EP0901525A2 - Von g-protein gekoppelte rezeptoren abgeleiteten peptide mit antagonistischer wirkung - Google Patents

Von g-protein gekoppelte rezeptoren abgeleiteten peptide mit antagonistischer wirkung

Info

Publication number
EP0901525A2
EP0901525A2 EP97916291A EP97916291A EP0901525A2 EP 0901525 A2 EP0901525 A2 EP 0901525A2 EP 97916291 A EP97916291 A EP 97916291A EP 97916291 A EP97916291 A EP 97916291A EP 0901525 A2 EP0901525 A2 EP 0901525A2
Authority
EP
European Patent Office
Prior art keywords
peptide
protein
receptor
coupled receptor
activity
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.)
Withdrawn
Application number
EP97916291A
Other languages
English (en)
French (fr)
Inventor
Michel Bouvier
Thomas P. Loisel
Terence E. Montreal Cardiology Unit Inst. HEBERT
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.)
Universite de Montreal
Original Assignee
Universite de Montreal
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 Universite de Montreal filed Critical Universite de Montreal
Publication of EP0901525A2 publication Critical patent/EP0901525A2/de
Withdrawn legal-status Critical Current

Links

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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70571—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
    • 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 present invention relates to novel peptides and/or peptidomimetic compounds that can
  • GPCRs G protein-linked receptors
  • GPCRs share a common signalling mechanism, whereby signal
  • G intracellular transducer elements
  • the conformation of the receptor changes so that it can interact with
  • GDP guanosine diphosphate
  • GTP triggering another conformational change in the G protein.
  • the G protein regulates the activity of an effector.
  • effectors include
  • enzymes such as adenylyl cyclase and phospholipase C, channels that are specific for
  • GPCRs activation of GPCRs by transmitters will induce one or another of the following
  • effector responses activation of adenylyl cyclase, inhibition of adenylyl cyclase or stimulation of phospholipase C activity.
  • effector adenylyl cyclase is either
  • cAMP adenosine monophosphate
  • PIP 2 phosphatidylinositol-bisphosphate
  • IP 3 inositol triphosphate
  • DAG diacylglycerol
  • Receptors may be classified according to the type of signaling pathway they activate in cells.
  • Gs-like which mediate adenylyl cyclase activation
  • Gi-like which mediate
  • the signal can be greatly amplified through
  • GPCRs include neurotransmitters such as dopamine, acetylcholine
  • hormones of the endocrine system such as somatostatin, glucagon and
  • lipid mediators such as prostaglandins and leukotrienes.
  • Adrenergic receptors have been extensively smdied. In fact the human ⁇ , receptor has been
  • the receptor for insulin-like growth factor II directly activates G, .2 , has only a
  • G protein-coupled receptors are ubiquitous and widely used in G protein-coupled receptors. Since G protein-coupled receptors are ubiquitous and widely used in G protein-coupled receptors. Since G protein-coupled receptors are ubiquitous and widely used in G protein-coupled receptors. Since G protein-coupled receptors are ubiquitous and widely used in G protein-coupled receptors. Since G protein-coupled receptors are ubiquitous and widely used in G protein-coupled receptors. Since G protein-coupled receptors are ubiquitous and widely used in
  • this invention has utility for different industries
  • the pharmaceutical industry including: the pharmaceutical industry, the pest-control industry, the aquaculture industry,
  • the pharmaceutical sector is particularly interested in the potential therapeutic applications
  • the present invention resides in the discovery that novel compounds modelled on the
  • transmembrane region of GPCRs are potent GPCR antagonists. Specifically, the present
  • invention relates to novel peptides and/or peptidomimetic compounds that are modeled on
  • peptide and peptidiomimetic antagonists of this invention may be utilized in
  • compositions and methods for specifically controlling certain GPCR functions are provided.
  • invention also involves a process for antagonizing GPCR activity in mammals which comprises, administering to a subject an effective amount of the novel compoujd to
