WO2005093430A1 - 蛋白質のアミロイド性の構造変化を検出する方法、アミロイド性の構造変化に影響を与える活性を有する物質を探索する方法、アミロイド関連疾患の治療薬又は診断薬を探索する方法 - Google Patents
蛋白質のアミロイド性の構造変化を検出する方法、アミロイド性の構造変化に影響を与える活性を有する物質を探索する方法、アミロイド関連疾患の治療薬又は診断薬を探索する方法 Download PDFInfo
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- WO2005093430A1 WO2005093430A1 PCT/JP2005/005410 JP2005005410W WO2005093430A1 WO 2005093430 A1 WO2005093430 A1 WO 2005093430A1 JP 2005005410 W JP2005005410 W JP 2005005410W WO 2005093430 A1 WO2005093430 A1 WO 2005093430A1
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- protein
- amyloid
- structural change
- sample film
- substrate
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2203/00—Investigating strength properties of solid materials by application of mechanical stress
- G01N2203/02—Details not specific for a particular testing method
- G01N2203/026—Specifications of the specimen
- G01N2203/0262—Shape of the specimen
- G01N2203/0278—Thin specimens
- G01N2203/0282—Two dimensional, e.g. tapes, webs, sheets, strips, disks or membranes
Definitions
- Method for detecting amyloid structural change of protein Method for searching for substance having activity affecting amyloid structural change, method for searching for therapeutic or diagnostic agent for amyloid-related disease
- the present invention relates to a method for detecting an amyloid structural change of a protein using a mechanochemical sensor. Further, the present invention provides a method of searching for a substance having an activity affecting an amyloid structural change by detecting an amyloid structural change of a protein using a mechanochemical sensor, and a method for treating an amyloid-related disease. How to search for drugs or diagnostics.
- Amyloid-related diseases including Aluno, Ima disease, immune cell-mediated amyloidosis, reactive amyloidosis, familial amyloidosis, etc. are diseases caused by incorrectly folded protein structures.
- Aluno a drug that temporarily slows the progress of Ima's disease is a force
- These amyloid-related diseases are often intractable.
- Amyloid having the above structure is a fibrous protein, and amyloid fibers cause dysfunction by laying down in blood vessels and other tissues under certain pathological conditions.
- Amyloid fibrils have a layered / 3-sheet structure composed of thousands of non-covalently bound proteins or peptides. It has been suggested that inhibiting this amyloid structural change may increase disease instability by increasing amyloid protein instability (P. Hammarstrom et al., Science, 2001, 293). , 2459). As described above, it is important to detect structural changes in amyloid protein, and searching for compounds that suppress amyloid structural changes may help find therapeutic agents for amyloid-related diseases. .
- protein aggregation is usually produced and detected with a force of about 4 hours to 1 week, and therefore, there is a problem that evaluation takes time. Therefore, the activity can be efficiently evaluated by using a sensor capable of detecting amyloid protein aggregation in a short time.
- an object of the present invention is to provide means for detecting and measuring the process of amyloid protein aggregation as a change in tension, Z or elasticity in real time using a force sensor. This makes it possible to easily and quickly detect a structural change caused by amyloid protein aggregation.
- amyloid structural changes that occur when a test substance is added to a sample membrane made of amyloid protein carp can be detected by changes in the tension, Z, or elasticity of the sample membrane.
- the present invention has been completed.
- the method of the present invention is considered to be effective for efficiently searching for a substance having an activity that affects the structural change of amyloid protein from a large number of substances.
- the present invention provides a method for forming a sample membrane comprising a protein that causes an amyloid structural change, a fragment of the protein, a mutant of the protein, a tagged protein, or an antibody protein against the protein on a substrate. Then, the substrate having the sample film is placed on a force sensor, and changes in tension and Z or elasticity of the sample film when the test sample is applied to the sample film are detected by the force sensor. Amyloid structure of proteins It is intended to provide a method for detecting a structural change.
