WO2001057525A1 - Remedes contre la maladie de behcet - Google Patents

Remedes contre la maladie de behcet Download PDF

Info

Publication number
WO2001057525A1
WO2001057525A1 PCT/JP2001/000766 JP0100766W WO0157525A1 WO 2001057525 A1 WO2001057525 A1 WO 2001057525A1 JP 0100766 W JP0100766 W JP 0100766W WO 0157525 A1 WO0157525 A1 WO 0157525A1
Authority
WO
WIPO (PCT)
Prior art keywords
protein
disease
hla
mica
peptide
Prior art date
Application number
PCT/JP2001/000766
Other languages
English (en)
Japanese (ja)
Inventor
Hidetoshi Inoko
Original Assignee
Hidetoshi Inoko
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hidetoshi Inoko filed Critical Hidetoshi Inoko
Priority to AU2001230573A priority Critical patent/AU2001230573A1/en
Publication of WO2001057525A1 publication Critical patent/WO2001057525A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to a method for screening for a drug for treating peet's disease and a compound for treating the same.
  • Behcet's disease is a chronic inflammatory disease with recurrent oral and reproductive tracts, uveitis, and vasculitis, in addition to mucocutaneous mucositis, arthritis, and neurologic manifestations.
  • Behcet's disease is distributed throughout the world, it is biased in countries from Japan to the Middle and Middle Mediterranean—along the silk hordes of silk.
  • the inventors and other groups have shown an association between Behcet's disease and HLA, and have found that HLA-B51 is one of the most powerful genetic markers in the ethnic group S in these countries. (Ohno S, et al. (1982) Arch Ophthalmol 100: 1455 -1458) o
  • Behcet's disease Although the etiology of Behcet's disease has not yet been elucidated, its onset is thought to be caused by the same external environmental factors in individual leave with a particular genetic profile. Most patients with Behcet's disease, especially those with severe illness, are male, with an average age of onset of c in their thirties, and their children are rarely infected and few have been reported on neonates.
  • a recent study reported an increase in ⁇ / (5 T cells in peripheral blood and related tissues and an increase in ⁇ / (5 T cells with different phenotypes at sites of inflammation (Suzuki Y, et al. (1992) ) J Rheumatol 19: 588-592, Hamzaoui K, et al.
  • MHC major histocompatibility complex
  • MIC major histocompatibility complex
  • the MICA gene located only 46 kb centromeric to HLA-B, is a member of the family's highly polymorphic forms, hi 1 (exon 2), hi 2 (exon 3), and hi 3 There are more than 20 alleles at the amino acid level in the (Exon 4) domain (Fodil N, et al. (1996) 44:35 357, Fodil N, et al. Immunogenetics. In Press).
  • MICA encodes a cell surface glycoprotein unrelated to?
  • MICA expression has been detected in fibroblasts and epithelial cell lines, intestinal epithelium, keratinocytes, endothelial cells, and monocytes (Bahram S, et al. (1994) 91: 6259-6263 ⁇ Groh V, et al. (1996) Proc Natl Acad Sci US A 93: 12445-12450, Zwirner NW, et al. (1998) Immunogenetics 47: 139-148).
  • MICA gene is controlled by a promoter heat shock element similar to that of the hsp70 ⁇ gene, and therefore the steady-state levels of MICA mRNA and protein are increased upon exposure to heat shock (Groh V, et al. al. (1996) Proc Natl Acad Sci USA 93: 12445-12450).
  • MICA molecules have been found to be recognized by a variety of V51 ⁇ / (5 T cell receptor-expressing special T cells extracted from tumors of the gastrointestinal epithelium (Groh V, et al. (1998) Science 279: 1737-1740.) Thus, it is suggested that this molecule plays an important role as a stress-inducing autoantigen and broadly regulates defense responses mediated by epithelial V51 ⁇ / ⁇ cells. It has been
  • the present inventors have recently conducted a study on 8 microsatellite repetitive polymorphisms distributed over a 100 kb region near MICA and HLA-B in Japanese patients with Behcet's disease. Based on mapping by ffl-function analysis, the Behcet's disease-onset region in human MHC was located in the 46 kb region between the MICA gene and the HL-B gene (Ota M, et al. (1999) Am J Hum Genet 64: 1406-1410).
  • HLA_B * 51 HLA-B gene allele
  • MICA009 MICA gene allele
  • the present invention has been made in view of such a situation, and elucidates a part of the molecular mechanism of Behcet's disease onset, and provides a screening method for a therapeutic drug for Peet's disease using the same. Further, the present invention provides a therapeutic agent for Behcet's disease which can be isolated by the screening.
