WO2012062953A1 - PEPTIDE INHIBITEUR DE p38 ET SES APPLICATIONS - Google Patents

PEPTIDE INHIBITEUR DE p38 ET SES APPLICATIONS Download PDF

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Publication number
WO2012062953A1
WO2012062953A1 PCT/ES2011/070774 ES2011070774W WO2012062953A1 WO 2012062953 A1 WO2012062953 A1 WO 2012062953A1 ES 2011070774 W ES2011070774 W ES 2011070774W WO 2012062953 A1 WO2012062953 A1 WO 2012062953A1
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Prior art keywords
peptide
disease
mapk
seq
amino acid
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PCT/ES2011/070774
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English (en)
Spanish (es)
Inventor
Federico MAYOR MENÉNDEZ
Cristina Murga Montesinos
Pedro Manuel Campos Muelas
Jacoba Johanna Heijnen
Anna Maria Agnes Antonius Kavelaars
Antonio MORREALE DE LEÓN
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Universidad Autónoma de Madrid
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Publication of WO2012062953A1 publication Critical patent/WO2012062953A1/fr

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    • 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
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4716—Muscle proteins, e.g. myosin, actin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors

Definitions

  • the present invention relates, in general, to a method for inhibiting the activation or biological activity of the mitogen-activated protein kinase (MAPK) p38 and to a method for treating a subject suffering from a disease that can be alleviated by inhibition. of the activation or biological activity of said MAPK p38 with a peptide.
  • the invention also relates to said peptide, pharmaceutical compositions comprising said peptide and its applications.
  • the p38 protein is a member kinase of a family of signaling molecules known as the family of mitogen-activated protein kinases (MAPK), a family of Ser / Thr kinases responsible for numerous cellular processes such as cell growth, proliferation, cell death and differentiation in response to a broad spectrum of stimuli.
  • Other members of that family include c-Jun N-terminal kinases (JNKs) and extracellular signal regulated kinases (ERKs).
  • JNKs c-Jun N-terminal kinases
  • ERKs extracellular signal regulated kinases
  • the p38 subfamily responds to numerous stress stimuli, for example, ultraviolet light, osmotic shock, heat, and inflammatory cytokines such as tumor necrosis factor alpha (TNF- ⁇ ) and interleukin 1 beta (IL- ⁇ ).
  • p38 MAPK isoforms known as ⁇ 38 ⁇ , ⁇ 38 ⁇ 2, ⁇ 38 ⁇ and ⁇ 38 ⁇ are known, which differ in their tissue expression profiles (p38a and ⁇ 38 ⁇ 2 are expressed in almost all tissues, ⁇ 38 ⁇ is mainly expressed in muscle and ⁇ 38 ⁇ in lung and kidney), use of substrates, response to direct and indirect stimuli, and susceptibility to kinase inhibitors.
  • p38a is the most studied isoform and, apparently, the most physiologically relevant, all isoforms have a high degree of sequence identity: more than 70% between p38a and ⁇ 38 ⁇ 2 and about 60% between the isoforms ⁇ 38 ⁇ and ⁇ 38 ⁇ with respect to p38a .
  • MAPK p38 is activated by phosphorylation in the TGY consensus sequence (Thr-Gly-Tyr), by action of its MAPK kinase activator kinases (MAPKK or MKK), mainly MKK3 / 3b and MKK6, and, to a lesser extent, MKK4. Under physiological conditions, the activation of MAPK p38 seems to be transient. Once activated, the MAPK p38 mediates the stabilization of messenger AR (AR m) for various inflammatory mediators, including TNF-a, IL- ⁇ ⁇ , interleukin 6 (IL-6), and cyclooxygenase 2 (COX-2)).
  • AR m messenger AR
  • MAPK p38 seems to play an important role in very diverse processes, such as in inflammation, in cell differentiation (for example, in the conversion of myoblasts to myotubes, in the differentiation of preadipocytic cells, in the differentiation of thymocytes, etc.), in the regulation of cell migration in response to various stimuli (for example, endothelial cell migration stimulated by endothelial growth factor (VEGF), etc.), and in the cell cycle (where the p38-MK2 pathway regulates the "checkpoint" G2 / M in response to ultraviolet light or the "checkpoint" G0 and Gl / S).
  • VEGF endothelial growth factor
  • TAT-MK 3b peptide represents a good proof of concept that peptides that bind to the p38 anchor domain can inhibit the intracellular signaling pathway of this kinase
  • the efficacy of this first approach has only been relative. that both the length of the peptide (24 aas) and the doses at which it should be used to be effective are manifestly improvable, as the authors themselves acknowledge.
  • MAP38 p38 inhibitors have been described, there is still a need to identify new inhibitors of said kinase, potentially useful in human therapy, in order to increase the arsenal of therapeutic remedies against MAPK-mediated diseases p38 that may be relieved by inhibiting the biological activity of said MAPK p38.
  • the invention relates to a peptide, whose amino acid sequence comprises the amino acid sequence shown in SEQ ID NO: 1, capable of inhibiting p38 MAPK.
  • SEQ ID NO: 2 [KPDLRVVICP] not only reduces the activation and biological activity of said MAPK p38 as well as the cytokine secretion dependent on the MAPK p38 but also reduces inflammation-induced hyperalgesia in an animal model, at similar levels but more permanently than other established MAPK p38 inhibitors, so that MAPK p38 inhibitor peptide can potentially be used not only in the treatment of diseases that occur with inflammatory processes but also in the treatment of pain.
  • the invention relates to a peptide inhibiting the activation or biological activity of MAPK p38 whose amino acid sequence comprises the amino acid sequence shown in SEQ ID NO: 1.
