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WO1992020362A1 - Peptides favorisant le developpement de cellules nerveuses et leurs utilisations - Google Patents

Peptides favorisant le developpement de cellules nerveuses et leurs utilisations Download PDF

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Publication number
WO1992020362A1
WO1992020362A1 PCT/US1991/003346 US9103346W WO9220362A1 WO 1992020362 A1 WO1992020362 A1 WO 1992020362A1 US 9103346 W US9103346 W US 9103346W WO 9220362 A1 WO9220362 A1 WO 9220362A1
Authority
WO
WIPO (PCT)
Prior art keywords
fragment
ependymin
protein
sequence
amino acid
Prior art date
Application number
PCT/US1991/003346
Other languages
English (en)
Inventor
Victor E. Shashoua
Original Assignee
Shashoua Victor E
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 Shashoua Victor E filed Critical Shashoua Victor E
Priority to PCT/US1991/003346 priority Critical patent/WO1992020362A1/fr
Publication of WO1992020362A1 publication Critical patent/WO1992020362A1/fr

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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
    • C07K14/475—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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 invention provides novel molecules that are protein fragments capable of stimulating nerve growth.
  • the protein fragments correspond to amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids having amino acids
  • nerve growth can be modulated to correct genetic and systemic disorders and to treat nervous system disorders resulting from trauma
  • Figure 3B shows the effect of the mono-docosohexa-enoic acid derivative of sequence I.D.
  • the protein fragments preferably are no larger than about 80 amino acids long, and most preferably are between about 5 and about 16 amino acids long.
  • the term includes protein fragments of this length and functional equivalents thereof.
  • the term "functional equivalents" is meant to encompass any modifications in peptide bonding.
  • blood-brain barrier and protein fragment(s) of this invention is referred to as a "prodrug”.
  • Determination of the BPI is made by measuring the quantity of the compound (e.g. secondary
  • the preferred carrier can be a fatty acid which has between about 16 and about 26 carbon atoms, and more preferably between about 20 and about 24 carbon atoms. Most preferably, the secondary molecule is the all cis form of 4, 7, 10, 13, 16, 19
  • the preferred bonds for coupling secondary molecules to the protein fragments are those capable of surviving the environment of the stomach, thereby allowing oral administration of the prodrug.
  • the preferred bonds also hydrolyze when the prodrug is introduced into the brain.
  • An example of such a bond is believed to be an amide bond.
  • the preferred method for facilitating bond coupling of the secondary molecules to the protein fragments of the invention is through one or more basic amino acids.
  • These basic amino acid acids are preferably lysine and arginine. These amino acids can be part of the basic amino acid side chains of
  • sustained release delivery systems include, but are not limited to: (a) erosional systems in which the protein fragment is contained in a form within a matrix, found in
  • neuronotrophic proteins are by now well known (see references in Tables I and II, the citations of which are incorporated herein by reference).
  • sequences derived from ependymin digests can be compared with known sequences from a wide variety of neuronotrophic proteins using computer database analysis.
  • the gamma-polypeptide chain was also known as the gamma-polypeptide chain.
  • a tissue culture system has been developed to serve as a bioassay for ependymin fragments.
  • the assay is based on the fact that certain cholinergic and adrenergic cell lines have the capacity to grow neurites and establish connections resembling synapses in vitro. Normally, such cells require about 4-7 days of culture before 50-80% of them begin to show neurite growth. This process can be accelerated by addition of drugs such as cyclic
  • This example illustrates the dose-response relationship of fragment I.D. No. 27 corresponding to a portion of the gamma-chain of ependymin in promoting nerve growth.
  • polypeptide was readily observable after only 1-2 days in culture.
  • the time course of development of type (2+) cells for a dose of 1.5 ⁇ g/ml of the peptide showed that within 24 hr, 60-80% of the cells plated developed neurites as compared to
  • Example is identical to that described previously in Example 3.
  • molecules of this invention may be useful as treatments to enhance recovery after stroke, as a factor that promotes neurite outgrowth and regeneration. These molecules might be useful in enhancing long term memory capacity that is lost during the normal process of aging. Thus, molecules of this invention may restore the aging-related decline in capacity of brain cells to form new connections.

