WO2005079832A1 - Utilisation de peptides hcnp pour moduler la physiologie cardiovasculaire et la diurese - Google Patents

Utilisation de peptides hcnp pour moduler la physiologie cardiovasculaire et la diurese Download PDF

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Publication number
WO2005079832A1
WO2005079832A1 PCT/EP2004/008549 EP2004008549W WO2005079832A1 WO 2005079832 A1 WO2005079832 A1 WO 2005079832A1 EP 2004008549 W EP2004008549 W EP 2004008549W WO 2005079832 A1 WO2005079832 A1 WO 2005079832A1
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Prior art keywords
peptide
modulation
medicament
xaa
modification
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PCT/EP2004/008549
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English (en)
Inventor
Yannick Goumon
Marie-Hélène METZ-BOUTIGUE
Dominique Aunis
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Institut National De La Sante Et De La Recherche Medicale
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Publication of WO2005079832A1 publication Critical patent/WO2005079832A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • HCNP peptides for the modulation of cardio-vascular physiology and diuresis
  • the present invention relates to a method of use of HCNP peptides or their derivatives or functional equivalents as active ingredients in medicaments for the modulation of cardiac physiology, diuresis, as well as modification of cardiac cells cytoskeleton and induction of cardiac cells actin cytoskeleton modification.
  • PEBP Phosphatidylethanolamine-binding protein
  • HCNP derived peptides were detected by immunohistochemistry in nerve cell terminals of neurons in rat brain and small intestine.
  • HCNP was shown to be released from rat hippocampal. More recently, HCNP has also been detected in the cerebrospinal fluid of Alzheimer patients.
  • EP0 390 602 discloses neurotrophic peptides derived from brain hipocampal tissue in mammals able to enhance synthesis of acetylcholine in cholinergic neurons, as well as pharmaceutical compositions comprising these neurotrophic peptides for the treatment of neurological degenerative disorders and dementia.
  • This patent discloses in particular a neurotrophic peptide of sequence Ala Ala Asp He Ser Gin Trp Ala Gly Pro Leu which is rat HCNP peptide as well as HCNP derivatives having a smaller molecular weight.
  • EPO 511 816 discloses the human-derived neurotrophic peptides of HCNP or derivatives thereof. These peptides are also useful for the treatment of neurological degenerative disorders and dementia.
  • HCNP and HCNP derivatives or functional equivalents modulate the cardiac physiology and diuresis as well as modification of cardiac cells cytoskeleton and induction of cardiac cells actin cytoskeleton modification.
  • HCNP and PEBP are natural, stable and are easy to synthetize. As these peptides are present in all organisms, there is no possible antigenicity between species. Accordingly, one aspect of the invention is to provide a therapeutic method of use of a polypeptide containing at least the amino acid sequence of formula SEQ ID N°l or derivative or functional equivalent of this sequence for the modulation of cardiac physiology.
  • N°l or derivatives and functional equivalents for the modulation of diuresis Another aspect of the invention is the use of a peptide of sequence SEQ ID N°l or derivatives and functional equivalents for the modification of cardiac cells cytoskeleton. Another aspect of the invention is the use of a peptide of sequence SEQ ID
  • N° 1 or derivatives and functional equivalents for the induction of cardiac cells actin cytoskeleton modification Another aspect of the invention is a medicament comprising at least one peptide, derivative and functional equivalent of the invention for the modulation of cardiac physiology. Another aspect of the invention is a medicament comprising at least one peptide, derivative and functional equivalent of the invention for the modulation of diuresis. Another aspect of the invention is a medicament comprising at least one peptide, derivative and functional equivalent of the invention for the modification of cardiac cells cytoskeleton. Another aspect of the invention is a medicament comprising at least one peptide, derivative and functional equivalent of the invention for the induction of cardiac cells actin cytoskeleton modification.
  • polypeptide comprising at least a peptide of sequence Xaa 1 Xaa 2 AspXaa SerXaa 6 TrpXaa 8 GlyProLeu (SEQ ID N°l) in which Xaai is Pro or Ala, Xaa is Val or Ala, Xaa 4 is Leu or He, Xaa 6 is Lys or Glu and Xaa 8 is Ser or Ala, derivatives or functional equivalents of this peptide for the preparation of a medicament for the modulation of cardiac physiology, diuresis, the modification of cardiac cells cytoskeleton and/or the induction of cardiac cells actin cytoskeleton modification.
  • the term “derivatives” as used herein means NH2 and/or COOH terminal modified sequences of the peptide of the invention. Modifications encompass, but are not limited to, modifications resulting from posttranslational process, or chemical modifications by known techniques in the art (glycosylation, phosphorylation, sullfatation, addition of methyl group, acetyl group, amide group, lipid binding, fatty acid binding, nucleotides binding, cyclization).
  • the term “functional equivalent” as used herein means sequences which function in a similar way but may have deletions, additions and/or substitutions that do not substantially change the activity or function of the sequences.
