WO2014095977A1 - Nouveau peptide pellino - Google Patents

Nouveau peptide pellino Download PDF

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Publication number
WO2014095977A1
WO2014095977A1 PCT/EP2013/077059 EP2013077059W WO2014095977A1 WO 2014095977 A1 WO2014095977 A1 WO 2014095977A1 EP 2013077059 W EP2013077059 W EP 2013077059W WO 2014095977 A1 WO2014095977 A1 WO 2014095977A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
peptide
inflammatory
isolated peptide
pharmaceutically acceptable
Prior art date
Application number
PCT/EP2013/077059
Other languages
English (en)
Inventor
Paul Moynagh
Original Assignee
National University Of Ireland, Maynooth
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 National University Of Ireland, Maynooth filed Critical National University Of Ireland, Maynooth
Publication of WO2014095977A1 publication Critical patent/WO2014095977A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22

Definitions

  • This invention relates to a novel peptide.
  • it relates to a peptide having antiinflammatory activity, pharmaceutical compositions containing it and its use in the treatment or prophylaxis of inflammatory-based diseases and disorders.
  • Inflammatory-based diseases and disorders are rarely mediated by a single molecule but instead are due to a number of mediators acting in a complex interacting network. Most of the prior art has focused on targeting a single mediator and yet this may be insufficient to effectively treat the inflammatory-based disease.
  • LPS lipopolysaccharide
  • IL-1 and TNF LPS-induced pro-inflammatory cytokines
  • IL- 1 and TNF are entirely logical but the similar biological activities of these cytokines may dictate that the activities of both cytokines need to be blocked. Furthermore, these products are proteins and their production is associated with high costs.
  • an isolated peptide having the partial sequence of human full-length Pellino-3 protein comprising amino acid residues 37 - 51 of said Pellino-3 protein, or an analogue thereof having anti-inflammatory activity, in which the natural amino acid sequence other than the tyrosine residue at position 44, has been modified by substitution, insertion or deletion of amino acids, or a pharmaceutically acceptable salt thereof.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogues and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, including
  • amino acids that are modified after incorporation into a polypeptide e.g., hydroxyproline, O-phosphoserine, O-phosphotyrosine, gamma-carboxyglutamate and cysteine.
  • Amino acid analogues refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an alpha-carbon that is bound to a hydrogen, a carboxyl group, an amino group and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
  • Such analogues have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but which function in a manner similar to a naturally occurring amino acid.
  • the amino acid residues described herein are preferably in the "L” isomeric form. However, residues in the "D" isomeric form can be substituted for any L-amino acid residue, as long as the desired antiinflammatory activity is retained by the peptide.
  • the amino-terminal NH 2 group and carboxy- terminal COOH group of free peptides are typically not set forth in a formula.
  • a hyphen at the amino- or carboxy-terminus of a sequence typically indicates the presence of a further sequence of amino acid residues or a respective NH 2 or COOH terminal group.
  • Amino acids may be referred to herein by either their commonly known three-letter symbols or by their one-letter symbols, as shown in the following Table of Correspondence:
  • a peptide of the invention comprises the following sequence of amino acid residues: B-Xn- PGEEPIKYGELIVLG -, wherein:
  • B is an amino-terminal group
  • a peptide of the invention consists of the following sequence of amino acid residues:
  • B is an amino-terminal group
  • Z is a carboxy-terminal group
  • the membrane-translocating peptide when present, may be any suitable membrane-translocating peptide. Particularly preferred is a 16-amino acid sequence from the Drosophila protein,
  • Antennapedia known as penetratin and consisting of the following sequence of amino acid residues: RQIKIWFQNRRMKWKK (SEQ ID NO: 3).
  • the peptide of the invention consists of the following sequence of amino residues corresponding to amino acid residues 37 - 51 of human Pellino-3: PGEEPIKYGELIVLG (SEQ ID NO: 1 ); or the peptide is tandemly linked to a membrane-translocating peptide and consists of the following sequence of amino acid residues corresponding to amino acid residues 37 - 51 of human Pellino-3 contiguous with the 16-amino acid sequence from the
  • Drosophila protein Antennapedia, known as penetratin, referred to above:
  • RQIKIWFQNRRMKWKK-PGEEPIKYGELIVLG (SEQ ID NO: 2).
  • the peptide of the invention or a pharmaceutically acceptable salt thereof may be used in the treatment or prophylaxis of inflammatory-based diseases and disorders.
  • Inflammatory-based diseases and disorders that may be treated or prevented using a peptide of the invention include inflammatory bowel disease, including Crohn's colitis, sepsis, multiple sclerosis, lupus and sarcoidosis.