  • HLA-B and MICA have conducted intensive studies on the relationship between HLA-B and MICA in Behcet's disease in order to solve the above-mentioned problems, and as a result, the transmembrane region of MICA has an HLA-B allele.
  • HLA-B51 shows a strong correlation (Ohno S. et al. (1982) Arch Ophthalmol. 100: 1455-1458; Mizuk i N. et al. ( (1993) Am J Ophthalmol.
  • the present invention is based on such findings, and it is possible to inhibit the binding of MICA to HLA-B51 or a method for screening a therapeutic agent for Beetie's disease using MICA fragmentation as an index, and to be isolated by the screening.
  • a therapeutic agent for Behcet's disease more specifically, the present invention
  • a method for screening for a therapeutic agent for Pettiet's disease comprising:
  • MICA009 protein (iii) transmembrane domain peptide of the protein according to (i) or (ii)
  • a method for screening for a therapeutic agent for Pettiet's disease comprising:
  • an agent for treating Behcet's disease comprising as an active ingredient a compound that inhibits the binding of HLA-B51 protein to MICA protein;
  • a therapeutic agent for Behcet's disease comprising as an active ingredient a compound that inhibits the binding between the HLA-B51 protein and a peptide containing the crotch transit region of MICA protein;
  • a therapeutic agent for Behcet's disease comprising as an active ingredient a compound that inhibits binding of the HLA-B51 protein to a peptide comprising the amino acid sequence of SEQ ID NO: 1;
  • a therapeutic agent for Behcet's disease comprising as an active ingredient a compound that inhibits fragmentation of MICA protein
  • a kit for screening a therapeutic agent for Peycet's disease comprising a peptide comprising the amino acid sequence of SEQ ID NO: 1.
  • the present invention provides a method for screening a therapeutic agent for Behcet's disease.
  • One embodiment of the method for screening a therapeutic agent for Beet's disease according to the present invention is a method using the inhibition of the binding between the HLA-B51 protein and the MlCA protein as an index.
  • This screening involves (a) contacting the HLA-B51 protein with the MICA protein in the presence of the test sample, (b) detecting the binding of these molecules, and (c) detecting the absence of the test sample. By selecting a compound that inhibits the binding as compared with the case, it can be carried out.
  • the HLA-B51 protein and MICA protein used in the screening may be a recombinant protein or a naturally-occurring protein. Also, it may be artificially synthesized.
  • the HLA-B51 protein used for screening is not particularly limited as long as it can bind to the MICA protein or its transmembrane domain peptide, but is preferably a full-length protein.
  • the nucleotide sequence and amino acid sequence of HLA-B51 see our, J and Parham, P. (1992) Human Immunology 34, 225-241, Parham, P. et al.
  • the MICA protein used for screening is not particularly limited as long as it can bind to the HLA-B51 protein.
  • it is a MICA protein whose transmembrane region contains an amino acid sequence consisting of "AAAAAIFVI (SEQ ID NO: 1)".
  • MlCA protein examples include MICA009 protein, MICA001 protein, MICA003 protein and the like.
  • a peptide containing a transmembrane region can be used in addition to the full-length protein. It is also possible to use a peptide containing an amino acid sequence consisting of “AAAAAIFVI (SEQ ID NO: 1)”.
  • nucleotide sequences and amino acid sequences of various MICAs and their transmembrane regions refer to the literature (Fodil, N. et al. (1996) I. recitation genetics 44, 351-257).
  • Test samples include, for example, cell extracts, cell culture supernatants, enzymatic microbial products, marine organism extracts, human extracts, slime or crude proteins, peptides, non-peptide compounds, synthetic Examples include, but are not limited to, low molecular weight compounds and natural compounds.
  • Suitable test samples include antibodies that bind to the HLA-B51 protein, and antibodies that bind to the MICA protein, its transmembrane region, or the peptide consisting of the amino acid sequence of SEQ ID NO: 1.
  • the form of these antibodies is not particularly limited, and includes monoclonal antibodies in addition to polyclonal antibodies. Also included are antisera obtained by immunizing immunized animals such as rabbits with the protein of the present invention, polyclonal antibodies and monoclonal antibodies of all classes, as well as human antibodies and humanized antibodies obtained by genetic recombination. Preparation of these antibodies can be performed by a method known to those skilled in the art.