  • substitutions well known of the skilled man in the art encompass substitution of an amino acid by another one having same characteristics (charge, size hydrophilicity, etc.... For example substitution between Asp and Glu, between Lys
  • polypeptides according to the invention may be constituted of amino acids residues of configuration D or L. These functional equivalent encompass also retropeptides.
  • the peptides according to the invention may be natural or prepared by methods including (but not restricted to) solid or solution phase chemical synthesis of polypeptide or/and by recombinant DNA/genetic engineering procedures using well known methods.
  • this polypeptide is the Phosphatidylethanolamine Binding
  • PEBP Polyethylene glycoprotein
  • the PEBP protein can be obtained by means described in the article "Purification and characterization of a basic 23kDa cytosolic protein from bovine origin” (I. Bernier & P. Jolles, (1984) Biochimica and
  • the polypeptide PEBP of the invention is the human PEBP or the murine PEBP (including mouse or rat).
  • a peptide of sequence SEQ ID N°l or a derivative or a functional equivalent thereof is used for the manufacture of a medicament for the modulation of cardiac physiology and diuresis or for either the modification of cardiac cells cytoskeleton or the induction of cardiac cells actin cytoskeleton modification.
  • the peptide of sequence SEQ ID N°l is the Hippocampal Cholinergic Neurostimulating Peptide (HCNP).
  • the peptide used according to the invention is the HCNP in which amino acids Xaa 1; Xaa 2 , Xaa 4 , Xaa 6 and Xaa 8 are defined as in SEQ ID N°2.
  • the amino acid sequence of the peptide according to the invention is the amino acid sequence of human HCNP.
  • the peptide used according to the invention is the HCNP in which amino acids Xaa,, Xaa 2 , Xaa 4 , Xaag and Xaa 8 are defined as in SEQ
  • amino acid sequence of the peptide according to the invention is the amino acid sequence of murine HCNP.
  • ⁇ -adrenergic stimulation like the stimulation with catecholamines, is indeed known to display a positive inotropic effect on the mechanical cardiac performance.
  • the peptides according to the invention are able to display a dramatic negative inotropic effect and are able to inhibit isoproterenol (ISO which is a ⁇ -adrenergic agonist inducing a positive inotropic effect) stimulation of the heart (as shown in FIG. 1). Since catecholamines are in particular secreted in response to a stress, the peptides of the invention are also useful in case of pathologies related to stress.
  • ISO isoproterenol
  • the coronary pathologies represent the most important cause of people death (almost 12 %). These pathologies are either due to natural causes (most of the heart failures) or are genetically linked (familial hypertrophic cardiomyopathy). Heart failures are often linked to myocardiac remodeling and contractility. Thus, the myocardium can lost a part of its contractility resulting from a lack of cell oxygenation caused by the remodeling of the coronary arteries (fat deposit on the artery walls) or can be due to a myocardiac cell inflammations. In addition, cardiac tissue could lose dilatory properties related to a fibrosis that decrease heart contractility or myocardial hypertrophy.
  • cytoskeleton is an important scaffold in cardiac myocytes, which provides structural support and compartmentalization of intracellular components (Watson PA, et al. (1991) Mol. Cell Biochem. 104(1-2):51- 6).
  • Experimental studies have shown that the cytoskeleton is implicated in several cardiac pathologies including hypertrophy, failure and playing a key role causing contractile and diastolic dysfunctions (Tagawa H, et al. ( 1998) Circ. Res.
  • the peptides of the invention are useful for the preparation of a medicament intended to modulate cardiac physiology and diuresis.
  • modulation of cardiac physiology encompasses the decrease of cardiac performances also called inotropic negative effect linked to myocardial infarction or heart failure.
  • the peptides of the invention are useful for the preparation of a medicament intended to modulate diuresis.
  • Peptides of the invention can be incorporated in a composition containing a pharmaceutically acceptable medium for the preparation of the medicament for the modulation of cardiac physiology or diuresis.
  • Peptides of the invention can be incorporated in a composition containing a pharmaceutically acceptable medium for the preparation of the medicament for the modification of skeleton of cardiac cells or for the induction of of cardiac cells actin cytoskeleton modification, for example the induction of actin polymerization of cardiac cells.
  • the concentration of the peptide, derivative or functional equivalent according to the invention is from 10 ⁇ n to 10 "4 moles/L in the peripheral blood.
  • the peptides, derivatives and functional equivalent thereof according to the invention are used on a pharmaceutically acceptable salt form.
  • These pharmaceutically acceptable salts include conventional non-toxic salts of these peptides and quaternary salts thereof. These salts may be formed from inorganic or organic acids or bases. Examples of such acid addition salts are salts of acetic acid, butyric acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, succinic acid, fumaric acid, hydrochloric acid, hydrobromic acid and sulfuric acid. Salts of bases are ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with amino acids such as arginine, lysine, etc. Such salts can be readily produced by known methods.
