WO2002054077A3 - Validating biological molecules as drug targets by metal-ion chelates in animal test models - Google Patents

Validating biological molecules as drug targets by metal-ion chelates in animal test models Download PDF

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Publication number
WO2002054077A3
WO2002054077A3 PCT/DK2001/000867 DK0100867W WO02054077A3 WO 2002054077 A3 WO2002054077 A3 WO 2002054077A3 DK 0100867 W DK0100867 W DK 0100867W WO 02054077 A3 WO02054077 A3 WO 02054077A3
Authority
WO
WIPO (PCT)
Prior art keywords
biological target
target molecule
metal
silent
metal ion
Prior art date
Application number
PCT/DK2001/000867
Other languages
French (fr)
Other versions
WO2002054077A2 (en
Inventor
Birgitte Holst Lange
Oeystein Rist
Thue W Schwartz
Original Assignee
7Tm Pharma As
Birgitte Holst Lange
Oeystein Rist
Thue W Schwartz
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
Priority claimed from PCT/EP2000/013389 external-priority patent/WO2001050127A2/en
Application filed by 7Tm Pharma As, Birgitte Holst Lange, Oeystein Rist, Thue W Schwartz filed Critical 7Tm Pharma As
Priority to AU2002215888A priority Critical patent/AU2002215888A1/en
Priority to PCT/DK2002/000456 priority patent/WO2003003009A1/en
Publication of WO2002054077A2 publication Critical patent/WO2002054077A2/en
Publication of WO2002054077A3 publication Critical patent/WO2002054077A3/en

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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
    • G01N33/5306—Improving reaction conditions, e.g. reduction of non-specific binding, promotion of specific binding
    • 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
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
    • 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
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Abstract

A target validation process for testing or validating the physiological importance and/or the therapeutic or pharmacological potential of biological target molecules, notably proteins such as, e.g., receptors and especially 7TM receptors in test animals expressing the biological target molecule with, notably, a silent, engineered metal-ion site. A test animal suitable for use in the present invention is normally a genetically modified animal. At any given time during the development of the test animal or in adult life, it is then possible to turn the biological target molecule (such as, e.g., the receptor) on or off - depending on the engineered site with a pharmacological tool, i.e. a metal-ion chelate formed between a metal-ion and a metal-ion chelator. The thus developed pharmacologically controlled 'knock-out' methods are useful in the evaluation of biological target molecules such as, e.g., proteins as drug targets as well as in the characterization of the physiological role of orphan receptors. The process comprises i) introduction of a silent metal ion site in the biological target molecule to obtain a silent metal ion engineered biological target molecule, ii) in vitro testing of a test compound for its ability to bind to the introduced silent metal ion site in the silent metal ion engineered biological target molecule, iii) optionally, chemically optimising the test compound and/or the biological target molecule to create secondary interaction(s) with chemical groups in the vicinity of the metal ion site in the silent metal ion engineered biological target molecule, iv) optionally, repeating any of steps ii) and iii) to obtain a suitable binding affinity in the in vitro test, v) optionally, chemically optimising the test compound to improve the pharmacokinetic and/or biopharmaceutical properties of the test compound, vi) preparing a genetically modified test animal containing the silent metal ion site engineered biological target molecule, vii) in vivo testing of the optionally optimised test compound in the genetically modified test animal, and monitoring the biochemical, physiological and/or behaviour parameters of the genetically modified test animal.
PCT/DK2001/000867 2000-12-29 2001-12-21 Validating biological molecules as drug targets by metal-ion chelates in animal test models WO2002054077A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002215888A AU2002215888A1 (en) 2000-12-29 2001-12-21 Validating biological molecules as drug targets by metal-ion chelates in animal test models
PCT/DK2002/000456 WO2003003009A1 (en) 2001-06-29 2002-06-28 Use of metal-ion chelates in validating biological molecules as drug targets in test animal models

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
PCT/EP2000/013389 WO2001050127A2 (en) 1999-12-30 2000-12-29 Screening using biological target molecules with metal-ion binding sites
EPPCT/EP00/13389 2000-12-29
US28023701P 2001-03-30 2001-03-30
DKPA200100536 2001-03-30
US60/280,237 2001-03-30
DKPA200100536 2001-03-30

Publications (2)

Publication Number Publication Date
WO2002054077A2 WO2002054077A2 (en) 2002-07-11
WO2002054077A3 true WO2002054077A3 (en) 2003-07-24

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2001/000867 WO2002054077A2 (en) 2000-12-29 2001-12-21 Validating biological molecules as drug targets by metal-ion chelates in animal test models

Country Status (1)

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WO (1) WO2002054077A2 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY37806A (en) 2017-07-11 2020-01-31 Vertex Pharma CARBOXAMIDES AS MODULATORS OF SODIUM CHANNELS
CN113274538B (en) * 2021-05-28 2022-09-06 中国科学院过程工程研究所 bFGF slow-release nano dressing with wound surface active repair function and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996040293A1 (en) * 1995-06-07 1996-12-19 Rhomed Incorporated Structurally determined metallo-constructs and applications
WO1998012156A1 (en) * 1996-09-20 1998-03-26 President And Fellows Of Harvard College Combinatorial approach for generating novel coordination complexes
WO1999022733A1 (en) * 1997-10-31 1999-05-14 Smithkline Beecham Corporation Novel metal complexes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996040293A1 (en) * 1995-06-07 1996-12-19 Rhomed Incorporated Structurally determined metallo-constructs and applications
WO1998012156A1 (en) * 1996-09-20 1998-03-26 President And Fellows Of Harvard College Combinatorial approach for generating novel coordination complexes
WO1999022733A1 (en) * 1997-10-31 1999-05-14 Smithkline Beecham Corporation Novel metal complexes

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ELLING CHRISTIAN E ET AL: "Connectivity and orientation of the seven helical bundle in the tachykinin NK-1 receptor probed by zinc site engineering.", EMBO JOURNAL, vol. 15, no. 22, 1996, pages 6213 - 6219, XP002174723 *
ELLING CHRISTIAN E ET AL: "Conversion of agonist site to metal-ion chelator site in the beta2-adrenergic receptor.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES, vol. 96, no. 22, 26 October 1999 (1999-10-26), Oct. 26, 1999, pages 12322 - 12327, XP002174721 *
ELLING CHRISTIAN E ET AL: "Disulfide bridge engineering in the tachykinin NK1 receptor.", BIOCHEMISTRY, vol. 39, no. 4, 1 February 2000 (2000-02-01), pages 667 - 675, XP002174724, ISSN: 0006-2960 *
HOLST B ET AL: "Partial agonism through a zinc-Ion switch constructed between transmembrane domains III and VII in the tachykinin NK(1) receptor.", MOLECULAR PHARMACOLOGY., vol. 58, no. 2, August 2000 (2000-08-01), pages 263 - 270, XP002233294 *
NORREGAARD LENE ET AL: "Delineation of an endogenous zinc-binding site in the human dopamine transporter.", EMBO JOURNAL, vol. 17, no. 15, 3 August 1998 (1998-08-03), pages 4266 - 4273, XP002174722 *
SZURDOKI F REN D WALT D R: "A combinatorial approach to discover new chelators for optical metal ion sensing", ANALYTICAL CHEMISTRY, vol. 72, no. 21, 1 November 2000 (2000-11-01), pages 5250 - 5257, XP002902763 *

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Publication number Publication date
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