WO2017068020A1 - Analogue de peptide w - Google Patents

Analogue de peptide w Download PDF

Info

Publication number
WO2017068020A1
WO2017068020A1 PCT/EP2016/075176 EP2016075176W WO2017068020A1 WO 2017068020 A1 WO2017068020 A1 WO 2017068020A1 EP 2016075176 W EP2016075176 W EP 2016075176W WO 2017068020 A1 WO2017068020 A1 WO 2017068020A1
Authority
WO
WIPO (PCT)
Prior art keywords
lys
amino acid
peptide
met
trp
Prior art date
Application number
PCT/EP2016/075176
Other languages
English (en)
Inventor
Thomas Boesen
Thomas Engelbrecht Nordkild JONASSEN
Original Assignee
Txp Pharma Gmbh
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 Txp Pharma Gmbh filed Critical Txp Pharma Gmbh
Publication of WO2017068020A1 publication Critical patent/WO2017068020A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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 W-Peptide analogues comprising a W-Peptide, such as the hexapeptide W-Peptide (SEQ ID NO:1 ) and functional variants thereof, and one or more branched amino acid probes.
  • a W-Peptide such as the hexapeptide W-Peptide (SEQ ID NO:1 ) and functional variants thereof, and one or more branched amino acid probes.
  • Proteins and peptides are widely employed for therapeutic purposes whether in their native forms, variant forms or analogues thereof. Protein therapeutics tend to be specific for their targets, leading to potentially fewer side effects, but often with lower bioavailability, poorer membrane permeability, and metabolic instability, as compared to small molecules. Protein-based drugs are generally referred to as 'biologies' and include molecules such as insulin, growth factors, and engineered antibodies.
  • Proteinaceous molecules typically require injection; nevertheless, biologies have been an extremely successful class of therapeutics including antibodies for treatment of arthritis and various cancers, soluble proteins for diabetes, myelosuppression and renal anemia; as well as short injectable peptides for multiple sclerosis, cancers,
  • Peptides represent a class of molecules that have the specificity and potency of larger protein biologies, but are smaller in size and more accessible and cheaper to manufacture using chemical methods, thus potentially combining some of the advantages of proteins with those of small molecules.
  • Protein and peptide compounds can be modified in various ways in order to improve one or more features of the compound, or address one or more potential draw-backs of the compound.
  • a stabilizing peptide sequence may be added to the N- and/or C-terminus of pharmacologically active peptides potentially making them less susceptible to degradation (WO 99/46283).
  • a linear amino acid probe of 6 amino acids selected from Lys or Glu added to the N-terminus of a-MSH potentially increases efficacy compared to the native peptide (WO 07/22774).
  • Known peptide-drug conjugates further include addition of polycationic peptides CPP (cell-penetrating peptides) to improve transport across the cell lipid bi-layer.
  • CPP cell-penetrating peptides
  • the present invention provides W-Peptide analogues comprising one or more branched amino acid probes (abbreviated BAP herein).
  • BAP branched amino acid probes
  • the present invention also provides W-Peptide analogues comprising butyric acid residues.
  • the W-Peptide analogues provided herein have one or more improved properties compared to the corresponding W-Peptide without one or more BAPs ('native' W-peptide).
  • addition of one or more branched amino acid probes to a W-Peptide potentially improves one or more features of the peptide, such as
  • W-Peptide improve or increase an inherent effect of the W-Peptide (including for example increasing the activity, affinity and/or efficacy of a pharmacologically active peptide; improved binding to and/or activation of one or more relevant receptors);
  • W-Peptide alters an inherent effect of the W-Peptide (including for example an altered receptor binding profile), or
  • W-Peptide analogue comprising a W- Peptide and one or more branched amino acid probes
  • said branched amino acid probe comprises a first amino alkyl amino acid residue
  • said first amino alkyl amino acid residue optionally being covalently linked to a second amino alkyl amino acid residue, or to a second and a third amino alkyl amino acid residue, to form a linear chain of 2 or 3 amino alkyl amino acid residues,
  • side chain of one or more of said first, second and/or third amino alkyl amino acid residues are each modified by attaching to the side chain amino group a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) p -AAA q ; AAA q -(aa 3 ) P ; [(aa 3 )-AAA] p and [AAA-(aa 3 )] P ;
  • q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; AAA is an amino alkyl amino acid residue; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala,
  • said first amino alkyl amino acid residue is covalently linked to the N-terminus of said W-Peptide, covalently linked to the C-terminus of said W-Peptide, and/or covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide,
  • said branched amino acid probe consists of 2 to 9 amino acid residues.
  • a W-Peptide according to the present invention is any functional W-Peptide, including W-Peptide (SEQ ID NO:1 ) and any functional variant thereof.
  • the present invention also encompasses pharmaceutical compositions comprising the W-Peptide analogues of the present invention, as well as the analogues of the present invention for use as a medicament.
  • the invention is in one embodiment directed to a W-Peptide analogue according to the present invention for use in the treatment of an ischemic condition, an inflammatory condition, an infection and/or a metabolic condition.
  • Figure 1 Schematic representation of the branched amino acid probe Ac-(Ac-Lys-
  • Lys)Lys- showing the first amino alkyl amino acid residue being a lysine residue (Lysi), covalently linked to the N-terminus of a 'peptide sequence' via a regular peptide bond, said first lysine being acetylated (COCH 3 ), and said first lysine modified by attaching to the ⁇ -amino group of said first lysine residue two further lysine residues wherein one is also acetylated (the outermost).
  • Lysi lysine residue
  • COCH 3 acetylated
  • Figure 2 Binding affinity (a) and receptor efficacy (b) against the human FPR2 receptor of W-peptide analogue #1 : Ac-(Ac-Lys-Lys)Lys-Trp-Lys-Tyr-Met-Val-DMet-NH2 and the control hexapeptide Trp-Lys-Tyr-Met-Val-Met-NH2 (for details see Example 2 and 3) .
  • Figure 3 Binding affinity (a) and receptor efficacy (b) against the human FPR2 receptor of W-peptide analogue #2: Ac-(Ac-Lys-Lys)Lys-Trp-Lys-Tyr-Met-Pro-DMet-NH2 and the control hexapeptide Trp-Lys-Tyr-Met-Val-Met-NH2 (for details see Example 2 and 3).
  • FIG 4 Binding affinity (a) and receptor efficacy (b) against the human FPR2 receptor of W-peptide analogue #3: Ac-(Ac-Lys-Lys)Lys-Trp-Lys-Tyr-Met-Abu-DMet-NH2; where Abu is 2-Aminobutyric acid and the control hexapeptide Trp-Lys-Tyr-Met-Val-Met-NH2 (for details see Example 2 and 3).
  • Figure 5 Binding affinity (a) and receptor efficacy (b) against the human FPR2 receptor of W-peptide analogue #4: Ac-(Ac-Lys)Lys-Trp-Lys-Tyr-Met-Val-DMet-NH2 and the control hexapeptide Trp-Lys-Tyr-Met-Val-Met-NH2 (for details see Example 2 and 3.
  • Figure 6 Binding affinity (a) and receptor efficacy (b) against the human FPR2 receptor of W-peptide analogue #5: Ac-(Ac-Lys)Lys-Trp-Lys-Tyr-Met-Pro-DMet-NH2 and the control hexapeptide Trp-Lys-Tyr-Met-Val-Met-NH2 (for details see Example 2 and 3).
  • Figure 7 Binding affinity (a) and receptor efficacy (b) against the human FPR2 receptor of W-peptide analogue #6: Ac-(Ac-Lys)Lys-Trp-Lys-Tyr-Met-Abu-DMet-NH2; and the control hexapeptide Trp-Lys-Tyr-Met-Val-Met-NH2 (for details see Example 2 and 3).
  • phagocytosis and destruction of microorganisms Phagocytic leukocyte recruitment to sites of inflammation and infection is dependent upon the presence of a gradient of locally produced chemotactic factors.
  • the bacterial peptide N-formyl-methionyl-leucyl- phenylalanine (fMLP) was one of the first of these to be identified and is a highly potent leukocyte chemoattractant. It interacts with receptors on the neutrophil membrane, activating these cells through a G-protein-coupled pathway.
  • the formyl peptide receptors belong to a class of G protein-coupled receptors involved in chemotaxis. These receptors were originally identified by their ability to bind N-formyl peptides such as N-formylmethionine produced by the degradation of either bacterial or host cells. Hence formyl peptide receptors are involved in mediating immune cell response to infection. These receptors may also act to suppress the immune system under certain conditions.
  • W-Peptide The synthetic leukocyte-activating hexapeptide Trp-Lys-Tyr-Met-Val-Met-NH 2 denoted W-Peptide (WKYMVM; SEQ ID NO: 1 ) as well as its D-conformer Trp-Lys-Tyr-Met-Val- DMet-NH 2 (WKYMVm) are known to activate FPRs.
  • W-Peptide variants have been disclosed, e.g. the tritiated peptide WK[3,5 3 H 2 )]YMVM (Christophe et al., J Biol Chem.
  • W-Peptide modified by addition of one or more branched amino acid probes.
  • the W-Peptide analogues are conjugates comprising a W-Peptide and one or more branched amino acid probes.
  • the W-Peptide of the invention comprise W-Peptide (SEQ ID NO:1 ) and functional variants thereof.
  • the W-Peptide analogues as provided herein have certain improved properties compared to the corresponding native or unconjugated W-Peptide.
  • the W-Peptide analogues provided herein have increased binding affinity and/or activation of one or more relevant receptors, such as FPRs.
  • the W-Peptide analogues provided herein are more stable, such as less susceptible to proteases. Still further, in one embodiment the W-Peptide analogues have higher solubility.
  • said branched amino acid probe comprises a first amino alkyl amino acid residue, said first amino alkyl amino acid residue optionally being covalently linked to a second amino alkyl amino acid residue, or to a second and a third amino alkyl amino acid residue, to form a linear chain of 2 or 3 amino alkyl amino acid residues,
  • side chain of one or more of said first, second and/or third amino alkyl amino acid residues are each modified by attaching to the side chain amino group a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) p -AAA q ; AAA q -(aa 3 ) P ; [(aa 3 )-AAA] p and [AAA-(aa 3 )] P ;
  • q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; AAA is an amino alkyl amino acid residue; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala,
  • said first amino alkyl amino acid residue is covalently linked to the N-terminus of said W-Peptide, covalently linked to the C-terminus of said W-Peptide, and/or covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide,
  • said branched amino acid probe consists of 2 to 9 amino acid residues.
  • N-terminal amino acid residue of the molecule is acetylated at the alpha amino group.
  • said first amino alkyl amino acid residue is linked by a peptide bond (amide) formed by a reaction of the carboxylic acid, or a derivative thereof, of said first amino alkyl amino acid with the alpha amino group of the N-terminal amino acid residue of said W-Peptide; linked by a peptide bond to the C-terminal amino acid residue of said W-Peptide formed by reacting the alpha amino group of said amino alkyl amino acid residue with the carboxylic acid, or derivative thereof, of said C- terminal amino acid residue; and/or linked to an amino alkyl amino acid residue within said W-Peptide by an amide formed by a reaction of the carboxylic acid, or a derivative thereof, of said first amino alkyl amino acid residue with the alkyl amino group of the amino alkyl amino acid residue.
  • amide amide
  • said first amino alkyl amino acid residue is covalently linked to the N-terminal Trp of said W-Peptide, covalently linked to the C-terminal Met or DMet of said W-Peptide, and/or covalently linked to the side chain amino group of a Lys or Orn residue within said W-Peptide, such as covalently linked to Lys at position 2 of said W- Peptide.
  • an amino acid residue being covalently linked to further amino acid residues and/or a peptide in one embodiment means that a peptide bond is present.
  • an amino acid residue being covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide means that an amide bond is present.
  • a peptide bond (amide bond) is a covalent chemical bond formed between two molecules when the carboxyl group of one molecule reacts with the amino group of the other molecule, causing the release of a molecule of H 2 0. The process usually occurs between amino acids. If the branched amino acid probe is to be covalently linked to the N-terminus of said W- Peptide, the N-terminal amino alkyl amino acid residue of the backbone of the branched amino acid probe is preferably acetylated.
  • the N-terminal amino alkyl amino acid residue of the backbone of the branched amino acid probe is preferably acetylated.
  • the C-terminal amino alkyl amino acid residue of the backbone of the branched amino acid probe is preferably a carboxylic acid, an aldehyde, an ester, or an amide, such as a primary amide; most preferably amidated.
  • amino alkyl amino acid residues (or AAA) and the amino acid residues (aa 3 ) according to the invention may each be the same (identical) or different (non-identical).
  • an 'amino alkyl amino acid residue' is an amino acid having the conventional amine (-NH 2 ) and carboxylic acid (-COOH) functional groups, and a side chain covalently linked to the first (alpha-) carbon atom, wherein the side-chain comprises an amino alkyl group (-CnH2nNH 2 ).
  • amino alkyl amino acid residue is an amino acid with a side chain comprising or consisting of an amino alkyl group (-CnH2nNH 2 ), in one embodiment denoted a side chain amino alkyl group.
  • the side chain alkyl group is derived from the group consisting of methyl (CH 3 -), ethyl (C 2 H 5 -), propyl (C 3 H 7 -), butyl (C 4 H 9 -), pentyl (C 5 H i ), hexyl (C 6 H 13 - ), heptyl (C 7 H 15 -), octyl (C 8 H 17 -), nonyl (C 9 H 19 -), decyl (Ci 0 H 2 i-), undecyl (CnH 23 -) and dodecyl (Ci 2 H 25 -).
  • butyl is meant to include n-butyl, sec-butyl, isobutyl and t-butyl.
  • the side chain amino group (NH 2 ) of said amino alkyl amino acid residue is the amine of methylamine, the amine of ethylamine, the amine of propylamine, the amine of n-butylamine, the amine of pentylamine, the amine of n- hexylamine, the amine of heptylamine, the amine of octylamine, the amine of nonylamine, the amine of decylamine, the amine of undecylamine or the amine of dodecylamine.
  • the side chain amino alkyl group according to the invention is selected from the group consisting of methylamine (-CH 2 NH 2 ), ethylamine (-C 2 H 4 NH 2 ), propylamine (-C 3 H 6 NH 2 ), n-butylamine (-C 4 H 8 NH 2 ), pentylamine (-C 5 H 1 oNH 2 ), n- hexylamine (-C 6 H 12 NH 2 ), heptylamine (-C 7 H 14 NH 2 ), octylamine (-C 8 H 16 NH 2 ), nonylamine (.C 9 H 18 NH 2 ), decylamine (-CioH 20 NH 2 ), undecylamine (-CnH 22 NH 2 ) and dodecylamine (. C"
  • amino alkyl amino acid residue wherein the side chain is n-butylamine and the side chain amino group is the ⁇ (epsilon) amino group is lysine (Lys, K).
  • ⁇ -amino group is covalently linked to the fourth carbon beginning from the a-carbon.
  • An amino alkyl amino acid residue wherein the side chain is propylamine and the side chain amino group is the ⁇ (delta) amino group is ornithine (Orn).
  • Ornithine is formed in cells by deguanidation of arginine. While it is not used in proteinogenesis in vivo it is a participant in several enzyme pathways and appears to play a role in nitrogen balance in vivo as it can be gaunidated enzymatically to form arginine.
  • amino acid according to the present invention may be in the L- or D-configuration. If nothing is specified, reference to the L-isomeric form is preferably meant. It follows that the amino alkyl amino acid residues of the invention in one embodiment are individually in the L- or D- configuration. In one embodiment the amino alkyl amino acid residues are in the L- configuration. In one embodiment the amino alkyl amino acid residues comprised in the branched amino acid probe are individually selected from the group consisting of lysine and ornithine.
  • amino alkyl amino acid residues of the invention are selected from the group consisting of lysine and D-lysine. In a particular embodiment the amino alkyl amino acid residues of the invention are lysine residues.
  • amino alkyl amino acid residues of the invention are selected from the group consisting ornithine and D-ornithine.
  • a W-Peptide analogue comprising a W-Peptide and one or more branched amino acid probes
  • said branched amino acid probe comprises a first amino acid residue selected from lysine and ornithine,
  • said first amino acid residue optionally being covalently linked to a second, or to a second and a third amino acid residue selected from lysine or ornithine, to form a linear chain of 2 or 3 lysine or ornithine residues,
  • Orn q -Orn (aa 3 ) p -Orn q ; Orn q -(aa 3 ) p ; [(aa 3 )-Orn] p and [Orn-(aa 3 )] p ;
  • Orn p -Lys p Lys p -Orn p ; [Orn-Lys] p and [Lys-Orn] p ;
  • q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala,
  • said first lysine or ornithine residue is covalently linked to the N-terminus of said W-Peptide, covalently linked to the C-terminus of said W-Peptide, and/or covalently linked to the ⁇ -amino group of a lysine residue or the ⁇ -amino group of an ornithine residue within said W-Peptide,
  • said branched amino acid probe consists of 2 to 9 amino acid residues.
  • a W-Peptide analogue comprising a W-Peptide and one or more branched amino acid probes
  • said branched amino acid probe comprises a first lysine residue
  • said first lysine residue optionally being covalently linked to a second, or to a second and a third lysine residue, to form a linear chain of 2 or 3 lysine residues,
  • the side chain of one or more of said first, second and/or third lysine residues are modified by attaching to the ⁇ -amino group of said lysine a molecule independently selected from the group consisting of Lys q -Lys; (aa 3 ) -Lys q ; Lys q -(aa 3 ) ; [(aa 3 )-Lys] p ; [Lys-(aa 3 )] P ; wherein q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala,
  • said first lysine residue is covalently linked to the N-terminus of said W- Peptide, covalently linked to the C-terminus of said W-Peptide, and/or covalently linked to the ⁇ -amino group of a lysine or ⁇ -amino group of an ornithine residue within said W- Peptide,
  • said branched amino acid probe consists of 2 to 9 amino acid residues.
  • a branched amino acid probe according to the present invention in one embodiment consists of 2 to 9 amino acid residues.
  • each of said one or more branched amino acid probe consist of from 2 to 3 amino acid residues, such as from 3 to 4 amino acid residues, for example from 4 to 5 amino acid residues, such as from 5 to 6 amino acid residues, for example from 6 to 7 amino acid residues, such as from 7 to 8 amino acid residues, for example from 8 to 9 amino acid residues.
  • each of said one or more branched amino acid probe consist of 2 amino acid residues, such as 3 amino acid residues, for example 4 amino acid residues, such as 5 amino acid residues, for example 6 amino acid residues, such as 7 amino acid residues, for example 8 amino acid residues, such as 9 amino acid residues.