  • the citrates can be prepared by dissolving the peptide according to the invention in water and adding a necessary amount of citric acid to the solution.
  • Such compositions may further contain protease inhibitors as, for example, PMSF or PHP.
  • peptides of the invention are on a citrate salt form. Indeed, in case of intravenous route, this formulation as a citrate salt avoids coagulation.
  • Peptides of the invention may be used alone, in combination of two or more peptides and/or in combination with others conventional cardiomodulateurs.
  • the composition further comprises other cardiomodulators.
  • Such modulators are for example beta-blockers, such as carvedilol, metropolol-XL, and diuretics as spironolactone, angiotensin-converting enzyme inhibitors and nesiretide (commercially available).
  • Animal to which the peptides of the present invention are applicable is not limited.
  • the peptides of the present invention can be applied to human beings as well as to other various species of mammals such as mouse, rat, dog, calf, horse, goat, sheep, rabbit, hog, etc.
  • the peptides of the invention can be administered to these animals and human by ordinary routes, for example, orally, intramuscularly, intravenously, subcutaneously, intraperitoneally and pernasally.
  • the peptides can be administered to adult in a daily dose once or in several portions.
  • examples of pharmaceutical compositions include powders, granules, tablets, capsules, suppositories, injections, nasal preparations, etc.
  • the pharmaceutical compositions can be prepared in a conventional manner, using conventional carriers for preparations. That is, in the case of preparing oral preparations, excipients or carriers are added to the active ingredient and if necessary, binders, disintegrators, lubricants and coloring agents are further added thereto and then prepared into tablets, granules, powders, capsules, etc...
  • pH regulators In the case of preparing injections, pH regulators, buffers stabilizers, solubilizing agents, etc., are added depending upon necessity and prepared into injections in a conventional manner.
  • buffers stabilizers In the case of preparing injections, pH regulators, buffers stabilizers, solubilizing agents, etc., are added depending upon necessity and prepared into injections in a conventional manner.
  • solubilizing agents etc.
  • Example 1 Synthesis of HCNP peptide Peptides were synthesized on an Applied Biosystems 432A peptide synthesizer (Synergy, Foster City, USA), using the stepwise solid-phase synthetic approach with 9-fluoromethoxycarbonyl (Fmoc chemistry). Then, the synthetic peptides were purified by liquid high performance chromatography (Akta Purifier, Amersham Biosciences, Orsay, France) on a C18 column (Vydac, Hesperia, USA; 218 TP 5 ⁇ 10 _ 250 mm).
  • Akta Purifier Amersham Biosciences, Orsay, France
  • Example 2 Effects of HCNP on isolated and perfused working heart physiology
  • the saline buffer composition was: 115mM NaCl, 2.5mM KC1, l.OmM CaC12, 5.6mM anhydrous glucose, 2.15mM Na2HPO4, 0.85mM NaH2PO4, pH 7.2 equilibrated with air.
  • Mean input pressure and minimal output pressure were regulated by moving the reservoirs up or down with reference to the level of the atrium and the aortic trunk, respectively.
  • the hearts were stabilized at basal conditions (see below) for 15-20min before being treated with drugs. Pressure was measured through T-tubes placed immediately before the input cannula and after the output cannula, using two MP-
  • HCNP chromogranin A amino-terminal fragment (CGA 4 . 16 ) synthesized with the same method as for the HCNP (10 to 200 nM) did not affect the hemodynamic parameters (SV and SW). Since HCNP can be released together with catecholamines, its effect has been examined during the stimulation of cardiac ⁇ -adrenergic receptors with isoproterenol, the ⁇ -adrenergic agonist known to produce a positive inotropic effect
  • Example 3 cytoskeletal modulation in rat cardiac myocytes
  • a model of tumoral cardiomytes H9c2 (rat DB1X heart myoblast from ATCC #8809204) was tested for its ability to respond to HCNP.
  • glass slides (VWR) were sterilized and coated with poly-L-lysine (0.1%, m/v; Sigma-Aldrich). After two days of culture of
  • H9c2 on these slides glass slides were treated for 2 hours with control medium containing HCNP, or chromogranin B (CGB, bovine chromogranin B602-626), or isoproterenol. Cells were then fixed with 2% de paraformaldehyde in DMEM medium (Sigma-Aldrich). After fixation, a labeling with phalloidin-TRIC (Sigma-Aldrich) is performed to detect the filamentous actin involved in the cytoskeleton and with stained with Hoechst (Sigma-Aldrich ) to detect nucleus.
  • control medium containing HCNP
  • CGB bovine chromogranin B602-626
  • isoproterenol Cells were then fixed with 2% de paraformaldehyde in DMEM medium (Sigma-Aldrich). After fixation, a labeling with phalloidin-TRIC (Sigma-Aldrich) is performed to detect the filamentous actin involved in the cyto
  • Example 4 Formulation of a medicament containing peptides of the invention
  • the peptides are formulated as a citrate salt form for intravenous injections as it was reported for others commercialized vasoactive peptides (nesiritide). Briefly, the peptide according to the invention is diluted in 100/ of physiological serum to obtain a final concentration of 1.5xlO "5 M of peptide. This composition is then placed in sealed sterile vials before use. For a rat, an intravenous injection is made every 3 hours during heart crisis.