  • the invention also provides a method for the treatment or prevention of an inflammatory-based disease or disorder in a subject comprising administering to the subject a therapeutically effective amount of a peptide of the invention or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of a peptide of the invention or a pharmaceutically acceptable salt thereof in the treatment or prophylaxis of an inflammatory-based disease or disorder in a subject.
  • the peptides of the invention may be formulated in any vehicle suitable for in vivo, in vitro or therapeutic use.
  • the peptides may be formulated for oral or parenteral administration or they may be formulated in a cream or ointment for topical application.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a peptide according to the invention or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier, diluent or excipient therefor.
  • the pharmaceutical composition may be in any form suitable for administration, e.g., oral, topical or parenteral administration.
  • the pharmaceutical composition of the invention may be used in the treatment or prophylaxis of inflammatory-based diseases and disorders.
  • a peptide of the invention may be obtained by chemical synthesis using any appropriate
  • the peptide may be obtained using a peptide synthesizer and a suitable resin such as 2-chlorotrityl chloride resin and suitable scavengers such as thioanisole, DTT, and phenol, or phenol, water and triisopropylsilane, followed by purification using, e.g., HPLC.
  • a suitable resin such as 2-chlorotrityl chloride resin and suitable scavengers such as thioanisole, DTT, and phenol, or phenol, water and triisopropylsilane
  • septic shock septic shock
  • the peptide of the invention inhibits the ability of LPS to trigger the intracellular signalling pathways that promote the inflammatory response and thus may be used in the treatment of sepsis.
  • the peptide of the invention specifically inhibits the ability of LPS to activate intracellular signalling pathways that normally induce pro-inflammatory proteins.
  • a membrane-translocating peptide such as penetratin (a 16 amino acid sequence from the Drosophila protein Antennapedia)
  • penetratin a 16 amino acid sequence from the Drosophila protein Antennapedia
  • the peptide specifically inhibits LPS signalling and not other agents that employ signalling pathways similar to LPS.
  • the peptide of the invention has the advantage of simultaneously targeting a number of the mediators, a feature that makes it an extremely effective anti-inflammatory agent.
  • Nucleotide-binding oligomerisation domain-2 (NOD2) is an intracellular protein that recognises breakdown products of bacterial peptidoglycan and responds by inducing pro-inflammatory cytokines. Mutations and polymorphisms in NOD2 are associated with diseases such as Crohn's disease. Applicant has found that NOD2 signalling is defective in the absence of Pellino-3 protein, suggesting that the peptide of the invention may be used as an anti-inflammatory agent in the treatment of colitis, including Crohn's colitis.
  • the invention is illustrated in the following non-limiting Examples.
  • the peptide was dissolved in phosphate-buffered saline (PBS) to a stock concentration of 5mM.
  • PBS phosphate-buffered saline
  • HEK293 cells expressing TLR4 were cultured in DMEM supplemented with 10% (v/v) fetal bovine serum, 100 U/ml penicillin and 100 ⁇ g ml streptomycin and maintained in a 37°C humidified atmosphere with 5% C0 2 .
  • HEK-TLR4 cells were seeded (1.5 x 10 5 cells/ml; 200 ⁇ in 96-well plates and grown for 24 h.
  • Pellino3 peptide protects against LPS-induced sepsis
  • LPS lipopolysaccharide
  • Pellino3 Given the role for Pellino3 in negatively regulating pro-inflammatory signalling, the applicant generated a Pellino3 knockout and assessed the effect of Pellino3 deficiency on inflammatory diseases. Colitis was chosen as an inflammatory disease model. Mice were treated with 2.5% DSS dissolved in the drinking water for 5 d, followed by 5 d on normal water. Body weight, occult blood in faeces, and stool consistency/diarrhoea were recorded daily for each mouse to determine the disease activity index (DAI).
  • DAI disease activity index
  • the maximum DAI score was 12 based on assigning a 1-4 scoring system for each parameter: score 0, no weight loss, normal stool, and no blood; score 1 , 1-3% weight loss; score 2, 3-6% weight loss, loose stool (a loose stool was defined as the formation of a stool that readily becomes paste upon handling), and blood visible in stool; score 3, 6-9% weight loss; and score 4, ⁇ 9% weight loss, diarrhoea, and gross bleeding. When mice were killed, the lengths of the colon were measured.
  • the results, which are illustrated in Figure 3 (a)-(e), reveal that PellinoS-deficient mice showed exacerbation of colitis-associated pathology. In Figure 3, the following applies: ":p ⁇ 0 05; **:p ⁇ 0.01 ; ***:p ⁇ 0.001.
  • DMEM Dulbecco's Modified Eagle's Medium
  • HEK Human Embryonic Kidney
  • IL-1 lnterleukin-1
  • JNK Jun N-terminal protein kinase
  • LPS Lipopolysaccharide
  • PBS Phosphate-Buffered Saline
  • TLR Toll-Like Receptor
  • TNF Tumour Necrosis Factor