  • each of said one or more branched amino acid probes consist of 3 amino acid residues.
  • the branched amino acid probe comprises a first amino alkyl amino acid residue (also denoted AAA-i), which first amino alkyl amino acid residue is connected to a W-Peptide to provide a W-Peptide analogue according to the invention.
  • the first amino alkyl amino acid of (each of) the one or more branched amino acid probe(s) is covalently linked to the N-terminus of said W-Peptide, covalently linked to the C-terminus of said W-Peptide, and/or covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide.
  • the first amino alkyl amino acid residue of (each of) the one or more branched amino acid probe(s) is covalently linked to the N-terminal Trp of said W-Peptide, covalently linked to the C-terminal Met or DMet of said W-Peptide, and/or covalently linked to the side chain of a Lys or Orn residue within said W-Peptide, such as covalently linked to Lys at position 2 of W-Peptide.
  • the branched amino acid probe comprises a first amino alkyl amino acid residue.
  • the side chain of said first amino alkyl amino acid residue is modified by attaching to the side chain amino group a molecule as defined herein.
  • first amino alkyl amino acid of the branched amino acid probe is acetylated at the alpha amino group. In one embodiment the N-terminus of the first amino alkyl amino acid residue of the branched amino acid probe is acetylated.
  • the N-terminus of the first amino alkyl amino acid residue of the branched amino acid probe is acetylated when the branched amino acid probe comprising said first amino alkyl amino acid residue is covalently linked to the N- terminus of the W-Peptide; or when the branched amino acid probe comprising said first amino alkyl amino acid residue is covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide.
  • the C-terminus of the first amino alkyl amino acid residue of the branched amino acid probe is a carboxylic acid, an aldehyde, an ester, or an amide, such as a primary amide (CONH 2 ).
  • the C-terminus of the first amino alkyl amino acid residue is amidated.
  • the C-terminus of the first amino alkyl amino acid residue of the branched amino acid probe is an amide when the branched amino acid probe comprising said first amino alkyl amino acid residue is covalently linked to the C- terminus of the W-Peptide.
  • said first amino alkyl amino acid residue is covalently linked to a second amino alkyl amino acid residue to form a linear chain of 2 amino alkyl amino acid residues.
  • the alpha-amino group of the second amino alkyl amino acid residue of the branched amino acid probe is acetylated.
  • the N-terminus of the second amino alkyl amino acid residue of the branched amino acid probe is acetylated.
  • the C-terminus of the second amino alkyl amino acid residue of the branched amino acid probe is a carboxylic acid, an aldehyde, an ester, or an amide, such as a primary amide (CONH 2 ).
  • the C-terminus of the second amino alkyl amino acid residue is amidated.
  • said first amino alkyl amino acid residue is covalently linked to a second and (covalently linked to) a third amino alkyl amino acid residue to form a linear chain of 3 amino alkyl amino acid residues.
  • the alpha-amino group of the third amino alkyl amino acid residue of the branched amino acid probe is acetylated.
  • the N-terminus of the third amino alkyl amino acid residue of the branched amino acid probe is acetylated.
  • the C-terminal of the third amino alkyl amino acid residue of the branched amino acid probe is a carboxylic acid, an aldehyde, an ester, or an amide, such as a primary amide (CONH 2 ).
  • the C-terminus of the third amino alkyl amino acid residue is amidated.
  • first amino alkyl amino acid residue have both the second and third amino alkyl amino acid residues attached at its amine group. In one embodiment the first amino alkyl amino acid residue have both the second and third amino alkyl amino acid residues covalently linked to its carboxylic acid group. In one embodiment the first amino alkyl amino acid residue have the second amino alkyl amino acid residue attached at its amine group and the third amino alkyl amino acid residue attached at its carboxylic acid group.
  • the second and third amino alkyl amino acid residues may be denoted AAA 2 and AAA 3 , respectively.
  • each of said first, second and/or third amino alkyl amino acid residues is an amino acid having a side chain amino alkyl group selected from the group consisting of methylamine (-CH 2 NH 2 ), ethylamine (-C 2 H 4 NH 2 ), propylamine (. C 3 H 6 NH 2 ), n-butylamine ( -- C 4 H 8 NH 2 ), pentylamine (-C 5 H 1 oNH 2 ), n-hexylamine (.
  • each of the first, second and/or third amino alkyl amino acid residues of the branched amino acid probe are individually selected from the group consisting of lysine, D-lysine, ornithine and D-ornithine.
  • each of the first, second and third amino alkyl amino acid residues of the branched amino acid probe are lysine residues (including L-lysine and D-lysine).
  • the first, the second or the third amino alkyl amino acid residues of the branched amino acid probe are acetylated at the alpha amino group (Ac-AAA) (COCHs).
  • the first, the first and second, and the first, second and third amino alkyl amino acid residues of the branched amino acid probe are referred to as the amino alkyl amino acid backbone of the branched amino acid probe (AAA-i, AAA 1-2 , AAA 1-3 ).
  • first, the first and second, and the first and second and third amino alkyl amino acid residues are each lysine residues. In one embodiment the first, the first and second, and the first, second and third lysine residues of the branched amino acid probe are referred to as the lysine backbone of the branched amino acid probe (Lysi, Lysi -2 , Lysi -3 ).
  • the first lysine residue, or the second lysine residue, or the third lysine residue of the lysine backbone of the branched amino acid probe is acetylated at the alpha-amino group (Ac-Lys).
  • the side chain of one of said first, second and/or third amino alkyl amino acid residues are modified by attaching to the side chain amino group a molecule as defined herein.
  • the branched amino acid probe comprises a first amino alkyl amino acid residue, wherein the side chain of said first amino alkyl amino acid residue is modified by attaching to the side chain amino group a molecule as defined herein.
  • the branched amino acid probe comprises a first and a second amino alkyl amino acid residue, wherein the side chain of said first amino alkyl amino acid residue is modified by attaching to the side chain amino group a molecule as defined herein.
  • the branched amino acid probe comprises a first and a second amino alkyl amino acid residue, wherein the side chain of said second amino alkyl amino acid residue is modified by attaching to the side chain amino group a molecule as defined herein.
  • the branched amino acid probe comprises a first and a second amino alkyl amino acid residue, wherein the side chains of said first and second amino alkyl amino acid residue are modified by attaching to the side chain amino group a molecule as defined herein.
  • the side chain of two of said first, second and/or third amino alkyl amino acid residues are modified by attaching to the side chain amino group a molecule as defined herein.
  • the side chain of all three of the first, second and third amino alkyl amino acid residues are modified by attaching to the side chain amino group a molecule as defined herein.
  • the side chain of i) the first amino alkyl amino acid residue, ii) the second amino alkyl amino acid residue, iii) the third amino alkyl amino acid residue, iv) the first and the second amino alkyl amino acid residues, v) the first and the third amino alkyl amino acid residues, vi) the second and the third amino alkyl amino acid residues, or vii) the first, the second and the third amino alkyl amino acid residues, are modified by attaching to the side chain amino group a molecule as defined herein.
  • first lysine residue, or the second lysine residue, or the third lysine residue, or the first and the second lysine residues, or the first and the third lysine residues, or the second and the third lysine residues, or the first, the second and the third lysine residues of the lysine backbone of the branched amino acid are modified by attaching a molecule to the ⁇ -amino group.
  • the side chain of one or more of each of said first, second and/or third amino alkyl amino acid residues is modified by attaching to the side chain amino group a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) -AAA q ; AAA q -(aa 3 ) ; [(aa 3 )-AAA] p and [AAA-(aa 3 )] ; wherein q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; AAA is an amino alkyl amino acid residue; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala.
  • N-terminal AAA or (aa) 3 of the molecule is acetylated at the alpha amino group.
  • side chain of one or more of each of said first, second and/or third amino alkyl amino acid residues is modified by attaching to the side chain amino group a molecule independently selected from the group consisting of
  • Lys q -Lys (aa 3 ) P -Lys q ; Lys q -(aa 3 ) P ; [(aa 3 )-Lys] p ; [Lys-(aa 3 )] P ;
  • Orn q -Orn (aa 3 ) p -Orn q ; Orn q -(aa 3 ) p ; [(aa 3 )-Orn] p and [Orn-(aa 3 )] p ;
  • Orn p -Lys p Lys p -Orn p ; [Orn-Lys] p and [Lys-Orn] p ;
  • q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala.
  • the N-terminal Lys, Orn or (aa) 3 of the molecule is acetylated at the alpha amino group.
  • the side chain of one or more of each of said first, second and/or third amino alkyl amino acid residues is modified by attaching to the side chain amino group a molecule independently selected from the group consisting of Lys q -Lys; (aa 3 ) p - Lys q ; Lys q -(aa 3 ) p ; [(aa 3 )-Lys] p and [Lys-(aa 3 )] p ; wherein q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; Lys is a lysine residue selected from L-Lys and D-Lys; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala.
  • the N-terminal Lys or (aa) 3 of the molecule is acetylated at the alpha amino group.
  • the side chain of one or more of each of said first, second and/or third lysine residues of the lysine backbone is modified by attaching to the ⁇ -amino group of the side chain a molecule independently selected from the group consisting of Lys q -Lys; (aa 3 ) p -Lys q ; Lys q -(aa 3 ) p ; [(aa 3 )-Lys] p and [Lys-(aa 3 )] p ; wherein q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; Lys is a lysine residue selected from L-Lys and D-Lys; and (aa 3 ) is an amino acid residue
  • the N-terminal Lys or (aa) 3 of the molecule is acetylated at the alpha amino group.
  • the side chain of one or more of each of said first, second and/or third lysine residues of the lysine backbone are modified by attaching to the ⁇ -amino group of the side chain a molecule being Lys q -Lys; wherein q is a number selected from 0, 1 , 2 and 3.
  • the N-terminal Lys of the molecule is acetylated at the alpha amino group.
  • the molecule to be covalently linked to the ⁇ -amino group of the one or more lysine residues of the lysine backbone of the branched amino acid probe are independently selected from the group consisting of Lys q -Lys; (aa 3 ) -Lys q ; Lys q - (aa 3 ) ; [(aa 3 )-Lys] p and [Lys-(aa 3 )] P , wherein q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3, and (aa 3 ) is an amino acid residue
  • N-terminal Lys or (aa) 3 of the molecule is acetylated at the alpha amino group.
  • first lysine residue, or the second lysine residue, or the third lysine residue, or the first and the second lysine residues, or the first and the third lysine residues, or the second and the third lysine residues, or the first, the second and the third lysine residues of the branched amino acid probe are each modified by attaching to the ⁇ -amino group(s) a molecule independently selected from the group consisting of Lys q -Lys; (aa 3 ) p -Lys q ; Lys q -(aa 3 ) p ; [(aa 3 )-Lys] p and [Lys-(aa 3 )] p , wherein q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3, and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala
  • N-terminal Lys or (aa) 3 of the molecule is acetylated at the alpha amino group.
  • (aa 3 ) is an amino acid residue independently selected from Gly and Ala.
  • (aa 3 ) is Gly.
  • the molecules to be covalently linked to the side chain amino group(s) of said first, second and/or third alkyl amine amino acid residue are acetylated at the alpha amino group of the N-terminal amino acid residue.
  • the molecules are independently selected from the group consisting of Ac-AAA q -AAA; Ac-(aa 3 ) p -AAA q ; Ac-AAA q -(aa 3 ) p ; Ac-[(aa 3 )-AAA] p and Ac- [AAA-(aa 3 )] p ; and/or AAA q -AAA; (aa 3 ) p -AAA q ; AAAq-(aa 3 ) p ; [(aa 3 )-AAA] p and [AAA- (aa 3 )] P .
  • the molecules are independently selected from the group consisting of Ac-Orn q -Orn; Ac-(aa 3 ) p -Orn q ; Ac-Orn q -(aa 3 ) p ; Ac-[(aa 3 )-Orn] p ; Ac-[Orn- (aa 3 )] p ; Ac-Orn p -Lys p ; Ac-Lys p -Orn p ; Ac-[Orn-Lys] p and Ac-[Lys-Orn] p ; and/or Orn q -Orn; (aa 3 ) P -Orn q ; Orn q -(aa 3 ) P ; [(aa 3 )-Orn] p and [Orn-(aa 3 )] P ; Orn p -Lys p ; Lys p -Orn p ; [Orn-Lys]
  • the molecules are in one embodiment independently selected from the group consisting of Ac-Lys q -Lys; Ac-(aa 3 ) p -Lys q ; Ac-Lys q -(aa 3 ) p ; Ac-[(aa 3 )-Lys] p and Ac- [Lys-(aa 3 )] p ; and/or Lys q -Lys; (aa 3 ) p -Lys q ; Lys q -(aa 3 ) p ; [(aa 3 )-Lys] p and [Lys-(aa 3 )] p.
  • the molecule to be covalently linked to the side chain amino group(s) is Ac-AAA q -AAA or AAA q -AAA, wherein q is a number selected from 0, 1 , 2 and 3.
  • the branched amino acid probe consists of 2 to 9 amino alkyi amino acid residues.
  • said 2 to 9 amino alkyi amino acid residues are individually selected from the group consisting of lysine, D-lysine, ornithine and D-ornithine.
  • the molecule to be covalently linked to the side chain amino group(s) is Ac-Lys q -Lys or Lys q -Lys, wherein q is a number selected from 0, 1 , 2 and 3.
  • the branched amino acid probe consists of 2 to 9 lysine residues.
  • the branched amino acid probe comprises a maximum of 1 , 2, 3 or 4 amino acids selected from Arg, His, Gly and Ala (aa 3 ), wherein the remaining amino acids are amino alkyi amino acid residues.
  • the branched amino acid probe comprises a maximum of 1 Arg residue, and/or comprises a maximum of 1 His residue, and/or comprises a maximum of 1 Gly residue, and/or comprises a maximum of 1 Ala residue.
  • the molecule to be covalently linked to the side chain amino group(s) of one or more of the first, second and/or third amino alkyi amino acid residues is selected from the group consisting of AAA, Ac-AAA, AAA-AAA, Ac-AAA- AAA, AAA-AAA-AAA, Ac-AAA-AAA-AAA, AAA-AAA-AAA-AAA, Ac-AAA-AAA-AAA, AAA-Gly-AAA, Ac-AAA-Gly-AAA, AAA-AAA-Gly, Ac-AAA-AAA-Gly, AAA-Gly, Ac- AAA-Gly, AAA-Ala-AAA, Ac-AAA-Ala-AAA, AAA-AAA-Ala, Ac-AAA-AAA-AI a , AAA-Ala, Ac-AAA-Ala, AAA-His-AAA, Ac-AAA-His-AAA, AAA-AAA-His, Ac-AAA-AAA-His, AAA
  • the molecule to be covalently linked to the side chain amino group(s) of one or more of the first, second and/or third amino alkyl amino acid residues is selected from the group consisting of Lys, Ac-Lys, Lys-Lys, Ac-Lys-Lys,
  • Lys-Lys-Lys Ac-Lys-Lys-Lys, Lys-Lys-Lys-Lys, Ac-Lys-Lys-Lys-Lys, Lys-Gly-Lys, Ac- Lys-Gly-Lys, Ac- Lys-Gly-Lys, Lys-Lys-Gly, Ac-Lys-Lys-Gly, Lys-Gly, Ac-Lys-Gly, Lys-Ala-Lys, Ac-Lys- Ala-Lys, Lys-Lys-Ala, Ac-Lys-Lys-Ala, Lys-Ala, Ac-Lys-Ala, Ac-Lys-Ala, Ac-Lys-Ala, Ac-Lys-Ala, Lys-His-Lys, Ac-Lys-His- Lys, Lys-Lys-His, Ac-Lys
  • the molecule to be covalently linked to the ⁇ -amino group(s) of one or more of the first, second and/or third lysine residues is selected from the group consisting of Lys, Ac-Lys, Lys-Lys, Ac-Lys-Lys, Lys-Lys-Lys, Ac-Lys-Lys-Lys, Lys-Lys-Lys, Ac-Lys-Lys-Lys-Lys, Lys-Gly-Lys, Ac-Lys-Gly-Lys, Lys-Lys-Gly, Ac- Lys-Lys-Gly, Lys-Gly, Ac-Lys-Gly, Lys-Gly, Ac-Lys-Gly, Lys-Gly, Ac-Lys-Gly, Lys-Ala-Lys, Ac-Lys-Ala, Lys-Ala, Ac-Lys-Ala, Lys
  • the branched amino acid probe comprise or consist of a first lysine residue selected from Lys and D-Lys, said first lysine residue being optionally N-terminally acetylated or C-terminally amidated, wherein said first lysine residue is modified by attaching to the ⁇ -amino group of said first lysine residue a molecule selected from the group consisting of Lys, Ac-Lys, Lys-Lys, Ac-Lys-Lys, Lys- Lys-Lys, Ac-Lys-Lys-Lys, Lys-Lys-Lys-Lys, Ac-Lys-Lys-Lys-Lys, Lys-Gly-Lys, Ac-Lys- Gly-Lys, Lys-Lys-Gly, Ac-Lys-Gly, Lys-Gly, Ac-Lys-Gly, Lys-Gly, Ac-Lys-Gly
  • the branched amino acid probe comprise or consist of a first and a second lysine residue each selected from Lys and D-Lys, said second lysine residue being optionally N-terminally acetylated or C-terminally amidated, wherein i) said first lysine residue, ii) said second lysine residue, or iii) said first and second residue are each modified by attaching to the ⁇ -amino group of said lysine residue a molecule selected from the group consisting of Lys, Ac-Lys, Lys-Lys, Ac-Lys-Lys, Lys- Lys-Lys, Ac-Lys-Lys-Lys, Lys-Lys-Lys-Lys, Ac-Lys-Lys-Lys-Lys, Ac-Lys-Lys-Lys-Lys, Lys-Gly-Lys, Ac-Lys- Gly-Ly
  • the branched amino acid probe comprise or consist of a first, a second and a third lysine residue each selected from Lys and D-Lys, said third lysine residue being optionally N-terminally acetylated or C-terminally amidated, wherein i) said first lysine residue, ii) said second lysine residue, iii) said third lysine residue, iv) said first and second lysine residue, v) said first and third lysine residue, vi) said second and third lysine residue, or vii) said first, second and third lysine residues are each modified by attaching to the ⁇ -amino group of said lysine residue a molecule selected from the group consisting of Lys, Ac-Lys, Lys-Lys, Ac-Lys-Lys, Lys-Lys-Lys, Ac-Lys-Lys-Lys, Lys-Lys, Lys-
  • the branched amino acid probe comprises or consists of the formula: Ac-(Ac-Lys-Lys)Lysr (identical to Ac-(Ac-Lys-Lys)Lys-), wherein Lysi is the first lysine residue, which is acetylated, covalently linked to the N-terminus of a peptide such as W-Peptide, and (Ac-Lys-Lys) is the molecule covalently linked to the ⁇ -amino group of said first lysine residue Lysi.
  • Figure 1 illustrates this formula/structure.
  • Ac-(Ac-Lys-Lys)Lys- is covalently linked to the N-terminal of the W- peptide and/or to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide.
  • the branched amino acid probe comprises or consists of the formula: Ac-(Ac-Lys)Lysr.
  • the branched amino acid probe comprises or consists of the formula: (Ac-Lys-Lys)LysrNH 2 (identical to (Ac-Lys-Lys)Lys-NH 2 ), wherein Lysi is the first lysine residue, which is amidated (-NH 2 ) at the C-terminal, and (Ac-Lys-Lys) is the molecule attached to the ⁇ -amino group of said first lysine residue Lysi.
  • (Ac-Lys-Lys)LysrNH 2 is attached to the C-terminal of the W-peptide.
  • the branched amino acid probe comprises or consists of a formula selected from the group consisting of (AAA)AAA , (AAA-AAA)AAA , (AAA-AAA- AAA)AAA , (AAA-AAA-AAA-AAA)AAAr, (AAA-Gly-AAA)AAA , (AAA-AAA-Gly)AAA , (AAA-Gly)AAA-i-, (AAA-Ala-AAA)AAA , (AAA-AAA-Ala)AAA , (AAA-Ala)AAA , (AAA-Ala)AAA , (AAA- His-AAA)AAA , (AAA-AAA-His)AAA , (AAA-His)AAA , (AAA-Arg-AAA)AAA , (AAA- AAA- Arg)AAA , and (AAA-Arg)AAA .
