P-selectin peptide ligands

Abstract

The present invention relates to peptide ligands of P-selectin comprising a cyclic element.

Description

[0001] P-SELECTIN PEPTIDE LIGANDS TECHNICAL FIELD OF THE INVENTION The present invention relates to peptide ligands of P-selectin comprising a cyclic element. INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING SEQUENCE LISTING The present application is filed with a Sequence Listing in electronic form. The entire contents of the sequence listing are hereby incorporated by reference. BACKGROUND The P-selectin receptor (P-selectin) is a member of the selectin family of adhesion glycoproteins which also includes the L- and E-selectin receptors (GS Kansas Blood 1996; R McEver Cardiovasc Res 2015; Tvaroška I et al. Molecules 2020). The selectin receptors (selectins for short) mediate the recruitment, initial tethering and rolling, and adherence of leukocytes to sites of inflammation (Klaus L et al. Nat Rev Immunol 2007). The function of the P-selectin receptor is, at least partly, mediated by binding of P- selectin glycoprotein ligand 1 (PSGL-1) to the P-selectin receptor. Inhibition of the binding of PSGL-1 to the P-selectin receptor thus antagonizes the receptor function and may further inhibit binding of activated platelets or endothelial cells to immune cells or sickled red blood cells or platelets. Based on its role in the regulation of cellular trafficking, recruitment and adhesion antagonistic P-selectin ligands are suitable for use in preventing, suppressing, or treating a disease or disorder mediated by P-selectin, including a variety of inflammatory diseases and other thrombotic disorders and conditions which involve platelet, sickled red cell, leukocyte, lymphocyte, and / or endothelial cell adhesion, such as vaso-occlusive crisis (VOC) and sickle cell disease-related conditions. Peptide molecules binding and antagonizing P-selectin have previously been described (WO9533484, WO0175107, US2006217294, WO2022 / 155289 and WO22223969), and two antibodies antagonizing human P-selectin, Inclacumab and Crizanlizumab have been developed by Roche / Pfizer and Novartis, respectively. The dosage requirement for these antibodies is high, and therefore administration is only possibly by i.v. infusion and consequently such treatment requires hospitalization. Despite the progress obtained with these antibodies, improvements both with regards to treatment efficacy and are still warranted. SUMMARY The present invention relates to peptides capable of specifically binding to the human P-selectin receptor and not the human L- and E-selectin receptors. The peptides further inhibit platelet leukocyte aggregation. Based on the role of P-selectin in inflammation, such peptides are useful in the treatment of a variety of inflammatory diseases and other thrombotic disorders and conditions which involve platelet, sickled red cell, leukocyte, lymphocyte, and / or endothelial cell adhesion, including also sickle-cell disease. The peptides and peptide ligands identified herein are cyclic and display a common binding motif ensuring high binding affinity to the human P-selectin receptor. The peptides and peptide ligands preferably include only proteogenic amino acid residues, allowing for producing the peptides recombinantly, albeit post translational modification may in some situations be suitable. The peptides and peptide ligands may further display a long plasma