  • said peptide It is a peptide comprising the amino acid sequence shown in SEQ ID NO: 2.
  • the invention relates to a fusion protein comprising said peptide provided by this invention and a carrier peptide capable of internalizing a peptide in a cell.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, at least, said peptide or fusion protein provided by this invention.
  • the invention relates to the use of said activation or biological activity inhibitor peptide of MAPK p38, or said fusion protein, in the preparation of a medicament for the treatment of a disease mediated by MAPK p38 , such as a disease that can be relieved by inhibiting the activation or biological activity of said MAPK p38; or, alternatively, with said activation or biological activity inhibitor peptide of MAPK p38, or said fusion protein, for use in the treatment of a disease mediated by MAPK p38, such as a disease that can be alleviated by inhibition of the activation or biological activity of said MAPK p38.
  • diseases that can be relieved by inhibiting the activation or biological activity of MAPK p38 are inflammatory diseases, including autoimmune diseases; heart diseases; Cancer; neurodegenerative diseases; metabolic diseases including diabetes; and diseases that occur with pain; as well as pain.
  • the invention relates to a nucleic acid encoding said peptide or fusion protein provided by this invention.
  • Gene constructs, vectors and host cells comprising said nucleic acid constitute additional aspects of the present invention.
  • the invention in another aspect, relates to a method for producing said fusion peptide or protein provided by this invention comprising growing said host cell comprising said nucleic acid encoding said fusion peptide or protein provided by this invention under conditions that allow the production of said peptide, or said fusion protein, and, if desired, recover said peptide or fusion protein.
  • the invention relates to the use of said nucleic acid. or said a gene construct that contains it, in the elaboration of vectors and cells for the treatment and / or prevention of a disease mediated by MAPK p38, such as a disease that can be relieved by inhibiting the activation or biological activity of said MAPK p38; or, alternatively, with said nucleic acid or said gene construct containing it, or said vector comprising said nucleic acid or said gene construct, or said host cell comprising said nucleic acid, said gene construct, or said vector, for use in the treatment of a disease mediated by MAPK p38, such as a disease that can be relieved by inhibiting the activation or biological activity of said MAPK p38.
  • Figure 1 is a schematic representation of the structures of p38 MAPK complexes with the MKK3 and MEF2A proteins [Chang CI et al, 2002. Mol Cell. Vol 9, 1241-49], and with MK2 [White A, et al, Proc Nati Acad Sci USA. 2007 Apr 10; 104 (15): 6353-8].
  • Figure 2 is a schematic representation of the interactions established between a peptide derived from co-crystallized MEF2A next to MAPK p38 according to data obtained from Chang et al. (PDB coordinates: 1LEW) [Chang CI et al, 2002. Mol Cell. Vol 9, 1241-49].
  • the peptide is represented in the form of bars (red and blue) and MAPK p38 in a spatial filling model (green).
  • Figure 3 shows the results of the quantification of the effect of peptides derived from MEF2A on phosphorylation of MAPK p38 by MKK6 in vitro.
  • In vitro phosphorylation of the recombinant MAPK p38 by purified MKK6 was performed in the presence of the MEF2AxCys peptide (SEQ ID NO: 2) or peptides derived from the crystallized sequence of the MEF2A protein.
  • SEQ ID NO: 2 MEF2AxCys peptide
  • TGY the amount of phosphorylated p38 MAPK in the activation loop
  • the Figure 3B is a graph showing the quantification of the results of the inhibition of in vitro activation of MAPK p38 due to said peptides, normalized with the values obtained with a control peptide ["scrmbld” or L-MEF2A scrambled ].
  • the mean inhibitory concentration (IC 50 ) for this in vitro inhibitory effect obtained in each case is shown in Figure 3C.
  • Figure 4 is a graph showing the quantification of inhibition of in vitro phosphorylation of MAPK p38 by the peptide MEF2AxCys (SEQ ID NO: 2) in the presence or absence of a reducing agent [dithiothreitol (DTT)] ( Figure 4A ).
  • DTT dithiothreitol
  • Figure 5 shows the effect of the L-MEF2AxCys peptide (SEQ ID NO: 2) attached, by its amino terminus, to the TAT transport peptide (SEQ ID NO: 7) on the activation of MAPK p38, MK2 and Hsp27 in response to LPS in a human monocyte cell line (THP1).
  • THP1 cells were stimulated with bacterial lipopolysaccharide (LPS) in the absence or presence of the L-MEF2AxCys peptide (SEQ ID NO: 2).
  • LPS bacterial lipopolysaccharide
  • the cells were lysed and their proteins were analyzed by Western Blot with specific antibodies (Figure 5A).
  • Figure 6 shows the effect of the L-MEF2AxCys peptide [MEF2AxCys peptide (SEQ ID NO: 2) in which the amino acids have the L configuration] and the D-MEF2AxCys peptide [MEF2AxCys peptide (SEQ ID NO: 2) in which the amino acids have the D] configuration, each independently linked to the TAT transport peptide (SEQ ID NO: 7), on the secretion of tumor necrosis factor alpha (TNF- ⁇ ) in response to bacterial lipopolysaccharide (LPS) and survival in THP-1 monocytes.
  • TAT transport peptide SEQ ID NO: 7
  • Human THP-1 monocytes were stimulated with bacterial LPS in the presence of the L-MEF2AxCys or D-MEF2AxCys peptide dissolved in dimethylsulfoxide (DMSO) or equivalent amounts of control peptides with sequences containing the same amino acids but in a messy sequence ("scrambled"): "L-MEF2A scrambled” [MEF2AxCys peptide (SEQ ID NO: 8) in which the amino acids have the L] or "D-MEF2AxCys scrambled” configuration [MEF2A peptide (SEQ ID NO: 8) in which the amino acids have the D] configuration, each independently attached to the TAT transport peptide (SEQ ID NO: 7 ), and also dissolved in DMSO at the concentrations indicated in the ordinate axis.
