[go: up one dir, main page]

WO1994012203A1 - MEDICAMENTS CONTENANT LA PROTEINE reg EN TANT QU'INGREDIENT ACTIF - Google Patents

MEDICAMENTS CONTENANT LA PROTEINE reg EN TANT QU'INGREDIENT ACTIF Download PDF

Info

Publication number
WO1994012203A1
WO1994012203A1 PCT/JP1993/001746 JP9301746W WO9412203A1 WO 1994012203 A1 WO1994012203 A1 WO 1994012203A1 JP 9301746 W JP9301746 W JP 9301746W WO 9412203 A1 WO9412203 A1 WO 9412203A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
acid sequence
column
gin
asn
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1993/001746
Other languages
English (en)
Japanese (ja)
Inventor
Hiroshi Okamoto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Original Assignee
Shionogi and Co Ltd
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 Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Publication of WO1994012203A1 publication Critical patent/WO1994012203A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/474—Pancreatic thread protein; Reg protein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a drug containing reg protein K as an active ingredient, and more particularly, to a sugar level lowering agent in body fluid and an agent for cells.
  • the reg protein is a polypeptide encoded by the regII gene.
  • the regit gene is found as a gene that is specifically expressed in rat regenerative Langerhans ⁇ cells, and the human gene corresponding to the regit gene of this rat The regit gene has already been sculpted, and the production of reg proteins by the gene recombination method using yeast has been reported (JP 132388, JP 1-137994, JP 2-207007). )
  • reg protein has not been reported yet, but the expression of reg gene in various groups other than the 8th occupation has been reported. There is a need for clear elucidation of biological activity and its application to medicine.
  • reg protein B was administered to a 90X knee resection rat, significant blood and urinary glucose levels were observed compared to the 903 ⁇ 4 ⁇ resection rat without reg protein. I got a little.
  • reg protein would be involved in cell culture of Langerhans islets, and cultivated Langerhans islets at the invite mouth in the presence of reg proteins. Compared with cells cultured in the absence of protein K, significant increase in cell proliferation was observed. From such a fact, the inventors have completed the present invention.
  • the present invention relates to a saccharide in a body comprising, as an active ingredient, a polypeptide having any amino acid sequence selected from the following amino acid sequence groups (1) to (1): Value depressant:
  • the present invention further provides, as an active ingredient, a polypeptide having any one of the amino acid sequences selected from the following amino acid sequence E in (1) to (5).
  • Cell proliferating agent (1) Amino acid sequence from the 21st Gin to the 166th Asn, which is not shown in £ column number 1 of the £ column list:
  • Regular protein means a polypeptide having any amino acid sequence selected from the above amino acid sequence group 0
  • (1) to (3) are the amino acid sequences of the human reg protein. It is known that human reg protein undergoes various degradations in a living body, and there are those having the above three types of amino acid sequences. However, there may be those having an amino acid sequence other than these due to degradation in vivo, and these are also included in the reg protein of the present invention.
  • amino acid sequences of rat reg proteins are amino acid sequences of rat reg proteins. These amino acid sequences correspond to human reg proteins (1) to (3). Corresponding ones are also included in the present invention. In addition, there may be other proteins having an amino acid K sequence due to degradation in the living body. Reg protein.
  • amino acid sequences of (2) and (5) are used.
  • body fluid means all body fluids in a living body such as blood, urine, and aqueous humor, and blood or urine is a typical example.
  • FIG. 1 shows the count of thymidine incorporation into Langerhans islet cell DNA at various reg protein concentrations. Marauders are mean values ( ⁇ - I, I is standard error mean. *, ** and *** are p ⁇ , respectively, compared to values at reg protein concentration 0 / g / nl. 0.05, p-0.01 and p-0.001 represent statistically significant differences.
  • FIG. 2 shows the growth rate of Langerhans islet cells at various reg protein B concentrations based on the growth rate at a reg protein concentration of 0 ;: g / ml. ⁇ represents the average value, and I represents the difference average.
  • the human reg protein used in the present invention can be obtained by an extraction method, a synthesis method, or a gene recombination method. For example, see Japanese Patent Application Laid-Open No. 1-137334. It can be produced by the gene recombination method described above. Rat reg proteins can be easily manufactured by those skilled in the art by replacing the human regit gene with the rat regit gene according to this method.
  • the sugar level-lowering agent containing the reg protein of the present invention as an active ingredient is preferably administered as an injection.
