WO1999023493A1 - Procedes d'identification d'agents modulant une activite de la leptine - Google Patents

Procedes d'identification d'agents modulant une activite de la leptine Download PDF

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Publication number
WO1999023493A1
WO1999023493A1 PCT/US1998/022797 US9822797W WO9923493A1 WO 1999023493 A1 WO1999023493 A1 WO 1999023493A1 US 9822797 W US9822797 W US 9822797W WO 9923493 A1 WO9923493 A1 WO 9923493A1
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WO
WIPO (PCT)
Prior art keywords
ptp
leptin
phosphorylation
phosphorylated
agent
Prior art date
Application number
PCT/US1998/022797
Other languages
English (en)
Other versions
WO1999023493A9 (fr
Inventor
Cai Li
Jeffrey M. Friedman
Original Assignee
The Rockefeller University
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 The Rockefeller University filed Critical The Rockefeller University
Publication of WO1999023493A1 publication Critical patent/WO1999023493A1/fr
Publication of WO1999023493A9 publication Critical patent/WO1999023493A9/fr

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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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • 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
    • 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
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Definitions

  • NIDDM Neurodeficiency dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica dilutica diluticaally fibros, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma,
  • mice The most intensively studied mouse obesity mutations are the ob (obese) and db (diabetes) genes. Mice homozygous for either mutation are hyperphagic and hypometabolic, leading to an obese phenotype that is notable at one month of age. The weight of these animals tends to stabilize at 60-70 g (compared with 30-35 g in control mice).
  • Each of the rodent obesity models is accompanied by alterations in carbohydrate metabolism resembling those in Type II diabetes in man. In some cases, the severity of the diabetes depends in part on the background mouse strain [Leiter,
  • kinases in turn phosphorylate tyrosine residues on the receptor which serve as docking sites for SH2 proteins. Phosphorylation of SH2 proteins after receptor binding initiates signal transduction. Leptin binds to a homodimer of the Ob-Rb isoform of its receptor thus activating JAK2. While the Stat3 transcription is activated by leptin in vivo, the identity of other components of this signal transduction pathway have not yet been identified.
  • Figure IB shows the GST fusion fragments of the peptides spanning each of the three cytoplasmic tyrosines (Y 985, 1077, 1138) which were expressed in bacteria with or without co-expression of the elk tyrosine kinase. Co-expression of elk tyrosine kinase led to the specific phosphorylation of these three tyrosine residues.
  • the GST-Ob-Rb fragment 1 peptide (containing Y985) was incubated with protein extracts from bovine or mouse hypothalamus. After precipitation with anti-GST antibodies, the bound proteins were eluted, resolved on SDS PAGE, and stained with Coomassie Blue.
  • Figure 2 Immunoblots of the protein precipitate of GST-ObRb fragments.
  • Figure 2A depicts an immunoblot using anti-PTP-lD antibody.
  • Figure 2B depicts an immunoblot using anti-Stat3 antibody.
  • the phosphorylated and unphosphorylated GST-ObRb fusion fragments 1 and 3 were incubated with protein extracts of mouse hypothalamus.
  • PTP-ID was detected only in the material precipitated by the phosphorylated from of GST-ObRbTyrl .
  • Stat3 was detected only in the proteins precipitated by the phosphorylated form of GST-ObRbTyr3.
  • various host animals can be immunized by injection with any protein used in the present invention, including but not limited to rabbits, mice, rats, sheep, goats, etc.
  • Various adjuvants may be used to increase the immunological response, depending on the host species, including but not limited to Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Gueri ⁇ ) and Corynebacterium parvum .
  • BCG Bacille Calmette-Gueri ⁇
  • Corynebacterium parvum bacille Calmette-Gueri ⁇
  • Direct labels are one example of labels which can be used according to the present invention.
  • a direct label has been defined as an entity, which in its natural state, is readily visible, either to the naked eye, or with the aid of an optical filter and/or applied stimulation, e.g. UN. light to promote fluorescence.
  • colored labels include metallic sol particles, for example, gold sol particles such as those described by Leuvering (U.S. Patent 4,313,734); dye sole particles such as described by Gribnau et al. (U.S. Patent 4,373,932) and May et al.
  • Drug screening assays may be performed in cells that naturally encode the proteins involved in the signal transduction pathway initiated by leptin, preferably a cell is used that is transfected with a plasmid encoding the proteins of interest.
  • transient transfections can be performed with 50% confluent U3A cells using the calcium phosphate method as instructed by the manufacturer (Stratagene).
  • compositions may be prepared in liquid form, or may be in dried powder, such as lyophilized form.
  • Oral Delivery Contemplated for use herein are oral solid dosage forms, which are described generally in Martin, Remington's Pharmaceutical Sciences, 18th Ed. (1990 Mack Publishing Co. Easton PA 18042) at Chapter 89, which is herein incorporated by reference.
  • Solid dosage forms include tablets, capsules, pills, troches or lozenges, cachets or pellets.
  • liposomal or proteinoid encapsulation may be used to formulate the present compositions (as, for example, proteinoid microspheres reported in U.S.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Food Science & Technology (AREA)
  • Biochemistry (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne des nouveaux procédés d'identification de médicaments pouvant aider à réguler chez l'animal l'adiposité et la teneur en graisse, notamment chez les mammifères. La découverte que PTP-ID se fixe sur le récepteur phosphorylé de la leptine, lorsque ce récepteur contient une tyrosine-985 phosphorylée, a permis d'obtenir de nouveaux moyens d'identification d'agents aidant à la régulation de la surcharge pondérale et de l'adiposité. Ainsi, la présente invention exploite ce rôle jusqu'alors inconnu de la PTP-1D, en fournissant des moyens pour traiter et guérir potentiellement des anomalies du mécanisme de la leptine endogène, et permettre en même temps une modification choisie de la masse corporelle.
PCT/US1998/022797 1997-10-31 1998-10-27 Procedes d'identification d'agents modulant une activite de la leptine WO1999023493A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US96180997A 1997-10-31 1997-10-31
US08/961,809 1997-10-31
US17869198A 1998-10-26 1998-10-26
US09/178,691 1998-10-26