  • the protein (or peptide) of the present invention to be brought into contact with the test sample may be used as a purified protein, as a soluble protein, or as a carrier, depending on the screening method. It can be brought into contact with a test sample as a bound form, as a fusion protein with another protein, as a form expressed on a cell membrane, or as a membrane fraction.
  • the screening method of the present invention is exemplified below.
  • scintillation radiation emitted from one molecule labeled with an isotope collides with a luminescent substance (scintilant) bound to another molecule bound to the isotope, and the light emitted is emitted from a photomultiplier tube or phosphor. It can be measured by changing to a voltage pulse with a diode or the like.
  • a luminescent material a crystal such as Nal, Csl, ZnS or the like, or a powder, a crystal such as anthracene, naphthalene or the like is suitably used.
  • SPA scintillation proximity assay developed by Amersham (Bothworth N, and Towers P.
  • Radioisotopes, H C,: i2 P ,: 'Ca, 1 can have ffl a.
  • a micro tie plate containing a scintillant on the bottom of the plate For example, one unlabeled molecule is immobilized on the bottom surface of the plate, and the other molecule labeled with a radioisotope and the test sample are added thereto. When the two molecules bind, one of the molecules labeled with a radioisotope remains on the bottom of the plate, and the scintillant contained on the bottom of the plate absorbs the energy of the radioisotope and the light is investigated. You. When the amount of light decreases when a test sample is added, it can be determined that the test sample used inhibits the binding of both molecules.
  • a biosensor utilizing the surface plasmon resonance phenomenon is used to detect the interaction between the HLA-B51 protein or its partial peptide and the MICA protein or its partial peptide using a trace amount of protein or peptide and without labeling. It can be observed in real time as a surface plasmon resonance signal (for example, BIAcore, manufactured by Pharmacia). For example, it is possible to evaluate the binding of these molecules by using a biosensor such as BIAcore. Specifically, one molecule is immobilized on one cassette-type sensor chip, and the other molecule is injected on the sensor chip. One of the injected molecules is supplied on one sensor chip at a constant flow rate, and diffuses onto the other immobilized molecule.
  • the binding between molecules in the screening of the present invention can be detected using nuclear magnetic resonance ( ⁇ R).
  • NMR nuclear magnetic resonance
  • ⁇ R nuclear magnetic resonance
  • two molecules are dissolved in a solvent and a nuclear magnetic resonance signal is measured. Then, a test sample is added to detect a nuclear magnetic resonance signal, and if the signal is reduced as compared with the case where no test sample is added, the test sample used will bind to these molecules. It can be determined that it inhibits.
  • ELISA enzyme immunoprecipitation assay
  • the two molecules reacted under the appropriate conditions and the test sample are subjected to gel filtration.
  • the binding of these molecules can be detected by shifting the absorbance peak retention time.
  • the binding between molecules in the screening of the present invention is determined by a two-hybrid method for yeast or animal cells (Fields, S., and Sternglanz, R., Trends. Genet. (1994) 10, 286-292, Dalton S, and Treisman R (1992) Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response e complement.Cell 68, 597-612, ⁇ MATCH Awake KER Two-Hybrid Systemj, '' Ma painting alian MATCHMAKER Two -Hybrid Assay Kit “," MATCHMAKER One-Hybrid Systemj (both made by Clontech) and rnybriZAP Two-Hybrid Vector Systemj (made by Straugene) "2_ In the hybrid system, the vector expressing the fusion protein of the HLA-B51 protein or its partial peptide and the SRF DNA binding region or GAL4 DNA binding region, and the MICA protein or its partial peptide
  • a compound that reduces the reporter activity as compared with the case where detection is performed in the absence of a sample is selected.
  • the repo overnight gene used in the 2-hybrid system include, for example, HIS3 gene, Ade2 gene, LacZ gene, CAT gene, luciferase gene, PAI-1 (Plasminogen activator inhibitor typel) gene and the like. But not limited to these.