  • reg protein is dissolved or dissolved in distilled water, physiological saline, aqueous acetic acid, vegetable oil, glycols, etc., and if necessary, stabilizers and preservatives are used. It is prepared by adding a tonicity agent, a soothing agent, a buffer and the like. Or freeze-dried by adding stabilizers, preservatives, excipients, etc.
  • the glucose ffi-lowering effect of the reg protein of the present invention can be measured, for example, by administering a glucose-lowering agent of the present invention to a 90% excised rat and measuring blood glucose or urine level. Can be evaluated more. As shown in Example 1 below, administration of the sugar level lowering agent of the present invention containing a reg protein as an active ingredient significantly reduces urinary glucose and blood glucose utilization.
  • the concentration of the reg protein in the present invention is 100 ng / ml or more.
  • the dose may be maintained to maintain the above value, and for adults, 0.1 mg to lg, preferably lng to 500 mg, of reg protein may be administered per day.
  • the cell culture agent containing reg protein S of the present invention as an active ingredient can be used both in vitro and in vivo.
  • reg protein When using for in vitro cell culture, add reg protein to the growth medium of cells containing fetal serum, glucose, etc.
  • Reg protein is used by dissolving or suspending it in distilled water, physiological saline, acetic acid aqueous solution, propylene glycol or the like.
  • it When used in vivo, it is preferably used in the same manner as the above sugar level lowering agent.
  • the cell confluent of the present invention is preferably used at a concentration of 0.1 to 20 g / ral medium, and particularly preferably at a concentration of 0.3 to 10 tf g / inl medium.
  • the drug provided by the present invention which contains rat or human reg protein as an active ingredient, is involved in cell growth and enables regeneration of insulin-producing ⁇ 9 cells. I do. This will enable a diabetic patient's own ⁇ ) regenerative activation of 3 cells to be replaced by a regenerative therapy, instead of the conventional symptomatic treatment of insulin administration.
  • the sugar level in a body fluid can be reduced.
  • Rat reg protein was prepared by wrapping a human regit gene in accordance with the method described in JP-A-1-137994. The expression was replaced with the reg gene, and the product was isolated and purified.
  • the rats re g protein has a ⁇ Mi Roh acid E string at 22 th Gin or et al. 165 th Ala between the ⁇ in SEQ ID NO: 2.
  • the purified rat reg protein was dissolved in 50 mM citric acid to a concentration of 0.91 ng / nil to prepare a preparation for administration.
  • the 90X long excision rat was prepared by the method described in JP-A-1-132388. That is, the Wistar male rat was excised from 90X in the profession according to the method of Foglia, VG (Rev. Soc. Argent. Biol .. 20: 21-37 (1944)).
  • regt 2SL S10 s.uo is SO Average 280.S ⁇ 20.S .2 ⁇ ie 2.7 ⁇ ⁇ 2.J7 102.1 ⁇ 21.3
  • Rat reg protein which is a cell proliferating agent containing rat reg protein as an active ingredient, can be prepared by rat-regulating a rat according to the method described in JP-A-1-1379S4. It was expressed by substituting the reg gene, and isolated and purified. This rat reg protein has an amino acid sequence from the 22nd Gin to the 165th Ala described in Seq. ID No. 2 in the sequence listing. The purified rat reg protein K was dissolved at 0.91 ng / ml in 50 raM sodium hydroxide to obtain a cell crucible.
  • Langerhans ⁇ was isolated from the Wistar male rat (body weight 250-350 g) and incubated overnight in RPMI1640 medium containing 10% FCS and 11. ⁇ glucose. Cultured. After culturing, the cells are subjected to a microscopic uptake under ffl microfluidics to remove exocrine cells and Langerhans S, which have a poor state of swelling. The cells were further cultured in RPM # 640 medium containing the yeast.
  • the supplemented medium was adapted and converted. was used as a test medium.
  • test medium In 1 / ⁇ : 1
  • test medium was replaced with a new test medium, tritium 'thymidine was added (10 Ci / ral), and the cells were further cultured for 24 hours.
  • the Langerhans islets were collected, washed with Hanks' solution, and then sonicated in 350 ⁇ 1 ⁇ tris-acid buffer (pH 8.0) containing 5m EDTA. This was stored frozen until quantification.
  • Trichloric acid is added to the sonicated product obtained as described in section E above, and precipitated, and the amount of tritium incorporated in the insoluble fraction is removed. It was measured by the filter method. Figures 1 and 2 show the results.
  • the group cultivated in the culture solution containing the cell crucible had a higher amount of thymidine incorporation and a higher cell growth activity than the control group. high. Furthermore, it can be seen that the cell proliferation activity depends on the concentration of the reg protein: S used. (Sequence listing)
  • Arg lie Ser Cys Pro Glu Gly Thr. Asn Ala Tyr Arg Ser Tyr Cys Tyr