  • said first amino alkyl amino acid reside (AAA ) is
  • the branched amino acid probe comprises or consists of a formula selected from the group consisting of (Lys)Lysr, (Lys-Lys)Lysr, (Lys-Lys-Lys)Lysr, (Lys-Lys-Lys-Lys)Lysr, (Lys-Gly-Lys)Lysr, (Lys-Lys-Gly)Lysr, (Lys-Gly)Lysr, (Lys- Ala-Lys)Lysr, (Lys-Lys-Ala)Lysr, (Lys-Ala)Lysr, (Lys-His-Lys)Lysr, (Lys-Lys- His)Lysr, (Lys-His)Lysr, (Lys-Arg-Lys)Lysr, (Lys-Lys-Arg)L
  • the branched amino acid probe comprises or consists of a formula selected from the group consisting of Ac-(Ac-Lys)Lysr, Ac-(Ac-Lys-Lys)Lysr, Ac-(Ac- Lys-Lys-Lys)Lysr, Ac-(Ac-Lys-Lys-Lys)Lysr, Ac-(Ac-Lys-Gly-Lys)Lysr, Ac-(Ac- Lys-Lys-Gly)Lysr, Ac-(Ac-Lys-Gly)Lysr, Ac-(Ac-Lys-Gly)Lys , Ac-(Ac-Lys-Ala-Lys)Lys , Ac-(Ac-Lys-Lys- Ala)Lysr, Ac-(Ac-Lys-Ala)Lysr, Ac-(Ac-Lys-His
  • the branched amino acid probe comprises or consists of a formula selected from the group consisting of (Ac-Lys)LysrNH 2 , (Ac-Lys-Lys)LysrNH 2 , (Ac- Lys-Lys-Lys)Lysi-NH 2 , (Ac-Lys-Lys-Lys-Lys)LysrNH 2 , (Ac-Lys-Gly-Lys)Lys NH 2 , (Ac- Lys-Lys-Gly)Lys NH 2 , (Ac-Lys-Gly)Lys NH 2 , (Ac-Lys-Gly)Lys NH 2 , (Ac-Lys-Ala-Lys)Lys NH 2 , (Ac-Lys-Lys- Ala)Lys NH 2 , (Ac-Lys-Ala)Lys
  • the branched amino acid probe comprises or consists of a formula selected from the group consisting of Ac-(Ac-Lys)Lysi-, Ac-(Ac- Lys-Lys)Lysi-, Ac-(Ac-Lys-Lys-Lys)Lysi-, Ac-(Ac-Lys-Lys-Lys)Lysi-, Ac-(Ac-Lys- Gly-Lys)Lysr, Ac-(Ac-Lys-Lys-Gly)Lysr and Ac-(Ac-Lys-Gly)Lysr.
  • the branched amino acid probe comprises or consists of the formula: Ac-(Ac-Lys)Lys 2 -Lysi-, wherein Lysi is the first lysine residue, Lys 2 is the second lysine residue which is acetylated and covalently linked to Lysi via a peptide bond, and (Ac-Lys) is the molecule covalently linked to the ⁇ -amino group of said second lysine residue Lys 2 .
  • the branched amino acid probe comprises or consists of the formula: Ac-Lys 2 -(Ac-Lys)Lysi-, wherein the molecule (Ac-Lys) is covalently linked to the ⁇ -amino group of said first lysine residue Lysi.
  • branched amino acid probe(s) is selected from the group consisting of
  • the branched amino acid probe(s) is selected from the group consisting of Ac-(Ac-Lys)Lys-, Ac-(Lys)Lys-, (Ac-Lys) Lys-NH 2 , (Lys)Lys-NH 2 and (Lys)Lys-.
  • the branched amino acid probe is selected from the group consisting of Ac-(Ac-Lys)Lys 2 -Lysr, Ac-(Ac-Lys-Lys)Lys 2 -Lysr, Ac-(Ac-Lys-Gly)Lys 2 - Lysr, Ac-(Ac-Lys-Lys-Lys)Lys 2 -Lysr, Ac-(Ac-Lys-Lys-Lys-Lys)Lys 2 -Lysr, Ac-Lys 2 -(Ac- Lys)-Lysi-, Ac-Lys 2 -(Ac-Lys-Lys)-Lysr, Ac-Lys 2 -(Ac-Lys-Gly)-Lysr, Ac-Lys 2 -(Ac-Lys- Lys-Lys)-Lysi-, Ac-Lys
  • the branched amino acid probe is selected from the group consisting of Ac-(Ac-Lys)Lys 2 -Lysi-, Ac-(Ac-Lys-Lys)Lys 2 -Lysi-, Ac-(Ac-Lys- Gly)Lys 2 -Lysi-, Ac-Lys 2 -(Ac-Lys)-Lysr, Ac-Lys 2 -(Ac-Lys-Lys)-Lysr, Ac-Lys 2 -(Ac-Lys- Gly)-Lysr, Ac-(Ac-Lys)Lys 2 -(Ac-Lys-)-Lysr, Ac-(Ac-Lys)Lys 2 -(Ac-Lys-)-Lysr, Ac-(Ac-Lys)Lys 2 -(Ac-Lys-)-Lysr,
  • the branched amino acid probe is selected from the group consisting of Ac-Lys 3 - Lys 2- (Ac-Lys)Lysr, Ac-Lys 3 -(Ac-Lys)Lys 2 -Lysr, Ac-(Ac-Lys)Lys 3 - Lys 2 -Lysi-, Ac-Lys 3 -(Ac-Lys)Lys 2 -(Ac-Lys)Lysr, Ac-(Ac-Lys)Lys 3 -(Ac-Lys)Lys 2 -Lysr, and Ac-(Ac-Ly s ) Ly s 3 - Ly s 2 -(Ac- Ly s ) Ly s i - .
  • the branched amino acid probe is selected from the group consisting of Ac-(Ac-Lys)Lysr, Ac-(Ac-Lys-Lys)Lysi-, Ac-(Ac-Lys-Lys-Lys)Lysi-, Ac- (Ac-Lys-Lys-Lys)Lysr, Ac-(Ac-Lys-Gly-Lys)Lysi-, Ac-(Ac-Lys-Lys-Gly)Lysi-, Ac- (Ac-Lys-Gly)Lysr, Ac-(Ac-Lys-Gly)Lysr, Ac-(Ac-Lys)Lys 2 -Lysr, Ac-(Ac-Lys-Lys)Lys 2 -Lysr, Ac-(Ac-Lys- Gly)Lys 2 -Lysr, Ac-Lys
  • the branched amino acid probe consists of 2 or 3 lysine residues (selected from Lys and D-Lys). In a particular embodiment, the branched amino acid probe consists of 3 lysine residues. In another embodiment, the branched amino acid probe consists of 2 lysine residues.
  • the branched amino acid probe consists of a first and a second lysine residue selected from Lys and D-Lys, wherein one or both of the first and second lysine residues are modified by attaching to the ⁇ -amino group of said first and/or second lysine residue one lysine residue selected from Lys and D-Lys; wherein each of said lysine residues are optionally acetylated at the alpha amino group.
  • the branched amino acid probe consists of a first lysine residue selected from Lys and D-Lys, wherein said first lysine residue is modified by attaching to the ⁇ -amino group of said first lysine residue two lysine residues selected from Lys and D-Lys; wherein each of said lysine residues are optionally acetylated at the alpha amino group.
  • the first amino alkyl amino acid residue of each of the one or more branched amino acid probes is covalently linked to the N-terminus of a W- Peptide, covalently linked to the C-terminus of a W-Peptide, and/or covalently linked to the side chain amino group of an amino alkyl amino acid residue within a W-Peptide to be modified according to the invention.
  • covalently linked to the N-terminus of said W-Peptide means that the first amino alkyl amino acid residue of the branched amino acid probe is covalently linked to the alpha amino group of the most N-terminal amino acid residue of W-Peptide.
  • covalently linked to the C-terminus of said W-Peptide means that the alpha amino group of the first amino alkyl amino acid residue of the branched amino acid probe is covalently linked to the most C-terminal amino acid residue of W-Peptide.
  • a branched amino acid probe in one embodiment is covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide.
  • Peptide sequence is selected from the group consisting of an ornithine residue and a lysine residue.
  • said amino alkyl amino acid residue within said peptide sequence is a lysine residue.
  • the first amino alkyl amino acid residue of the branched amino acid probe is covalently linked to the ⁇ -amino group of an ornithine residue within said W- Peptide or the ⁇ -amino group of a lysine residue within said W-Peptide.
  • the first amino alkyl amino acid residue of the branched amino acid probe is covalently linked to the ⁇ -amino group of a lysine residue within said W- Peptide.
  • the first amino alkyl amino acid residue of the branched amino acid probe is covalently linked to the ⁇ -amino group of the lysine residue at position 2 of said W-Peptide.
  • first amino alkyl amino acid residue of the branched amino acid probe is covalently linked to the N-terminal Trp of said W-Peptide. In one embodiment the first amino alkyl amino acid residue of the branched amino acid probe is covalently linked to the C-terminal Met or DMet of said W-Peptide.
  • an amino alkyl amino acid residue within said peptide sequence means that the amino alkyl amino acid residue does not form part of the branched amino acid probe per se, but is a residue occurring within the existing amino acid sequence of the W-Peptide. Said amino alkyl amino acid residue can be positioned at any position of the W-Peptide.
  • a peptide analogue comprising one or more branched amino acid probes means that the peptide analogue in one embodiment comprises 1 branched amino acid probe, such as 2 branched amino acid probes, for example 3 branched amino acid probes, such as 4 branched amino acid probes, for example 5 branched amino acid probes, such as 6 branched amino acid probes.
  • the peptide analogue can comprise any number of branched amino acid probes provided they can be covalently linked to the peptide (N-terminally, C-terminally and/or one or more amino alkyl amino acid residues within said W-Peptide).
  • the W-Peptide analogue comprises 1 branched amino acid probe.
  • the W-Peptide analogue comprises 1 branched amino acid probe, which branched amino acid probe is covalently bound to the N-terminus of the W- Peptide. In one embodiment the W-Peptide analogue comprises 1 branched amino acid probe, which branched amino acid probe is covalently bound to the C-terminus of the W- Peptide.
  • the W-Peptide analogue comprises 1 branched amino acid probe, which branched amino acid probe is covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide.
  • the W-Peptide analogue comprises more than one (two or more) branched amino acid probe(s). In the embodiments wherein the W-Peptide analogue comprises more than one branched amino acid probe it is understood that the more than one branched amino acid probes may individually be the same (identical) or different (non-identical).
  • the W-Peptide analogue comprises 2 branched amino acid probes.
  • the W-Peptide analogue comprises 2 branched amino acid probes, wherein one branched amino acid probe is covalently bound to the N-terminus of the W-Peptide and another branched amino acid probe is covalently bound to the C- terminus of the W-Peptide. In one embodiment the W-Peptide analogue comprises 2 branched amino acid probes, wherein one branched amino acid probe is covalently bound to the N-terminus of the W-Peptide and another branched amino acid probe is covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide.
  • the W-Peptide analogue comprises 2 branched amino acid probes, wherein one branched amino acid probe is covalently bound to the C-terminus of the W-Peptide and another branched amino acid probe is covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide.
  • the peptide analogue comprises 2 branched amino acid probes, wherein each of the two branched amino acid probes are covalently linked to the side chain amino group of different (or separate) amino alkyl amino acid residues within said W-Peptide.
  • the W-Peptide analogue comprises 3 branched amino acid probes.
  • the W-Peptide analogue comprises 3 branched amino acid probes, wherein the first branched amino acid probe is covalently bound to the N-terminus of the W-Peptide, the second branched amino acid probe is covalently bound to the C- terminus of the W-Peptide and the third branched amino acid probe is covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W- Peptide.
  • the W-Peptide analogue comprises 3 branched amino acid probes, wherein the first branched amino acid probe is covalently bound to the N-terminus of the W-Peptide, and the second and third branched amino acid probes are each covalently linked to the side chain amino group of different amino alkyl amino acid residues within said W-Peptide.
  • the W-Peptide analogue comprises 3 branched amino acid probes, wherein the first branched amino acid probe is covalently bound to the C-terminus of the W-Peptide, and the second and third branched amino acid probes are each covalently linked to the side chain amino group of different amino alkyl amino acid residues within said W-Peptide.
  • the W-Peptide analogue according to the present invention comprises a W-peptide as defined herein and one or more branched amino acid probes.
  • a W-Peptide according to the invention comprises any functional W-Peptide, including W-Peptide (SEQ ID NO:1 ) and any functional variant thereof.
  • each amino acid of the hexapeptide W-peptide is referred to as Trp (position 1 ) - Lys (position 2) - Tyr (position 3) - Met (position 4) - Val (position 5) - Met (position 6).
  • a W-Peptide according to the present invention is Trp-Lys-Tyr-Met- Val-Met (SEQ ID NO:1 ) or a functional variant thereof. In one embodiment a W-Peptide according to the present invention is Trp-Lys-Tyr-Met-Val-DMet or a functional variant thereof.
  • a W-Peptide, or a functional variant thereof includes any W-Peptide which binds to one or more of the formyl peptide receptors, including Formyl Peptide Receptor 1 (FPR1 )(Uniprot P21462), Formyl Peptide Receptor 2 (FPR2)(Uniprot P25090) and Formyl Peptide Receptor 3 (FPR3)(Uniprot 25089).
  • FPR1 Formyl Peptide Receptor 1
  • FPR2 Formyl Peptide Receptor 2
  • FPR3 Formyl Peptide Receptor 3
  • a functional W-Peptide in one embodiment is a W-Peptide which activates and/or stimulates one or more of Formyl Peptide Receptor 1 (FPR1 ), Formyl Peptide Receptor 2 (FPR2) and Formyl Peptide Receptor 3 (FPR3).
  • FPR1 Formyl Peptide Receptor 1
  • FPR2 Formyl Peptide Receptor 2
  • FPR3 Formyl Peptide Receptor 3
  • a functional W-Peptide in one embodiment is a W-Peptide which is a ligand and/or agonist of one or more of Formyl Peptide Receptor 1 (FPR1 ), Formyl Peptide Receptor 2 (FPR2) and Formyl Peptide Receptor 3 (FPR3).
  • FPR1 Formyl Peptide Receptor 1
  • FPR2 Formyl Peptide Receptor 2
  • FPR3 Formyl Peptide Receptor 3
  • agonist in the present context refers to a W-Peptide as defined herein, capable of binding to, or in some embodiments, capable of binding to at least some extent and/or activating a receptor, or in some embodiments, activating a receptor to at least some extent.
  • a FPR2 agonist is thus capable of binding to and/or activating the FPR2.
  • An agonist may be an agonist of several different types of receptors, and thus capable of binding and/or activating several different types of receptors.
  • Said agonist can also be a selective agonist which only binds and activates one type of receptor.
  • antagonist in the present context refers to a substance capable of inhibiting the effect of a receptor agonist.
  • Full agonists bind (have affinity for) and activate a receptor, displaying full efficacy at that receptor.
  • "Partial agonists" in the present context are peptides able to bind and activate a given receptor, but having only partial efficacy at the receptor relative to a full agonist. Partial agonists can act as antagonists when competing with a full agonist for receptor occupancy and producing a net decrease in the receptor activation compared to the effects or activation observed with the full agonist alone.
  • Selective agonists in the present context are compounds which are selective and therefore predominantly bind and activates one type of receptor. Thus a selective FPR2 agonist is selective for the FPR2.
  • W-Peptides according to the present invention are in one embodiment capable of binding and activating to some extent one or several formyl peptide receptors and can have different binding affinities and/or different receptor activation efficacy for different receptors.
  • Affinity refers to the number and size of intermolecular forces between a peptide ligand and its receptor, and residence time of the ligand at its receptor binding site; and receptor activation efficacy refers to the ability of the peptide ligand to produce a biological response upon binding to the target receptor and the quantitative magnitude of this response.
  • such differences in affinity and receptor activation efficacy are determined by receptor binding/activation studies which are conventional in the art, for instance by generating EC 50 and Emax values for stimulation of ligand binding in cells expressing one or several types of receptors as mentioned herein, or on tissues expressing the different types of receptors.
  • High affinity means that a lower concentration of a ligand is needed to obtain a binding of 50% of the receptors compared to ligand peptides which have lower affinity
  • high receptor activation efficacy means that a lower concentration of the peptide is needed to obtain a 50% receptor activation response (low EC 5 o value), compared to peptides which have lower affinity and/or receptor activity efficacy (higher EC 50 value).
  • the peptides have differing affinities and/or receptor activation efficacies for two or more of the receptors selected from FPR1 , FPR2 and FPR3.
  • the receptor activation potency of peptide agonists can also be measured in p(A 50 ) values which is a conventional method for determining the receptor activation efficacy of an agonist.
  • a functional W-Peptide is a W-Peptide which has binding affinity and/or receptor efficacy for the Formyl Peptide Receptor 2 (FPR2). This may be tested using conventional methods, or as outlined in examples 2 and 3.
  • FPR2 Formyl Peptide Receptor 2
  • the W-Peptide is capable of binding to and activating FPR2.
  • said peptide is a full agonist of FPR2.
  • leukocytes such as phagocytic leukocytes
  • neutrophil chemotaxis mobilization of neutrophil complement receptor 3 (CR3), and activation of the neutrophil NADPH-oxidase, and/or h) inducing chemotaxis in phagocytic leukocytes.
  • CR3 neutrophil complement receptor 3
  • a W-peptide of the present invention is selected from Trp-Lys-Tyr- Met-Val-Met (SEQ ID NO:1 ) and a functional variant thereof.
  • a W-peptide of the present invention is selected from Trp-Lys-Tyr- Met-Val-Met (SEQ ID NO:1 ) and Trp-Lys-Tyr-Met-Val-DMet and a functional variant thereof.
  • the C-terminal of a W-Peptide is a carboxylic acid, an aldehyde, an ester, or an amide, such as a primary amide (CONH 2 ) or a secondary amide.
  • a W-peptide is C-terminally amidated (-NH 2 ).
  • a W-peptide of the present invention is not C-terminally amidated, in particular when a C- terminal branched amino acid probe is attached.
  • a W-peptide of the present invention is C-terminally amidated, in particular when a C-terminal branched amino acid probe is not attached.
  • a W-peptide is N-terminally acetylated (COCH 3 or Ac-). In one embodiment a W-peptide of the present invention is not N-terminally acetylated, in particular when an N-terminal branched amino acid probe is attached. In one embodiment a W-peptide of the present invention is N-terminally acetylated, in particular when an N-terminal branched amino acid probe is not attached.
  • a W-peptide is selected from Trp-Lys-Tyr-Met-Val-Met-NH 2 and Trp-Lys-Tyr-Met-Val-DMet-NH 2 and a functional variant thereof. In one embodiment a W-peptide is selected from Ac-Trp-Lys-Tyr-Met-Val-Met and Ac- Trp-Lys-Tyr-Met-Val-DMet and a functional variant thereof.
  • a W-peptide is selected from Trp-Lys-Tyr-Met-Val-Met-NH 2 and Ac- Trp-Lys-Tyr-Met-Val-DMet-NH 2 and a functional variant thereof.
  • a W-peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having one amino acid substitution.
  • One amino acid substitution means that the amino acid differs between the original sequence and the variant sequence at one position.
  • a W-peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having two amino acid substitutions.
  • a W-peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having three amino acid substitutions. In one embodiment a W-peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having an amino acid substitution at position 1 . In one embodiment a W-peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having an amino acid substitution at position 2.
  • a W-peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having an amino acid substitution at position 3.
  • a W-peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having an amino acid substitution at position 4.
  • a W-peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having an amino acid substitution at position 5.
  • a W-peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having an amino acid substitution at position 6.
  • a W-peptide comprises an ornithine residue.
  • a W-peptide comprises one ornithine residue.
  • a W-peptide comprises two ornithine residues.
  • a W-peptide of the present invention comprises an ornithine residue at position 2 of W-Peptide (whereby lysine is substituted with ornithine).
  • the W-peptide is Trp-Orn-Tyr-Met-Val- Met (SEQ ID NO:2) or Trp-Orn-Tyr-Met-Val-DMet.
