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WO2017218697A1 - Identification de composés qui ciblent la protéine tia-1 de liaison à l'arn comme régulateur important de la vulnérabilité au stress chez les souris et les êtres humains - Google Patents

Identification de composés qui ciblent la protéine tia-1 de liaison à l'arn comme régulateur important de la vulnérabilité au stress chez les souris et les êtres humains Download PDF

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Publication number
WO2017218697A1
WO2017218697A1 PCT/US2017/037544 US2017037544W WO2017218697A1 WO 2017218697 A1 WO2017218697 A1 WO 2017218697A1 US 2017037544 W US2017037544 W US 2017037544W WO 2017218697 A1 WO2017218697 A1 WO 2017218697A1
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WO
WIPO (PCT)
Prior art keywords
tia
compound
multimerization
yfp
cfp
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/US2017/037544
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English (en)
Inventor
Joseph B. RAYMAN
Eric R. Kandel
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.)
Columbia University in the City of New York
Original Assignee
Columbia University in the City of New York
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 Columbia University in the City of New York filed Critical Columbia University in the City of New York
Publication of WO2017218697A1 publication Critical patent/WO2017218697A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • 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
    • 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
    • G01N33/536—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
    • G01N33/542—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with steric inhibition or signal modification, e.g. fluorescent quenching