  • DMSO dimethylsulfoxide
  • the amount of TNF- ⁇ secreted to the medium in response to LPS was quantified by an ELISA assay.
  • Cell viability was quantified by flow cytometry (FACS) after staining of the cells treated with propidium iodide and quantification of the amount of cells positive for that staining.
  • Figure 7 shows the effect of the MEF2AxCys peptide (SEQ ID NO: 2) on hyperalgesia induced in BL6-GRK2 +/- mice by intraplantar injection of carrageenan. At 7 days post induction of the hyperalgesia, the latency time of the withdrawal of the paw in contact with the heat was determined as an indication of inflammatory pain at time 0.
  • L-MEF2AxCys scrambled [MEF2AxCys scrambled peptide (SEQ ID NO: 8) in which the amino acids have the configuration L] or L-MEF2AxCys (SEQ ID NO: 2) (2 ⁇ g), each one of them, independently, attached to the TAT transport peptide (SEQ ID NO: 7), and the latency periods of the leg withdrawal that are represented on the y axis were measured at the times indicated in the ordinate axis. .
  • Figure 8 shows the effect of the MEF2AxCys peptide (SEQ ID NO: 2) on hyperalgesia induced in BL6-GRK2 +/- mice by intraplantar injection of carrageenan. At 7 days post induction of the hyperalgesia, the latency time of the withdrawal of the paw in contact with the heat was determined as an indication of inflammatory pain at time 0.
  • L-MEF2AxCys scrambled [MEF2AxCys scrambled peptide (SEQ ID NO: 8) in which the amino acids have the configuration L] or L-MEF2AxCys (10 ⁇ g), each independently attached to the TAT transport peptide (SEQ ID NO: 7), and the latency periods of the withdrawal of the leg that were measured at the times indicated on the ordinate axis were measured represent on the y axis.
  • the invention relates to a peptide, hereinafter "peptide of the invention", whose amino acid sequence comprises the amino acid sequence shown in SEQ ID NO: 1:
  • Xaal is Arg or Lys
  • Xaa2 is Asp or Glu
  • Xaa3 is lie, Leu, Met or Val
  • Xaa4 is Arg or Lys
  • Xaa5 is lie, Leu, Met or Val
  • Xaa6 is lie, Leu, Met or Val
  • Xaa7 is lie, Leu, Met or Val
  • Cys is a cistern
  • Pro is proline
  • the peptide of the invention has the ability to inhibit the activation of MAPK p38; also, in a particular embodiment, the peptide of the invention has the ability to inhibit the biological activity of said p38 MAPK.
  • the peptide of the invention comprises the amino acid sequence shown in said SEQ ID NO: 1.
  • the peptide of the invention is constituted by the amino acid sequence shown in said SEQ ID NO: 1.
  • Xaal is Arg or Lys, preferably, Lys.
  • Xaa2 is Asp or Glu, preferably Asp.
  • Xaa3 is lie, Leu, Met or Val, preferably,
  • Xaa4 is Arg or Lys, preferably, Arg.
  • Xaa5 is lie, Leu, Met or Val, preferably, Val.
  • Xaa6 is lie, Leu, Met or Val, preferably, Val.
  • Xaa7 is lie, Leu, Met or Val, preferably lie.
  • the peptide of the invention comprises the amino acid sequence shown in SEQ ID NO: 2 [KPDLRVVICP]; said peptide is a potent inhibitor of the activation and biological activity of MAPK p38 (Examples 1 and 2).
  • peptide refers to a polymer formed by the binding, in a defined order, of alpha-amino acids by a peptide bond, and includes modifications or derivatives thereof, for example, glycosylation, phosphorylation. , acetylation, amidation, etc.
  • the amino acids of the peptide of the invention may belong to the L series or to the D series, preferably, to the L series.
  • pharmaceutically acceptable salts of the peptide of the invention are pharmaceutically acceptable salts of the peptide of the invention.
  • pharmaceutically acceptable salts includes the salts commonly used to form metal salts or acid addition salts. The nature of the salt is not critical as long as it is pharmaceutically acceptable.
  • Pharmaceutically acceptable salts of the peptide of the invention can be obtained from organic or inorganic acids or bases. Said salts can be obtained by conventional methods well known to those skilled in the art.
  • the peptide of the invention is an inhibitor of the activation or biological activity of MAPK p38, that is, a compound that inhibits the biological activity of MAPK p38.
  • the peptide of the invention acts directly on MAPK p38, binding to said kinase, which prevents its phosphorylation (activation) and, therefore, inhibiting its biological activity (Example 2 ).
  • the inhibitory effect of the peptide of the invention may be due, among other factors, to the presence of a cistern in the peptide of the invention, an effect that is not observed in other peptides with similar amino acid sequences but lacking cysteine (Figure 3).
  • Figure 4 it is observed in Figure 4 that the inhibitory effect of said peptide of the invention (SEQ ID NO: 2) is prevented in the presence of a reducing agent (which breaks the disulfide bridges), which highlights the probable implication of a disulfide bridge in the p38 MAPK inhibition mechanism by the peptide of the invention.
  • the peptide of the invention can be used in the treatment of a disease mediated by MAPK p38, such as a disease that can be relieved by inhibiting the activation or biological activity of said MAPK p38.
  • the peptide of the invention may be fused to another peptide thereby constituting a fusion protein. Since the interaction between the peptide of the invention and the MAPK p38 must occur inside the cell, the peptide to which the peptide of the invention is fused is, advantageously, a peptide capable of facilitating the entry of the peptide of the invention. inside the cell.