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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)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Toxicology (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouvelles molécules capables de favoriser la croissance de cellules nerveuses et des méthodes thérapeutiques utilisant ces molécules. Lesdites molécules contiennent un fragment de protéines pratiquement homologue à une région active d'une épendymine glycoprotéinique du cerveau. La région active est avant tout responsable de la capacité de développement des cellules nerveuses que possèdent ces molécules. Lesdites molécules peuvent être administrées à un sujet afin de corriger les troubles génétiques et systémiques et de traiter les troubles du système nerveux résultant d'un traumatisme.
PCT/US1991/003346 1991-05-14 1991-05-14 Peptides favorisant le developpement de cellules nerveuses et leurs utilisations WO1992020362A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US1991/003346 WO1992020362A1 (fr) 1991-05-14 1991-05-14 Peptides favorisant le developpement de cellules nerveuses et leurs utilisations

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1991/003346 WO1992020362A1 (fr) 1991-05-14 1991-05-14 Peptides favorisant le developpement de cellules nerveuses et leurs utilisations

Publications (1)

Publication Number Publication Date
WO1992020362A1 true WO1992020362A1 (fr) 1992-11-26

Family

ID=22225527

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/003346 WO1992020362A1 (fr) 1991-05-14 1991-05-14 Peptides favorisant le developpement de cellules nerveuses et leurs utilisations

Country Status (1)

Country Link
WO (1) WO1992020362A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004001A1 (fr) * 1994-08-05 1996-02-15 Molecular/Structural Biotechnologies, Inc. Complexes biomoleculaires diriges
US5716614A (en) * 1994-08-05 1998-02-10 Molecular/Structural Biotechnologies, Inc. Method for delivering active agents to mammalian brains in a complex with eicosapentaenoic acid or docosahexaenoic acid-conjugated polycationic carrier
WO1997044063A3 (fr) * 1996-05-22 1998-02-26 Neuromedica Inc Conjugues d'acide cis-docosahexanoïque et d'agents pharmaceutiques
WO1998011130A3 (fr) * 1996-09-11 1998-07-30 Takeda Chemical Industries Ltd Nouvelle proteine, sa fabrication et son utilisation
EP1008355A1 (fr) * 1998-12-08 2000-06-14 Debio Recherche Pharmaceutique S.A. Procédé d'identification des sites de liaison d'un polymère à des macromolecules par liaison rapporteuse d'acides aminés
US6225444B1 (en) 1998-02-10 2001-05-01 Protarga, Inc. Neuroprotective peptides and uses thereof
US6258836B1 (en) 1988-02-26 2001-07-10 Protarga, Inc. Dopamine analog amide
WO2001042280A3 (fr) * 1999-12-09 2002-03-07 Childrens Medical Center Peptides courts derives des regions b4 et b5 des proteines kinases modulant de maniere selective l'activite des proteines
EP1232174A4 (fr) * 1999-11-18 2004-03-31 Ceremedix Inc Compositions et methodes permettant de contrer les effets d'especes reagissant a l'oxygene et des radicaux libres
US6890896B1 (en) 1999-11-18 2005-05-10 Ceremedix, Inc. Compositions and methods for counteracting effects of reactive oxygen species and free radicals
US7235583B1 (en) 1999-03-09 2007-06-26 Luitpold Pharmaceuticals, Inc., Fatty acid-anticancer conjugates and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989007938A1 (fr) * 1988-02-26 1989-09-08 Shashoua Victor E Conjugue medicamenteux d'acide gras administrant le medicament a travers la barriere vasculaire du cerveau
US4868161A (en) * 1984-06-29 1989-09-19 City Of Hope Method for promoting nerve regeneration

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4868161A (en) * 1984-06-29 1989-09-19 City Of Hope Method for promoting nerve regeneration
WO1989007938A1 (fr) * 1988-02-26 1989-09-08 Shashoua Victor E Conjugue medicamenteux d'acide gras administrant le medicament a travers la barriere vasculaire du cerveau