  • peptide or peptidiomimetic compound sufficient to antagonize GPCR with a suitable pharmaceutical carrier.
  • Another aspect of this invention involves generating peptides and peptidiomimetic
  • control peptide TM VI Ala (closed circles), or second control peptide from TM VII of the
  • D2 dopamine receptor (open triangles). Isoproterenol stimulated adenylyl cyclase activity
  • isoproterenol and dopamine stimulated adenylyl cyclase activity were also investigated.
  • Membranes were prepared from Sf9 cells expressing either the human ⁇ ,AR (open circles)
  • Figure 2 depicts effects of TM VI peptide on ⁇ AR expressed in mammalian cells.
  • Peptides were used at a concentration of 0.15 ug/ul.
  • IP inositol phosphate
  • the abbreviation BASED is bis [ ⁇ -(4 azidosalicylamindo) ethyl] disulphide
  • 5-HT is 5-hydroxytryptamine.
  • DOI is 2.5-dimethoxy-4-iodoamphetamine hydrobromide.
  • PBS phosphate buffered saline
  • ⁇ 2 AR is ⁇ 2 -adrenergic receptor.
  • GPCR G protein-coupled receptor
  • GpA glycophorin A
  • HA influenza hemagglutinin.
  • TM VI transmembrane domain 6.
  • NDI nephrogenic diabetes insipidus.
  • any amino acid as used herein includes the L-isomers and D-isomers of the
  • Naturally occurring peptides are naturally occurring amino acids.
  • the naturally occurring amino acids are glycine, alanine,
  • valine leucine, isoleucine, serine, methionine, threonine, phenylaianine, tyrosine. trptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine.
  • amino acids include norleucine, norvaline, alloisoleucine. homoarginine . thioproline.
  • dehydroproline hydroxyproline (Hyp), isonipecotic acid (Inp), homoserine.
  • aminophenylgutyric acid Pba
  • phenylalanines substimted at the ortho, meta, or para position of the phenyl moiety with one or two of the following: a (C,-C 4 ) alkyl. a (C,-C 4 )
  • phospho-tyrosine 4-methane sulfonic acid ester of tyrosine, 4-methane phosphonic acid ester of tyrosine, 3,5-diiodotyrosine, 3-nitrotyrosine, e-alkyl lysine, delta-alkyl ornithine,
  • acids referred to in this application are in the L-form.
  • positively charged amino acid includes any namrally
  • positively charged amino acids are arginine, lysine, histidine, homoarginine, ornithine and delta-alkyl ornithine.
  • amino acid containing an aryl side chain as used herein means any amino acid
  • Tyrosine, phenylaianine, tryptophan, O-sulfate esters of tyrosine and 5-nitrotyrosine exemplify such amino acids.
  • polar amino acid means any amino acid having an uncharged side chain which
  • Examples include glutamine, asparagine, glycine, serine,
  • hydrophobic amino acid mans any amino acid having an uncharged side chain
  • norleucine norvaline. alloisoleucine. thioproline, dehydroproline, cyclohexylalanine and
  • patient refers to any mammal, especially humans.
  • backbone chain refers to the portion of a chemical strucmre that
  • the atomic components that make up a backbone chain may comprise any atoms that are capable of forming bonds with at least two other atoms.
  • peptide-lead refers to the underivitized peptide that is modelled
  • parent GPCR refers to the GPCR from which the peptide-lead
  • Molecules of this invention are designed using the peptide-lead as the model for antagonists that are selectively inhibitory towards the parent GPCR or closely related receptors.
  • the present invention relates to novel peptides and/or peptidomimetic compounds that are
  • peptidergic molecules of this invention selectively bind to the GPCR from which they were designed. This property allows the molecules of this invention to inhibit those functions of the GPCR that are mediated through this receptor.
  • the GPCR antagonists of the present invention are N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the antagonists of this invention are further characterized by: (1) the ability to inhibit the
  • TMS Candidate Transmembrane Sequences
  • This peptide itself can potentially be a GPCR antagonist of the present invention.
  • Each transmembrane sequence provides a potential model for a peptide-lead that will be
  • the first step is to identify the transmembrane domain of the receptor of interest
  • the secondary strucmre can also be analyzed to identify alpha-helix