half-life. The peptides and peptide ligands are further well suited for pharmaceutical use as they are highly soluble and stable in liquid formulation. In comparison to antibodies, the peptides and peptide ligands as described herein are much smaller and thus advantageous in terms of dosing options as a high concentration of peptide can be obtained and the volume to be administered reduced. The peptides and peptide ligands are further shown to be suitable for subcutaneous administration, and displaying a fast uptake, leading to an early high plasma exposure that combined with a long plasma half-life support the use of such peptides and peptides ligand in both prophylactic and acute treatment. BRIEF DESCRIPTION OF DRAWINGS Fig.1 outlines the interaction of monocytes, neutrophils, activated platelets and T- lymphocytes which all binds to P-selectin via the PSGL-1 membrane embedded receptor in the blood flow. Fig.2 shows HMWP formation (%) at each time point for the different dimeric peptide derivatives. Lower right panel shows delta HWMP formation of the highest concentration (60 mg / ml) from time zero to 4 weeks. Fig.3 shows the content of each dimeric peptide derivatives at different concentrations at week 0,1, 2 and 4. Fig.4 shows the plasma exposure of dimeric peptide derivatives # 39 (Compound 39 in figure) and # 44 (Compound 44 in figure) after subcutaneous administration to minipigs. 4A provides the exposure in minipig for the time period 0 – 264 hours and 4B is an expanded view of the time period 0 to 24 hours. DESCRIPTION P-Selectin receptor, ligands and antagonists The human P-selectin receptor is a member of the selectin family of adhesion glycoproteins which also includes the L- and E-selectins receptors. The selectin receptors (selectins for short) mediate the recruitment, initial tethering and rolling, and adherence of leukocytes to sites of inflammation. Inhibition of the binding of PSGL-1 to the P-selectin receptor thus antagonizes the receptor function and may further inhibit binding of activated platelets or endothelia cells to immune cells or sickled red blood cells or platelets. In one embodiment the peptide binds the human P-selectin receptor as determined by surface plasmon resonance (SPR). In one embodiment the peptide has a high affinity, such as an estimated affinity (Kd) in the nano-molar range. In one embodiment the Kd is at most 100 nM, such as at most 50 nM, such as at most 10 nM when determined by SPR as described in Example 3 herein. The binding and inhibition of PSGL-1 binding to human P-selectin may be determined in a cell-based P-selectin PSGL-1 binding assay as described herein (PLA assay). In one embodiment the peptide inhibits binding of activated platelets or endothelia cells to immune cells or sickled red blood cells or platelets as determined in a Platelet Leukocyte Aggregates (PLA) assay as described herein. In one embodiment the inhibitory activity is on par with the activity of crizanlizumab. In one embodiment the inhibitory activity is improved compared to crizanlizumab. In one embodiment the inhibitory activity is measured as the IC50and / or IC90in an PLA assay as described herein. P-Selectin peptide ligands The present invention relates to peptides specifically binding human P-selectin but not E and L-selectin comprising a binding motif -W-C2-X3-X4-X5-X6-X7-D-D-X10-X11-X12-C13- (SEQ ID NO.: 3). An aspect of the invention relates to a peptide comprising the