- the present invention provides a method for forming, on a substrate, a sample membrane comprising a protein causing an amyloid structural change, a fragment of the protein, a mutant of the protein, the tagged protein, or an antibody protein against the protein. Placing the substrate having the sample film on a force sensor
- a substance having an activity of affecting the amyloid structural change comprising detecting the change in the tension and Z or elasticity of the sample film when the test sample is applied to the sample film by the force sensor. It provides a way to search.
- the present invention further provides a sample membrane comprising a protein that causes an amyloid structural change, a fragment of the protein, a mutant of the protein, the tagged protein, or an antibody protein against the protein, formed on a substrate. Placing the substrate having the sample film on a force sensor
- a method for searching for a therapeutic or diagnostic agent for an amyloid-related disease comprising detecting a change in the tension and Z or elasticity of the sample film when the test sample is applied to the sample film by the force sensor.
- a method for detecting an amyloid structural change in a protein using a mechanochemical sensor, a method for screening a therapeutic or diagnostic agent for an amyloid-related disease using the method, and amyloid A method has been provided for searching for a substance having an activity that affects structural changes in sex.
- the method of the present invention is considered to be useful for the purpose of obtaining a novel therapeutic agent or diagnostic agent for amyloid disease.
- FIG. 1 shows the effect of ZnCl and EDTA on the change in tension and elasticity of amyloid ⁇ (1-42).
- Figure 2 shows the dependence of ZnCl concentration on the tensile and elastic changes of amyloid
- FIG. 1 A first figure.
- Fig. 3 shows the effect of CuCl and EDTA on changes in tension and elasticity of amyloid
- Fig. 4 shows the dependence of ZnCl concentration on changes in tension and elasticity of ⁇ -synuclein.
- FIG. 1 A first figure.
- amyloid protein aggregation activity has been detected by creating amyloid protein aggregates.
- conventional methods have required much labor and time.
- the present invention has made it possible to detect a structural change of amyloid protein simply and in real time by using a force sensor.
- protein that causes amyloid structural change refers to a protein that causes a structural change that forms an amyloid fiber having a specific layered ⁇ -sheet structure. Such proteins cause amyloid-related diseases.
- proteins known to cause amyloid structural changes include, but are not limited to, amyloid j8 protein, immunoglobulin light chain protein, amyloid A protein, transthyretin protein, lysozyme, BriL Protein, cystatin C protein, scrapie protein, j82 microglobulin, apolipoprotein Al, gelsolin, amyloid protein of the islet of Langerhans, fibrinogen, prolatatin, insulin, calcitonin, atrial sodium peptide, ⁇ -synuclein, prion protein, han Examples include tintin protein, superoxide dismutase, ⁇ -antichymotrypsi, and tau protein. Among them, the amyloid ⁇ protein is well known as a typical
- the most remarkable feature of the present invention is that a structural change in amyloid property of a strong protein is detected by a change in mechanical properties of a sample membrane of the strong protein.
- a mode in which the change in the mechanical properties of the sample film is measured using only tension, only elasticity, or both tension and elasticity as an index is possible, but the present invention is not limited to the above specific mode. Absent.
- a sample film which is a protein that causes an amyloid structural change
- the size of the sample film to be formed is preferably 50 m to 1000 ⁇ m in length, 200 ⁇ m to 2000 ⁇ m in width, and 0.3 ⁇ m to 10 ⁇ m in thickness.
- the substrate in the present invention is an appropriate film support that enables the sample film to be moved to the measuring device by forming the sample film thereon, and the material and size of the substrate are particularly Not limited.
- Body proteins can also be used as long as they maintain the activity of causing amyloid structural changes.
- the protein may be tagged for convenience of detection. Further, a similar effect can be obtained by using a membrane obtained by binding the protein to a membrane made of an antibody protein which can be formed from an antibody protein against the protein.
- Methods for preparing a sample film of a powerful protein include an ESD method in which a sample is deposited by electrospray (electrostatic spray) to form a thin film, and a drying method in which a film is formed by drying a solution. And the like.
- Powerful techniques are well known to those skilled in the art, and can be appropriately modified and used for the purpose of the present invention.
- a method for producing a deposit of a non-volatile substance containing a large biomolecule by electrostatic spraying described in JP-T-2002-511792 may be mentioned. it can.