  • membrane domains are well known in the art (for eg. , see: Krystek et al. , Endocrinology
  • the second consideration in designing the antagonists of this invention is secondary and
  • conformational requirements may be in the namre of overall three-dimensional strucmre and
  • peptides are preferred antagonists of the present invention. Conversely, those peptides are preferred antagonists of the present invention. Conversely, those peptides are preferred antagonists of the present invention. Conversely, those peptides are preferred antagonists of the present invention. Conversely, those peptides are preferred antagonists of the present invention. Conversely, those peptides are preferred antagonists of the present invention. Conversely, those peptides are preferred antagonists of the present invention. Conversely, those peptides
  • the hydrogen bond may be any hydrogen bond.
  • the hydrogen bond may be any hydrogen bond.
  • GPCR antagonists of this invention a single poisition deletion analysis is performed. In this procedure, a series of peptides containing single deletions at positions which do not affect inhibitor activity (as determined above) are synthesized and assayed for antagonist
  • Deletion peptides from this series which have significantly lower antagonist activity indicate the location of components which provide critical spacing in the antagonist. This may be
  • alkyl chain without a significant loss of activity confirms that spacing is critical at that part
  • GPCR antagonists of this invention may be designed and synthesized. This is achieved by
  • the replacement component will have approximately the same size, shape, hydrophobicity
  • charges for example, aspartic acid for glutamic acid, arginine for lysine, asparagine for
  • cyclohexylalanine for tyrosine
  • sarcosine for glycine
  • statine for threonine
  • substitutions typically involve the introduction of non-amino acid components which contain
  • a non-essential amino acid may simply
  • nonessential amino acid examples include, but are not limited to, straight
  • proline an amino
  • novel GPCR antagonists according to this invention may be designed by insertions
  • component may potentially be inserted, a series of peptides having a single alanine inse ⁇ ion
  • the inse ⁇ ions may potentially affect the molecular interactions between the antagonist and the GPCR and how they affect conformation of the antagonist.
  • the inse ⁇ ions may potentially affect the molecular interactions between the antagonist and the GPCR and how they affect conformation of the antagonist.
  • the molecule may then be synthesized and assayed for
  • Cyclization may be achieved by methods
  • One method is the formation of a disulfide bond between
  • the components which form such bonds may be side chains of amino acids, non-amino acid components or a combination of the two.
  • the most preferred antagonists of the present invention are modelled after the peptide-lead which comprises the formula: SEQ ID NO: 1: NH-GIIMGTFTLCWLPFFIVNIVH-
  • Any chemist skilled in the art of peptide synthesis can synthesize the GPCR peptide antagonists of this invention by standard solution methods. These include enzymatic
  • antagomst is entirely peptidic and is synthesized by solid-phase peptide synthesis techniques
  • non-protein amino acids are contained in the GPCR antagonist, they may be either
  • non-protein amino acid amino acid
  • non-protein amino acids may be added directly and which must be synthesized by
  • This technique involves the solid-phase synthesis of all or most of the peptide
  • the peptide chain can be prepared by a
  • esters of formula 1 e.g., dicyclohexylcarbodiimide or carbonyldunidazole, various active esters, e.g.. esters of
  • N-hydroxypthalimide or N-hydroxy-succinimide and the various cleavage reagents, e.g. , trifluoracetic acid (TFA), HCI in dioxane, boron tris-(trifluoracetate) and cyanogen
  • a preferred peptide synthesis method follows conventional Merrifield solid-phase procedures. See Merrifield, J. Amer. Chem. Soc. 85, 2149-54 (1963) and Science 150,
  • peptidomimetic a compound that mimics a peptide.
  • Methods for designing peptidomimetic compounds that are known in the art.
  • the starting point for designing a peptidomimetic compound is the sequence
  • the method involves computer