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 264, No. 23, issued 15 August 1989, KONIGSTORTER et al., "Biosynthesis of Ependymins from Gold Fish Brain", pages 13689-13692. *
THE EMBO JOURNAL, Vol. 6, No. 8, issued 1987, ROCCO et al., "Models of Fibronectin", pages 2343-2349. *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6258836B1 (en) 1988-02-26 2001-07-10 Protarga, Inc. Dopamine analog amide
US6407137B2 (en) 1988-02-26 2002-06-18 Protarga, Inc. Dopamine analog amide
US5716614A (en) * 1994-08-05 1998-02-10 Molecular/Structural Biotechnologies, Inc. Method for delivering active agents to mammalian brains in a complex with eicosapentaenoic acid or docosahexaenoic acid-conjugated polycationic carrier
WO1996004001A1 (fr) * 1994-08-05 1996-02-15 Molecular/Structural Biotechnologies, Inc. Complexes biomoleculaires diriges
WO1997044063A3 (fr) * 1996-05-22 1998-02-26 Neuromedica Inc Conjugues d'acide cis-docosahexanoïque et d'agents pharmaceutiques
US7199151B2 (en) 1996-05-22 2007-04-03 Luitpold Pharmaceuticals, Inc. DHA-pharmaceutical agent conjugates of taxanes
EP1466628A1 (fr) * 1996-05-22 2004-10-13 Luitpold Pharmaceuticals, Inc. Conjugués DHA et d'un agent pharmaceutique.
WO1998011130A3 (fr) * 1996-09-11 1998-07-30 Takeda Chemical Industries Ltd Nouvelle proteine, sa fabrication et son utilisation
US6613887B1 (en) 1996-09-11 2003-09-02 Takeda Chemical Industries, Ltd. Human ependymin-like protein
US6225444B1 (en) 1998-02-10 2001-05-01 Protarga, Inc. Neuroprotective peptides and uses thereof
US6627601B2 (en) 1998-02-10 2003-09-30 Protarga, Inc. Neuroprotective peptides and uses thereof
US6790942B1 (en) 1998-08-12 2004-09-14 Debio Recherche Pharmaceutique Biologically active conjugates having a detectable reporter moiety and method of identification of the derivative
WO2000033881A1 (fr) * 1998-12-08 2000-06-15 Debio Recherche Pharmaceutique S.A. Conjugues biologiquement actifs contenant un groupe rapporteur detectable et methode d'identification dudit derive
EP1008355A1 (fr) * 1998-12-08 2000-06-14 Debio Recherche Pharmaceutique S.A. Procédé d'identification des sites de liaison d'un polymère à des macromolecules par liaison rapporteuse d'acides aminés
US7235583B1 (en) 1999-03-09 2007-06-26 Luitpold Pharmaceuticals, Inc., Fatty acid-anticancer conjugates and uses thereof
EP1232174A4 (fr) * 1999-11-18 2004-03-31 Ceremedix Inc Compositions et methodes permettant de contrer les effets d'especes reagissant a l'oxygene et des radicaux libres
US6890896B1 (en) 1999-11-18 2005-05-10 Ceremedix, Inc. Compositions and methods for counteracting effects of reactive oxygen species and free radicals
US7524819B2 (en) 1999-11-18 2009-04-28 Ischemix, Inc. Compositions and methods for counteracting effects of reactive oxygen species and free radicals
US8034774B2 (en) 1999-11-18 2011-10-11 Ischemix, Inc. Compositions and methods for counteracting effects of reactive oxygen species and free radicals
US8772237B2 (en) 1999-11-18 2014-07-08 Ischemix, Inc. Compositions and methods for counteracting effects of reactive oxygen species and free radicals
WO2001042280A3 (fr) * 1999-12-09 2002-03-07 Childrens Medical Center Peptides courts derives des regions b4 et b5 des proteines kinases modulant de maniere selective l'activite des proteines

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