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un peptide isolé comportant la séquence partielle de la protéine humaine pleine longueur Pellino-3 comprenant les résidus d'acides aminés 37 à 51 de ladite protéine Pellino-3, ou son analogue présentant une activité anti-inflammatoire, des compositions pharmaceutiques contenant ledit peptide ou analogue et son utilisation dans le cadre du traitement ou de la prophylaxie des maladies et d'affections inflammatoires.
PCT/EP2013/077059 2012-12-21 2013-12-18 Nouveau peptide pellino WO2014095977A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1223114.8A GB201223114D0 (en) 2012-12-21 2012-12-21 Novel peptide
GB1223114.8 2012-12-21

Publications (1)

Publication Number Publication Date
WO2014095977A1 true WO2014095977A1 (fr) 2014-06-26

Family

ID=47682356

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/077059 WO2014095977A1 (fr) 2012-12-21 2013-12-18 Nouveau peptide pellino

Country Status (2)

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GB (1) GB201223114D0 (fr)
WO (1) WO2014095977A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2539449B1 (fr) * 2010-02-26 2018-04-25 Qiagen GmbH Procédé d'isolation et/ou de nettoyage parallèle d'ARN et d'ADN
CN111253466A (zh) * 2020-01-19 2020-06-09 华南理工大学 抗炎四肽及其提取分离方法和在制备改善记忆类药物中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083739A2 (fr) * 2000-04-28 2001-11-08 Immunex Corporation Polypeptides pellino humains
US20030165945A1 (en) * 2000-04-28 2003-09-04 Bird Timothy A. Human Pellino polypeptides
WO2007014391A2 (fr) * 2005-07-27 2007-02-01 Nastech Pharmaceutical Company Inc. Composantes peptidiques modulant la jonction serree permettant d'ameliorer le degagement des muqueuses
WO2008016356A2 (fr) * 2006-08-02 2008-02-07 Genizon Biosciences Carte génique des gènes humains associés au psoriaris
WO2009143987A1 (fr) * 2008-05-26 2009-12-03 National University Of Ireland, Maynooth Protéine pellino à codage viral et ses utilisations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083739A2 (fr) * 2000-04-28 2001-11-08 Immunex Corporation Polypeptides pellino humains
US20030165945A1 (en) * 2000-04-28 2003-09-04 Bird Timothy A. Human Pellino polypeptides
WO2007014391A2 (fr) * 2005-07-27 2007-02-01 Nastech Pharmaceutical Company Inc. Composantes peptidiques modulant la jonction serree permettant d'ameliorer le degagement des muqueuses
WO2008016356A2 (fr) * 2006-08-02 2008-02-07 Genizon Biosciences Carte génique des gènes humains associés au psoriaris
WO2009143987A1 (fr) * 2008-05-26 2009-12-03 National University Of Ireland, Maynooth Protéine pellino à codage viral et ses utilisations

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2539449B1 (fr) * 2010-02-26 2018-04-25 Qiagen GmbH Procédé d'isolation et/ou de nettoyage parallèle d'ARN et d'ADN
CN111253466A (zh) * 2020-01-19 2020-06-09 华南理工大学 抗炎四肽及其提取分离方法和在制备改善记忆类药物中的应用
CN111253466B (zh) * 2020-01-19 2021-09-17 华南理工大学 抗炎四肽及其提取分离方法和在制备改善记忆类药物中的应用

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Publication number Publication date
GB201223114D0 (en) 2013-02-06

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