EP0931145A1 - Ptx-sensitive g-proteine, ihre herstellung und verwendung - Google Patents

Ptx-sensitive g-proteine, ihre herstellung und verwendung

Info

Publication number
EP0931145A1
EP0931145A1 EP97944809A EP97944809A EP0931145A1 EP 0931145 A1 EP0931145 A1 EP 0931145A1 EP 97944809 A EP97944809 A EP 97944809A EP 97944809 A EP97944809 A EP 97944809A EP 0931145 A1 EP0931145 A1 EP 0931145A1
Authority
EP
European Patent Office
Prior art keywords
protein
disease
nucleic acid
acid sequence
gene
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.)
Withdrawn
Application number
EP97944809A
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German (de)
English (en)
French (fr)
Inventor
Winfried Siffert
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Individual
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP0931145A1 publication Critical patent/EP0931145A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • 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
    • C07K14/4722—G-proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention relates to new human G-Proteme, in particular ß3-Schemhe ⁇ ten G-Proteme, processes for their preparation and their use in diagnostics and therapy
  • G-proteins are of outstanding importance in intracellular signal transduction. They mediate the forwarding of extra cellular signals after stimulation of hormone receptors and other receptors, which undergo a conformational change after receptor activation. This leads to the activation of G-proteins, which can subsequently activate or inhibit intracellular effectors (e.g. ion channels, enzymes). Heterotomeric G-proteins are composed of three subunits, the ⁇ , ⁇ and ⁇ subunits. So far, several different ⁇ subunits, 5 ⁇ subunits and approx.
  • PTX pertussis tox
  • ß ⁇ subunits perform essential functions in G-prototype activation and in the modulation of intracellular reactions. All previously known G-protein ß subunits have high homologies at the level of the nucleotide sequence and at the level of the amino acid sequence. These similarities are not only within the human ß subunits found (ßl, ß2, ß3) but also in comparison to ß subunits of other species, for example fruit flies or yeast.
  • All previously known G-Prot ß subunits belong to the so-called "WD repeat" proteins.
  • the N-terminus of the ß-subunit mainly interacts with ⁇ -subunits, the C-terminus is involved in the interaction with receptors.
  • ß sub-units form so-called propeller structures.
  • the ß-propellers of the Gß subunits consist of 7 "ß-propellers - blades", each propeller blade consisting of 4 amino acid regions arranged in antiparallel.
  • the seven-fold symmetry of the ß-propeller can be demonstrated at the level of the amino acid sequence, which contains 7 so-called WD repeats.
  • a WD repeat motif comprises approximately 40 amino acids and has a number of conserved amino acids, including Trp-Asp dipeptide sequences. This WD mot v often ends the WD repeat (Fig. 1).
  • hypertensives have G-protein ⁇ 3 subunits which consist only of 6 instead of the otherwise described 7 WD repeat motifs. These hypertensives showed an increased cellular activation of PTX-sensitive G proteins compared to normotonics.
  • the molecular analysis revealed a new amino acid sequence for the ß3 subunit in these hypertensives, which is shortened by 41 amino acids compared to the known sequence.
  • the sequence is shown in SEQ ID NO: 2. Formally, it emerges from the well-known human ⁇ 3 subunit by deleting amino acids 167-207.
  • the reason for the appearance of the truncated Gß3 subunit in hypertensives is probably an alternative splicing of the corresponding gene.
  • the intron begins behind nucleotide 497 of the open reading frame (numbering according to SEQ ID NO: 1).
  • An intron could also be detected using PCR on genomic DNA, starting at nucleotide 620.
  • the shortened form is evidently the result of the deletion of a complete exon.
  • Another object of the invention is a method for producing shortened forms of human Gß3 subunits as mentioned above, by expressing a nucleic acid sequence coding therefor in a host organism.