  • a W-peptide comprises a proline residue. In one embodiment a W-peptide comprises one proline residue. In one embodiment a W-peptide comprises two proline residues. In one embodiment a W-peptide of the present invention comprises a proline residue at position 5 of W-Peptide. In one embodiment the W-peptide is Trp- Lys-Tyr-Met-Pro-Met (SEQ ID NO:3) or Trp-Lys-Tyr-Met-Pro-DMet.
  • a W-peptide comprises an isoleucine residue. In one embodiment a W-peptide comprises one isoleucine residue. In one embodiment a W-peptide comprises two isoleucine residues. In one embodiment a W-peptide of the present invention comprises an isoleucine residue at position 4 of W-Peptide (whereby Met is substituted with isoleucine). In one embodiment the W-peptide is Trp-Lys-Tyr-lle-Val- Met (SEQ ID NO:4) or Trp-Lys-Tyr-lle-Val-DMet. In one embodiment a W-peptide comprises a phenylalanine residue. In one embodiment a W-peptide comprises one phenylalanine residue.
  • a W-peptide comprises two phenylalanine residues.
  • a W-peptide of the present invention comprises a phenylalanine residue at position 3 of W-Peptide (whereby Tyr is substituted with phenylalanine).
  • the W-peptide is Trp-Lys-Phe-Met-Val-Met (SEQ ID NO:5) or Trp-Lys-Phe-Met-Val-DMet.
  • a W-peptide has the sequence Trp-Lys-Tyr-Met-aa-Met (SEQ ID NO:10) or Trp-Lys-Tyr-Met-aa-DMet, wherein aa is an amino acid having the structure R 1 R 2 C(NH 2 )-COOH, wherein R 1 is a functional group selected from the group consisting of -H, alkyl, alkenyl, cycloalkyl and cycloalkenyl, and wherein R 2 is a functional group selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl.
  • a W-peptide comprises an alpha-amino n-butyric acid residue. In one embodiment a W-peptide comprises one alpha-amino n-butyric acid residue. In one embodiment a W-peptide comprises two alpha-amino n-butyric acid residues. In one embodiment a W-Peptide comprises an alpha-amino n-butyric acid residue at position 5 of W-Peptide. In one embodiment a W-peptide comprises an alfa-amino butyric acid residue (2- Aminobutanoic acid, Abu), such as comprises an alfa-amino butyric acid residue at position 5 of W-Peptide.
  • a W-peptide comprises an alfa-amino isobutyric acid residue (alfa- methylalanine or 2-methylalanine, Aib), such as comprises an alfa-amino isobutyric acid residue at position 5 of W-Peptide.
  • the W-peptide is Trp-Lys-Tyr-Met-Abu-Met (SEQ ID NO:6) or Trp- Lys-Tyr-Met-Abu-DMet. In one embodiment the W-peptide is Trp-Lys-Tyr-Met-Aib-Met (SEQ ID NO:7) or Trp- Lys-Tyr-Met-Aib-DMet.
  • a W-peptide is X-Lys-Tyr-X-Val-Met (SEQ ID NO:8) or X-Lys-Tyr- X-Pro-Met (SEQ ID NO:9), wherein X is individually any amino acid.
  • embodiment X is selected from Trp and Met.
  • a W-peptide is Trp - X2 - X3 - X4 - X5 - X6 (SEQ ID NO:1 1 ), wherein
  • X2 is selected from Lys and Orn,
  • X3 is selected from Tyr and Phe,
  • X4 is selected from Met and lie
  • X5 is selected from Val, Pro, Abu, Aib and aa
  • X6 is selected from Met and DMet
  • aa is an amino acid having the structure R1 R2C(NH2)-COOH, wherein R1 is a functional group selected from the group consisting of -H, alkyl, alkenyl, cycloalkyi and cycloalkenyl, and wherein R2 is a functional group selected from the group consisting of alkyl, alkenyl, cycloalkyi and cycloalkenyl,
  • R1 is a functional group selected from the group consisting of -H, alkyl, alkenyl, cycloalkyi and cycloalkenyl
  • R2 is a functional group selected from the group consisting of alkyl, alkenyl, cycloalkyi and cycloalkenyl
  • a W-peptide is selected from the group consisting of
  • Trp-Lys-Tyr-Met-Val-Met SEQ ID NO:1
  • Trp-Orn-Tyr-Met-Val-Met SEQ ID NO:2
  • Trp-Lys-Tyr-Met-Pro-Met SEQ ID NO:3
  • Trp-Lys-Tyr-lle-Val-Met SEQ ID NO:4
  • Trp-Lys-Phe-Met-Val-Met SEQ ID NO:5
  • Trp-Lys-Tyr-Met-Abu-Met SEQ ID NO:6
  • Trp-Lys-Tyr-Met-Aib-Met SEQ ID NO:7
  • X-Lys-Tyr-X-Val-Met wherein X is any amino acid (SEQ ID NO:8), X-Lys-Tyr-X-Pro-Met, wherein X is any amino acid (SEQ ID NO:9), Trp-Lys-Tyr-Met-aa-Met (SEQ ID NO: 10) and Trp-Lys-Tyr-Met-aa-DMet, wherein aa is an amino acid having the structure R 1 R 2 C(NH 2 )-COOH, wherein R 1 is a functional group selected from the group consisting of -H, alkyl, alkenyl, cycloalkyl and cycloalkenyl, and wherein R 2 is a functional group selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl,
  • Trp - X2 - X3 - X4 - X5 - X6 (SEQ ID NO:1 1 ), wherein X2 is selected from Lys and Orn, X3 is selected from Tyr and Phe, X4 is selected from Met and lie, X5 is selected from Val, Pro, Abu, Aib and aa; and X6 is selected from Met and DMet,
  • a variant of a W-peptide can in principle have one or more substitutions at one or more positions. Individual amino acid residues in the W-Peptide can be substituted with any given proteinogenic or non-proteinogenic amino acid.
  • the genetic code specifies 20 standard amino acids naturally incorporated into polypeptides (proteinogenic): Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Tyr, Thr, Trp, Val, and 2 which are incorporated into proteins by unique synthetic mechanisms: Sec (selenocysteine, or U) and Pyl (pyrrolysine, O). These are all L-stereoisomers.
  • Non-standard amino acids are usually formed through modifications to standard amino acids, such as post-translational modifications.
  • Examples of unnatural amino acid residues are Abu, Aib, NIe (Norleucine), DOrn (D-ornithine, deguanylated arginine), Nal (beta-2-naphthyl-alanine), D-Nal (beta-2-naphthyl-D-alanine), DArg, DTrp, DPhe and DVal.
  • Any amino acids according to the present invention may be in the L- or D-configuration. If nothing is specified, reference to the L-isomeric form is preferably meant.
  • the term peptide also embraces post-translational modifications introduced by chemical or enzyme-catalyzed reactions, as are known in the art. Such post- translational modifications can be introduced prior to partitioning, if desired.
  • functional equivalents may comprise chemical modifications such as ubiquitination, labeling (e.g., with radionuclides, various enzymes, etc.), pegylation (derivatization with polyethylene glycol), or by insertion (or substitution by chemical synthesis) of amino acids, which do not normally occur in human proteins.
  • W-Peptides with N-terminal alkylations and C-terminal esterifications are also encompassed within the present invention.
  • Functional equivalents also comprise glycosylated and covalent or aggregative conjugates formed with the same molecules, including dimers or unrelated chemical moieties.
  • Such functional equivalents are prepared by linkage of functionalities to groups which are found in a fragment including at any one or both of the N- and C-termini, by means known in the art.
  • the W-Peptides according are modified by acetylation, such as N-terminal acetylation. In some embodiments the W-Peptides are modified by C- terminal amidation. W-Peptide comprising alpha-amino n-butyric acid
  • Trp-Lys-Tyr-Met-aa-Met SEQ ID NO:10
  • Trp-Lys-Tyr-Met-aa-DMet Trp-Lys-Tyr-Met-aa-DMet
  • R 1 is a functional group selected from the group consisting of -H, alkyl, alkenyl, cycloalkyl and cycloalkenyl, and
  • R 2 is a functional group selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl.
  • R 1 and R 2 may each be the same (identical) or different (non-identical).
  • alkyl refers to linear, branched or cyclic hydrocarbon structures preferably having from 1 to 20 carbon atoms (a "C1 -C20 alkyl”) e.g., 1 to 10 carbon atoms or 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t- butyl, n-heptyl, octyl, cyclobutylmethyl, cyclopropylmethyl and the like. "Unsubstituted alkyl” refers to an alkyl group that is not substituted with any additional substituents.
  • alkenyl refers to linear, branched or cyclic hydrocarbon structures preferably having from 2 to 20 carbon atoms (a "C1 -C20 alkenyl”) and more preferably 2 to 10 carbon atoms or 2 to 6 carbon atoms and having at least 1 site of alkenyl unsaturation.
  • unsubstituted alkenyl refers to an alkenyl group that is not substituted with any additional substituents.
  • alkenyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed.
  • Cycloalkyi refers to a 3-, 4-, 5-, 6-, 7- or 8-membered saturated non- aromatic monocyclic cycloalkyi ring.
  • Representative groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the cycloalkyi group is substituted with one or more alkyl or alkenyl.
  • cycloalkenyl refers to a 3-, 4-, 5-, 6-, 7- or 8-membered non- aromatic monocyclic carbocyclic ring having at least one endocyclic double bond, but which is not aromatic.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, 1 ,3-cyclobutadienyl, cyclopentenyl, 1 ,3- cyclopentadienyl, cyclohexenyl, 1 ,3-cyclohexadienyl, cycloheptenyl, 1 ,3- cycloheptadienyl, 1 ,4-cycloheptadienyl, 1 ,3,5- cycloheptatrienyl, cyclooctenyl, 1 ,3- cyclooctadienyl, 1 ,4-cyclooctadienyl, or 1 ,3,5-cyclooctatrienyl.
  • the cycloalkenyl group is substituted with one or more alkyl or alkenyl.
  • a W-Peptide of sequence Trp-Lys-Tyr-Met-aa- Met-NH 2 (SEQ ID NO:10), wherein aa is an amino acid having the structure
  • R 1 R 2 C(NH 2 )-COOH, wherein R 1 is H and R 2 is selected from the group consisting of methyl (C1 alkyi), ethyl (C2 alkyi), propyl (C3 alkyi), butyl (C4 alkyi), pentyl (C5 alkyi) and hexyl (C6 alkyi).
  • R 1 is H
  • R 2 is methyl
  • the amino acid aa of SEQ ID NO:10 is alanine.
  • R 1 and R 2 are methyl and the amino acid aa of SEQ ID NO:10 is 2-amino isobutyric acid; (CH 3 ) 2 CH(NH 2 )-COOH (Aib).
  • R 1 is H
  • R 2 is ethyl (C2 alkyi) and the amino acid aa of SEQ ID NO:10 is 2-amino n-butyric acid; CH 3 CH 2 CH(NH 2 )-COOH (Abu).
  • R 1 is H and R 2 is selected from the group consisting of propyl (C3 alkyi) including n-propyl and isopropyl.
  • Examples of amino acids aa include valine and norvaline.
  • R 1 is H and R 2 is selected from the group consisting of butyl (C4 alkyi) including n-butyl, sec-butyl, isobutyl and t-butyl.
  • amino acids aa include leucine, isoleucine and norleucine.
  • a novel W-Peptide variant comprising an alpha- amino n-butyric acid residue.
  • Alpha-amino n-butyric acid may exist in its L- or D- conformation (S- or R-conformation).
  • a W-Peptide comprising one or more alfa-amino butyric acid residues.
  • Alfa-amino butyric acid (AABA) or 2-Aminobutanoic acid (Abu) also known as homoalanine, is a non-proteinogenic alpha amino acid with chemical formula CH 3 CH 2 CH(NH 2 )-COOH.
  • a W-Peptide comprising one or more alfa-amino isobutyric acid residues, also known as alfa-methylalanine or 2-methylalanine (Aib), with structural formula (CH 3 ) 2 CH(NH 2 )-COOH.
  • the W-Peptide comprises an alpha-amino n-butyric acid at one or more positions, such as at one or more positions selected from position 1 , position 2, position 3, position 4, position 5 and position 6 of W-Peptide.
  • the W-Peptide comprises an alpha-amino n-butyric acid residue at more than one position, such as at two positions or three positions.
  • the W-Peptide comprises alpha-amino n-butyric acid at position 5 of W-Peptide.
  • Met of SEQ ID NO:1 is substituted with an alpha- amino n-butyric acid.
  • Trp-Lys-Tyr-Met-Abu-DMet-NH 2 Trp-Lys-Tyr-Met-Abu-Met-NH 2 (SEQ ID NO:6), Trp- Lys-Tyr-Met-Aib-DMet-NH 2 and Trp-Lys-Tyr-Met-Aib-Met-NH 2 (SEQ ID NO:7).
  • the W-Peptide comprising an alpha-amino n-butyric acid further comprises one or more branched amino acid probes.
  • the W-Peptide analogues may be prepared by any suitable methods known in the art.
  • the W-Peptide and the branched amino acid probe are each prepared by standard peptide-preparation techniques, such as solution synthesis or solid phase peptide synthesis (SPPS) such as Merrifield-type solid phase synthesis.
  • SPPS solid phase peptide synthesis
  • the W-Peptide analogues are in one embodiment prepared by solid phase synthesis by first constructing the pharmacologically active W-Peptide sequence, using well- known standard protection, coupling and de-protection procedures, thereafter sequentially coupling the branched amino acid probe onto the active W-Peptide in a manner similar to the construction of the active W-Peptide, and finally cleaving off the entire W-Peptide analogue from the carrier.
  • This strategy yields a W-Peptide, wherein the branched amino acid probe is covalently bound to the pharmacologically active W- Peptide at the N-terminal nitrogen atom of the W-Peptide.
  • the alpha nitrogen on the final amino acid in the branched amino acid sequence is capped with acetyl, using standard acylation techniques, prior to or after coupling of the branched amino acid sequence on the active W-Peptide.
  • Reactive moieties at the N- and C-termini which facilitates amino acid coupling during synthesis, as well as reactive side chain functional groups, can interact with free termini or other side chain groups during synthesis and peptide elongation and negatively influence yield and purity. Chemical groups are thus developed that bind to specific amino acid functional groups and block, or protect, the functional group from
  • N-terminal protecting groups are t-Boc and Fmoc, commonly used in solid-phase peptide synthesis.
  • C-terminal protecting groups are mostly used in liquid-phase synthesis. Because N-terminal deprotection occurs continuously during peptide synthesis, protecting schemes have been established in which the different types of side chain protecting groups (benzyl;Bzl or tert-butyl;tBu) are matched to either Boc or Fmoc, respectively, for optimized deprotection.
  • the protection group for Lys is Mtt, which as Fmoc protected amino acid is commercially available (Fmoc-Lys(Mtt)-OH; N - a - Fmoc - N - ⁇ - 4 - methyltrityl - L - lysine, CAS# 167393-62-6).
  • Lys(Mtt) allows for capping Lys with acetyl or extending the sequence at the alpha amino group of lysine as it is not cleaved under the conditions that cleave Fmoc, and may be removed without cleavage of other side chain protection groups.
  • the protection group for Lys is ivDde, which as Fmoc protected amino acid is commercially available (Fmoc-Lys(ivDde)-OH; N - a - Fmoc-N-e-1 -(4,4-dimethyl-2,6-dioxocyclohex-1 -ylidene)-3-methylbutyl-L-lysine, CAS# 204777-78-6).
  • Lys(ivDde) allows for extending the sequence at the alpha amino group of lysine or capping Lys with acetyl as it is not cleaved under the conditions that cleave Fmoc, and may be removed without cleavage of other side chain protection groups.
  • the method of preparation is in some embodiments optimized by routine methods in the art that may increase the yield and/or quality of the thus prepared synthetic W- Peptide. For instance, use of pseudoproline (oxazolidine) dipeptides in the Fmoc SPPS of serine- and threonine-containing peptides may lead to improvements in quality and yield of crude products and may help avoid unnecessary repeat synthesis of failed sequences.
  • dipeptides are easy to use: simply substitute a serine or threonine residue together with the preceding amino acid residue in the peptide sequence with the appropriate pseudoproline dipeptide.
  • the native sequence is regenerated on cleavage and deprotection.
  • sequence of the pharmacologically active W-Peptide and the branched amino acid probe are each prepared separately by for example solution synthesis, solid phase synthesis, recombinant techniques, or enzymatic synthesis, followed by coupling of the (at least) two sequences by well- known segment condensation procedures, either in solution or using solid phase techniques, or a combination thereof.
  • the W-Peptide is prepared by recombinant DNA methods and the branched amino acid probe is prepared by solid or solution phase synthesis.
  • the conjugation of the W-Peptide and the branched amino acid probe is in one embodiment carried out by using chemical ligation. This technique allows for the assembling of totally unprotected peptide segments in a highly specific manner.
  • the conjugation is performed by protease-catalysed peptide bond formation, which offers a highly specific technique to combine totally unprotected peptide segments via a peptide bond.
  • the C-terminal amino acid of the branched amino acid probe or the C-terminal amino acid of the W-Peptide is covalently linked to the solid support material by means of a common linker such as 2,4-dimethoxy-4'-hydroxy-benzophenone, 4-(4- hydroxy-methyl-3-methoxyphenoxy)-butyric acid, 4-hydroxy-methylbenzoic acid, 4- hydroxymethyl- phenoxyacetic acid, 3-(4-hydroxymethylphenoxy)propionic acid, or p - ⁇ (R,S) - a - [1 - (9H - Fluoren - 9 - yl) - methoxyformamido] - 2,4 - dimethoxybenzyl ⁇ - phenoxyacetic acid (Rink amide linker).
  • a common linker such as 2,4-dimethoxy-4'-hydroxy-benzophenone, 4-(4- hydroxy-methyl-3-methoxyphenoxy)-butyric acid, 4-hydroxy-methyl
  • suitable solid support materials are e.g., functionalised resins such as polystyrene, polyacrylamide, polydimethylacrylamide, polyethyleneglycol, cellulose, polyethylene, polyethyleneglycol grafted on polystyrene, latex, dynabeads, etc.
  • the produced W-Peptide analogues of the invention are in some embodiment cleaved from the solid support material by means of an acid such as trifluoracetic acid, trifluoromethanesulfonic acid, hydrogen bromide, hydrogen chloride, hydrogen fluoride, etc.
  • a base such as ammonia, hydrazine, an alkoxide, such as sodium ethoxide, an hydroxide, such as sodium hydroxide, etc.
  • the produced W-peptide analogues are isolated as salts, such as an acetate salt or maleate salt or any other salt known to the skilled person.
  • the W-Peptide analogues may be prepared or produced by recombinant techniques.
  • the peptide is produced by host cells comprising a first nucleic acid sequence encoding the W- Peptide or W-Peptide analogue operably associated with a second nucleic acid capable of directing expression in said host cells.
  • the second nucleic acid sequence comprises or even consists of a promoter that will direct the expression of protein of interest in said cells.
  • a skilled person will be readily capable of identifying useful second nucleic acid sequences (e.g. vectors and plasmids) for use in a given host cell.
  • the process of producing a recombinant peptide in general comprises the steps of: providing a host cell, preparing a gene expression construct comprising a first nucleic acid encoding the peptide operably linked to a second nucleic acid capable of directing expression of said protein of interest in the host cell, transforming the host cell with the construct and cultivating the host cell, thereby obtaining expression of the peptide.
  • the recombinantly produced peptide is excreted by the host cells.
  • the host cell include any suitable host cell known in the art, including prokaryotic cells, yeast cells, insect cells and mammalian cells.
  • the recombinant peptide thus produced is isolated by any conventional method and may be linked via conventional peptide bond forming chemistry to any suitably protected branched amino peptide moiety.
  • the skilled person will be able to identify suitable protein isolation steps for purifying the peptide.
  • W-Peptide analogues as defined according to the present invention for use as a medicament.
  • the present invention provides methods for treatment, prevention or alleviation of a medical condition.
  • Such methods according to the present invention in one embodiment comprise one or more steps of administration or release of an effective amount of a W-Peptide analogue according to the present invention, or a pharmaceutical composition comprising one or more such W-Peptides, to an individual in need thereof.