amino acid sequence -W-C2-X3-X4-X5- X7-D-D-X10-X11-X12-C13- (SEQ ID NO.: 3) wherein X3is S or D, X4is I or V, X5is S, D, N or H, X6is S or P, X7is any amino acid residue except P, X10is A, S, T, D, E, Q, N or K, X11is A, S, T, I, V or H and X12is A, S, T, G, D, E, Q, N, L, V, K, R or H. In one embodiment C2and C13are covalently linked by a disulfide bridge. In one embodiment X3is D. In one embodiment X4is I. In one embodiment X4is V. In one embodiment X5is S or N In one embodiment X5is N. In one embodiment X6is P. In one embodiment X7is any amino acid except for proline (P). In one embodiment X7is S, T, L, I, W, Y, F, K, R or H. In one embodiment X7is I, W, F or R. In one embodiment X7is W or F. In one embodiment X7is R. In one embodiment X7 is W. In one embodiment X7is F. In one embodiment X10is S, T, D, E or Q. In one embodiment X10is S. In one embodiment X11is A, S, T, I, V or H. In one embodiment X11is S, I, V or H. In one embodiment X11is I, V or H. In one embodiment X11is I. In one embodiment X12is A, S, T, G, D, E, Q, N, L, V, K, R or H. In one embodiment X12is A, S, T, G, D, E, Q, N or H. In one embodiment X12is A, S, T, D, E, Q or N. In one embodiment X12is S or T. In one embodiment the peptide comprises the amino acid sequence - WCDINPWDDSITC- (SEQ ID NO.: 4) or a variant hereof comprising at most 4 amino acid substitutions, such as at most 3 amino acid substitutions, such as at most 2 amino acid substitutions or such as at most 1 amino acid substitutions. In one embodiment the peptide comprises an amino acid sequence selected from - WCDINPFDDSITC- (SEQ ID NO.: 4), WCDINPWDDSITC- (SEQ ID NO.: 5) and WCDINPRDDSITC- (SEQ ID NO.: 6). In one embodiment the peptide comprises the amino acid sequence - WCDINPFDDSITC- (SEQ ID NO.: 4). In one embodiment the peptide comprises the amino acid sequence - WCDINPWDDSITC- (SEQ ID NO.: 5). In one embodiment the peptide comprises the amino acid sequence - WCDINPRDDSITC- (SEQ ID NO.: 6). In further embodiments the peptide comprises additional amino acid residues at the N-terminal and / or C-terminal, which are herein named N-terminal flanking sequence (Nflank), C-Terminal flanking sequence, N-terminal extension sequence (Next) and C-Terminal extension sequence (Cext). In one embodiment the peptide is at least 20 amino acids, such as at least 25, such as at least 30 amino acids in length. In one embodiment the peptide is at most 50 amino acids, such as at least 45, such as at least 40 amino acids in length. In one embodiment the peptide is 20-50, 25-45, 20-40, 25-40, 30-45 or 30-40 amino acids in length. In one embodiment the peptide comprises an N-terminal flanking sequence (Nflank) and / or a C-Terminal flanking sequence (Cflank). In one embodiment the peptide comprises an N-terminal flanking sequence (Nflank) and a C-Terminal flanking sequence (Cflank). The Nflan and the Cflank may vary in length, but usually the Nflan and / or the Cflank are short peptide segments, comprising up to 20 amino acid residues. In one embodiment the Nflank is an extension of 1-10 amino acid residues, such as 2-8 amino acid residue, such as 2-6, amino acid residues, such as 3-5 amino acid residues. In one embodiment the Nflank is selected from the group consisting of: LGD, EGDI (SEQ ID NO.: 7), LGDI (SEQ ID NO.: 8) and GGDI (SEQ ID NO.: 9). In one embodiment the Nflank is EGDI (SEQ ID NO.: 7). In one embodiment Nflank is LGDI (SEQ ID NO.: 8). In one embodiment the Cflank is