  • the HLA-B51 protein or its partial peptide is incubated with the MICA protein or its partial peptide in the presence of the test sample, and conjugated with an antibody against one of the proteins or an antibody against a tag fused to the protein. After recovering, the binding of these two molecules can be evaluated by detecting the other protein by running an antibody against the protein and the like. If the other protein is labeled with another tag or the like, detection can be facilitated.
  • one protein is bound to a support, the other protein is bound, a test sample is brought into contact with the protein, and the effect of the test sample is detected by detecting whether the bound protein is dissociated. You can find out. It is also possible to carry out screening using ELISA.
  • cells expressing the HLA-B51 gene and expressing them on the cell surface are treated with the MICA protein or its protein in the presence of the test sample. It can be carried out by contacting a partial peptide and detecting the binding of these molecules. Detection of this binding can be performed using labeled antibodies that bind to these molecules.
  • test sample used is determined to be a candidate compound for a therapeutic agent for Behcet's disease.
  • the HLA-B51 protein or its partial peptide is fluorescently labeled with either the MICA protein or its partial peptide, and these proteins or partial peptides are contacted in the presence of a test sample. Apply polarized excitation light and measure the degree of polarization or depolarization. Screening for compounds that inhibit the binding between these two peptides by selecting a compound that reduces the degree of polarization or increases the degree of depolarization compared to the case where measurement is performed in the absence of the test sample It can be performed.
  • Another embodiment of the method of the present invention for screening for a therapeutic agent for Beetet's disease is a method using fragmentation of MlCA protein as an index.
  • the transmembrane peptide of the MICA protein was found to bind to the HLA-51 protein, but the transmembrane peptide of the MICA protein that binds to the HLA-51 protein is degraded and fragmented in vivo. Doing It is thought that. Therefore, this fragmentation is considered to be an important indicator for the screening of drugs for treating Pettiet's disease.
  • This screening method involves comparing (a) bringing a test sample into contact with cells expressing the MICA protein, (b) detecting fragmentation of the MICA protein, and (c) detecting the fragmentation in the absence of the test sample. And selecting a compound that inhibits the fragmentation.
  • a test sample is brought into contact with cells in which the MICA gene has been introduced and expressed, and the presence of the peptide in the culture supernatant is determined by using an antibody that binds to the transmembrane domain peptide of the MICA protein. What is necessary is just to detect by the immunoprecipitation method etc. which utilized. As a result, if the amount of the peptide in the culture supernatant is reduced as compared with the case where the test sample is not contacted, it is determined that the test sample inhibits the fragmentation of MICA protein.
  • the compound that inhibits the binding of the HLA-B51 protein to the MICA protein or the compound that inhibits the fragmentation of the MICA protein, which can be isolated by the above-mentioned screening of the present invention, can be a therapeutic agent for Behcet's disease.
  • the compound that inhibits the binding of the HLA-B51 protein to the MICA protein used for the treatment of Behcet's disease is preferably a compound that inhibits the antigen presentation of the HLA-B51 protein.
  • mice rats, guinea pigs, egrets, chicks, cats, dogs, higgs, bush, mosquitoes, monkeys, baboons, and chimpanzees
  • a pharmaceutical composition formulated by a known pharmaceutical method.
  • pharmacologically acceptable carriers or vehicles specifically, sterile water or saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, Formulated by combining as appropriate with preservatives, binders, etc., and mixing in the unit dosage form required for accepted pharmaceutical practice It is possible to do.
  • the amount of the active ingredient in these pharmaceutical compositions is such that an appropriate dose in the specified range can be obtained.
  • Additives that can be incorporated into tablets and capsules include, for example, binders such as gelatin, corn starch, tragacanth gum, acacia, excipients such as crystalline cellulose, corn starch, gelatin, and alginic acid.
  • binders such as gelatin, corn starch, tragacanth gum, acacia
  • excipients such as crystalline cellulose, corn starch, gelatin, and alginic acid.