  • steps of administration or release according to the present invention are simultaneous, sequential or separate.
  • An individual in need as referred to herein is in one embodiment an individual that benefits from the administration of a W-Peptide analogue or pharmaceutical composition according to the present invention.
  • Such an individual in one embodiment suffers from a disease or condition or is at risk of suffering therefrom.
  • the individual is in one embodiment any human being, male or female, infant, middle-aged or old.
  • the disorder to be treated or prevented in the individual in one embodiment relates to the age of the individual, the general health of the individual, the medications used for treating the individual and whether or not the individual has a prior history of suffering from diseases or disorders that may have or have induced the condition in the individual.
  • treatment refers to the management and care of a patient for the purpose of combating a condition, disease or disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the W-Peptide analogue for the purpose of: alleviating or relieving symptoms or complications; delaying the progression of the condition, partially arresting the clinical manifestations, disease or disorder; curing or eliminating the condition, disease or disorder; and/or preventing or reducing the risk of acquiring the condition, disease or disorder, wherein "preventing” or “prevention” is to be understood to refer to the management and care of a patient for the purpose of hindering the development of the condition, disease or disorder, and includes the administration of the active compounds to prevent or reduce the risk of the onset of symptoms or complications.
  • the patient to be treated is preferably a mammal, in particular a human being. Treatment of animals, such as mice, rats, dogs, cats, cows, horses, sheep and pigs, is, however, also within the scope of the present invention.
  • the patients to be treated according to the present invention can be of various ages, for example, adults, children, children under 16, children age 6-16, children age 2-16, children age 2 months to 6 years or children age 2 months to 5 years.
  • the invention is in one embodiment directed to a W-Peptide analogue according to the present invention for use in the treatment of an ischemic condition, an inflammatory condition, an infection and/or a metabolic condition.
  • the invention is in one embodiment directed to use of a W-Peptide analogue according to the present invention for the manufacture of a medicament for the treatment of an ischemic condition, an inflammatory condition, an infection and/or a metabolic condition.
  • the invention is in one embodiment directed to a method for treatment of an ischemic condition, an inflammatory condition, an infection and/or a metabolic condition, said method comprising administering an effective amount of a W-Peptide analogue according to the present invention to an individual in need thereof.
  • the invention is in one embodiment, directed to a W-Peptide analogue for use in the treatment of an ischemic and/or inflammatory condition in the tissue of one or more organs of a mammal.
  • said treatment is prophylactic, ameliorative and/or curative.
  • said mammal is a human (homo sapiens).
  • the invention in certain embodiments is also directed to a method for treatment of an ischemic and/or inflammatory condition in the tissue of one or more organs, said method comprising the step of administering a therapeutically effective amount of a W- Peptide analogue according to the present invention to an individual in need thereof.
  • the invention is also directed to use of a W-Peptide analogue for manufacturing of a medicament for the treatment of an ischemic and/or
  • said organ is in one embodiment selected from the group consisting of kidney, liver, brain, heart, muscles, bone marrow, skin, skeleton, lungs, the respiratory tract, spleen, exocrine glands, bladder, endocrine glands, reproduction organs including the phallopian tubes, eye, ear, vascular system, the gastroinstestinal tract including small intestines, colon, rectum, canalis analis and the prostate gland.
  • the ischemic and/or inflammatory condition in the tissue of one or more organs is an acute, subacute or chronic condition.
  • the ischemic and/or inflammatory condition in the tissue of one or more organs is an ischemic condition. In another embodiment, the ischemic and/or inflammatory condition in the tissue of one or more organs is an inflammatory condition.
  • the ischemic condition in the tissue of one or more organs is secondary ischemia.
  • Secondary ischemia is ischemia which is caused by an underlying condition such that the ischemia typically is secondary to e.g. stroke, injury, septic shock, systemic hypotension, cardiac arrest due to heart attack, cardiac arrhythmia, atheromatous disease with thrombosis, embolism from the heart or from blood vessel from any organ, vasospasm, aortic aneurysm or aneurisms in other organs, coronary stenosis, myocardial infarction, angina pectoris, pericarditis, myocarditis, myxodemia, or endocarditis.
  • stroke e.g. stroke, injury, septic shock, systemic hypotension, cardiac arrest due to heart attack, cardiac arrhythmia, atheromatous disease with thrombosis, embolism from the heart or from blood vessel from any organ, vasospasm, aortic aneurysm or aneurisms in other organs, coronary stenosis,
  • An aortic aneurysm is in one embodiment thoracal or abdominal or dissecting aortic aneurysm.
  • Systemic hypotension is in one embodiment hypotension due to heart disease, hypotension due to systemic disease including infection or allergic reactions, or hypotension due to one or more toxic compound or poison(s) or drug(s).
  • said ischemic and/or inflammatory condition in the tissue of one or more organs is due to (or caused by) a condition selected from stroke, injury, septic shock, systemic hypotension, cardiac arrest due to heart attack, cardiac arrhythmia, atheromatous disease with thrombosis, embolism from the heart or from blood vessel from any organ, vasospasm, aortic aneurysm or aneurisms in other organs, coronary stenosis, myocardial infarction, angina pectoris, pericarditis, myocarditis, myxodemia, or endocarditis.
  • said ischemic condition is myocardial ischemia.
  • said ischemic and/or inflammatory condition in the tissue of one or more organs is due to crdiac arrhythmia.
  • said cardiac arrhythmia is the primary disease or secondary to another condition of the individual, including acute infections particularly those affecting the lungs, pulmonary embolism, hypotension, shock, anoxaemia and anaemia.
  • Cardiac arrhythmias include ventricular or supra ventricular tachyarrhythmias, atrioventricular block, sinus node disease, Wolff-Parkinson- White syndrome, Lenegres disease, Lev's disease any syndrome involving an abnormal myocardial connection between atrium and ventricle.
  • secondary ischemia can also be observed in connection with a range of other diseases and conditions, including but not limited to diabetes mellitus, hyperlipidaemia, thromboangiitis obliterans, Takayasu 's syndrome, arteritis temporalis, mucocutaneous lymph node syndrome (Kawasaki disease), cardiovascular syphilis, connective tissue disorders such as Raynaud 's disease, phlegmasia coerulae dolens, blood vessel trauma including iatrogene trauma such as cannulation, conditions with increased fasting levels of LDL-Cholesterol, triglycerid, and/or HDL- Cholesterol, retroperitoneal fibrosis, rheumatic diseases, systemic lupus erythematosus, polyarteritis nodosa, scleroderma, polymyositis, dermatomyositis, rheumatoid arthritis, neuromyopathic disorders such as progressive muscular disorders, and
  • the invention is in one embodiment, directed to a W-Peptide analogue for use in the treatment of infection.
  • infections include infections by protozoa, virus, bacteria and fungus and include conditions such as AIDS, bacterial septicemia, systemic fungal infections, Rickettsial diseases, toxic shock syndrome, infectious mononucleosis, chlamydia thrachomatis, chlamydia psittaci, cytomegalovirus infection, Campylobacter, salmonella, influenza, poliomyelitis, toxoplasmosis, Lassa Fever, Yellow Fever, billharziose, colibacteria, enterococcus, preteus, klebsiella, pseudomonas, staphylococcus aureus,
  • staphylococcus epidermidis staphylococcus epidermidis, Candida albicans, tuberculosis, mumps, infectious mononucleosis, hepatitis and Coxackie virus.
  • the condition to be treated is caused by a cancer or a by premalignant disorder having an impact on the organ, e.g. on the respiratory system including lung, bronchiole, upper airways, and/or on the heart and/or on the kidney and/or on the gastrointestinal system, including acute leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, lymphosarcoma, myeloma, metastasizing carcinoma of any origin.
  • the W-Peptide analogue are used in the treatment or prevention of said conditions.
  • the ischemic and/or inflammatory condition in the tissue of one or more organs is caused by a physical trauma including electromagnetic radiation.
  • Major surgical interventions including cardiothoracic surgery, abdominal surgery, surgery on the aorta and other major blood vessels, as well as organ transplantation such as lung or heart or combined lung and heart transplantation, liver transplantation or renal transplantation induce a systemic inflammatory response (SIR; or systemic inflammatory response syndrome SIRS) and is associated with post-surgical organ dysfunction including development of renal failure.
  • SIR systemic inflammatory response
  • SIRS systemic inflammatory response syndrome
  • Renal failure is a consequence of the SIR and the reduced blood flow generated during the surgical intervention.
  • the result is post-surgical acute kidney injury (AKI) which for a large fraction deteriorates into chronic renal failure.
  • AKI post-surgical acute kidney injury
  • GFR Glomerular filtration rate
  • cardiac surgery such as repair of one or more cardiac valves, cardiac artery bypass grafting (CABG), surgery on the aortic root, or aortic branch including the common carotic arteries, or combined cardiac surgery such as valve(s) replacement and CABG and/or aortic root surgery is associated with development of renal impairment that, when present, is associated with increased morbidity and mortality.
  • CABG cardiac artery bypass grafting
  • treatment with a W-Peptide analogue according to the present invention reduce the degree of renal impairment. In one embodiment this is achieved by reducing the fall in GFR post-surgery; by reducing the degree of post-surgical increases in serum creatinine or cystatin C or the more immediate increases in urinary excretion of AKI markers NGAL, IL18 or KIM-1 ; and/or or by reducing the degree of post-surgical SIR (for example by reduced circulating levels of IL-6 and other proinflammatory markers).
  • Lung transplantation is the ultimate treatment modality for end-stage lung disease.
  • LTX chronic renal failure
  • Nephrotoxicity and post-transplant lymphoproliferative diseases where the latter can be considered as a consequence of the degree of immune-suppression needed to avoid chronic organ rejection - "too much” keeps the rejection on distance, but gives infections and PTLD, while giving "too little” puts the patients at an increased risk of rejecting the graft.
  • PTLD post-transplant lymphoproliferative diseases
  • Neprotoxicity and development of CRF is despite of extensive research during the last 30 years, still a significant problem. Five years after LTX none of the patients retain normal kidney function and 20% of the long term survivors will end with a kidney transplant as well.
  • Calcineurin inhibitor treatment (Tacrolimus, Cyclosporin A) is the corner-stone in the immune-suppressive treatment strategy for successful solid organ transplantation.
  • the limiting factor in using calcineurin inhibitors is the acute and chronic irreversible nephrotoxicity.
  • kidney function (measured as reduction in GFR) is reduced with 40% within the first 14 days after LTX and that this reduction is irreversible.
  • HTX Heart transplantation
  • the invention is thus in one embodiment directed to a W-Peptide analogue according to the present invention for use in the treatment of an ischemic and/or inflammatory condition in the tissue of one or more organs of a mammal, wherein said ischemic and/or inflammatory condition is associated with surgery.
  • said surgery is major surgery or major surgical intervention.
  • said surgery is selected from the group consisting of
  • cardiothoracic surgery abdominal surgery, surgery on the aorta and/or other major blood vessels, repair of one or more cardiac valves, cardiac artery bypass grafting (CABG), surgery on the aortic root or the aortic branch including the common carotic arteries, and combined cardiac surgery such as valve(s) replacement and CABG and/or aortic root surgery.
  • CABG cardiac artery bypass grafting
  • said surgery encompasses surgical insertion transplants, devices, grafts, prostheses or other biomedical compounds or devices inserted by surgical operations.
  • said major surgery comprises organ transplantation.
  • organ transplantation It follows that the invention in one embodiment is directed to a W-Peptide analogue according to the present invention for use in the treatment of an ischemic and/or inflammatory condition in the tissue of one or more organs of a mammal, wherein said ischemic and/or inflammatory condition is associated with organ transplantation.
  • said organ transplantation is solid organ transplantation.
  • said solid organ transplantation is heart transplantation, lung transplantation, combined heart and lung transplantation, liver transplantation or kidney (renal) transplantation.
  • the invention in another embodiment is directed to a W-Peptide analogue according to the present invention for use in the treatment of post-surgical systemic inflammatory response syndrome (SIRS), post-surgical organ dysfunction and/or post-surgical renal failure such as acute kidney injury (AKI), neprotoxicity and/or chronic renal failure (CRF).
  • SIRS systemic inflammatory response syndrome
  • AKI acute kidney injury
  • CRF chronic renal failure
  • the invention is in one embodiment directed to a W-Peptide analogue according to the present invention for reducing the degree of renal impairment associated with major surgery, in one embodiment organ transplantation.
  • Reperfusion injury is tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen.
  • the absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function.
  • Reperfusion injuries may occur in connection with surgery, such as major surgical interventions including organ transplantations. It is a primary concern when performing liver transplantations, and also during cardiac surgery.
  • said ischemic and/or inflammatory condition in the tissue of one or more organs is associated with reperfusion injury.
  • the present invention is directed to a W-Peptide analogue according to the present invention for use in the treatment of an ischemic and/or inflammatory condition in the tissue of one or more organs of a mammal, wherein said ischemic and/or inflammatory condition is associated with reperfusion injury.
  • the peptides or compositions of the present invention are to be administered before and/or during surgery and/or organ transplantation.
  • the ischemic and/or inflammatory condition in the tissue of one or more organs as described herein is caused by toxin- or drug-induced cell, tissue or organ failure.
  • the invention is thus in one embodiment directed to a W-Peptide analogue according to the present invention for use in the treatment of an ischemic and/or inflammatory condition in the tissue of one or more organs of a mammal, wherein said ischemic and/or inflammatory condition is caused (or induced) by toxin- or drug-induced cell, tissue or organ failure.
  • Said drug includes but are not restricted to cancer chemotherapeutics including cisplatin, carboplatin, dacarbezine, procarbazine, altretamine, semustine, lomustine, carmustine, busulfan, thiotepa, melphalan, cyclophosphamide, chlorambucil, mechlorethamine, azadtidine, cladrrbine, cytorabine, fludarabine, fluorouracil, mercaptopurine, metrotrexate, thioguanine, allopurinol, bleomycin, dactinomycin, daunorubicin, docetaxel, doxorubicin (adriamycin), etoposide, idarubicin, irinotecan, mitomycin, paclitaxel, plicamycin, topotecan, vinblastine, vincristine, vinorelbine, amasacrine, asparagina
  • Inflammation is a localized defensive response of the body against pathogens and injury. Immune cells and soluble factors take part in this process to neutralize the injurious agent and initiate tissue repair to restore homeostasis. Loss of regulation of these mechanisms can prevent the final resolution of the inflammatory process, leading to chronic inflammation.
  • Chronic inflammation is extremely relevant in today's modern medicine, as it contributes to the pathogenesis of the most important diseases of the industrialized societies including atherosclerosis, acute and chronic heart failure, cancer, diabetes, and obesity-associated diseases.
  • Recent insight into endogenous anti-inflammatory pathways have identified a number of natural anti-inflammatory and pro-resolving molecules and pathways suitable for pharmacological intervention that would make it possible to develop drugs that mimic the natural course of resolving inflammation. Among these natural anti-inflammatory and pro-resolving pathways is Annexin A1 acting through FPR2 stimulation.
  • FPR-2 agonists exerted through inhibition of inflammatory mediators and by inhibition of inflammatory cell migration.
  • FPR-2 agonists exert these effects in a variety of cells including monocytes, macrophages, subtypes of T-cells, endothelial cells and epithelial cells.
  • Joint diseases such as rheumatoid arthritis (RA) and gout are characterized by episodes with acute exacerbations, in RA the exacerbations (often described as flairs) typically develop on top of chronic symptoms and develop despite intense rheumatoid arthritis (RA) and gout are characterized by episodes with acute exacerbations, in RA the exacerbations (often described as flairs) typically develop on top of chronic symptoms and develop despite intense rheumatoid arthritis (RA) and gout are characterized by episodes with acute exacerbations, in RA the exacerbations (often described as flairs) typically develop on top of chronic symptoms and develop despite intense
  • the invention is thus in one embodiment directed to a W-Peptide analogue according to the present invention for use in the treatment of an inflammatory condition in the tissue of one or more organs of a mammal, wherein said ischemic and/or inflammatory condition is an inflammatory disease.
  • said inflammatory disease is Arthritis.
  • said inflammatory disease is selected from the group consisting of an arthropathy (a disease of a joint, Arthritis (including diseases associated with arthritis), osteoartritis, rheumatoid arthritis; spondylarthropathies (e.g.