an extension of 1-10 amino acid residues, such as 2-8 amino acid residue, such as 2-6, amino acid residues, such as 3-5 amino acid residues. In one embodiment the Cflank is selected from the group consisting of: SRWV (SEQ ID NO.: 10), SRWL (SEQ ID NO.: 11) and TRWV (SEQ ID NO.: 12). In one embodiment the Cflank is SRWV (SEQ ID NO.: 10). In further embodiments the peptide may comprises an additional peptide extension at the N-terminal and / or C-terminal. In one embodiment the peptide comprises an N-terminal extension sequence (Next) and / or a C-terminal extension sequence (Cext). In one embodiment the peptide comprises an N-terminal extension sequence (Next) and a C-Terminal extension sequence (Cext). In one embodiment the Next is an extension of 1-10 amino acid residues, such as 2- 8 amino acid residue, such as 2-6, amino acid residues, such as 3-5 amino acid residues. In one embodiment the Next is selected from the group consisting of: GE, GS, GP, GPE, EGE, GAQP (SEQ ID NO.: 13), GEQP (SEQ ID NO.: 14), GAQPP (SEQ ID NO.: 15), GEGDI (SEQ ID NO.: 16), GGPGG (SEQ ID NO.: 17), GGSGG (SEQ ID NO.: 18), GSGSGS (SEQ ID NO.: 19), GEPGEQP (SEQ ID NO.: 20), GAQPGAQPG (SEQ ID NO.: 21) and GAQPKGEQP (SEQ ID NO.: 22). In one embodiment the Next is selected from the group consisting of: GP, GAQP (SEQ ID NO.: 13), GAQPP (SEQ ID NO.: 15), GEGDI (SEQ ID NO.: 16) and GAQPKGEQP (SEQ ID NO.: 22). In one embodiment the Next is selected from the group consisting of: G, GE, GG, GS, GP, GPE, EGE, GAQP (SEQ ID NO.: 13), GEQP (SEQ ID NO.: 14), GAQPP (SEQ ID NO.: 15), GGPGG (SEQ ID NO.: 17), GGSGG (SEQ ID NO.: 18), GSGSGS (SEQ ID NO.: 19), GEPGEQP (SEQ ID NO.: 20), GAQPGAQPG (SEQ ID NO.: 21) and GAQPKGEQP (SEQ ID NO.: 22). In one embodiment the Next is selected from the group consisting of: GP, GAQP (SEQ ID NO.: 13), GAQPP (SEQ ID NO.: 15) and GAQPKGEQP (SEQ ID NO.: 22). In one embodiment the Cext is an extension of 1-20 amino acid residues, such as 2- 18 amino acid residue, such as 5-15, amino acid residues, such as 8-12 amino acid residues. In one embodiment the Cext is selected from the group consisting of: K, E,GK, EEK, EEGAQPK (SEQ ID NO.: 23), EEGEQPE (SEQ ID NO.: 24), EGEGEQPKE (SEQ ID NO.: 25), EEGEQPGEQPK (SEQ ID NO.: 26), GEPGEGGPEGGPEGK (SEQ ID NO.: 27), EEGEQPGEQPGEQPK (SEQ ID NO.: 28), EEGSK (SEQ ID NO.: 66), GEQPK (SEQ ID NO.: 67), GSEEK (SEQ ID 70). In one group EEGAQPK (SEQ ID NO.: 23), EEGEQPE (SEQ ID NO.: 24), EGEGEQPKE (SEQ ID NO.: 25), EEGEQPGEQPK (SEQ ID NO.: 26), GEPGEGGPEGGPEGK (SEQ ID NO.: 27), and EEGEQPGEQPGEQPK (SEQ ID NO.: 28). A peptide as described herein above may thus comprise: -Next-Nflank-binding motif-Cflank-Cext- wherein the binding motif is defined by SEQ ID NO.: 3, and each of Next, Nflank, Cflank and Cext are defined as described herein above. In one embodiment the peptide sequence is selected from the group consisting of: GEPGEQPEGDIWCDINPFDDSITCSRWVEGEGEQPKE (SEQ ID NO.: 29), GAQPPEGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 30), GPEGDIWCDINPFDDSITCSRWVGEPGEGGPEGGPEGK (SEQ ID NO.: 31), GAQPKGEQPEGDIWCDINPFDDSITCSRWVEEGEQPE (SEQ ID NO.: 32), GEGDIWCDINPFDDSITCSRWVEEGEQPGEQPK (SEQ ID NO.: 33), GAQPEGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 34), GAQPGGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 35), LGDIWCDINPFKDSITCSRWVEE (SEQ ID NO.: 50), LGDIWCDINPFDKSITCSRWVEE (SEQ ID NO.: 51), LGDIWCDINPFDDKITCSRWVEE (SEQ ID NO.: 52), LGDIWCDINPFDDSKTCSRWVEE (SEQ ID NO.: 53), LGDIWCDINPFDDSIKCSRWVEE (SEQ ID NO.: 54), LGDIWCDINPFDDSITCSRWVGSGSGSEEK (SEQ ID NO.: 55), LGDIWCDINPFDDSITCSRWVGSEEK (SEQ ID NO.: 56), LGDIWCDINPFDDSITCSRWVEEGSK (SEQ ID NO.: 57), GSLGDIWCDINPFDDSITCSRWVGEQPK (SEQ ID NO.: 58), GSLGDIWCDINPFDDSITCSRWVGK (SEQ ID NO.: 59), GSGSGSLGDIWCDINPFDDSITCSRWVGK (SEQ ID NO.: 60), LGDIWCDINPFDDSITCSRWVEEK (SEQ ID NO.: 61), LGDIWCDINPFDDSITcSRWVK (SEQ ID NO.: 62), GGLGDIWCDINPFDDSITCSRWVK (SEQ ID NO.: 63), GGPGGLGDIWCDINPFDDSITCSRWVK (SEQ ID NO.: 64) and GSLGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 65). In one embodiment the peptide sequence is selected from the group consisting of: LGDIWCDINPFKDSITCSRWVEE (SEQ ID NO.: 50), LGDIWCDINPFDKSITCSRWVEE (SEQ ID NO.: 51), LGDIWCDINPFDDKITCSRWVEE (SEQ ID NO.: 52), LGDIWCDINPFDDSKTCSRWVEE (SEQ ID NO.: 53), LGDIWCDINPFDDSIKCSRWVEE (SEQ ID NO.: 54), (SEQ ID NO.: 55), LGDIWCDINPFDDSITCSRWVGSEEK (SEQ ID NO.: 56), LGDIWCDINPFDDSITCSRWVEEGSK (SEQ ID NO.: 57), GSLGDIWCDINPFDDSITCSRWVGEQPK (SEQ ID NO.: 58), GSLGDIWCDINPFDDSITCSRWVGK (SEQ ID NO.: 59), GSGSGSLGDIWCDINPFDDSITCSRWVGK (SEQ ID NO.: 60), LGDIWcDINPFDDSITCSRWVEEK (SEQ ID NO.: 61), LGDIWCDINPFDDSITCSRWVK (SEQ ID NO.: 62), GGLGDIWCDINPFDDSITCSRWVK (SEQ ID NO.: 63), GGPGGLGDIWCDINPFDDSITCSRWVK (SEQ ID NO.: 64) and GSLGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 65). In one embodiment the peptide sequence is selected from the group consisting of: GEPGEQPEGDIWCDINPFDDSITCSRWVEGEGEQPKE (SEQ ID NO.: 29), GAQPPEGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 30), GPEGDIWCDINPFDDSITCSRWVGEPGEGGPEGGPEGK (SEQ ID NO.: 31), GAQPKGEQPEGDIWCDINPFDDSITCSRWVEEGEQPE (SEQ ID NO.: 32), GEGDIWCDINPFDDSITCSRWVEEGEQPGEQPK (SEQ ID NO.: 33), GAQPEGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 34) and GAQPGGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 35). In one embodiment the peptide sequence is selected from the group consisting of: GAQPPEGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 30), GPEGDIWCDINPFDDSITCSRWVGEPGEGGPEGGPEGK (SEQ ID NO.: 31) and GAQPEGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 34) The peptide may further comprise a modification of the N-terminal amino acid residue. In one embodiment the N-terminal amino acid residue(s) comprise(s) a regular amino group (NH2), an acylation (-CH2-CO-NH-) or an alkylation (-CH2-NH-). In one embodiment the N-terminal amino group may be the attachment point for a linker as described further below. The peptide may further comprise a modification of the C-terminal amino acid residue. In one embodiment the C-terminal amino acid residue(s) comprise(s) a regular carboxyl acid group (-COOH) or an amide (-CO-NH2). In one embodiment the C-terminal amino acid residue(s) comprise(s) a regular carboxyl acid group (-COOH). The peptide may further comprise a functional group covalently attached to the peptide, which are herein referred to as a substituent and described in detail here below. Substituent A substituent is a moiety covalently to the peptide. According to the invention it is preferred that the moiety e.g., the substituent has no or minimal effect on the biological functionality of the peptide while adding other beneficial properties, such as longer half-life and / or improved exposure after administration, by intravenous (iv), subcutaneous (sc) and / or oral dosing (po). The plasma half-life of a peptide can be determined by method known in the art and in an