  • the invention relates to a fusion protein of the invention comprising:
  • a peptide of the invention (i) a peptide of the invention, and (ii) a transporter peptide capable of internalizing a peptide in a cell.
  • a “transport peptide capable of internalizing a peptide in a cell”, sometimes identified in this description as a “transport peptide”, is a peptide capable of crossing the cell membrane and penetrating a cell from the outside, a characteristic that can be conferred to the peptide (eg, peptide of the invention) to which it is fused thereby providing an alternative to the transport of peptides of interest (eg, peptide of the invention) into the target cells.
  • This mechanism of entry of peptides into the cell is known as "protein transduction or delivery”.
  • Various carrier peptides with the ability to internalize a peptide in a cell are known [Schwarze S.R.
  • any transporter peptide capable of internalizing a peptide in a cell can be used for the implementation of the present invention; however, in a particular embodiment, said carrier peptide is a peptide comprising a segment "PTD" (from the English “protein transduction domain").
  • proteins comprising said protein transduction domains include Drosophila melanogaster homeotic transcription factor Antennapedia (Antp) and VP22 DNA binding protein of simple herpesviruses 1 (HSV-1), although it has also been suggested that this property of internalizing peptides in cells is possessed by other proteins such as influenza virus hemagglutinin, lactoferrin, fibroblast growth factor 1, fibroblast growth factor 2 and Hoxa-5 proteins, Hoxb-4 and Hoxc-8 [Ford KG et al. , Gene Therapy, 2001; 8: 1-4].
  • said carrier peptide is derived from the TAT protein (from the "transacting translational protein") of human immunodeficiency virus 1 (HIV-1), and comprises the amino acid sequence shown in SEQ ID NO: 7 [GRKKRRQRRRPP].
  • the peptide of the invention may be attached to any of the terminal (amino or carboxyl) ends of the transporter peptide capable of internalizing a peptide of the invention in a cell.
  • the carboxyl terminal end of the peptide of the invention is attached to the amino terminal end of said carrier peptide, while, in another particular embodiment, the amino terminal end of the peptide of the invention is attached to the carboxyl end. terminal of said transporter peptide.
  • the peptide of the invention can be directly or not directly linked to said transport peptide capable of internalizing a peptide in a cell. Therefore, in a particular embodiment, the peptide of the invention [peptide (i)] is directly linked to said carrier peptide [peptide (ii)], while, in another particular embodiment, the peptide of the invention [peptide (i )] is linked to said transporter peptide [peptide (ii)] through a spacer peptide ("linker” or "spacer") between said peptides (i) and (ii).
  • the fusion protein of the invention may further contain a spacer peptide located between said peptide of the invention [peptide (i)] and said carrier peptide [peptide (ii)].
  • said spacer peptide is a structurally flexible peptide, such as a peptide that gives rise to an unstructured domain.
  • any peptide with structural flexibility can be used as a spacer peptide; however, illustrative, non-limiting examples of such spacer peptides include peptides that contain repeats of amino acid residues, e.g., of Gly and / or Ser, or any other suitable repetition of amino acid residues.
  • the fusion protein of the invention may include an amino acid sequence useful for the isolation or purification of the fusion protein of the invention. Said sequence will be located in a region of the fusion protein of the invention that does not adversely affect the functionality of the peptide of the invention. Virtually any amino acid sequence that can be used to isolate or purify a fusion protein (generically referred to as "tag" or “tag” peptides) may be present in said fusion protein of the invention.
  • said amino acid sequence useful for isolating or purifying a fusion protein can be, for example, an arginine tail (Arg-tag), a histidine tail (His-tag), FLAG-tag, Strep -tag, an epitope capable of being recognized by an antibody, such as c-myc-tag, SBP-tag, S-tag, calmodulin binding peptide, cellulose binding domain, chitin binding domain, glutathione S-transferase-tag, maltose binding protein , Wildebeest, TrxA, DsbA, Avi-tag, etc. [Terpe K., Appl. Microbiol Biotechnol (2003), 60: 523-525], ⁇ -galactosidase, VSV-glycoprotein, etc.
  • the peptide of the invention is a potent inhibitor of p38 MAPK.
  • Various tests carried out by the inventors have shown that said peptide not only reduces the activation and activity on substrates of said MAPK p38 as well as the secretion of inflammatory cytokines but also reduces hyperalgesia in an animal model.
  • the peptide of the invention, as well as the fusion protein of the invention can be used in the treatment of a disease mediated by MAPK p38, such as a disease that can be relieved by inhibiting activation or activity.
  • MAPK p38 biological of said MAPK p38, for example, an inflammatory disease, including autoimmune diseases; a heart disease; Cancer; a neurodegenerative disease; a metabolic disease, for example, diabetes; and a disease that is painful; as well as pain [for a recent review see Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA. Trends Mol Med. 2009 Aug; 15 (8): 369-79.
  • the peptide of the invention as well as the fusion protein of the invention will be formulated in an appropriate pharmaceutical composition.
  • the invention relates to a pharmaceutical composition, hereinafter "pharmaceutical composition of the invention", which comprises a therapeutically effective amount of a peptide of the invention, or of a fusion protein of the invention, or of its pharmaceutically acceptable salts, together with at least one pharmaceutically acceptable carrier.
  • pharmaceutical composition is useful for administration and / or application to a subject.
  • subject refers to a member of a species of a mammalian animal and includes, but is not limited to, domestic animals, primates and humans; preferably said subject is a male or female human being of any age or race.