Definitions

  • Post-traumatic stress disorder is a mental disorder that develops after an individual experiences a traumatic disorder such as sexual assault, abuse, death, or warfare.
  • a traumatic disorder such as sexual assault, abuse, death, or warfare.
  • the majority of people who experience a traumatic event will not develop PTSD.
  • Factors that contribute one's susceptibility to PTSD are unclear.
  • psychotherapy is the best treatment; pharmacological agents have been largely ineffective.
  • This invention provides a method of ameliorating the symptoms of, or treating post-traumatic stress disorder in a mammal, the method comprising administering to the mammal an effective amount of a compound that upregulates TIA-1 multimerization.
  • This invention also provides a method of ameliorating the symptoms of, or treating post-traumatic stress disorder in a mammal, the method comprising administering to the mammal an effective amount of a compound that inhibits TIA-1 multimerization.
  • This invention also provides a method for determining whether a predetermined compound upregulates or inhibits TIA-1 multimerization, using fluoresence resonance energy transfer (FRET) , the method comprising : a. expressing recombinant TIA-CFP and TIA-YFP; b. exposing the recombinant TIA-CFP and TIA-YFP to such predetermined compound; c. exciting the TIA-CFP with a laser; and d.
  • FRET fluoresence resonance energy transfer
  • TIA-YFP measuring the fluorescence of TIA-YFP, wherein an increase in fluorescence relative to TIA-CFP and TIA- YFP not exposed to the predetermined compound indicates that the predetermined compound upregulates TIA-1 multimerization and a decrease in fluorescence relative to TIA-CFP and TIA-YFP not exposed to the predetermined compound indicates that the predetermined compound inhibits TIA-1 multimerization.
  • This invention provides a method of ameliorating the symptoms of, or treating post-traumatic stress disorder in a mammal, the method comprising administering to the mammal an effective amount of a compound that upregulates TIA-1 multimerization.
  • compound is D-alpha- tocopherol succinate (TS) or a pharmaceutically acceptable salt thereof.
  • This invention also provides a method of ameliorating the symptoms of, or treating post-traumatic stress disorder in a mammal, the method comprising administering to the mammal an effective amount of a compound that inhibits TIA-1 multimerization.
  • the compound is oxytetracyline dihydrate or a pharmaceutically acceptable salt thereof.
  • the compound is moxalactam disodium or a pharmaceutically acceptable salt thereof.
  • the compound is L-ascorbate or a pharmaceutically acceptable salt thereof.
  • This invention also provides a method for determining whether a predetermined compound upregulates or inhibits TIA-1 multimerization, using fluoresence resonance energy transfer (FRET) , the method comprising : a. expressing recombinant TIA-CFP and TIA-YFP; b. exposing the recombinant TIA-CFP and TIA-YFP to such predetermined compound; c. exciting the TIA-CFP with a laser; and d.
  • FRET fluoresence resonance energy transfer
  • TIA-1 is a prion-related RNA binding protein that regulates multiple aspects of RNA metabolism, including translation and alternative splicing.
  • KO TIA-1 knockout mice
  • PTSD post-traumatic stress disorder
  • this and other stress-induced behavioral phenotypes occur only in female KO mice, and are accompanied by altered synaptic plasticity in areas of the brain that are critical for the normal processing of fear memory, such as the hippocampus and amygdala.
  • TIA-1 may be a useful therapeutic target in the treatment of stress-related psychiatric disorders such as PTSD.
  • TIA-1 physiological aggregation of TIA-1 is essential for dynamic splicing of the glucocorticoid receptor during stress, and that aggregation serves a positive function in this context.
  • TIA aggregation may be therapeutically modulated by pharmacological intervention.
  • Prions are classically regarded as agents of neurodegenerative disease, where aggregation ultimately leads to cell death.
  • a number of prion-related proteins such as TIA-1 serve normal physiological roles in their aggregated state.
  • the functional state of TIA-1 is likely determined by whether it exists in monomeric versus aggregated conformation.
  • FRET-based assay to study the interaction between recombinant TIA-1 proteins in vitro (TIA-CFP and TIA-YFP, a compatible FRET pair) .
  • TIA-1 is highly responsive to redox changes in the cell
  • the inventors began screening an antioxidant compound library, observing the effects of each drug on TIA-1 FRET signal and therefore TIA-1 homotypic interaction (multimerization or aggregation) .
  • the inventors identified at least one compound that upregulates TIA- 1 self-interaction (D-alpha-tocopherol succinate) , and at least one drug that inhibits interaction (L-ascorbate) .
  • TS D-alpha- tocopherol succinate
  • Inventors have also identified two additional compounds that inhibit TIA-1 multimerization in vitro: oxytetracyline dihydrate and moxalactam disodium.
  • mice were trained in contextual fear conditioning (standard protocol of 2 x 2 sec. shocks at .7 mA ), and then either TS, L-ascorbate (LA), or vehicle (DMSO) were injected (i.p., 10 mg/kg) one hour later.
  • TS L-ascorbate
  • DMSO vehicle
  • a FRET-based drug screen using purified, recombinant TIA-1 led to the identification of D-alpha-tocopherol succinate as a potent inducer of TIA-1 multimerization .
  • injecting tocopherol succinate into naive mice causes endogenous TIA-1 to form high molecular weight, SDS-resistant complexes that may be comprised of TIA-1 multimers.
  • a single intraperitoneal injection of tocopherol succinate (10 mg/kg) into mice within 1 hour after fear conditioning significantly enhances avoidance behavior at 3 weeks following training. As discussed earlier, this result is essentially the opposite of what we would predict for this particular manipulation.
  • mice behavioral studies can be used to determine the therapeutic effects of any of various dosage amounts any other compound identified as a modulator of TIA-1 multimerization (such as oxytetracyline dehydrate, moxalactam disodium, L-ascorbate, or others identified in the future as affecting TIA-1 multimerization) .
  • a modulator of TIA-1 multimerization such as oxytetracyline dehydrate, moxalactam disodium, L-ascorbate, or others identified in the future as affecting TIA-1 multimerization
  • CDER The U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) provides a table of Conversion of Animal Doses to Human Equivalent Doses Based on Body Surface Area (Table 1) . Data from mice studies can therefore be converted to approximate therapeutically effective doses in humans.
  • the 4 mg/kg dosage of TS that was determined to ameliorate PTSD-like symptoms in mice would be approximately equivalent to 0.325 mg/kg in humans.
  • the search for novel therapies is of paramount importance.
  • the drugs (and target) identified in the study represent a completely novel biochemical pathway that may be targeted to modulate adaptive behavior and long-term memory in the context of traumatic stress.
  • glucocorticoid treatment has shown some potential in treating PTSD, its application is limited because of toxic side effects.
  • the drugs identified in this study target the glucocorticoid pathway, but have little or no known toxicity.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Urology & Nephrology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé permettant d'améliorer les symptômes d'un trouble de stress post-traumatique, ou de traiter ce dernier, chez un mammifère, le procédé consistant à administrer au mammifère une quantité efficace d'un composé qui régule à la hausse la multimérisation de la protéine TIA-1. La présente invention concerne également un procédé permettant d'améliorer les symptômes d'un trouble de stress post-traumatique, ou de traiter ce dernier, chez un mammifère, le procédé consistant à administrer au mammifère une quantité efficace d'un composé qui inhibe la multimérisation de la protéine TIA-1. La présente invention concerne également un procédé permettant de déterminer si un composé prédéterminé régule à la hausse ou inhibe la multimérisation de la protéine TIA-1, à l'aide d'un transfert d'énergie par résonance de fluorescence (FRET pour Fluorescence Resonance Energy Transfer), le procédé consistant : à exprimer les protéines recombinantes TIA-CFP et TIA-YFP ; à exposer les protéines recombinantes TIA-CFP et TIA-YFP à un tel composé prédéterminé ; à exciter la protéine TIA-CFP avec un laser ; et à mesurer la fluorescence de la protéine TIA-YFP, une augmentation de la fluorescence par rapport aux protéines TIA-CFP et TIA-YFP non exposées au composé prédéterminé indiquant que le composé prédéterminé régule à la hausse la multimérisation de la protéine TIA-1 et une diminution de la fluorescence par rapport aux protéines TIA-CFP et TIA-YFP non exposées au composé prédéterminé indiquant que le composé prédéterminé inhibe la multimérisation de la protéine TIA-1.
PCT/US2017/037544 2016-06-17 2017-06-14 Identification de composés qui ciblent la protéine tia-1 de liaison à l'arn comme régulateur important de la vulnérabilité au stress chez les souris et les êtres humains Ceased WO2017218697A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662351787P 2016-06-17 2016-06-17
US62/351,787 2016-06-17