appropriate model, such as in Male Sprague Dawley rats or in minipigs as described in Example 7. Although plasma half-life’s differs between species, there is generally a good relative correlation, such that animal models can be used to identify peptides with an extended half-life and comparing half-life’s of different peptides. The present application describes peptides with an extended half-life. In one embodiment the peptide has a plasma half-life after iv administration in mini-pigs above 24 hours, 36 hours, 48 hours, or 60 hours. In one embodiment the plasma half-life is determined in mini-pigs as described in Example 7. In some embodiments the peptide is absorbed quickly, leading to a fast increase in plasma exposure after subcutaneous administrations. Subcutaneous absorption profile (plasma exposure) may be evaluated in appropriate models, such as in minipigs used herein. The fast absorption is assessed by the early plasma exposure and evaluated using regular pharmacokinetic parameters such as Cmax and Tmax as described in Example 7. The peptide described herein have a fast absorption and can thus act fast, which is highly attractive when acute symptoms are experienced by a patient. In one embodiment Cmax is reached by at most 12 hours, such as by 10 hours or 8 hours after subcutaneous administration when determined in a minipig as described in example 7. In one embodiment the substituent comprises an albumin binding moiety. In one embodiment the peptide comprises two substituents comprising an albumin binding moiety. In one embodiment the substituent comprising an albumin binding moiety is covalently attached to the peptide. In one embodiment the substituent comprising an albumin binding moiety is attached via a lysine residue. In one embodiment the substituent comprising an albumin binding moiety is attached to the peptide via an epsilon nitrogen of a lysine residue. In one embodiment the substituent is covalently attached to the peptide via an amino acid residue in Nflank, Next, Cflank or Cext. In some embodiments the substituent comprises a fatty acid or a fatty diacid. In some embodiments the substituent comprises a C14, C16, C18 or C20 fatty acid. In some embodiments the substituent a C14, C16, C18 or C20 fatty diacid. In some embodiments the substituent comprises a C16, C18 or C20 fatty acid. In some embodiments the substituent comprises a C16, C18 or C20 fatty diacid. In further embodiments the albumin binding moiety is selected from the group consisting of: Chem.1: HOOC-(CH2)n-CO-* wherein n is an integer in the range of 8-20, Chem.2: 5-tetrazolyl-(CH2)n-CO-* wherein n is an integer in the range of 8-20, Chem.3: HOOC-(C6H4)-O-(CH2)n-CO-* wherein n is an integer in the range of 6-20, Chem.4: HO-S(O)2-(CH2)n-CO-* wherein n is an integer in the range of 8-20, Chem.5: MeS(O)2NH(CO)NH-(CH2)n-CO-* wherein n is an integer in the range of 8- 20 and Chem.6: 3-HO-Isoxazole-(CH2)n-CO-* wherein n is an integer in the range of 8-20 wherein the symbol * indicates the attachment point to a linker (see further below) or the peptide. In a further embodiment the substituent comprises Chem.1: HOOC-(CH2)n-CO-* wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or 19. In some embodiments n is in the range of 13 to 19, such as in the range of 13 to 17. In some embodiments n is 13, 15 or 17. In some embodiments n is 13. In some embodiments n is 15. In some embodiments n is 17. In a further embodiment