- Japanese Patent Application Laid-Open No. 2003-136005 describes an apparatus for producing a thin film or a spot by fixing while retaining the activity of a biopolymer or the like.
- JP-T-2002-503332 describes a method and an apparatus for measuring a ligand that binds to a protein or DNA.
- Japanese Unexamined Patent Publication No. 2002-503332 it is possible to mechanistically (mechanochemically) measure the action of a chemical substance on a sample membrane composed of a biopolymer or the like. Therefore, it is a preferable embodiment of the present invention to detect the change in the tension and the Z or elasticity of the sample film using the device described in JP-T-2002-503332.
- providing an intermediate layer made of a water-soluble polymer between the substrate and the sample film is a preferred embodiment.
- 1.2% polyvinylpyrrolidone (PVP) is used as such an intermediate layer.
- PVP polyvinylpyrrolidone
- the strength is within the range of 0.1% force 5%, preferably 0.3% force 2%.
- the concentration of the force PVP is not particularly limited. It is also possible to use other water-soluble polymers.
- Examples of the material that can be used as the intermediate layer include, as described in JP-T-2002-503332, (1) a layer of a water-soluble polymer such as polyacrylamide or polyethylene glycol. (2) a layer of polymer with a disulfide bond reduced by mercaptoethanol, (3) a layer of carbon that has a low adhesion to the biological molecules to be deposited, and (4) A layer having a conductive composition of a carbon polymer having a low melting point.
- the protein constituting the sample membrane can be immobilized by cross-linking the protein, and the vigorous cross-linking is effective also for the purpose of maintaining the form and strength of the sample membrane as a membrane. It is.
- Cross-linking reagents that can be used to polymerize biological molecules are well known to those skilled in the art and are described, for example, in Hermanson et al, Immobilized Affinity Ligand
- a reagent used for cross-linking a protein glutaraldehyde used in the following Examples is most preferable.
- zero-length cross-linking reagents such as 1-ethyl-3- (3-dimethylamino) piperpyrcarbodiimide (EDC), homobivalent cross-linking reagents such as dimethyladipimidate (DMA), and succinimidyl 3- (2-pyridyldithio) Heterobivalent cross-linking reagents such as propionate (SPDP), and trivalent cross-linking reagents such as 4-azido-2-trophenyl-rubiocytin-4-trophenyl ester is not.
- the time for performing the cross-linking reaction is not particularly limited.
- the cross-linking time of dartalaldehyde in the following examples is 5 minutes. The optimal conditions can be appropriately selected within the range of about 0 to 3 hours. it can.
- the sample film thus prepared is placed in, for example, a detection device described in JP-T-2002-503332 and immersed in an appropriate buffer to prepare the sample film to allow the test sample to act.
- the buffer used here is not limited to those which can be used, such as Hepes buffer and Tris buffer, which are commonly used in this technical field.
- the pH of the buffer is also limited in particular can be suitably select an appropriate P H in the range of pH3 to Nag about pH 9.
- the buffer may have an appropriate salt strength, and it is preferable in the present invention to add about 0.15M sodium chloride to the buffer as in the following examples. U, embodiment. However, it is considered that the measurement can be performed without adding an electrolyte for imparting salt strength, and such a mode is also within the scope of the present invention.
- the electrolyte to be added is not limited to sodium chloride.
- the buffer solution is replaced with a buffer solution containing a test sample to be tested, and is applied to the sample film.
- the change in tension and Z or elasticity of the sample membrane before and after addition of the test sample is measured with a force sensor to evaluate the effect of the amyloid protein on the structural change.
- Changes in tension and z or elasticity can be measured by force sensors, preferably by mechanochemical sensors. It is a particularly preferred embodiment of the present invention to perform the measurement using a mechanochemical sensor using an apparatus described in Japanese Patent Application Laid-Open No. 2002-503332.
- test sample substances can be employed as a test sample for examining the effect of a protein on amyloid structural change.
- test sample substances include proteins, peptides, amino acids, sugars, lipids, nucleic acids, metals, and organic compounds.
- the present invention is not particularly limited thereto.