  • the recombinant expression is preferably carried out by producing a gene construct which, in addition to the coding nucleic acid sequence, also contains further signal and regulatory sequences, such as promoters, terminators, riboseal binding sites, polyadenylation sites and the like.
  • the general procedure for the recombinant expression of a gene is familiar to the person skilled in the art.
  • Another object of the invention is the use of the nucleic acid sequences according to the invention for the production of medicaments for gene therapy treatment.
  • these nucleic acid sequences in direct form or after producing a corresponding gene vector in the cells of patients, an increased activatability of G proteins can be achieved in these.
  • Diseases which are associated with a G protein malfunction are to be understood as diseases in which the G protein is involved in signal transduction and does not fulfill its function in a physiological manner.
  • the diseases include cardiovascular diseases, metabolic disorders and immune diseases.
  • Cardiovascular diseases include: hypertension, gestational hypertension (gestosis, "hypertension in pregnancy"), coronary heart disease, localized and / or generalized atherosclerosis, stenosis of the blood vessels, restenosis after revascularizing vascular interventions (e.g. PTCA with and without stent implantation), Apoplex tendency. Thrombosis tendency and increased platelet aggregation.
  • Metabolic disorders include: Metabolic syndrome, insulin resistance and hyperinsulinemia, type II diabetes mellitus, diabetic complications (e.g. nephropathy, neuropathy, retmopathy, etc.). Disorders, disturbed central chemoreception (C0 2 tolerance, acidosis tolerance, sudden child death (SIDS)).
  • immune diseases disturbed strength of the body's immune response (formation of immunoglobulins, aggressiveness of T cells and NK cells), impaired general tendency to proliferate including wound healing ability, tendency to tumor development and proliferation including metastatic potential of malignant transformed cells, duration of the Latency after HIV infection until the clinical onset of the disease, Kaposi's sarcoma, tendency to cirrhosis of the liver, graft tolerance and graft rejection.
  • Another object of the invention is the use of the nucleic acid sequences according to the invention for the diagnosis of
  • Another object of the invention is the use of nucleic acid sequences which are complementary to the nucleic acid sequences coding for the shortened form of the Gß3 subunit. Such sequences can be used as antisense constructs for the treatment or prevention of diseases which are associated with a G-protein malfunction.
  • Another object of the invention is a method for determining a relative risk of disease in diseases associated with G-protein malfunction for a subject, characterized in that the gene sequence for human G-protein ⁇ 3-lower unit of the subject with the gene sequence SEQ ID NO : l compares and, if it matches SEQ ID N0: 1, assigns the subject an increased risk of disease.
  • body material which contains the genetic information of the subject is removed from a subject. This will usually achieved by taking blood and isolating the nucleic acid from it.
  • the gene structure for the G-protein ⁇ 3 subunit is determined from the isolated nucleic acid of the test subject and compared with the sequence given in SEQ ID N0: 1.
  • the gene structure can be determined by sequencing the nucleic acid. This can be done either directly from the genomic DNA or after amplification of the nucleic acid, for example using the PCR technique.
  • the gene structure can occur at the mRiMA or cDNA level.
  • the determination by sequencing after PCR amplification of the cDNA is preferred.
  • the primers suitable for the PCR reaction can easily be derived for the person skilled in the art from the sequences set out in SEQ ID NO: 1.
  • the procedure is advantageously such that a strand and counter strand binding primer are chosen before and after the deletion site.
  • gene comparison can also be carried out using other methods, for example by selective hybridization or by appropriate mapping with restriction enzymes.