the substituent comprises Chem.1: HOOC-(CH2)n-CO-* wherein n is at least 10, such as n is 12, 14, 16, or 18. The diacid part may also be referred to using a systematic name as follows. Systematic Name Structural Formula Lipid Numbers HOOC-(CH2)n-CO-* Decanedioyl HOOC-(CH2)8CO- C10:0 n=8 Undecanedioyl HOOC-(CH2)9CO- C11:0 n =9 Dodecanedioyl HOOC-(CH2)10CO- C12:0 n =10 Tridecanedioyl HOOC-(CH2)11CO- C13:0 n =11 Tetradecanedioyl HOOC-(CH2)12CO- C14:0 n =12 Pentadecanedioyl HOOC-(CH2)13CO- C15:0 n =13 Hexadecanedioyl HOOC-(CH2)14CO- C16:0 n =14 Heptadecanedioyl HOOC-(CH2)15CO- C17:0 n =15 Octadecanedioyl HOOC-(CH2)16CO- C18:0 n =16 Nonadecanedioyl HOOC-(CH2)17CO- C19:0 n =17 Eicosanedioyl HOOC-(CH2)18CO- C20:0 n =18 In some embodiments the substituent comprises Chem.3: HOOC-(C6H4)-O-(CH2)n- CO-* wherein n is an integer in the range of 6-14. In some embodiments the substituent comprises Chem 3b (3b), wherein the carboxy group is in position 2, 3 or 4 of the is an integer in the range of 8-11. In some substituent comprises Chem 3 or Chem 3b wherein n / m is in the range of 6 to 14, such as in the range of 8 to 11. In some embodiments the substituent comprises Chem 3 or Chem 3b, wherein n / m is 8, 10 or 12. In some embodiments the substituent comprises Chem 3 or Chem 3b, wherein n / m is 9. In some embodiments the substituent comprises Chem 3 or Chem 3b, wherein / m is 11. Additional elements may be referred to as linkers, and it follows that the substituent may then comprise or consist of an albumin binding moiety and one or more linker elements which are referred to as linker A, linker B and linker C elements herein. The overall structure of the substituent may thus be described by the formular (I) Formular (I): Albumin binding moiety - linker A - linker B(n=0-5) - linker C -* wherein linker A and linker C are optional elements, and wherein the linker B element(s) is / are individually selected and n=0-5 indicates that the substituent comprises 0, 1, 2, 3, 4 or 5 linker B elements. In one embodiment the substituent comprises a linker A element selected from Chem.7: *-NH-SO2-(CH2)3-CO-* or Chem 7b: and Chem.8: *-NH-CH2-(C6H10)-CO-* or Chem.8b: . In further comprises one or more linker B elements. In one B is / are selected from the group consisting of: Glu, γGlu, Gly, Ser, Ala, Thr, Ado (or OEG), Aeep, Aeeep and TtdSuc. Glu, Gly, Ser, Ala, Thr are amino acid residues well known in the art. γGlu (or gGlu) is of formula Chem.9: *-NH-CH(COOH)-(CH2)2-CO-* which is the same as Chem.9b: which is the same as Ado (or OEG) is of formula Chem.11: *-NH-(CH2)2-O-(CH2)2-O-CH2-CO-* may also be referred to as 8-amino-3,6-dioxaoctanoic acid and which is the same as Aeep is of formula Chem.12: *NH-CH2CH2OCH2CH2OCH2CH2CO*, which may also be referred to as Chem. Aeeep is of formula Chem.13: *NH-CH2CH2OCH2CH2OCH2CH2OCH2CH2CO*, which may also be referred to as Chem. ε-Lys is defined by Chem.14: *-NH-(CH2)4-CH(NH2)-CO-* which may also be described by Chem.14b: . In some embodiments the substituent comprises one or more 8-amino-3,6- dioxaoctanoic acid (Ado), such as two Ado elements. In some embodiments the substituent comprises one or more ε-Lys, such as two ε- Lys elements. In one embodiment the substituent may further comprise a linker C element of Chem.15: *-NH-CH2-(C6H4)-CH2-*, which may also be referred to as . In one one or two substituent(s) is / are selected from the group of substituents consisting of: 1.HOOC-(CH2)18-CO-gGlu-2xAdo-2.HOOC-(CH2)18-CO-NH-CH2-(C6H10)-CO-gGlu-2xAdo-3.HOOC-(CH2)16-CO-gGlu-2xAdo-4.HOOC-(CH2)16-CO-gGlu-2xAdo-NH-CH2-(C6H4)-CH2-5.HOOC-(CH2)16-CO-gGlu-6. HOOC-(CH2)16-CO-NH-CH2-(C6H10)-CO-gGlu-2xAdo- 7. HOOC-(CH2)14-CO-gGlu-2xAdo- 8.HOOC-(CH2)14-CO-gGlu-9.HOOC-(CH2)14-CO-gGlu-2xAdo-10.HOOC-(CH2)12-CO-gGlu--11.4-HOOC-(C6H4)-O-(CH2)10-CO-12.4-HOOC-(C6H4)-O-(CH2)10-CO-gGlu-3xAdo-13.4-HOOC-(C6H4)-O-(CH2)10-CO-gGlu-14. 