- changes in tension and Z or elasticity of amyloid protein can be detected quickly and in real time. Therefore, since the amyloid structural change in many samples can be efficiently evaluated, the time spent searching for a substance that inhibits the amyloid structural change can be significantly reduced, and a large number of substances can be easily evaluated. Substances having a teasing activity can be selected.
- a substance that inhibits amyloid structural changes can be a good candidate for a therapeutic or diagnostic agent for amyloid disease. Specifically, if a substance that inhibits amyloid structural change can be obtained, it is considered that it is possible to further investigate safety and develop a new therapeutic agent for amyloid disease.
- Example 1 Effect of ZnCl on Needle for Amyloid ⁇ Tension and Damage Change
- Amyloid (1-42) (Bachem AG, Bubendorf, Switzerland) is dissolved in 0.1% aqueous ammonia at a concentration of 1 mg / mL, and the solution is subjected to electrostatic spraying described in JP-T-2002-511792. Spraying in dry air using an apparatus or an immobilization apparatus described in JP-A-2003-136005, passing through a mask having holes of 400 m in length and 800 m in width, and electrostatic spraying (ESD method) A 1 ⁇ m-thick membrane was prepared on 1.2% polyvinylpyrrolidone, and the protein was cross-linked with daltaraldehyde.
- This membrane is placed on an apparatus described in Japanese Patent Publication No. 2002-503332 or US Patent No. US6033913 having a mechanochemical sensor, and a 10 mM Hepes pH 7.4 buffer containing 0.15 M NaCl is placed. It was immersed in a liquid (hereinafter abbreviated as buffer). The buffer was allowed to flow over the membrane present on the detector at a flow rate of 0.1 to 0.2 mL / min to stabilize the tension. Then, at the same flow rate, a ZnCl solution dissolved in the above buffer solution is flowed, and changes in tension and elasticity are detected.
- buffer a liquid
- the action of 22 is thought to be reversible.
- the uniform state that is, the place where the horizontal line rises, indicates the point at which the tension is applied to the sample film, and the compliance is detected at the vibrating part.
- the results in FIG. 1 show that the present invention allows detection of a specific interaction between amyloid j8 (1-42) and ZnCl in minutes.
- the ZnCl concentration can be reduced.
- the magnitude of the transformation is concentration-dependent.
- a film of amyloid ⁇ 8 (1-42) was prepared as described in Example 1 and also on the detector.
- the change in tension and elasticity of CuCl dissolved in the buffer was examined (Fig. 3).
- Example 3 Effect of ZnCl on tension and elasticity change of ⁇ -synuclein
- a membrane of ⁇ -synuclein (BIOMOL International LP, PA, USA) was prepared as described in Example 1 and placed on the detector. Tension and elasticity of ZnCl dissolved in buffer
- the present invention provides a method for detecting amyloid structural change of a protein using a mechanochemical sensor.
- the present invention further provides a method for searching for a substance having an activity that affects amyloid structural change, and a method for searching for a therapeutic or diagnostic agent for an amyloid-related disease using the above detection method.
- the method of the present invention is considered to contribute to the purpose of obtaining a novel therapeutic agent for amyloid disease 'diagnostic agent.