  • the proteins according to the invention can be used to produce specific antibodies which specifically recognize the shortened form of the Gß3 subunit. Using such antibodies, protein-chemical tests can then be carried out in addition to or alternatively to the genetic tests, if necessary using conventional ELISA methods.
  • Another object of the invention is the production of transgenic animals that carry the gene modification described above (shortening the Gß3-Sche ⁇ nhe ⁇ t). Such transgenic animals are particularly important as animal models for the investigation and therapy of the diseases described above.
  • the methods for producing transgenic animals are generally known to the person skilled in the art.
  • G proteins The activation of G proteins from cells of normotensive subjects and hypertensive patients was characterized in detail.
  • the stimulated incorporation of radioactively labeled [ 35 S] GTP ⁇ S according to the method described by Wieland et al. described method (Wieland, T., Liedel, K., Kaldenberg Stasch, S., Meyer zu He ⁇ ngdorf, D, Schmidt, M, and Jakobs, K H. Analysis of receptor-G protem mteractions m permeabilized cells Naunyn - Schmiedeberg 's Arch. Pharmacol 351: 329 336, 1995).
  • G proteins were first activated by stimulation of cells permeabilized with Digitonm using the peptide mastoparan-7.
  • This peptide mimics the configuration of an activated, G protein-coupled receptor, so that it can be used to induce receptor-independent, direct G protein activation (Ross, EM and Higashi ia, T. Regulation of G-protein activation by mastoparan and other cationic peptides. Methods Enzy ol. 237: 27-38, 1994).
  • the binding of GTP ⁇ S induced by MAS - 7 is completely PTX-sensitive, so that the activation of heterotimeric G-type proteins of the Gi type is thus quantified.
  • Fig. 2 shows the concentration dependence of the G protein activation induced by Mast ⁇ paran-7 (MAS-7) in normotonia (NT) and hypertension (HT).
  • MAS-7 induces a strong [ 35 S] GTP ⁇ S binding on HT cells, the EC50 of which is approx. 5 ⁇ iM (Fig. 2). A binding maximum is reached at about 25 to 50 ⁇ M MAS-7. In contrast, the same [ 35 S] GTP ⁇ S binding to NT cells requires a tenfold higher concentration (Fig. 2).
  • Fig. 3 shows the time course of the binding of [ 35 S] GTP ⁇ S stimulated by mastoparan-7 to cell lines of the normotome nucleus (NT) and hypertensive (HT).
  • Fig. 4 shows the GDP dependency of the binding of [ 35 S] GTP ⁇ S, which was muted by mastoparan-7 st, to isolated cell membranes of normotome nuclei and hypertensives. It can be seen that the maximum of the stimulated [ 35 S] GTP ⁇ S binding on membranes of hypertensive patients is already at lower concentrations of GDP takes place (approx. 0.2 ⁇ mol / L), whereas a concentration of 1 ⁇ mol / L GDP is required for the same effect with normotome cores.
  • G proteins were extracted from membranes of normotonic and hypertensive cells by adding cholate (Mitchell, J., Northup, JK, and Schimmer, BP Defective guanyl nucleotidebmdmg prote ß ⁇ sub units in a forskolin resistant mutant of the Yl adrenocortical cell lme. Proc.Natl. Acad. Sci. U. S. A. 89 (19): 8933-8937, 1992).
  • Fig. 6 shows the influence of cholate extracts from normotonic and hypertensive cells on the Rhodopsm-stimulated binding of [ 35 S] GTP ⁇ S to ⁇ t.
  • cholate extracts from hypertensive cells require the rhodopsm-catalyzed binding of [ 35 S] GTP ⁇ S to ⁇ t to be significantly higher than is mediated by cholate extracts from normotome nuclei.
  • the new protein consists of 299 amino acids. Compared to the previously described human Gß3 subunit, there is a deletion in the area of the 4th WD repeat. However, due to the regularity of the sequence of certain amino acids, it can be predicted that the new, short Gß3 protein also forms a regular propeller structure, whereby this new propeller no longer consists of seven (Fig. 1), but now consists of 6 propeller blades (Fig 7).
  • the intron begins behind base 497 of the open reading frame when the A of the ATG start codon is defined as +1.
  • GGA CAC CAC GTG ⁇ tgaggctgaacattgctggtgctggggcttgggagtgggcccgg cctttctaaca ⁇ tctccctccatttt ⁇ ca ⁇ TGC CTT GTG GGA
  • MOLECULE TYPE cDNA to mRNA
  • HYPOTHETICAL NO
  • ANTISENSE NO
  • MOLECULE TYPE Protein