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Abstract

L'invention concerne un procédé d'utilisation de peptides HCNP ou de dérivés ou ces peptides ou d'équivalents fonctionnels en tant qu'ingrédients actifs dans des médicaments pour moduler la physiologie cardiaque et la diurèse, ainsi que pour modifier le cytosquelette de cellules cardiaques et/ou induire une modification du cytosquelette d'actine de cellules cardiaques.
PCT/EP2004/008549 2004-02-13 2004-07-13 Utilisation de peptides hcnp pour moduler la physiologie cardiovasculaire et la diurese WO2005079832A1 (fr)

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EPPCT/EP04/002395 2004-02-13
PCT/EP2004/002395 WO2005079831A1 (fr) 2004-02-13 2004-02-13 Utilisation de peptides hcnp pour la modulation de la physiologie cardio-vasculaire et de la diurese

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WO2006111355A1 (fr) * 2005-04-19 2006-10-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Compositions conçues pour la prevention et le traitement de la douleur renfermant des molecules derivees de proteines de liaison de phosphatidylethanolamine (pebp)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0390602A1 (fr) * 1989-03-30 1990-10-03 Sumitomo Pharmaceuticals Company, Limited Peptides neurotrophiques
EP0476933A1 (fr) * 1990-09-12 1992-03-25 Sumitomo Pharmaceuticals Company, Limited Dérivés de peptides neurotrophiques
EP0511816A2 (fr) * 1991-04-27 1992-11-04 Sumitomo Pharmaceuticals Company, Limited Dérivé d'un peptide neurotrophique
US6312694B1 (en) * 1998-07-13 2001-11-06 Board Of Regents, The University Of Texas System Cancer treatment methods using therapeutic conjugates that bind to aminophospholipids
WO2003038055A2 (fr) * 2001-10-31 2003-05-08 Mds Proteomics, Inc. Proteines impliquees dans la regulation des adipocytes et utilisations associees

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0390602A1 (fr) * 1989-03-30 1990-10-03 Sumitomo Pharmaceuticals Company, Limited Peptides neurotrophiques
EP0476933A1 (fr) * 1990-09-12 1992-03-25 Sumitomo Pharmaceuticals Company, Limited Dérivés de peptides neurotrophiques
EP0511816A2 (fr) * 1991-04-27 1992-11-04 Sumitomo Pharmaceuticals Company, Limited Dérivé d'un peptide neurotrophique
US6312694B1 (en) * 1998-07-13 2001-11-06 Board Of Regents, The University Of Texas System Cancer treatment methods using therapeutic conjugates that bind to aminophospholipids
WO2003038055A2 (fr) * 2001-10-31 2003-05-08 Mds Proteomics, Inc. Proteines impliquees dans la regulation des adipocytes et utilisations associees

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GOUMON, YANNICK ET AL: "The Hippocampal Cholinergic Neurostimulating Peptide, the N-terminal Fragment of the Secreted Phosphatidylethanolamine-binding Protein, Possesses a New Biological Activity on Cardiac Physiology", JOURNAL OF BIOLOGICAL CHEMISTRY , 279(13), 13054-13064 CODEN: JBCHA3; ISSN: 0021-9258, 26 March 2004 (2004-03-26), XP001184063 *

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