  • preparations such as tissues, tissue extracts, cells or extracts thereof, containing the specific
  • Test assays measure the consquence of receptor activity on other cellular components
  • guanyl neucleotide analogue GTPgS35 or hydrolysis of GTP by activated G protein can be measured These types of measurements may also be made by measuring the activity of
  • effector enzymes such as adenyl cyclase activation (Gs-coupled receptors) and inhibition
  • membrane fragments from cells can be used for assay by measuring conversion of radioactive ATP to cAMP by adenlyl cyclase.
  • Receptor activation of Gq-coupled receptors can be measured in mtact cells by production of inositol
  • Downstream events can also be measured to monitor receptor activity including: protein kinase A activity (which is under control of cAMP levels) for Gs and Gi-coupled receptors,
  • intracellular calcium concentrations can be measured using specific fluorscent probes (e.g.
  • fura-2 for Gq receptors; activation or inhibition of transcription of specific genes under
  • control of receptor activity can be measured either directly (e.g. measure mRNA levels) or by reporter gene assays which replace namral gene with readily measured marker enzyme
  • receptor activity can be assayed by measuring
  • Glandular cells cell proliferation, etc.
  • aqueous solution containing peptide, derivative, or peptidiomimetic compound to be tested to solution contaimng a GPCR preparation (tissue, cell or extract); adding agonist
  • Antagonist can be further characterized by testing: varying concentrations of peptide with
  • compound on distantly-related receptor can be performed to determine selectivity.
  • Antagonist activity of peptide or peptidiomimetic compounds can also be assessed by
  • the present invention also provides a method for treatment of G protein-coupled receptor
  • mediated disease in patients such as mammals, including humans, which comprises the step
  • the present invention also provides pharmaceutical compositions which comprise a
  • Therapeutic methods of this invention comprise the step of
  • compositions may be in the form of tablets, capsules, caplets, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the therapeutic agents of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers.
  • the proportion of each carrier is determined by
  • administration may be tablets and capsules and may contain conventional excipients.
  • binding agents such as acacia, gelatin, sorbitol, or polyvinylpyrolidone: fillers.
  • lactose such as lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine: tabletting lubricants such as magnesium stearate; disintegrants, such as starch, polyvinylpyrrolidone.
  • wetting agents such as sodium lauryl sulphate.
  • the compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously.
  • parentemal administration the compound may be used in the form of
  • sterile solutions containing other solutes for example, sufficient saline or glucose to make the solution isotonic.
  • the compounds may be administered orally in the form of tablets, capsules, or granules
  • the compounds may be administered orally in the form of solutions which may contain
  • flavouring and/or flavouring agents may also be administered sublingually.
  • the solid oral compositions may be prepared by conventional methods of blending, filling,
  • the tablets may be coated according to methods
  • Oral liquid preparations may be in the form of emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may or may not contain conventional additives.
  • Such liquid preparations may or may not contain conventional additives.
  • suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose. carboxymethylcellulose, aluminium stearate gel, or hydrogenated edible fats; emulsifying
  • non-aqueous vehicles which may include
  • edible oils such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of lycerine, propylene glycol, ethylene glycol, and ethyl alcohol; preservatives,
  • metyl para-hydroxybenzoate for instance metyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, n-propyl parahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and, if desired, conventional flavoring or coloring agents.
  • fluid unit dosage forms may be prepared by utilizing the