  • therapeutically effective amount means the amount of peptide of the invention or fusion protein of the invention necessary to achieve the desired effect which, in this particular case, is the treatment and / or prevention of a disease mediated by MAPK p38, such as a disease that can be alleviated by inhibiting the activation or biological activity of said MAPK p38, for example, inflammatory diseases, including autoimmune diseases; heart diseases; Cancer; neurodegenerative diseases; metabolic diseases including diabetes; and diseases that occur with pain; as well as pain.
  • the amount of peptide of the invention, or fusion protein of the invention, or of its pharmaceutically acceptable salts that may be present in the pharmaceutical composition of the invention may vary within a wide range.
  • the therapeutically effective amount of the peptide according to the present invention to be administered will depend, among other factors, on the subject to be treated, on his age, on his condition, on the severity of the disease suffered by said subject, on the chosen method of administration, of the route and frequency of administration of the fusion peptide or protein of the invention to be administered, etc. For this reason, the doses to be administered will be adjusted by a person skilled in the art, depending on the circumstances.
  • pharmaceutically acceptable vehicle refers to a vehicle that must be approved by a federal government regulatory agency or a state government or listed in the US Pharmacopoeia or European Pharmacopoeia, or other generally recognized pharmacopoeia for use in animals, and more specifically in humans.
  • vehicle refers to a diluent, adjuvant, excipient or carrier with which the peptides of the invention or fusion proteins of the invention should be administered; obviously, said vehicle must be compatible with said peptides and fusion proteins of the invention.
  • the pharmaceutical composition of the invention may contain combinations of two or more peptides of the invention or fusion proteins of the invention, as well as combinations of peptides of the invention and fusion proteins of the invention.
  • the pharmaceutical composition of the invention may contain a peptide of the invention together with, optionally, one or more, anti-inflammatory compounds, analgesics, etc., other than said peptide of the invention. Practically, any anti-inflammatory, analgesic, etc. compound, other than said peptide of the invention, may be present, if desired, in the pharmaceutical composition of the invention.
  • anti-inflammatory compounds other than the peptide of the invention, which may be used in conjunction with the peptide of the invention include, but are not limited to, non-steroidal anti-inflammatories, for example, acid derivatives.
  • aminoarylcarboxylic acids eg, fiufenamic acid, niflumic acid, etc.
  • derivatives of arylacetic acid eg, diclofenac, indomethacin, oxametacin, etc.
  • derivatives of arylbutyric acid eg, butibuphene, etc.
  • derivatives of arylcarboxylic acid eg , ketorolac, etc.
  • arylpropionic acid derivatives eg, ibuprofen, ketoprofen, etc.
  • pyrazoles eg, diphenamizol, etc.
  • pyrazolones eg, phenylbutazone, etc.
  • acetylsalicylic acid derivatives eg, acid acetylsalicylic, etc.
  • thiazinecarboxamides eg, isoxicam, piroxicam, etc.
  • others eg, celecoxib, inf
  • analgesic compounds other than the peptide of the invention, which may be used together with the peptide of the invention include, but are not limited to, acetylsalicylic acid, calcium acetylsalicylate, perisoxal, sodium salicylate, etc. . Additional illustrative examples of such anti-inflammatory or analgesic compounds can be found in The Merck Index, 13th Edition, in the "Therapeutic Category and Biological Activity Index" section.
  • the active ingredient (peptide of the invention and / or fusion protein of the invention) contained in the pharmaceutical composition of the invention can be administered by any means that causes contact of said peptide of the invention or fusion protein of the invention with the site of action thereof in the human or animal body.
  • compositions of the invention may be presented in any form of administration, for example, solid, liquid, etc., and may be administered by any appropriate route of administration, for example, orally, parenterally (eg, subcutaneously, intramuscularly, intraperitoneally , intrathecal, intravenous, etc.), rectal, topical, etc., for which they will include the pharmaceutically acceptable carriers necessary for the formulation of the desired administration form.
  • parenterally eg, subcutaneously, intramuscularly, intraperitoneally , intrathecal, intravenous, etc.
  • rectal topical
  • topical etc.
  • pharmaceutical forms of oral administration include tablets, capsules, granules, solutions, suspensions, etc., which may contain the appropriate conventional carriers, such as binders, diluents, disintegrants, lubricants, humectants, etc.
  • compositions of the invention can also be adapted for parenteral administration, in the form of, for example, sterile freeze-dried solutions, suspensions or products, in the appropriate dosage form; in this case, said pharmaceutical compositions of the invention will include suitable pharmaceutically acceptable carriers, such as buffers, surfactants, etc., and can be prepared by conventional methods known to those skilled in the art.
  • suitable pharmaceutically acceptable carriers such as buffers, surfactants, etc.
  • Other forms of administration of the pharmaceutical composition of the invention include aerosols, eye drops, ointments, etc., for which appropriate pharmaceutically acceptable carriers will be used.
  • pharmaceutically acceptable vehicles will be chosen based on the pharmaceutical form of administration selected.
  • Therapeutic uses of the peptide of the invention and of the fusion protein of the invention can be used in the treatment and / or prevention of a p38 MAPK-mediated disease, such as a disease that can be relieved by inhibiting the activation or biological activity of said p38 MAPK.
  • the expression "disease mediated by MAPK p38" or “disease that can be alleviated by inhibiting the activation or biological activity of MAP p38” “includes all types of diseases that occur with inflammation and / or pain, for example, inflammatory diseases, including autoimmune diseases; heart disease; cancer; neurodegenerative diseases; metabolic diseases including diabetes; and diseases that they are in pain, as well as in the treatment of pain [for a recent review see Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA. Trends Mol Med. 2009 Aug; 15 (8): 369-79. p38 ( MAPK): stress responses from molecular mechanisms to therapeutics].