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Agent favorisant la prolifération cellulaire et agent réducteur du taux de sucre chez l'homme, contenant tous deux une protéine reg humaine ou de rat en tant qu'ingrédient actif. Ces médicaments permettant la régénération des cellules β pancréatiques qui produisent l'insuline, il est possible de recourir à une thérapie visant les causes, c'est-à-dire à la régénération et à l'activation des cellules β pancréatiques d'un patient souffrant de diabète, au lieu de recourir à la thérapie symptomatique classique consistant à administrer de l'insuline. De plus, la protéine reg pouvant proliférer dans les îlots de Langerhans, lesdits médicaments sont utiles comme réducteurs du taux de sucre chez l'homme.
PCT/JP1993/001746 1992-12-01 1993-12-01 MEDICAMENTS CONTENANT LA PROTEINE reg EN TANT QU'INGREDIENT ACTIF Ceased WO1994012203A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP32212192 1992-12-01
JP4/322121 1992-12-01
JP5/91576 1993-04-19
JP09157693A JP3570557B2 (ja) 1992-12-01 1993-04-19 ｒｅｇタンパク質を有効成分とする薬剤

Publications (1)

Publication Number Publication Date
WO1994012203A1 true WO1994012203A1 (fr) 1994-06-09

Family

ID=26433015

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001746 Ceased WO1994012203A1 (fr) 1992-12-01 1993-12-01 MEDICAMENTS CONTENANT LA PROTEINE reg EN TANT QU'INGREDIENT ACTIF

Country Status (2)

Country Link
JP (1) JP3570557B2 (fr)
WO (1) WO1994012203A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0991319A4 (fr) * 1997-04-18 2000-10-18 Hadasit Med Res Service Traitement du diabete

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1135485A (ja) * 1994-06-24 1999-02-09 Ono Pharmaceut Co Ltd 蛋白質ｐ７２をチロシンリン酸化することを特徴とする糖尿病治療方法、糖尿病治療剤および糖尿病治療剤のスクリーニング方法
EP1297841B1 (fr) * 2000-06-02 2010-05-05 Takeda Pharmaceutical Company Limited Promoteur de la proliferation des cellules de langerhans beta pancreatiques et inhibiteur d'apoptose, ainsi que criblage de composes candidats pour ces medicaments