  • peptide and a sterile vehicle may be either suspended or dissolved in the vehicle. Once in solution, the compound may be injected and
  • Adjuvants such as a local anaesthetic, a preservative or a buffering
  • composition may be enhanced by freezing the composition after filling the vial and
  • suspensions may be prepared in substantially the same manner, except that the peptide
  • the compound should be suspended in the vehicle rather than being dissolved, and. further, sterilization is not achievable by filtration.
  • the compound may be sterilized, however, by exposing it to ethylene oxide before suspending it in the sterile vehicle.
  • a surfactant or wetting solution is not achievable by filtration.
  • Dosages may vary with the mode of administration and the particular peptide or
  • the dosage may vary with the particular
  • the dosage of the compound used in the treatment will vary,
  • Such therapy may extend for
  • peripheral tissues they can function in peripheral tissues to affect peripheral G protein coupled receptor
  • Peptides were synthesized based on: 1) the sixth transmembrane region of the ⁇ -AR.
  • ⁇ 2 AR TM VI peptides consisting of residues 276-296: NH-
  • GIIMGTFTLCWLPFFIVNIVH-COOH 2) a second peptide with Ala residues substimted at positions 276, 280, and 284 NH 2 -AIIMATFTACWLPFFIVNIVH-COOH, 3) a peptide
  • Mammalian or Sf9 cells were infected with recombinant bacuioviruses, encoding the
  • bacuioviruses at multiplicities of infection ranging from 3 - 5.
  • Sf9 cells were maintained at 27°C in serum-supplemented [10% fetal bovine serum (FBS)
  • CHW and LTK cell lines with and without stably transfected ⁇ >AR were maintained as described (34).
  • Cells were grown in Dulbecco's modified eagle medium (DMEM)
  • Stably transfected cell lines were grown in the presence of 150 ug/ml
  • V2 vasopressin receptors For transient expression of V2 vasopressin receptors the following prodecures were followed. COS-7 cells were maintained in supplemented DMEM as described above. Genomic DNA for the V2 vasopressin receptor was isolated from nephrogenic diabetes
  • NDI insipidus
  • COS-7 cells were transiently transfected with the expression vector
  • Membranes were prepared as follows and washed. Sf9 or mammalian cells were washed
  • protease inhibitor cocktail consisting of 5 mg/ml leupeptin, 10 mg/ml benzamidine and 5
  • Membrane adenylyl cyclase activity was assayed as previously described (Mouillac, B. , et al. , J. Biol. Chem. , 267:21733-21737, 1992;
  • Membranes were prepared and washed as described above. Again 10 uL of membranes (3-5).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cell Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Neurology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP97916291A 1996-04-22 1997-04-21 Von g-protein gekoppelte rezeptoren abgeleiteten peptide mit antagonistischer wirkung Withdrawn EP0901525A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US1589196P 1996-04-22 1996-04-22
US15891P 1996-04-22
PCT/CA1997/000263 WO1997040148A2 (en) 1996-04-22 1997-04-21 Peptide antagonists derived from the transmembrane domains of g protein-coupled receptors

Publications (1)

Publication Number Publication Date
EP0901525A2 true EP0901525A2 (de) 1999-03-17

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP97916291A Withdrawn EP0901525A2 (de) 1996-04-22 1997-04-21 Von g-protein gekoppelte rezeptoren abgeleiteten peptide mit antagonistischer wirkung

Country Status (4)

Country Link
EP (1) EP0901525A2 (de)
AU (1) AU2501297A (de)
CA (1) CA2252369A1 (de)
WO (1) WO1997040148A2 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2259132A1 (en) * 1996-07-01 1998-01-08 Biosignal Inc. Peptides and peptidomimetic compounds affecting the activity of g-protein-coupled receptors by altering receptor oligomerization
CA2375047A1 (en) 1999-05-28 2000-12-07 Synaptic Pharmaceutical Corporation Dna encoding snorf33 receptor
CA2388865A1 (en) * 1999-11-16 2001-05-25 Pharmacia & Upjohn Company Novel g protein-coupled receptors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9740148A3 *

Also Published As

Publication number Publication date
WO1997040148A2 (en) 1997-10-30
WO1997040148A3 (en) 1997-12-18
AU2501297A (en) 1997-11-12
CA2252369A1 (en) 1997-10-30

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