  • inflammatory diseases includes any disease caused by uncontrolled and continued activation of inflammatory responses that cause tissue damage; Said inflammatory response can be triggered by infectious agents, physical agents, chemical agents, tumors and cell death. Autoimmune diseases, to the extent that they also have an inflammatory component, fall within the term "inflammatory diseases” as used herein.
  • inflammatory diseases are classified according to damaged tissue, for example, (i) inflammatory bowel diseases that comprise a set of diseases whose main characteristic is the presence of chronic, sustained or recurrent inflammation in the intestine, such as Crohn's disease, ulcerative colitis, microscopic colitis (which include collagen colitis and lymphocytic colitis), eosinophilic enterocolitis, graft versus host disease (GVH) and actinic colitis among others; (ii) inflammatory diseases of the joints, for example, rheumatoid arthritis, gouty arthritis, polymyalgia rheumatica, tendinitis and bursitis, among others; (iii) other inflammatory diseases such as psoriasis and asthma; and (iv) diseases that occur with an inflammatory component although its etiology is not fundamentally inflammatory.
  • inflammatory bowel diseases that comprise a set of diseases whose main characteristic is the presence of chronic, sustained or recurrent inflammation in the intestine
  • pain refers to a sensory (objective) and emotional (subjective) experience, generally unpleasant, that all living beings who have a nervous system can experience. It is an experience associated with a tissue injury and can refer either to acute or chronic pain. Acute pain is caused by immediate tissue damage (for example, a burn or a cut). It is a natural defense mechanism in response to tissue damage, preventing the use of the damaged part of the body and the withdrawal of the painful stimulus. In contrast, chronic pain persists for three or more months, and even after the damage has healed, and can lead to significant changes in a patient's quality of life [Foley, Pain, Cecil Textbook of Medicine 100-107 , Bennett and F.
  • the peptides and fusion proteins of the invention can also be used for the treatment and / or prevention of inflammatory pain, which is generally the result of an inflammatory response to tissue damage, such as nerve pinching, surgical methods, cancer or arthritis [Brower, Nature Biotechnology 2000; 18: 387-391]. Most patients with inflammatory pain do not experience pain continuously, but experience more pain when they move the inflamed site.
  • the fusion peptides and proteins of the invention are used for the treatment and / or prevention of one of the following pain-related disorders: chronic pain, neuropathic pain, dental pain, post-operative pain, rheumatoid pain, osteoarthritis pain, back pain, visceral pain, cancer pain, neuralgia, migraine, neuropathies, pain related to diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, pain associated with nerve fiber damage, pain associated with ischemia, pain associated with neurodegeneration, pain associated with infarction, post-infarction pain, pain associated with multiple sclerosis, pain secondary to inflammatory disorders, pain associated with inflammatory bowel disease, pain associated with cystitis, pain associated with burns, pain associated with psoriasis .
  • treatment means administration of a peptide of the invention or fusion protein of the invention to alleviate or eliminate one of the diseases mentioned above or reduce or eliminate one or more symptoms associated with said disease
  • treatment also encompasses alleviating or eliminating the physiological sequelae of the disease.
  • prevention refers to the ability of a peptide of the invention or a fusion protein of the invention to prevent, minimize or hinder the onset or development of a disease or been before its appearance. In this case, diseases that are prevented and / or treated, without being limited to these, include diseases that occur with inflammation and / or pain.
  • the invention relates to the use of a peptide of the invention or a fusion protein of the invention in the preparation of a pharmaceutical composition (or medicament) for the prevention and / or treatment of a p38 MAPK-mediated disease, such as a disease that can be relieved by inhibiting the activation or biological activity of said p38 MAPK, eg, diseases that occur with inflammation and / or pain; or, alternatively, expressed in other terms, in another aspect, the invention relates to a peptide of the invention or to a fusion protein of the invention for use in the prevention and / or treatment of a disease mediated by MAPK.
  • p38 such as a disease that can be relieved by inhibiting the activation or biological activity of said MAPK p38, for example, diseases that occur with inflammation and / or pain.
  • the invention relates to a method for the treatment and / or prevention of a disease mediated by MAPK p38, such as a disease that can be relieved by inhibiting the activation or biological activity of said MAPK p38, by For example, a disease that occurs with inflammation and / or pain, which comprises administering to a subject in need of treatment a therapeutically effective amount of a peptide of the invention or a fusion protein of the invention.
  • a disease mediated by MAPK p38 such as a disease that can be relieved by inhibiting the activation or biological activity of said MAPK p38, by
  • a disease that occurs with inflammation and / or pain which comprises administering to a subject in need of treatment a therapeutically effective amount of a peptide of the invention or a fusion protein of the invention.
  • the peptide of the invention can be obtained by conventional synthetic methods, for example, by solid phase chemical synthesis techniques, and purified by conventional methods, for example, by high performance liquid chromatography (HPLC). Additionally, if desired, it can be analyzed by conventional techniques, eg, by sequencing and mass spectrometry, amino acid analysis, nuclear magnetic resonance, etc.
  • the peptide of the invention can be obtained by peptide synthesis following conventional procedures [Merrifield RB. J Am Chem Soc 1963; 85: 2149-2154] using the Fmoc variant of Atherton [Atherton, E., et al. 1989. Peptide synthesis II.
  • the peptide of the invention as well as the fusion protein of the invention can be obtained by recombinant DNA technology. Therefore, in another aspect, the invention provides a nucleic acid, hereinafter "nucleic acid of the invention", which encodes the peptide of the invention or the fusion protein of the invention.
  • nucleic acid of the invention which encodes the peptide of the invention or the fusion protein of the invention.
  • the nucleotide sequence of said nucleic acid of the invention can be easily deduced from the amino acid sequence of the peptide of the invention.
