caspase-1 inhibitor pre-treatment 1 hour of 40 μ M target livers, all the other with 2. organize identical; Collect at last culture supernatant, detect the secretion situation of IL-1 β in the culture supernatant with the ELISA detection kit (Abcam company) of IL-1 β.The result as shown in Figure 3, the ability that produces IL-1 β after the caspase-1 activation in the visible primary hepatocyte is by the caspase-1 inhibitor establishment of target liver, and this restraining effect presents dose-dependently.
5, the serum lactic dehydrogenase release experiment detects the caspase-1 inhibitor of target liver to the impact of the primary hepatocyte death of endogenous danger signal ATP startup
Human primary hepatocyte is seeded in 12 orifice plates cultivates every hole about 10
4Individual cell, set up 6 groups separately: 1. group does not add any reagent, is the sample control group; 2. group was hatched 24 hours altogether with 200ng/ml LPS, removed LPS, added 5 μ M ATP again and continued to stimulate 6 hours; 3. organize before adding LPS, use first the caspase-1 inhibitor pre-treatment 1 hour of 5 μ M target livers, all the other with 2. organize identical; 4. organize before adding LPS, use first the caspase-1 inhibitor pre-treatment 1 hour of 20 μ M target livers, all the other with 2. organize identical; 5. organize before adding LPS, use first the caspase-1 inhibitor pre-treatment 1 hour of 40 μ M target livers, all the other with 2. organize identical; 6. do not add any processing, process with 1%NP-40 behind the collecting cell, be the maximum enzyme activity group; Other establishes serum free medium is blank; Collect at last culture supernatant, add 60 μ l LDH testing liquid, mixing, the room temperature lucifuge was hatched 30 minutes, measure absorbancy in the 490nm place, and use 600nm to carry out dual wavelength as the reference wavelength and measure, each is organized absorbancy deducts the blank absorbancy to record absorbancy difference and represents, calculates as follows cell mortality: cell mortality (%)=[(sample preparation group absorbancy-sample control group absorbancy)/(maximum enzyme activity group absorbancy-sample control group absorbancy)] * 100.The result as shown in Figure 4, the caspase-1 inhibitor of visible target liver has suppressed the death of the primary hepatocyte that started by endogenous danger signal ATP effectively.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.
＜110〉Military Medical Univ No.3, P.L.A
＜120〉caspase-1 inhibitor and the application thereof of target liver
<160> 1
<210> 1
<211> 77
<212> PRT
＜213〉artificial sequence
<220>
＜223〉the caspase-1 inhibitor of target liver
<400> 1
Met Gly Gly Trp Ser Ser Lys Pro Arg Lys Gly Met Gly Thr Asn
1 5 10 15
Leu Ser Val Pro Asn Pro Leu Gly Phe Phe Pro Asp His Gln Leu
20 25 30
Asp Pro Ala Phe Gly Ala Asn Ser Asn Asn Pro Asp Trp Asp Phe
35 40 45
Asn Pro Ile Lys Asp Gly Gly Gly Tyr Val Ala Asp Tyr Val Ala
50 55 60
Asp Tyr Val Ala Asp Gly Gly Gly Val Ala Asp Val Ala Asp Val
65 70 75
Ala Asp
Claims (3)
1. the caspase-1 inhibitor of target liver, it is characterized in that, be formed by connecting by flexible joint and caspase-1 inhibitor by viruses of human hepatitis B Pre-S1 peptide, described Pre-S1 peptide is comprised of the 1-50 amino acids of Pre-S1 albumen, and three Molecularly Imprinted Polymers that described caspase-1 inhibitor is Tyr-Val-Ala-Asp-Tyr-Val-Ala-Asp-Tyr-Val-Ala-Asp by flexible joint and VAD tripeptides by three Molecularly Imprinted Polymers of YVAD tetrapeptide are that Val-Ala-Asp-Val-Ala-Asp-Val-Ala-Asp is formed by connecting.
2. the caspase-1 inhibitor of target liver according to claim 1 is characterized in that, the caspase-1 inhibitor of described target liver is comprised of the aminoacid sequence shown in the SEQ ID No.1.
3. the purposes in the medicine of the caspase-1 inhibitor of target liver claimed in claim 1 chronic inflammatory diseases in the liver that the endogenous danger signal that preparation is discharged by the damage liver cell causes.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160030538A1 (en) * | 2014-07-22 | 2016-02-04 | The University Of Vermont And State Agricultural College | Augmenting the immune response by promoting cell death of immune cells |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030224403A1 (en) * | 2002-02-27 | 2003-12-04 | Popov Serguei G. | Lethal toxin cytopathogenicity and novel approaches to anthrax treatment |
| WO2004031144A2 (en) * | 2002-10-01 | 2004-04-15 | Musc Foundation For Research Development | Use of caspase inhibitors as therapeutic agent against radiation-induced injury |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030224403A1 (en) * | 2002-02-27 | 2003-12-04 | Popov Serguei G. | Lethal toxin cytopathogenicity and novel approaches to anthrax treatment |
| WO2004031144A2 (en) * | 2002-10-01 | 2004-04-15 | Musc Foundation For Research Development | Use of caspase inhibitors as therapeutic agent against radiation-induced injury |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160030538A1 (en) * | 2014-07-22 | 2016-02-04 | The University Of Vermont And State Agricultural College | Augmenting the immune response by promoting cell death of immune cells |
| US9925230B2 (en) * | 2014-07-22 | 2018-03-27 | The University Of Vermont And State Agricultural College | Augmenting the immune response by promoting cell death of immune cells |
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