  • ankylosing spondilitis reactive arthritis (including arthritis following rheumatic fever), Henoch-Schonlein purpura, Reiter's disease, Juvenile Chronic arthritis including Still 's disease, juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, psoriasis, osteoarthritis, osteoarthritis secondary to hypermobilty, congenital dysplasias, slipped femoral epiphysis, Perthes' disease, intra-articular fractures, meniscectomy, obesity, recurrent dislocation, repetitive actions, crystal depositions and diseases and metabolic abnormalities of cartilage including pyrophosphate arthropathy, ochronosis, haemochromatosis, avascular necrosis including Sickle Cell disease, therapy with corticoids or other drugs, Caisson disease, septic or infectious arthitis (including tuberculous arthritis, meningococcal arthritis, gonococcal arthritis, salmonella arthritis), infective
  • said inflammatory disease is a connective tissue disorder; in one embodiment selected from the group consisting of systemic lupus erythematosus, polymyositis/dermatomyositis, systemic sclerosis, mixed connective tissue disease, sarcoidosis and primary Sjogrens syndrome including keratoconjunctivitis sicca, polymyalgia rheumatica, and other types of vasculitis, crystal deposition diseases (including gout), pyrophosphate arthropathy, and acute calcific periarthritis.
  • said inflammatory disease is a soft-tissue rheumatism including bursitis, tenosynovitis or peritendonitis, enthesitis, nerve compression, periarthritis or capsulitis, muscle tension and muscle dysfunction.
  • said inflammatory disease is selected from the group consisting of vasculitis including vasculitis secondary to rheumatoid arthritis, infective vasculitis due to infections with bacterial species including spirochaetal diseses as Lyme disease, syphilis, rickettsial and mycobacterial infections, fungal, viral or protozoal infections, non-infective vasculitis secondary to hypersensibility and leucocytoplastic vasculitis including Serum Sickness and Henoch-Schonlein purpura, Drug induced vasculitis, essential mixed cryoglobulinaemia, hypocomplentaemia, Vasculitis associated with other kinds of malignancy, non-infective vascultitis including Takayasu's
  • said inflammatory disease is inflammatory diseases of the gastrointestinal system.
  • Said inflammatory diseases of the gastrointestinal system may be selected from the group consisting of inflammatory bowel disease, coeliac disease, gluten sensitive enteropathy, eosinophilic gastroenteritis, intestinal lympangiectasia, inflammatory bowel disease (including Chrohn's disease and ulcerative colitis), diverticular disease of the colon, radiation enteritis, irritable bowel syndrome, Whipple 's diease, stomatitis of all kinds, salivary gland diseases (such as sarcoidosis, salivary duct obstruction and Sjogrens syndrome), inflammaton of the oesophagus (e.g.
  • said inflammatory disease is a neurodegenerative disease, such as a neurodegenerative disease having an inflammatory component, such as multiple sclerosis (MS).
  • a neurodegenerative disease such as a neurodegenerative disease having an inflammatory component, such as multiple sclerosis (MS).
  • MS multiple sclerosis
  • said inflammatory disease is selected from the group consisting of dermatitis, pemfigus, bulloid pemphigoid, benign mucous membrane pemphigoid, dermatitis herpitiformis, tropical sprue, systemic amyloidosis, primary biliary cirrhosis, Goodpasture syndrome, all kinds of deposition diseases as Gout, pyrophosphate arthopathy and acute calcific periarthritis, pancreatitis, septic discitis, tuberculosis, malignancies (such as matastases, myeloma and others), spinal tumours, ancylosing spondylitis, acute disc prolapse, chronic disc disease/osteoarthritis, osteoporosis, and osteomalacia, Pagets disease, hyperparathyroidism, renal osteodystrophy, spondylolisthesis, spinal senosis congenital abnormalities and fibromyalgia.
  • said inflammatory disease is selected from the group consisting of upper and lower airway diseases such as chronic obstructive pulmonary diseases (COPD), allergic and non-allergic asthma, allergic rhinitis, allergic and non-allergic conjunctivitis, allergic and non-allergic dermatitis and lung inflammation.
  • COPD chronic obstructive pulmonary diseases
  • allergic and non-allergic asthma allergic rhinitis
  • allergic and non-allergic conjunctivitis allergic and non-allergic dermatitis and lung inflammation.
  • the W-Peptide analogues of the present invention are combined with or comprise one or more further active ingredients which are understood as other therapeutic compounds or pharmaceutically acceptable derivatives thereof.
  • Methods for treatment according to the present invention thus further comprise one or more steps of administration of one or more further active ingredients, either concomitantly or sequentially, and in any suitable ratios.
  • Methods of treatment according to the present invention in one embodiment include a step wherein the pharmaceutical composition or W-Peptide analogue as defined herein is administered simultaneously, sequentially or separately in combination with one or more further active ingredients. Administration and dosage
  • a composition comprising a W-Peptide analogue as defined herein is in one embodiment administered to individuals in need thereof in pharmaceutically effective doses or a therapeutically effective amount.
  • a therapeutically effective amount of a W-Peptide analogue according to the present invention is in one embodiment an amount sufficient to cure, prevent, reduce the risk of, alleviate or partially arrest the clinical manifestations of a given disease or disorder and its complications.
  • the amount that is effective for a particular therapeutic purpose will depend on the severity and the sort of the disorder as well as on the weight and general state of the subject. An amount adequate to accomplish this is defined as a "therapeutically effective amount”.
  • the composition is administered in doses of from 1 ⁇ g day to 100 mg/day; such as from 1 ⁇ g/day to 10 Mg/day, such as 10 Mg/day to 100 Mg/day, such as 100 Mg/day to 250 Mg/day, such as 250 Mg/day to 500 Mg/day, such as 500 Mg/day to 750 Mg/day, such as 750 Mg/day to 1 mg/day, such as 1 mg/day to 2 mg/day, such as 2 mg/day to 5 mg/day, or such as 5 mg/day to 10 mg/day, such as 10 mg/day to 20 mg/day, such as 20 mg/day to 30 mg/day, such as 30 mg/day to 40 mg/day, such as 40 mg/day to 50 mg/day, such as 50 mg/day to 75 mg/day, or such as 75 mg/day to 100 mg/day.
  • 1 mg/day to 2 mg/day such as 2 mg/day to 5 mg/day
  • 5 mg/day to 10 mg/day such as 10 mg
  • one single dose of the composition is administered and may comprise of from 1 ⁇ g kg body weight to 100 mg/kg body weight; such as from 1 to 10 ⁇ g kg body weight, such as 10 to 100 g/day, such as 100 to 250 ⁇ g kg body weight, such as 250 to 500 ⁇ g kg body weight, such as 500 to 750 ⁇ g kg body weight, such as 750 ⁇ g kg body weight to 1 mg/kg body weight, such as 1 mg/kg body weight to 2 mg/kg body weight, such as 2 to 5 mg/kg body weight, such as 5 to 10 mg/kg body weight, such as 10 to 20 mg/kg body weight, such as 20 to 30 mg/kg body weight, such as 30 to 40 mg/kg body weight, such as 40 to 50 mg/kg body weight, such as 50 to 75 mg/kg body weight, or such as 75 to 100 mg/kg body weight.
  • 1 ⁇ g kg body weight to 100 mg/kg body weight such as from 1 to 10 ⁇ g kg body weight, such as 10 to 100 g/day, such as 100 to
  • a dose according to the present invention is administered one or several times per day, such as from 1 to 6 times per day, such as from 1 to 5 times per day, such as from 1 to 4 times per day, such as from 1 to 3 times per day, such as from 1 to 2 times per day, such as from 2 to 4 times per day, such as from 2 to 3 times per day.
  • the preferred route of administration will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, the location of the tissue to be treated in the body and the active ingredient chosen.
  • the route of administration allows for introducing the peptide analogue into the blood stream to ultimately target the sites of desired action.
  • the routes of administration is any suitable routes, such as an enteral route (including the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal and intraperitoneal administration), and/or a parenteral route (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal administration).
  • enteral route including the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal and intraperitoneal administration
  • parenteral route including subcutaneous, intramuscular, intrathecal, intravenous and intradermal administration.
  • Appropriate dosage forms may be prepared by conventional techniques.
  • Parenteral administration is any administration route not being the oral/enteral route whereby the medicament avoids first-pass degradation in the liver. Accordingly, parenteral administration includes any injections and infusions, for example bolus injection or continuous infusion, such as intravenous administration, intramuscular administration or subcutaneous administration. Furthermore, parenteral administration includes inhalations and topical administration.
  • the peptide analogue or composition is in one embodiment administered topically to cross any mucosal membrane of an animal to which the substance or peptide is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum, for example the mucosa of the nose, or mouth, and accordingly, parenteral administration may also include buccal, sublingual, nasal, rectal, vaginal and intraperitoneal administration as well as pulmonal and bronchial administration by inhalation or installation.
  • the peptide analogue is administered topically to cross the skin.
  • the intravenous, subcutaneous and intramuscular forms of parenteral administration are employed.
  • the peptide analogue or composition according to the invention is used as a local treatment, i.e. is introduced directly to the site(s) of action.
  • the peptide may be applied to the skin or mucosa directly, or the peptide may be injected into the site of action, for example into the diseased tissue or to an end artery leading directly to the diseased tissue.
  • the W-Peptide analogues or pharmaceutically acceptable derivatives thereof are administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions or peptides according to the invention may be formulated with
  • pharmaceutically acceptable derivative in the present context includes pharmaceutically acceptable salts, which indicate a salt which is not harmful to the patient. Such salts include pharmaceutically acceptable basic or acid addition salts as well as pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. A pharmaceutically acceptable derivative further includes
  • esters, prodrugs, or other precursors of a compound which may be biologically metabolized into the active compound, or crystal forms of a compound are particularly preferred.
  • the pharmaceutical composition or pharmaceutically acceptable composition may be specifically formulated for administration by any suitable route, such as an enteral route, the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
  • a suitable route such as an enteral route, the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
  • compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings, or they can be formulated so as to provide controlled release of the active ingredient, such as sustained or prolonged release, according to methods well known in the art. In the same solid dosage form two active ingredients may be combined so as to provide controlled release of one active ingredient and immediate release of another active ingredient.
  • Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also regarded as being within the scope of the present invention.
  • Other suitable administration forms include suppositories, sprays, ointments, cremes/lotions, gels, inhalants, dermal patches, implants, etc.
  • a W-Peptide analogue according to the present invention is generally utilized as the free substance or as a pharmaceutically derivative such as a pharmaceutically acceptable ester or such as a salt thereof.
  • a pharmaceutically derivative such as a pharmaceutically acceptable ester or such as a salt thereof.
  • examples of the latter are: an acid addition salt of a compound having a free base functionality, and a base addition salt of a compound having a free acid functionality.
  • pharmaceutically acceptable salt refers to a non-toxic salt of a W-Peptide analogue for use according to the present invention, which salts are generally prepared by reacting a free base with a suitable organic or inorganic acid, or by reacting an acid with a suitable organic or inorganic base.
  • a W-Peptide analogue according to the present invention contains a free base functionality
  • such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid.
  • a W-Peptide analogue according to the present invention contains a free acid functionality
  • such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base.
  • Physiologically acceptable salts of a W-Peptide analogue with a hydroxy group include the anionic form of the compound in combination with a suitable cation, such as sodium or ammonium ion.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, trifluoroacetate, trichloroacetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1 ,1 '-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • the W-Peptide analogues of the present invention are in crystalline forms, for example co-crystallized forms or hydrates of crystalline forms.
  • prodrug refers to peptides that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood or by metabolism in cells, such as for example the cells of the basal ganglia.
  • prodrugs include pharmaceutically acceptable, non-toxic esters of the compounds of the present invention. Esters of the compounds of the present invention may be prepared according to conventional methods "March's Advanced Organic Chemistry, 5 th Edition". M. B. Smith & J. March, John Wiley & Sons, 2001.
  • solutions of W-Peptide analogues according to the present invention in sterile aqueous solution, in aqueous propylene glycol or in sesame or peanut oil are employed.
  • Aqueous solutions should be suitably buffered where appropriate, and the liquid diluent rendered isotonic with, e.g., sufficient saline or glucose.
  • Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media to be employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • compositions formed by combining the compounds according to the present invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules or tablets, which each contain a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in- water or water-in-oil liquid emulsion.
  • compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient(s) in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may, for example, be: inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions may contain the compound for use according to the present invention in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium
  • dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • compositions comprising W-Peptide analogues according to the present invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agent.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conveniently employed as solvent or suspending medium.
  • any bland fixed oil may be employed using synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be in the form of suppositories for rectal administration of the compounds of the invention.
  • These compositions can be prepared by mixing the W- Peptide analogues with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • Such materials include, for example, cocoa butter and polyethylene glycols.
  • W-Peptide analogues of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as but not limited to cholesterol, stearylamine or
  • W-Peptide analogues of the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the invention.
  • a further embodiment provides a pharmaceutical composition comprising a W- Peptide analogue according to the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of Sequences
  • the C-terminal Met/DMet may be amidated (-NH 2 ). Trp-Lys-Tyr-Met-Val-DMet-(Ac-Lys)Lys-NH 2
  • the N-terminal Trp may be acetylated (Ac).
  • the N-terminal Trp may be acetylated (Ac) and the C-terminal Met/DMet may be amidated (-NH 2 ).
  • the C-terminal Met/DMet may be amidated (-NH 2 ).
  • the N-terminal Trp may be acetylated (Ac).
  • the N-terminal Trp may be acetylated (Ac) and the C-terminal Met/DMet may be amidated (-NH 2 ).
  • the C-terminal Met/DMet may be amidated (-NH 2 ).
  • the N-terminal Trp may be acetylated (Ac).
  • the N-terminal Trp may be acetylated (Ac) and the C-terminal Met/DMet may be amidated (-NH 2 ).
  • a W-Peptide analogue comprising a W-Peptide and one or more branched amino acid probes
  • said branched amino acid probe comprises a first amino alkyl amino acid residue
  • said first amino alkyl amino acid residue optionally being covalently linked to a second amino alkyl amino acid residue, or to a second and a third amino alkyl amino acid residue, to form a linear chain of 2 or 3 amino alkyl amino acid residues,
  • side chain of one or more of said first, second and/or third amino alkyl amino acid residues are each modified by attaching to the side chain amino group a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) p - AAA q ; AAA q -(aa 3 ) P ; [(aa 3 )-AAA] p and [AAA-(aa 3 )] P ;
  • q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; AAA is an amino alkyl amino acid residue; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala,
  • said first amino alkyl amino acid residue is covalently linked to the N- terminus of said W-Peptide, covalently linked to the C-terminus of said W-Peptide, and/or covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide,
  • said branched amino acid probe consists of 2 to 9 amino acid residues.
  • the W-Peptide analogue according to item 1 wherein said amino alkyl amino acid residue is an amino acid with a side chain comprising an amino alkyl group (- C n H2nNH 2 ); such as a side chain amino alkyl group selected from the group consisting of methylamine (-CH 2 NH 2 ), ethylamine (-C2H4NH2), propylamine (. C 3 H 6 NH 2 ), n-butylamine (-C4H 8 NH 2 ), pentylamine (-C 5 H 1 oNH2), n-hexylamine (. C 6 H 12 NH 2 ), heptylamine (-C 7 H 14 NH 2 ), octylamine (-C 8 H 16 NH 2 ), nonylamine (.
  • a side chain amino alkyl group selected from the group consisting of methylamine (-CH 2 NH 2 ), ethylamine (-C2H4NH2), propyl
  • dodecylamine (-Ci 2 H 24 NH 2 ).
  • the W-Peptide analogue according to the preceding items wherein the side chain amino group of said amino alkyl amino acid residue is selected from the group consisting of the ⁇ -amino group (methylamine); the ⁇ -amino group (ethylamine); the ⁇ -amino group (propylamine), the ⁇ -amino group (n-butylamine); the ⁇ -amino group (pentylamine); the ⁇ -amino group (n-hexylamine); the ⁇ -amino group (heptylamine); the i-amino group (octylamine); the ⁇ -amino group (nonylamine); the ⁇ -amino group (decylamine); the ⁇ -amino group (undecylamine); and the v- amino group (dodecylamine).
  • said branched amino acid probe comprises
  • a a first amino alkyl amino acid residue, wherein the C-terminus of said first amino alkyl amino acid residue is a carboxylic acid, an aldehyde, an ester, or an amide, such as a primary amide (CONH 2 ),