  • Said nucleic acid of the invention may be contained in a gene construct. Therefore, in another aspect, the invention provides a gene construct comprising said nucleic acid of the invention. Said gene construct may incorporate, operably linked, a sequence regulating the expression of the nucleic acid of the invention.
  • Control sequences are sequences that control and regulate transcription and, where appropriate, translation of the peptide of the invention, or of the fusion protein of the invention, and include promoter, terminator, etc. sequences functional in host cells. transformed comprising said nucleic acid of the invention or gene construct provided by this invention. In a particular embodiment, said expression control sequence is functional in bacteria.
  • said gene construct further comprises a marker or gene that encodes a motif or for a phenotype that allows the selection of the host cell transformed with said gene construct.
  • the gene construct provided by this invention can be obtained by using techniques well known in the prior art [Sambrook et al, "Molecular Cloning, a Laboratory Manual", 2nd ed., Cold Spring Harbor Laboratory Press, NY, 1989 Vol 1- 3].
  • the invention relates to a vector, such as an expression vector, comprising said nucleic acid of the invention or said gene construct provided by this invention.
  • a vector such as an expression vector
  • the choice of the vector will depend on the host cell into which it is to be introduced. later.
  • the vector where said nucleic acid of the invention is introduced can be a plasmid or a vector that, when introduced into a host cell, is integrated or not into the genome of said cell.
  • the obtaining of said vector can be carried out by conventional methods known to those skilled in the art [Sambrok et al, 1989, cited supra].
  • the invention relates to a host cell, such as a transformed host cell, comprising said nucleic acid or said gene construct provided by this invention or a vector as mentioned above.
  • Said cell can be a prokaryotic or eukaryotic cell.
  • the invention relates to a process for producing a peptide of the invention or a fusion protein of the invention comprising growing a host cell comprising the nucleic acid of the invention, or a gene construct or vector provided. by this invention, under conditions that allow the production of said peptide of the invention and, if desired, recover said peptide of the invention or said fusion protein of the invention.
  • the conditions for optimizing the culture of said host cell will depend on the host cell used.
  • the process for producing the peptide of the invention or the fusion protein of the invention further includes isolation and purification of said peptide of the invention or said fusion protein of the invention.
  • nucleic acid of the invention as well as the gene constructs provided by this invention can be used in the elaboration of vectors and cells to treat a disease mediated by MAPK p38, such as a disease that can be relieved by inhibition. of the activation or biological activity of said MAPK p38, for example, diseases that occur with inflammation and / or pain.
  • the invention relates to the use of said nucleic acid of the invention or of said gene constructs provided by this invention in the preparation of vectors and cells for the treatment of a disease mediated by MAPK p38, such as a disease that can be alleviated by inhibiting the activation or biological activity of said MAP38 p38, or, alternatively, with said nucleic acid of the invention, or said gene construct containing it provided by this invention, or said vector provided by the invention comprising said nucleic acid of the invention or said gene construct containing it, or said host cell provided by this invention comprising said nucleic acid of the invention, said gene construct, or said vector provided by this invention, for its use in the treatment of a disease mediated by MAPK p38, such as a disease that can be alleviated by inhibiting the activation or biological activity of said MAPK p38, for example, diseases that occur with inflammation and / or pain.
  • a disease mediated by MAPK p38 such as a disease that can be alleviated by inhibiting the activation or
  • said nucleic acid of the invention or said gene construct provided by this invention is contacted with a gene transfer vector, such as a viral or non-viral vector.
  • a gene transfer vector such as a viral or non-viral vector.
  • viral vectors suitable for practicing this embodiment of the invention include, but are not limited to, adenoviral vectors, adeno-associated vectors, retroviral vectors, lentiviral vectors, alpha-viral vectors, herpesviral vectors, coronavirus-derived vectors, etc.
  • Non-viral type vectors suitable for practicing this embodiment of the invention include, but are not limited to naked DNA, liposomes, polyamines, dendrimers, cationic glycopolymers, liposome-polycation complexes, proteins, receptor-mediated gene transfer systems, etc. .
  • the invention relates to a method for the treatment and / or prevention of a disease mediated by MAPK p38, such as a disease that can be relieved by inhibiting the activation or biological activity of said MAPK p38, by
  • a disease that occurs with inflammation and / or pain which comprises administering to a subject in need of treatment a therapeutically effective amount of a nucleic acid of the invention, or a gene construct containing it provided by this invention, or a vector provided by the invention comprising said nucleic acid of the invention or said gene construct containing it, or a host cell provided by this invention comprising said nucleic acid of the invention, said gene construct, or said vector provided by this invention.
  • a potent peptide inhibitory effect provided by this invention [MEF2AxCys (SEQ ID NO: 2)] is observed on in vitro phosphorylation of recombinant MAPK p38 by MKK6, an effect that is not observed in other peptides with similar amino acid sequences but they lack a cistern in the penultimate position.
  • human monocytic cells of said human monocyte cell line THP1 were stimulated with bacterial LPS (Sigma # L2654) at a concentration of between 1 and 1.0 mg / ml (which can vary depending on the batch) for 1 hour in the absence or presence of the L-MEF2AxCys peptide whose amino terminus was fused to the TAT sequence [GRKKRRQRRRPP (SEQ ID NO: 7)], synthesized by the Proteomics Service of the Severo Ochoa Molecular Biology Center (CBMSO), at different concentrations (1 ⁇ , 5 ⁇ and 10 ⁇ ) dissolved in dimethylsulfoxide (DMSO) at a final concentration of 0.1%.