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Wood Science & Technology (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Hematology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Microbiology (AREA)
  • Oncology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Neurosurgery (AREA)
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  • Neurology (AREA)
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EP97944809A 1996-09-13 1997-08-29 Ptx-sensitive g-proteine, ihre herstellung und verwendung Withdrawn EP0931145A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19637518 1996-09-13
DE19637518A DE19637518A1 (de) 1996-09-13 1996-09-13 PTX-sensitive G-Proteine, ihre Herstellung und Verwendung
PCT/EP1997/004709 WO1998011212A1 (de) 1996-09-13 1997-08-29 Ptx-sensitive g-proteine, ihre herstellung und verwendung

Publications (1)

Publication Number Publication Date
EP0931145A1 true EP0931145A1 (de) 1999-07-28

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ID=7805651

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97944809A Withdrawn EP0931145A1 (de) 1996-09-13 1997-08-29 Ptx-sensitive g-proteine, ihre herstellung und verwendung

Country Status (22)

Country Link
US (1) US6251853B1 (no)
EP (1) EP0931145A1 (no)
JP (1) JP2001501811A (no)
KR (1) KR20000036058A (no)
CN (1) CN1230222A (no)
AU (1) AU4619297A (no)
BG (1) BG103238A (no)
BR (1) BR9711475A (no)
CA (1) CA2265467A1 (no)
CZ (1) CZ73499A3 (no)
DE (1) DE19637518A1 (no)
EA (1) EA199900253A1 (no)
EE (1) EE9900092A (no)
HU (1) HUP9904110A3 (no)
IL (1) IL128746A0 (no)
IS (1) IS4987A (no)
NO (1) NO991227L (no)
PL (1) PL332417A1 (no)
SK (1) SK34099A3 (no)
TR (1) TR199900500T2 (no)
WO (1) WO1998011212A1 (no)
ZA (1) ZA978220B (no)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19619362A1 (de) * 1996-05-14 1997-11-20 Basf Ag Verwendung einer Genveränderung im Gen für humanes G-Protein beta-3-Untereinheit zur Diagnostik von Erkrankungen
WO1999058669A1 (en) * 1998-05-11 1999-11-18 Axys Pharmaceuticals, Inc. Rhoh genes and their uses
WO2000015785A2 (de) * 1998-09-10 2000-03-23 Winfried Siffert GENVERÄNDERUNG IM GEN FÜR DIE Gβ3-UNTEREINHEIT DES HUMANEN G-PROTEINS
FR2803525B1 (fr) * 2000-01-06 2002-05-03 Sod Conseils Rech Applic Inhibiteur de la transduction des signaux des proteines g heterotrimeriques associe a un agent anti-hypertenseur dans le traitement de l'hypertension arterielle
AU2001240585A1 (en) * 2000-02-03 2001-08-14 Snip Biotech Gmbh & Co. Kg Use of a mutation in the gene for the beta3-subunit of human g-protein

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5587561A (en) 1995-07-28 1996-12-24 Budayr; Mahdi Stethoscope shield
DE19619362A1 (de) * 1996-05-14 1997-11-20 Basf Ag Verwendung einer Genveränderung im Gen für humanes G-Protein beta-3-Untereinheit zur Diagnostik von Erkrankungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9811212A1 *

Also Published As

Publication number Publication date
BR9711475A (pt) 1999-08-24
AU4619297A (en) 1998-04-02
EA199900253A1 (ru) 1999-10-28
HUP9904110A2 (en) 2000-07-28
TR199900500T2 (xx) 1999-06-21
CN1230222A (zh) 1999-09-29
IL128746A0 (en) 2000-01-31
JP2001501811A (ja) 2001-02-13
EE9900092A (et) 1999-10-15
BG103238A (bg) 2000-06-30
SK34099A3 (en) 2000-05-16
PL332417A1 (en) 1999-09-13
ZA978220B (en) 1999-03-12
IS4987A (is) 1999-02-26
NO991227D0 (no) 1999-03-12
KR20000036058A (ko) 2000-06-26
HUP9904110A3 (en) 2001-09-28
WO1998011212A1 (de) 1998-03-19
CA2265467A1 (en) 1998-03-19
US6251853B1 (en) 2001-06-26
DE19637518A1 (de) 1998-04-09
NO991227L (no) 1999-03-12
CZ73499A3 (cs) 1999-07-14

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