Publications (1)

Publication Number Publication Date
WO2017218697A1 true WO2017218697A1 (fr) 2017-12-21

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040014739A1 (en) * 1999-08-16 2004-01-22 Koppel Gary A. Neurotherapeutic clavulanate composition and method
US7157566B2 (en) * 2001-02-26 2007-01-02 The Regents Of The University Of California Monomeric and dimeric fluorescent protein variants and methods for making same
US20120034193A1 (en) * 2009-01-24 2012-02-09 Daryl Rees Treatment of neurotrophic factor mediated disorders
WO2015025323A1 (fr) * 2013-08-21 2015-02-26 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Traitement des troubles de l'humeur et des troubles liés au stress
US20150139972A1 (en) * 2013-11-18 2015-05-21 Gerald Haase Micronutrient Formulation For Concussive Head Injuries
WO2015160843A1 (fr) * 2014-04-14 2015-10-22 Flex Pharma, Inc. Activateurs des canaux ioniques et leurs procédés d'utilisation
US9309196B2 (en) * 2010-10-29 2016-04-12 Ramot At Tel-Aviv University Ltd. Indole derivatives and process for their preparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040014739A1 (en) * 1999-08-16 2004-01-22 Koppel Gary A. Neurotherapeutic clavulanate composition and method
US7157566B2 (en) * 2001-02-26 2007-01-02 The Regents Of The University Of California Monomeric and dimeric fluorescent protein variants and methods for making same
US20120034193A1 (en) * 2009-01-24 2012-02-09 Daryl Rees Treatment of neurotrophic factor mediated disorders
US9309196B2 (en) * 2010-10-29 2016-04-12 Ramot At Tel-Aviv University Ltd. Indole derivatives and process for their preparation
WO2015025323A1 (fr) * 2013-08-21 2015-02-26 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Traitement des troubles de l'humeur et des troubles liés au stress
US20150139972A1 (en) * 2013-11-18 2015-05-21 Gerald Haase Micronutrient Formulation For Concussive Head Injuries
WO2015160843A1 (fr) * 2014-04-14 2015-10-22 Flex Pharma, Inc. Activateurs des canaux ioniques et leurs procédés d'utilisation

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ARIMOTO-MATSUZAKI ET AL.: "TIA1 oxidation inhibits stress granule assembly and sensitizes cells to stress-induced apoptosis", NATURE COMMUNICATIONS, vol. 7, no. 10252, 7 January 2016 (2016-01-07), pages 1 - 10, XP055449724 *
ASH ET AL.: "Pathological Stress Granules in Alzheimer's Disease", BRAIN RESEARCH, vol. 1584, 7 August 2014 (2014-08-07), pages 52 - 58, XP029064522 *
JUSTICE ET AL.: "Posttraumatic Stress Disorder-Like Induction Elevates beta-Amytoid Levels, Which Directly Activates Corticotropin-Releasing Factor Neurons to Exacerbate Stress Responses", JOURNAL OF NEUROSCIENCE, vol. 35, no. 6, 11 February 2015 (2015-02-11), pages 2612 - 2623, XP055449729 *
LI ET AL.: "Functional Role of Tia1/Pub1 and Sup35 Prion Domains: Directing Protein Synthesis Machinery to the Tubulin Cytoskeleton", MOLECULAR CELL, vol. 55, no. 2, 17 July 2014 (2014-07-17), pages 305 - 318, XP029038179 *
PRUSINER: "Biology and Genetics of Prions Causing Neurodegeneration", ANNUAL REVIEW OF GENETICS, vol. 47, 5 May 2014 (2014-05-05), pages 601 - 623, XP055449731 *

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