  • a suitable bulking agent such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such as peppermint, cocoa oil or cherry
  • the above materials may further contain a liquid carrier such as oil and fat.
  • Sterile compositions for injection can be formulated according to normal pharmaceutical practice using a vehicle such as distilled water for injection.
  • Aqueous injection solutions include, for example, saline, isotonic solutions containing glucose and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, and suitable solubilizing agents.
  • glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, and suitable solubilizing agents.
  • alcohols specifically ethanol, polyalcohols such as propylene glycol, polyethylene glycol, nonionic surfactants such as polysorbate 80 (TM) and HCO-50 may be used in combination.
  • the oily liquid includes sesame oil and soybean oil, and may be used in combination with benzyl benzoate or benzyl alcohol as a solubilizer.
  • a buffer for example, a phosphate buffer, a sodium acetate buffer, a soothing agent, for example, proforce hydrochloride, a stabilizer, for example, benzyl alcohol, phenol, or an antioxidant may be blended.
  • the prepared injection solution is usually filled into an appropriate ampoule.
  • Administration to patients can be performed, for example, by intraarterial injection, intravenous injection, subcutaneous injection, etc., or intranasally, transbronchially, intramuscularly, transdermally, or orally by a method known to those skilled in the art. It can do better.
  • the dose varies depending on the weight and age of the patient, the administration method, and the like, but those skilled in the art can appropriately select an appropriate dose.
  • the compound can be encoded by DNA, the DNA is incorporated into a gene therapy vector. However, gene therapy may be used.
  • the dose and the administration method vary depending on the patient's body weight, age, symptoms and the like, but can be appropriately selected by those skilled in the art.
  • the dose of the compound varies depending on the symptoms, but in the case of oral administration, generally, for an adult (assuming a body weight of 60 kg), the daily dose is about O. Olmg to lg, preferably about 1. Omg to 100 mg, Preferably, it will be between about 1.0 mg and 20 mg.
  • the single dose varies depending on the administration target, target organ, symptoms, and administration method. For example, in the case of an injection, it is usually 1 day for adults (with a body weight of 60 kg). It may be convenient to administer about O. Olmg to 30 mg, preferably about 0.1 mg to 20 mg, more preferably about 0.1 mg to about 10 mg per iv. In the case of other animals, the dose can be administered in terms of the amount converted per 60 kg body weight or the amount converted per body surface area.
  • the present invention also provides a peptide comprising the amino acid sequence of SEQ ID NO: 1.
  • a peptide can be used in a kit for screening a therapeutic drug for Behcet's disease.
  • the “peptide comprising the amino acid sequence of SEQ ID NO: 1” includes the transmembrane domain peptide of the MICA protein. Preferably, it is a transmembrane domain peptide of MICA010 protein, MICA001 protein or MICA003 protein.
  • the kit of the present invention may further include an antibody that binds to HLA-B51 protein, MICA protein or HLA-B51 protein.
  • the peptide containing the amino acid sequence of SEQ ID NO: 1 can also be used as an antigen peptide for inducing immune tolerance.
  • Administration of the peptide for inducing immune tolerance to humans and other mammals can be performed by injection, or by injection or nasal mucosal administration (HL Weiner et al., Annu. Rev. Immunol, 12: 809-837 (1994), J. Mestecky et al., Annals of the New York Accademy of Science, 778: 194-201 (1996)).
  • a substance that inhibits transmission of a co-stimulatory signal for example, an anti-CD28 antibody or the like.
  • FIG. 1 shows the results of analyzing the binding affinity between the transmembrane domain peptide of MICA and HLA class I molecules. The score indicates the half-life of dissociation of the molecule.
  • TM transmembrane domain
  • MICA010 was detected using HLA-A2402 and HLA-A2101 as a negative control.
  • HLA-B510U HLA-B5102, HLA-B5103 strong binding of the transmembrane region of MICA to HLA-B51
  • HLA-A was used for other HLA-B alleles.
  • binding of the transmembrane region of MICA was not detected (score of 20 or less). Therefore, it was considered that HLA-B51 presents the transmembrane region of MICA as an antigen.