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006511504A JPWO2005093430A1 (ja) | 2004-03-25 | 2005-03-24 | 蛋白質のアミロイド性の構造変化を検出する方法、アミロイド性の構造変化に影響を与える活性を有する物質を探索する方法、アミロイド関連疾患の治療薬又は診断薬を探索する方法 |
CA002561246A CA2561246A1 (en) | 2004-03-25 | 2005-03-24 | Method of detecting conformational change of an amyloid protein, a method of searching a substance having an activity that affects to conformational change of an amyloid protein, and a method of searching a therapeutic or diagnostic agent for amyloid-related diseases |
US10/593,880 US20080003691A1 (en) | 2004-03-25 | 2005-03-24 | Method of Detecting Conformational Change of an Amyloid Protein, a Method of Searching a Substance Having an Activity that Affects to Conformational Change of an Amyloid Protein, and Method of Searching a Therapeutic or Diagnostic Agent for Amyloid-Related Diseases |
EP05727132A EP1729132A4 (en) | 2004-03-25 | 2005-03-24 | METHOD FOR DETECTING AN AMYLOID STRUCTURE MODIFICATION IN PROTEIN, METHOD FOR SEARCHING FOR A SUBSTANCE WITH ACTIVITY CONCERNING AMYLOID STRUCTURE MODIFICATION, AND METHOD FOR SEARCHING FOR A COURAGE OR A DIAGNOSTIC FOR A DISEASE IN CONNECTION WITH AMYLOID |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP2004089282 | 2004-03-25 | ||
JP2004-089282 | 2004-03-25 |
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WO2005093430A1 true WO2005093430A1 (ja) | 2005-10-06 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP2005/005410 WO2005093430A1 (ja) | 2004-03-25 | 2005-03-24 | 蛋白質のアミロイド性の構造変化を検出する方法、アミロイド性の構造変化に影響を与える活性を有する物質を探索する方法、アミロイド関連疾患の治療薬又は診断薬を探索する方法 |
Country Status (5)
Country | Link |
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US (1) | US20080003691A1 (ja) |
EP (1) | EP1729132A4 (ja) |
JP (1) | JPWO2005093430A1 (ja) |
CA (1) | CA2561246A1 (ja) |
WO (1) | WO2005093430A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013508720A (ja) * | 2009-10-23 | 2013-03-07 | ジーイー・ヘルスケア・バイオサイエンス・アクチボラグ | 巨大分子多量体の測定方法 |
Families Citing this family (5)
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JP2006133164A (ja) * | 2004-11-09 | 2006-05-25 | Fyuuensu:Kk | カルモデュリンの構造変化を検出する方法、カルモデュリンの構造変化に影響を与える活性を有する物質を探索する方法 |
US20100310462A1 (en) * | 2007-04-18 | 2010-12-09 | Biochromix Ab | Binding of pathological forms of proteins using conjugated polyelectrolytes |
US20100310461A1 (en) * | 2007-04-18 | 2010-12-09 | Biochromix Pharma Ab | Binding of pathological forms of proteins using conjugated polyelectrolytes |
US7790410B2 (en) * | 2008-04-25 | 2010-09-07 | General Electric Company | Method and apparatus for determining hemocompatibility |
CN111751415B (zh) * | 2020-06-15 | 2022-08-12 | 华南师范大学 | 一种胰岛素淀粉样纤维化的电化学检测方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2002097444A2 (en) * | 2001-05-31 | 2002-12-05 | Arete Associates | Misfolded protein sensor method |
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JP3784074B2 (ja) * | 1996-06-20 | 2006-06-07 | ニューヨーク ユニヴァーシティ | ポリマ材料と相互作用するリガンドの検出 |
-
2005
- 2005-03-24 JP JP2006511504A patent/JPWO2005093430A1/ja not_active Withdrawn
- 2005-03-24 EP EP05727132A patent/EP1729132A4/en not_active Withdrawn
- 2005-03-24 WO PCT/JP2005/005410 patent/WO2005093430A1/ja active Application Filing
- 2005-03-24 US US10/593,880 patent/US20080003691A1/en not_active Abandoned
- 2005-03-24 CA CA002561246A patent/CA2561246A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002097444A2 (en) * | 2001-05-31 | 2002-12-05 | Arete Associates | Misfolded protein sensor method |
Non-Patent Citations (2)
Title |
---|
MOGAMI ET AL: "Mechanochemical Sensor.", MATERIALS SCIENCE AND TECHNOLOGY., vol. 41, no. 1, 20 February 2004 (2004-02-20), pages 6 - 10, XP002998320 * |
See also references of EP1729132A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013508720A (ja) * | 2009-10-23 | 2013-03-07 | ジーイー・ヘルスケア・バイオサイエンス・アクチボラグ | 巨大分子多量体の測定方法 |
Also Published As
Publication number | Publication date |
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CA2561246A1 (en) | 2005-10-06 |
EP1729132A1 (en) | 2006-12-06 |
JPWO2005093430A1 (ja) | 2008-02-14 |
US20080003691A1 (en) | 2008-01-03 |
EP1729132A4 (en) | 2008-04-02 |
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