Publications (2)

Publication Number Publication Date
WO1999023493A1 true WO1999023493A1 (fr) 1999-05-14
WO1999023493A9 WO1999023493A9 (fr) 1999-09-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/022797 WO1999023493A1 (fr) 1997-10-31 1998-10-27 Procedes d'identification d'agents modulant une activite de la leptine

Country Status (1)

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WO (1) WO1999023493A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001025797A2 (fr) * 1999-10-06 2001-04-12 Sumitomo Chemical Company, Limited Procedes evaluant si un agent d'essai affecte ou non un recepteur de la leptine
WO2001079287A2 (fr) * 2000-04-17 2001-10-25 Sa Majesté La Reine Du Chef Du Canada - Agriculture Et Agroalimentaire Canada Facteurs de modulation de la steatose et leur utilisation
WO2002042489A1 (fr) * 2000-11-27 2002-05-30 The Hospital For Sick Children Methodes faisant intervenir la proteine tyrosine phosphatase de lymphocyte t
WO2003029422A2 (fr) 2001-10-01 2003-04-10 Mount Sinai School Of Medicine Gene du syndrome de noonan
US8022189B2 (en) 1998-08-21 2011-09-20 Albany Medical College Isolated antibodies against biologically active leptin-related peptides

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008017A1 (fr) * 1992-10-06 1994-04-14 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Ptp 1d: nouvelle tyrosine phosphatase proteique
WO1996022308A2 (fr) * 1995-01-20 1996-07-25 Zymogenetics, Inc. Facteur de suppression d'appetit et procedes connexes
WO1996038586A1 (fr) * 1995-05-30 1996-12-05 Smithkline Beecham Plc Procede de detection de composes modulant les effets de la proteine ob
WO1997026523A2 (fr) * 1996-01-18 1997-07-24 Progenitor, Inc. Detection d'une variante du recepteur de la leptine et de regulation de l'obesite

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008017A1 (fr) * 1992-10-06 1994-04-14 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Ptp 1d: nouvelle tyrosine phosphatase proteique
WO1996022308A2 (fr) * 1995-01-20 1996-07-25 Zymogenetics, Inc. Facteur de suppression d'appetit et procedes connexes
WO1996038586A1 (fr) * 1995-05-30 1996-12-05 Smithkline Beecham Plc Procede de detection de composes modulant les effets de la proteine ob
WO1997026523A2 (fr) * 1996-01-18 1997-07-24 Progenitor, Inc. Detection d'une variante du recepteur de la leptine et de regulation de l'obesite

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8022189B2 (en) 1998-08-21 2011-09-20 Albany Medical College Isolated antibodies against biologically active leptin-related peptides
US8067545B2 (en) 1998-08-21 2011-11-29 Albany Medical College Isolated antibodies against biologically active leptin-related peptides
WO2001025797A2 (fr) * 1999-10-06 2001-04-12 Sumitomo Chemical Company, Limited Procedes evaluant si un agent d'essai affecte ou non un recepteur de la leptine
WO2001025797A3 (fr) * 1999-10-06 2002-05-10 Sumitomo Chemical Co Procedes evaluant si un agent d'essai affecte ou non un recepteur de la leptine
WO2001079287A2 (fr) * 2000-04-17 2001-10-25 Sa Majesté La Reine Du Chef Du Canada - Agriculture Et Agroalimentaire Canada Facteurs de modulation de la steatose et leur utilisation
WO2001079287A3 (fr) * 2000-04-17 2002-09-06 Majeste La Reine Du Chef Du Ca Facteurs de modulation de la steatose et leur utilisation
WO2002042489A1 (fr) * 2000-11-27 2002-05-30 The Hospital For Sick Children Methodes faisant intervenir la proteine tyrosine phosphatase de lymphocyte t
WO2003029422A2 (fr) 2001-10-01 2003-04-10 Mount Sinai School Of Medicine Gene du syndrome de noonan
EP1448587A2 (fr) * 2001-10-01 2004-08-25 Mount Sinai School of Medicine Gene du syndrome de noonan
EP1448587A4 (fr) * 2001-10-01 2005-06-08 Sinai School Medicine Gene du syndrome de noonan
US7335469B2 (en) 2001-10-01 2008-02-26 Mt. Sinai School Of Medicine Of New York University Methods for diagnosing Noonan syndrome

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Publication number Publication date
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