Abstract

On a découvert que le domaine de transmembrane de MICA peut se lier fortement à HLA-B51 qui est l'un des allèles de HLA-B. Cette liaison est spécifique pour HLA-B51 et on ne peut observer chez aucun autre allèle une capacité de liaison aussi importante. On a également découvert qu'il est possible de développer des remèdes contre la maladie de Behçet au moyen de ce mécanisme moléculaire.
PCT/JP2001/000766 2000-02-03 2001-02-02 Remedes contre la maladie de behcet WO2001057525A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001230573A AU2001230573A1 (en) 2000-02-03 2001-02-02 Remedies for behcet's disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000032690 2000-02-03
JP2000-32690 2000-02-03

Publications (1)

Publication Number Publication Date
WO2001057525A1 true WO2001057525A1 (fr) 2001-08-09

Family

ID=18557257

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/000766 WO2001057525A1 (fr) 2000-02-03 2001-02-02 Remedes contre la maladie de behcet

Country Status (2)

Country Link
AU (1) AU2001230573A1 (fr)
WO (1) WO2001057525A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111279193A (zh) * 2017-10-24 2020-06-12 高丽大学校产学协力团 利用尿代谢组分析诊断白塞氏病的方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
NASSIMA FODIL ET AL.: "Allelic perertoire of the human MHC class I MICA gene", IMMUNOGENETICS, vol. 44, 1996, pages 351 - 357, XP002942031 *
NOBUHISA MIZUKI ET AL.: "Triplet repeat polymorphism in the transmembrane region the MICA gene: A strong association of six GCT repetitions with Behcet disease", PROC. NATL. ACAD. SCI. USA, vol. 94, 1997, pages 1298 - 1303, XP002942032 *
NOBUHISA MIZUKI: "Behcet-byo mo genin idenshi no mapping oyobi screening", HEISEI 9-NENDO KOUSEISHO TOKUTEI SHIKKAN CHOSA KENKYU JIGYO, TOKUTEI SHIKKAN IDENSHI KAISEKI PROEJCT KENKYU HOKOKUSHUU, 1998, pages 54 - 57, XP002942033 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111279193A (zh) * 2017-10-24 2020-06-12 高丽大学校产学协力团 利用尿代谢组分析诊断白塞氏病的方法

Also Published As

Publication number Publication date
AU2001230573A1 (en) 2001-08-14

Similar Documents

Publication Publication Date Title
US11744875B2 (en) Peptides and methods for treating disease
WO2000024890A1 (fr) Nouvellesroteines receptrices couplees aux proteines g, leurs adn et leursigands
Ohshiro et al. Molecular identification and characterization of the dog motilin receptor
Baldwin et al. POPDC1 scaffolds a complex of adenylyl cyclase 9 and the potassium channel TREK‐1 in heart
US20090214519A1 (en) Compositions and Methods for Treating Inflammation
US20110219462A1 (en) G-Protein Coupled Receptor 30 (GPR30) transgenic animals as a model for cardiovascular diseases
US20160258966A1 (en) Compositions and Methods for Diagnosing and Treating Diseases and Disorders Associated With D-DT
JP2008537481A (ja) Ｇタンパク質シグナリングを阻害する組成物及び方法
EP0845529A2 (fr) Récepteur humain couplé à la protéine G, cloné à partir d'une banque d'ADN complémentaire de cerveau foetal
US7977069B2 (en) DNA encoding a CCK-8S G-protein coupled receptor, and vectors, transformants, cell kits, and methods employing such DNA
WO2001057525A1 (fr) Remedes contre la maladie de behcet
Kerov et al. Interaction of transducin-α with LGN, a G-protein modulator expressed in photoreceptor cells
US7622264B2 (en) Methods for screening for modulators of CXCR3 signaling
US7138249B2 (en) Screening method
EP1693456B1 (fr) Procede d'identification de modulateurs d'un recepteur couple a la proteine g
WO2009123145A1 (fr) Récepteur de parasporine-1 et son utilisation
US20040029224A1 (en) Novel g protein-coupled receptor protein and dna thereof
US20080160033A1 (en) Novel Screening Method
Torrens et al. Tachykinin receptors: binding and cellular activity assays
US20100183584A1 (en) Conformation and activity of gbeta5 complexes
US20030171545A1 (en) Novel Protein
AU2006241710B2 (en) Method for identification of compound having antidepressant effect
JP4637378B2 (ja) スクリーニング方法
US20030082648A1 (en) Novel mass receptor-analogous protein and dnas thereof
JP2005128010A (ja) インスリン抵抗性改善剤のスクリーニング方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2001 556322

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 69(1) EPC

122 Ep: pct application non-entry in european phase