  • a first and a second amino alkyl amino acid residue wherein the C-terminus of said second amino alkyl amino acid residue is a carboxylic acid, an aldehyde, an ester, or an amide, such as a primary amide (CONH 2 ), or
  • the branched amino acid probe comprises a first amino alkyl amino acid residue, said first amino alkyl amino acid residue being optionally N-terminal acetylated or C-terminal amidated, wherein the side chain amino group of said first amino alkyl amino acid residue is modified by attaching a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) P -AAA q ; AAA q -(aa 3 ) P ; [(aa 3 )-AAA] p and [AAA-(aa 3 )] P ; wherein q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; AAA is an amino alkyl amino acid residue; (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala, and the N-terminal AAA or (aa) 3 of the molecule is optionally
  • the branched amino acid probe comprises a first amino alkyl amino acid residue covalently linked to a second amino alkyl amino acid residue, to form a linear chain of 2 amino alkyl amino acid residues
  • said second amino alkyl amino acid residue being optionally N-terminal acetylated or C-terminal amidated
  • the side chain amino group of said first and/or said second amino alkyl amino acid residue is modified by attaching a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) p -AAA q ; AAA q -(aa 3 ) p ; [(aa 3 )-AAA] p and [AAA-(aa 3 )] p ; wherein q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; AAA is an amino alkyl amino acid residue; (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala, and the N- terminal AAA or (aa) 3 of the molecule is optionally acetylated.
  • the W-Peptide analogue according to the preceding items wherein the branched amino acid probe comprises a first and a second amino alkyl amino acid residue, wherein the side chain of said first amino alkyl amino acid residue is modified by attaching a molecule to the side chain amino group.
  • the W-Peptide analogue according to the preceding items wherein the branched amino acid probe comprises a first and a second amino alkyl amino acid residue, wherein the side chain of said second amino alkyl amino acid residue is modified by attaching a molecule to the side chain amino group.
  • the branched amino acid probe comprises a first amino alkyl amino acid residue covalently linked to a second and a third amino alkyl amino acid residue to form a linear chain of 3 amino alkyl amino acid residues
  • said third amino alkyl amino acid residue being optionally N-terminal acetylated or C-terminal amidated
  • the side chain amino group of said first, second and/or third amino alkyl amino acid residues is modified by attaching a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) -AAA q ; AAA q -(aa 3 ) ; [(aa 3 )-AAA] p and [AAA-(aa 3 )] P ; wherein q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; AAA is an amino alkyl amino acid residue; (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala, and the N- terminal AAA or (aa) 3 of the molecule is optionally acetylated.
  • the W-Peptide analogue according to the preceding items, wherein the branched amino acid probe comprises a first, a second and a third amino alkyl amino acid residue, wherein
  • the side chain of said second amino alkyl amino acid residue is modified by attaching a molecule to the side chain amino group
  • the side chain of said first and third amino alkyl amino acid residue is modified by attaching a molecule to the side chain amino group
  • the W-Peptide analogue according to the preceding items wherein the amino alkyl amino acid residues of the branched amino acid probe are individually selected from the group consisting of lysine and ornithine. 15. The W-Peptide analogue according to the preceding items, wherein each of the first, second and/or third amino alkyl amino acids of the branched amino acid probe are individually selected from the group consisting of lysine and ornithine.
  • each AAA of the molecules AAA q -AAA; (aa 3 ) P -AAA q ; AAA q -(aa 3 ) P ; [(aa 3 )-AAA] p and [AAA-(aa 3 )] P are individually selected from the group consisting of lysine and ornithine.
  • the W-Peptide analogue according to the preceding items wherein the amino alkyl amino acid residues of the branched amino acid probe are lysine residues.
  • the molecule to be covalently linked to said side chain amino group is Lys q -Lys; wherein q is a number selected from 0, 1 , 2 and 3 and the N-terminal Lys residue is optionally acetylated at the alpha amino group.
  • 24. The W-Peptide analogue according to the preceding items, wherein the molecule to be covalently linked to said side chain amino group is independently selected from the group consisting of
  • Orn p -Lys p Ac-Lys p -Orn p ; Ac-[Orn-Lys] p and Ac-[Lys-Orn] p ,
  • q is a number selected from 0, 1 , 2 and 3; p is a number selected from 1 , 2 and 3; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala.
  • W-Peptide analogue according to the preceding items, wherein the branched amino acid probe consist of 2 to 3 amino acid residues, such as 3 to 4 amino acid residues, for example 4 to 5 amino acid residues, such as 5 to 6 amino acid residues, for example 6 to 7 amino acid residues, such as 7 to 8 amino acid residues, for example 8 to 9 amino acid residues.
  • the W-Peptide analogue according to the preceding items, wherein the branched amino acid probe consist of 2 amino acid residues, such as 3 amino acid residues, for example 4 amino acid residues, such as 5 amino acid residues, for example 6 amino acid residues, such as 7 amino acid residues, for example 8 amino acid residues, such as 9 amino acid residues.
  • the W-Peptide analogue according to the preceding items, wherein the molecule to be covalently linked to the side chain amino group(s) of one or more of the first, second and/or third amino alkyl amino acid residues is selected from the group consisting of AAA, Ac-AAA, AAA-AAA, Ac-AAA-AAA, AAA-AAA-AAA, Ac-AAA- AAA-AAA, AAA-AAA-AAA, Ac-AAA-AAA-AAA-AAA, AAA-Gly-AAA, Ac-AAA- Gly-AAA, AAA-AAA-Gly, Ac-AAA-AAA-Gly, AAA-Gly, Ac-AAA-Gly, AAA-Ala-AAA, Ac-AAA-Ala-AAA, AAA-AAA-Ala, Ac-AAA-AAA-AI a , AAA-Ala, Ac-AAA-Ala, AAA- His-AAA, Ac-AAA-His-AAA, AAA-AA
  • the W-Peptide analogue according to the preceding items, wherein the molecule to be covalently linked to the side chain amino group(s) of one or more of the first, second and/or third amino alkyl amino acid residues is selected from the group consisting of Lys, Ac-Lys, Lys-Lys, Ac-Lys-Lys, Lys-Lys-Lys, Ac-Lys-Lys-Lys, Lys- Lys-Lys-Lys, Lys- Lys-Lys-Lys, Ac-Lys-Lys-Lys, Lys-Gly-Lys, Ac-Lys-Gly-Lys, Lys-Lys-Gly, Ac- Lys-Lys-Gly, Lys-Lys-Gly, Ac- Lys-Lys-Gly, Lys-Lys-Gly, Lys- Lys-Gly, Lys-Lys-Gly,
  • the W-Peptide analogue according to the preceding items wherein the branched amino acid probe is selected from the group consisting of Ac-(Ac-Lys)Lys-, Ac- (Lys)Lys-, (Ac-Lys)Lys-NH 2 , (Lys)Lys-NH 2 and (Lys)Lys-.
  • amino alkyl amino acid residue is covalently linked to the ⁇ -amino group of a lysine residue within said W-Peptide, such as covalently linked to the ⁇ -amino group of the lysine residue at position 2 said W-Peptide.
  • amino alkyl amino acid residue is covalently linked to the C-terminus of said W- Peptide.
  • amino alkyl amino acid residue is covalently linked to the C-terminal Met or DMet of said W-Peptide.
  • the W-Peptide analogue according to the preceding items comprising 1 branched amino acid probe covalently linked to the N-terminus of said W-Peptide.
  • the W-Peptide analogue according to the preceding items comprising 1 branched amino acid probe covalently linked to the C-terminus of said W-Peptide.
  • the W-Peptide analogue according to the preceding items comprising 1 branched amino acid probe covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide; such as covalently linked to the ⁇ -amino group of an ornithine residue within said W-Peptide or the ⁇ -amino group of a lysine residue within said W-Peptide.
  • one branched amino acid probe is covalently bound to the N-terminus of the W- Peptide and another branched amino acid probe is covalently bound to the C- terminus of the W-Peptide;
  • one branched amino acid probe is covalently bound to the N-terminus of the W- Peptide and another branched amino acid probe is covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide;
  • one branched amino acid probe is covalently bound to the C-terminus of the W- Peptide and another branched amino acid probe is covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide;
  • each of the two branched amino acid probes are covalently linked to the side chain amino group of separate amino alkyl amino acid residues within said W- Peptide.
  • the W-Peptide analogue according to the preceding items comprising 3 branched amino acid probes.
  • the W-Peptide analogue according to the preceding items comprising 3 branched amino acid probes, wherein
  • the first branched amino acid probe is covalently bound to the N-terminus of the W-Peptide
  • the second branched amino acid probe is covalently bound to the C- terminus of the W-Peptide
  • the third branched amino acid probe is covalently linked to the side chain amino group of an amino alkyl amino acid residue within said W-Peptide
  • the first branched amino acid probe is covalently bound to the N-terminus of the W-Peptide, and the second and third branched amino acid probes are each covalently linked to the side chain amino group of different amino alkyl amino acid residues within said W-Peptide; or
  • the first branched amino acid probe is covalently bound to the C-terminus of the W-Peptide, and the second and third branched amino acid probes are each covalently linked to the side chain amino group of different amino alkyl amino acid residues within said W-Peptide; or iv) each of the first, the second and the third branched amino acid probes are covalently linked to the side chain amino group of different amino alkyl amino acid residues within said W-Peptide.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having one amino acid substitution.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having two amino acid substitutions.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having three amino acid substitutions.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having an amino acid substitution at position 1 .
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having an amino acid substitution at position 2.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having an amino acid substitution at position 3.
  • the W-Peptide analogue according to the preceding items wherein said W- Peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having one amino acid substitution at position 5.
  • the W-Peptide analogue according to the preceding items wherein said W- Peptide is Trp-Lys-Tyr-Met-Val-Met (SEQ ID NO:1 ) or a functional variant thereof having one amino acid substitution at position 6.
  • the W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Pro-Met (SEQ ID NO:3) or Trp-Lys-Tyr-Met-Pro-DMet.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is a variant comprising a phenylalanine residue.
  • W-Peptide analogue according to the preceding items wherein said W- Peptide is Trp-Lys-Phe-Met-Val-Met (SEQ ID NO:5) or Trp-Lys-Phe-Met-Val-DMet.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is a variant comprising an alpha-amino n-butyric acid residue, such as an alfa-amino butyric acid residue (Abu) and/or an alfa-amino isobutyric acid residue (Aib).
  • alpha-amino n-butyric acid residue such as an alfa-amino butyric acid residue (Abu) and/or an alfa-amino isobutyric acid residue (Aib).
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Abu-Met (SEQ ID NO:6) or Trp-Lys-Tyr-Met-Abu-DMet.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-Aib-Met (SEQ ID NO:7) or Trp-Lys-Tyr-Met-Aib-DMet.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is X-Lys-Tyr-X-Val-Met (SEQ ID NO:8) or X-Lys-Tyr-X-Pro-Met (SEQ ID NO:9), wherein X is individually any amino acid, such as Trp or Met.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp-Lys-Tyr-Met-aa-Met (SEQ ID NO:10) or Trp-Lys-Tyr-Met-aa-DMet, wherein aa is an amino acid having the structure R 1 R 2 C(NH 2 )-COOH, wherein R 1 is a functional group selected from the group consisting of -H, alkyl, alkenyl, cycloalkyi and cycloalkenyl, and wherein R 2 is a functional group selected from the group consisting of alkyl, alkenyl, cycloalkyi and cycloalkenyl.
  • W-Peptide analogue according to the preceding items, wherein said W- Peptide is Trp - X2 - X3 - X4 - X5 - X6 (SEQ ID NO:1 1 ), wherein X2 is selected from Lys and Orn, X3 is selected from Tyr and Phe, X4 is selected from Met and lie, X5 is selected from Val, Pro, Abu, Aib and aa; and X6 is selected from Met and DMet.
  • Peptide is selected from the group consisting of
  • Trp-Lys-Tyr-Met-Val-Met SEQ ID NO:1
  • Trp-Orn-Tyr-Met-Val-Met SEQ ID NO:2
  • Trp-Orn-Tyr-Met-Val-DMet Trp-Orn-Tyr-Met-Val-DMet
  • Trp-Lys-Tyr-Met-Pro-Met SEQ ID NO:3
  • Trp-Lys-Tyr-lle-Val-Met SEQ ID NO:4
  • Trp-Lys-Phe-Met-Val-Met SEQ ID NO:5
  • Trp-Lys-Tyr-Met-Abu-Met SEQ ID NO:6
  • Trp-Lys-Tyr-Met-Aib-Met SEQ ID NO:7
  • X-Lys-Tyr-X-Val-Met wherein X is any amino acid (SEQ ID NO:8), X-Lys-Tyr-X-Pro-Met, wherein X is any amino acid (SEQ ID NO:9), Trp-Lys-Tyr-Met-aa-Met (SEQ ID NO: 10) and Trp-Lys-Tyr-Met-aa-DMet, wherein aa is an amino acid having the structure R 1 R 2 C(NH 2 )-COOH, wherein R 1 is a functional group selected from the group consisting of -H, alkyl, alkenyl, cycloalkyl and cycloalkenyl, and wherein R 2 is a functional group selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl, and
  • Trp - X2 - X3 - X4 - X5 - X6 (SEQ ID NO: 1 1 ), wherein X2 is selected from
  • X3 is selected from Tyr and Phe
  • X4 is selected from Met and lie
  • X5 is selected from Val, Pro, Abu, Aib and aa
  • X6 is selected from Met and DMet
  • FPR1 Formyl Peptide Receptor 1
  • FPR2 Formyl Peptide Receptor 2
  • FPR3 Formyl Peptide Receptor 3
  • FPR1 Formyl Peptide Receptor 1
  • FPR2 Formyl Peptide Receptor 2
  • FPR3 Formyl Peptide Receptor 3
  • leukocytes such as phagocytic leukocytes, and/or
  • phagocytic leukocytes' effector functions such as inducing neutrophil chemotaxis, mobilization of neutrophil complement receptor 3 (CR3), and activation of the neutrophil NADPH-oxidase, and/or
  • a pharmaceutical composition comprising a W-Peptide analogue according to any of the preceding items.
  • said organ is selected from the group consisting of kidney, liver, brain, heart, muscles, bone marrow, skin, skeleton, lungs, the respiratory tract, spleen, exocrine glands, bladder, endocrine glands, reproduction organs including the phallopian tubes, eye, ear, vascular system, the gastroinstestinal tract including small intestines, colon, rectum, canalis analis and prostate gland.
  • said ischemia is due to stroke, injury, septic shock, systemic hypotension, cardiac arrest due to heart attack, cardiac arrhythmia, atheromatous disease with thrombosis, embolism from the heart or from blood vessel from any organ, vasospasm, aortic aneurysm or aneurisms in other organs, coronary stenosis, myocardial infarction, angina pectoris, pericarditis, myocarditis, myxodemia, or endocarditis.
  • CABG cardiac artery bypass grafting
  • transplantation such as solid organ transplantation.
  • AKI acute kidney injury
  • CRF chronic renal failure
  • said inflammatory disease is selected from the group consisting of arthropathy (joint disease), rheumatoid arthritis (RA), gout, inflammatory diseases of the gastrointestinal system, and multiple sclerosis.
  • RA rheumatoid arthritis
  • said method comprising administering an effective amount of a W-Peptide analogue according to any of the preceding items to an individual in need thereof.
  • BAP modified peptides were synthesized using standard Fmoc chemistry using 1 - [Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro- phosphate (HATU) or 2-(6-Chloro-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3-tetramethylaminium hexafluorophosphate (HCTU) as the coupling reagents with Hunig's Base (N,N- diisopropylethylamine, DIPEA).
  • Hunig's Base N,N- diisopropylethylamine, DIPEA
  • lysine analogues such as Fmoc-Lys(MTT)-OH, Fmoc-Lys(ivDde)-OH and Fmoc-Lys(Boc)-OH were sequentially added and selectively deprotected, before acetylation to ensure appropriate side chain and acetyl addition.
  • BAP was added to other amino alkyl residues than lysine by analogously using Fmoc/4-methyltrityl protected amino alkyl amino acids. BAP attached in the N-terminus of the sequence
  • N - a - Fmoc - N - ⁇ - 4 - methyltrityl - L - lysine was added to N-terminal of the sequence, Fmoc was removed, the sequence acetylated at the N-terminus, and the metyltrityl group was removed. Additional No Fmoc-Ne-Boc-L-lysine was then added to the side chain and acetylated when desired.
  • Branching on other than the N-terminal lysine analogously to attaching BAP to lysines in the sequence between the N- and C-termini (METHOD 2).
  • Control peptide (W-peptide; SEQ I D NO: 1 ): Trp-Lys-Tyr-Met-Val-Met-NH 2
  • Analogue 3 (by METHOD 3): Ac-(Ac-Lys-Lys)Lys-Jrp-Lys-Jyr-Met-Abu-DMet-N 2 Purity: 97.5%, MS: 437.6, 655.9
  • Radioligand competition binding was performed in duplicate in the wells of a 96 well plate (Master Block, Greiner, 786201 ) containing binding buffer (50 mM Tris HCI pH 7.4, saponin 10 ⁇ g/ml and 0.5% protease free BSA), FPR2 membrane extracts ( ⁇ . ⁇ protein/well), 2 nM [125l]-WHYMV(D-met)-NH2 (PerkinElmer, NEX386) and test compound at increasing concentrations. Nonspecific binding was determined by co- incubation with 200-fold excess of non labelled agonist. The samples were incubated in a final volume of 0.1 ml for 60 min at 25°C and then filtered over GF/C filters (Perkin
  • Test compounds i.e. W-Peptide analogues 1 -6 and the W-Peptide control compound (SEQ ID NO:1 ) were tested in duplicate in a concentration range of 0.01 to 10,000 nM.
  • the IC50 i.e. the concentration that induced 50% displacement of radioactive agonist
  • the graph pad software version 6.0
  • recombinant human FPR2 receptor were grown 18 hours prior to the test in media without antibiotics.
  • the cells were detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer containing DMEM/HAM's F12 with HEPES + 0.1 % BSA (protease free). Cells were incubated at room temperature for at least 4h with coelenterazine h (Molecular Probes).
  • FDSS 6000 Hamamatsu Functional Drug Screening System 6000
  • Agonist activity of test compound was expressed as a percentage of the activity of the reference agonist at its EC100 concentration.
  • Test compounds i.e. W-Peptide analogues 1 -6 were tested in duplicate in a concentration range of 0.0001 to 1000 nM.
  • the control compound (W-Peptide, SEQ ID NO:1 ) was tested in a range of 0.0001 to 100 nM.
  • the EC50 i.e. the concentration that induced 50% of maximal agonist response
  • the graph pad software version 6.0
  • W-Peptide control compound is a full agonist against the human FPR2 receptor with an EC50 value of 0.2 nM.
  • the BAP-modified W-Peptide analogues all induced full agonist activity (see figures 2b- 7b).
  • the potency as evaluated by EC50 is high for all the tested analogues.
  • the EC50 was obtained at concentration more than 3 decades lower that for the control compound:

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des analogues de peptides W comprenant un peptide W, tel qu'un peptide W et des variants fonctionnels de celui-ci, et une ou plusieurs sondes d'acides aminés ramifiées.
PCT/EP2016/075176 2015-10-20 2016-10-20 Analogue de peptide w WO2017068020A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA201570679 2015-10-20
DKPA201570679 2015-10-20

Publications (1)

Publication Number Publication Date
WO2017068020A1 true WO2017068020A1 (fr) 2017-04-27

Family

ID=57208263

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/075176 WO2017068020A1 (fr) 2015-10-20 2016-10-20 Analogue de peptide w

Country Status (1)

Country Link
WO (1) WO2017068020A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020152723A (ja) * 2019-03-19 2020-09-24 ノバセル テクノロジー インコーポレイテッド 新規な多重機能性ペプチド及びその用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999046283A1 (fr) 1998-03-09 1999-09-16 Zealand Pharmaceuticals A/S Conjugues peptidiques pharmacologiquement actifs ayant une tendance reduite a l'hydrolyse enzymatique
WO2007022774A1 (fr) 2005-08-26 2007-03-01 Action Pharma A/S ANALOGUES α-MSH THÉRAPEUTIQUEMENT ACTIFS
KR20100133688A (ko) * 2009-06-12 2010-12-22 포항공과대학교 산학협력단 히알루론산-펩타이드 컨쥬게이트의 제조 방법, 및 이에 의해 제조된 히알루론산-펩타이드 컨쥬게이트
EP2722340A1 (fr) 2012-10-19 2014-04-23 TXP Pharma GmbH Analogues d'alpha- et gamma-MSH

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999046283A1 (fr) 1998-03-09 1999-09-16 Zealand Pharmaceuticals A/S Conjugues peptidiques pharmacologiquement actifs ayant une tendance reduite a l'hydrolyse enzymatique
WO2007022774A1 (fr) 2005-08-26 2007-03-01 Action Pharma A/S ANALOGUES α-MSH THÉRAPEUTIQUEMENT ACTIFS
KR20100133688A (ko) * 2009-06-12 2010-12-22 포항공과대학교 산학협력단 히알루론산-펩타이드 컨쥬게이트의 제조 방법, 및 이에 의해 제조된 히알루론산-펩타이드 컨쥬게이트
EP2722340A1 (fr) 2012-10-19 2014-04-23 TXP Pharma GmbH Analogues d'alpha- et gamma-MSH
WO2014060606A1 (fr) 2012-10-19 2014-04-24 Txp Pharma Gmbh Analogues de alpha- et gamma-msh

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BAEK ET AL., J BIOL CHEM, 1996
EDWARD B. ROCHE,: "Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
GENNARO,: "Remington: The Science and Practice of Pharmacy, 20th Edition,", 2000, MACK PUBLISHING CO.
J. JACOB STROUSE ET AL: "A novel fluorescent cross-reactive formylpeptide receptor/formylpeptide receptor-like 1 hexapeptide ligand", CYTOMETRY. PART A, vol. 75A, no. 3, 1 March 2009 (2009-03-01), US, pages 264 - 270, XP055334190, ISSN: 1552-4922, DOI: 10.1002/cyto.a.20670 *
M. B. SMITH; J. MARCH: "March's Advanced Organic Chemistry, 5th Edition", 2001, JOHN WILEY & SONS
SANG DOO KIM ET AL: "The immune-stimulating peptide WKYMVm has therapeutic effects against ulcerative colitis", EXPERIMENTAL & MOLECULAR MEDICINE, vol. 45, no. 9, 1 September 2013 (2013-09-01), pages e40, XP055334091, DOI: 10.1038/emm.2013.77 *
T. HIGUCHI; V STELLA: "A.C.S. Symposium Series", vol. 14, article "Pro-drugs as Novel Delivery Systems"
WAN ET AL: "Discovery of Trp-Nle-Tyr-Met as a novel agonist for human formyl peptide receptor-like 1", BIOCHEMICAL PHARMACOLOGY, ELSEVIER, US, vol. 74, no. 2, 11 June 2007 (2007-06-11), pages 317 - 326, XP022112699, ISSN: 0006-2952, DOI: 10.1016/J.BCP.2007.04.016 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020152723A (ja) * 2019-03-19 2020-09-24 ノバセル テクノロジー インコーポレイテッド 新規な多重機能性ペプチド及びその用途
CN113614099A (zh) * 2019-03-19 2021-11-05 诺娃细胞科技公司 新型多功能肽及其用途

Similar Documents

Publication Publication Date Title
US9951116B2 (en) Alpha- and gamma-MSH analogues
US11141455B2 (en) Peptide analogues with branched amino acid probe(s)
US20230295255A1 (en) Annexin a1-derived polypeptide analogues
US20150297672A1 (en) Alpha- and gamma-MSH analogues
US20150376254A1 (en) Gamma-msh analogues
WO2017068020A1 (fr) Analogue de peptide w
AU2023226134A1 (en) Annexin a1-derived polypeptide analogues
AU6610390A (en) Reduced irreversible bombesin antagonists
US20230303640A1 (en) Exendin-4 peptide analogs
AU630715B2 (en) Irreversible bombesin antagonists

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16787769

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WPC Withdrawal of priority claims after completion of the technical preparations for international publication

Ref document number: PA 2015 70679

Country of ref document: DK

Date of ref document: 20180323

Free format text: WITHDRAWN AFTER TECHNICAL PREPARATION FINISHED

122 Ep: pct application non-entry in european phase

Ref document number: 16787769

Country of ref document: EP

Kind code of ref document: A1