  • bacterial LPS Sigma # L2654
  • GRKKRRQRRRPP SEQ ID NO: 7
  • the MEF2AxCys scrambled (“scrmbl”) peptide was used [corresponds to a peptide with the same amino acids as the MEF2AxCys peptide but in a disordered sequence (SEQ ID NO: 8)] fused at its amino end to said TAT sequence (SEQ ID NO: 7), also synthesized by the Proteomics Service of the CBMSO.
  • the cells were lysed in a 100 mM Tris / HCl buffer pH 7.5, 200 mM EDTA, 1 ⁇ benzamidine, STI (from soybean trypsin inhibitor - soybean trypsin inhibitor) 10 mg / ml, bacitracin 10 mg / ml, aprotinin 80 mU / ml, phenylmethylsulfonyl fluoride (PMSF) 100 ⁇ and p ho STOP (Ro che, Ref. # 04906845001). The samples were subsequently analyzed by Western Blot with specific antibodies.
  • STI from soybean trypsin inhibitor - soybean trypsin inhibitor
  • PMSF phenylmethylsulfonyl fluoride
  • p38 MAPK activation was analyzed by quantifying by densitometry the amount of phosphorylated p38 MAPK in the activation loop (TGY) by Western Blot with anti-phospho-T180-Y182-p38 antibodies (Cell Signaling, Ref. # 9211) and normalizing the values with those obtained for the total p38 MAPK levels in each lysate.
  • the activity of MAPK p38 was quantified by densitometry of the phosphorylation of its MK2 and Hsp27 substrates analyzed by Western Blot with specific antibodies against said phosphorylated proteins: anti-phospho-T334-MK2 (Cell Signaling, Ref. # 3041) and anti-phospho-S78-HSP27 (Cell Signaling, Ref # 2405) and normalizing the values with those obtained for the total MAP38 p38 levels in each lysate.
  • the positive (C +) and negative (C-) controls contained the same amount of DMSO as the peptide points, without LPS in the case of the negative (C-) controls. Additional control was performed with the L-MEF2AxCys scrambled (“scrbl") peptide [corresponding to the MEF2AxCys scrambled peptide (SEQ ID NO: 8) in which the amino acids have the L configuration] attached at their amino terminus to the TAT sequence ( SEQ ID NO: 7), also dissolved in DMSO at a concentration of 10 ⁇ .
  • scrbl L-MEF2AxCys scrambled
  • TNF- ⁇ secreted to the medium in response to LPS was quantified by an ELISA assay (BioTrak, Ref. # RPN2758, GE-Amersham) following the manufacturer's instructions.
  • Cell viability was quantified by FACS flow cytometry (FACScalibur, Becton Dickinson) after staining the cells treated with propidium iodide (1 mg / 1) and quantifying the amount of positive cells for this staining (Software Cell Quest Pro). The results obtained are shown in Table 2 and in Figure 6.
  • IC 50 Average inhibitory concentration [concentration of compound that produces a 50% inhibition of a biological or biochemical function]
  • mice Female BL6-GRK2 +/- mice (C57BL / 6 hemicigotes for GRK2 since the homozygous GRK2 - / - are lethal, obtained from the laboratory of Dr. Marc Carón of Duke University, USA; and described in Jaber M et al. . (1996) Essential role of betaadrenergic receptor kinase 1 in cardiac development and function. Proc Nati Acad Sci USA 93: 12974-12979) (2 mice per group, 4 legs for each condition) underwent an intraplantar injection of carrageenan (Sigma -Aldrich, 5 of a 1% solution in saline) to induce inflammatory hyperalgesia in the extremities.
  • carrageenan Sigma -Aldrich, 5 of a 1% solution in saline
  • the established MAPK p38 inhibitor SB239063 [tra / 75-4- [4- (4-fluorophenyl) -5- (2- methoxy-4-pyrimidinyl) -lH-imidazol-l- was injected intrathecally. il] cyclohexanol] (5 ⁇ g in 5 of 20% DMSO), or the peptides:
  • L-MEF2AxCys 10 ⁇ g in 5 ⁇ of 20% DMSO; or L-MEF2AxCys scrambled [corresponds to the MEF2AxCys scrambled peptide (SEQ ID NO: 8) in which the amino acids have the L configuration], 10 ⁇ g in 5 ⁇ of 20% DMSO.

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Abstract

L'invention concerne un peptide capable d'inhiber l'activation ou l'activité biologique de la protéine kinase activée par le mitogène (MAPK) p38, et son utilisation pour le traitement d'une maladie susceptible d'être soulagée par l'inhibition de l'activation ou de l'activité biologique de ladite MAPK p38, par exemple une maladie inflammatoire ou une maladie s'accompagnant de douleurs.
PCT/ES2011/070774 2010-11-12 2011-11-11 PEPTIDE INHIBITEUR DE p38 ET SES APPLICATIONS WO2012062953A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107556368A (zh) * 2017-07-17 2018-01-09 北京博肽聚康生物技术有限公司 一种蛋白激酶多肽抑制剂

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHUNG I C ET AL.: "Crystal structuctures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activatorMKK3b", MOLECULAR CELL, vol. 9, 2002, pages 1241 - 1249 *
SHEN-HSI Y. ET AL.: "Targeting ofp38 Mitogen-Activated Protein Kinases to MEF2 Transcription Factors", MOLECULAS AND CELLULAR BIOLOGY, 1999, pages 4028 - 4038 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107556368A (zh) * 2017-07-17 2018-01-09 北京博肽聚康生物技术有限公司 一种蛋白激酶多肽抑制剂
WO2019015383A1 (fr) * 2017-07-17 2019-01-24 北京博肽聚康生物技术有限公司 Polypeptide inhibiteur de la protéine kinase
CN107556368B (zh) * 2017-07-17 2019-06-25 北京博肽未名生物技术有限公司 一种蛋白激酶多肽抑制剂

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