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01132388A (ja) * 1987-04-09 1989-05-24 Shionogi & Co Ltd ｒｅｇ遺伝子および該遺伝子にコードされる蛋白質
JPH01137994A (ja) * 1987-08-10 1989-05-30 Shionogi & Co Ltd ｒｅｇ蛋白質
JPH02200700A (ja) * 1989-01-30 1990-08-08 Shionogi & Co Ltd 新規ｒｅｇ蛋白質

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01132388A (ja) * 1987-04-09 1989-05-24 Shionogi & Co Ltd ｒｅｇ遺伝子および該遺伝子にコードされる蛋白質
JPH01137994A (ja) * 1987-08-10 1989-05-30 Shionogi & Co Ltd ｒｅｇ蛋白質
JPH02200700A (ja) * 1989-01-30 1990-08-08 Shionogi & Co Ltd 新規ｒｅｇ蛋白質

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0991319A4 (fr) * 1997-04-18 2000-10-18 Hadasit Med Res Service Traitement du diabete

Also Published As

Publication number Publication date
JP3570557B2 (ja) 2004-09-29
JPH06219963A (ja) 1994-08-09

Similar Documents

Publication Publication Date Title
JP7711967B2 (ja) 糖尿病、高血圧および高コレステロール血症を治療するための組成物および方法
CN104066440A (zh) 白介素-22在治疗和预防神经损伤疾病或神经退行性疾病中的用途
US3928580A (en) Injectable glycoproteins containing terminal {37 C{38 {0 ends of human immunoglobulins
US20040132644A1 (en) Composition and method for treating diabetes
US9642917B2 (en) Use of G-CSF dimer in preparation of medicament for treatment of neurodegenerative diseases
CN114621324B (zh) 促进肝细胞增殖和/或抑制肝细胞凋亡的多肽及其用途
US5700776A (en) Medicaments comprising glicentin as active ingredient
CN107151263B (zh) 一种抑制胰岛淀粉样多肽聚集的短肽抑制剂
WO1994012203A1 (fr) MEDICAMENTS CONTENANT LA PROTEINE reg EN TANT QU'INGREDIENT ACTIF
AU659723B2 (en) Remedy for airway diseases
KR102669871B1 (ko) 빈혈 치료 약물 제조에서 항혈소판 트롬볼리신의 응용
WO2024109153A1 (fr) Utilisation de ly2922470 dans la préparation d'un médicament pour la prévention ou le traitement de maladies rénales
WO2022054825A1 (fr) Médicament pour prévenir ou traiter un symptôme ou un trouble chez un sujet affecté par une infection virale
CN117298086B (zh) 索法酮在制备预防和/或治疗nlrp3炎性小体介导的疾病的药物中的应用
CN116199743B (zh) 抗焦亡多肽及其应用
US20090176702A1 (en) Use of long-acting recombinant human soluble tumor necrosis factor alpha receptor in manufacture of a medicament for the treatment and/or prophylaxis of hepatic failure
WO1983004260A1 (fr) Enzyme analogue de la pepsine de leucocyte humain et agent therapeutique contenant cette enzyme en tant qu'ingredient effectif pour le traitement de troubles allergiques, de maladies auto-immunitaires et de tumeurs
CN101130769B (zh) 核苷酸分子sr4b及其在制备抗糖尿病药物中的应用
CN101130773B (zh) 核苷酸分子sr5b2及其在制备抗糖尿病药物中的应用
KR20230022876A (ko) 바이러스성 내피염 치료용 bbeta-15-42
MANOGUE et al. Cachectin (tumor necrosis factor)
CN101130564A (zh) 核苷酸分子sr2b2及其在制备抗糖尿病药物中的应用
CA2051044A1 (fr) Agent cytostatique
HK40076131A (en) Formulations comprising recombinant acid alpha-glucosidase
JPH0288526A (ja) 血糖低下剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

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
122 Ep: pct application non-entry in european phase