4-HOOC-(C6H4)-O-(CH2)10-CO-2xgGlu- 15.4-HOOC-(C6H4)-O-(CH2)10-CO-gGlu-3xGly-16.4-HOOC-(C6H4)-O-(CH2)10-CO-2xgGlu-2xAdo-17.4-HOOC-(C6H4)-O-(CH2)10-CO-gGlu-TtdSuc-18.4-HOOC-(C6H4)-O-(CH2)9-CO-19.4-HOOC-(C6H4)-O-(CH2)10-CO-gGlu-4xAdo-20.4-HOOC-(C6H4)-O-(CH2)10-CO-NH-CH2-(C6H10)-CO-gGlu-2xAdo-21. 4-HOOC-(C6H4)-O-(CH2)9-CO-gGlu-2xAdo- 22.3-HOOC-(C6H4)-O-(CH2)9-CO-gGlu-2xAdo-23.3-HO-Isoxazole-(CH2)12-CO-gGlu-2xAdo-24.HOS(O)2-(CH2)15-CO-gGlu-2xAdo-NH-CH2-(C6H4)-CH2-25.HOS(O)2-(CH2)13-CO-gGlu-2xAdo-26.Tetrazolyl-(CH2)15-CO-NH-SO2-(CH2)3-CO-Ado-Ado-NH-CH2-(C6H4)-CH2-27. Tetrazolyl-(CH2)12-CO-gGlu-2xAdo- 28. Tetrazolyl-(CH2)15-CO-gGlu-2xAdo- 29.MeS(O)2NH(CO)NH-(CH2)12-CO-gGlu-2xAdo-30.HOOC-(CH2)14-CO-gGlu-2xεLys-31.HOOC-(CH2)16-CO-gGlu-2xεLys-32.HOOC-(CH2)18-CO-gGlu-2xεLys-As an example, 4-HOOC-(C6H4)-O-(CH2)10-CO-NH-CH2-(C6H10)-CO-gGlu-2xAdo is a substituent of Formular (I) consisting of: Albumin binder moiety - linker A - linker B(n=3)-* wherein the albumin binder moiety is Chem 3(n=10), linker A is Chem.8 and the linker B elements are gGlu, and 2xAdo. In some embodiments the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17- carboxyheptadecanoylamino) butyrylamino]ethoxy}ethoxy)acetylamino] ethoxy}ethoxy)acetyl]. In some embodiments the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4- [(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl} amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]. In one embodiment the substituent is selected from the group consisting of: HOOC- (CH2)12-CO-gGlu-2xAdo-, HOOC-(CH2)14- 2xAdo-, HOOC-(CH2)16-CO-gGlu-2xAdo- and HOOC-(CH2)18-CO-gGlu-2xAdo-. In one embodiment the substituent is HOOC-(CH2)16- CO-gGlu-2xAdo. Exemplary peptides comprising a substituent In one embodiment the peptide is selected from the group of substituted peptides, also referred to as peptide derivatives, which may be identified by the amino acid sequence, the linker and albumin binding moiety of the substituent and the amino acid residue of the peptide serving as attachment site for the substitution. In one embodiment the peptide is selected from peptide derivatives # 1-24 identified below. albumin Attach Peptide SEQ ID Sequence Linker binding ment derivative NO moiety site LGDIWCDINPFK*DSITCSRWVGA gGlu- C18 1 50 K12 QPEE 2xOEG diacid LGDIWCDINPFDK*SITCSRWVGA gGlu- C18 2 51 K13 QPEE 2xOEG diacid LGDIWCDINPFDDK*ITCSRWVGA gGlu- C18 3 52 K14 QPEE 2xOEG diacid LGDIWCDINPFDDSK*TCSRWVG gGlu- C18 4 53 K15 AQPEE 2xOEG diacid LGDIWCDINPFDDSIK*CSRWVGA gGlu- C18 5 54 K16 QPEE 2xOEG diacid LGDIWCDINPFDDSITCSRWVGS gGlu- C18 6 55 K30 GSGSEEK* 2xOEG diacid LGDIWCDINPFDDSITCSRWVGS gGlu- C18 7 56 K26 EEK* 2xOEG diacid LGDIWCDINPFDDSITCSRWVEE gGlu- C18 8 57 K26 GSK* 2xOEG diacid GSLGDIWCDINPFDDSITCSRWV gGlu- C18 9 58 K28 GEQPK* 2xOEG diacid GSLGDIWCDINPFDDSITCSRWV gGlu- C18 10 59 K25 GK* 2xOEG diacid albumin Attach Peptide SEQ ID Sequence Linker binding ment derivative NO moiety site GSGSGSLGDIWCDINPFDDSITCS gGlu- C18 11 60 K29 RWVGK* 2xOEG diacid LGDIWCDINPFDDSITCSRWVEE gGlu- C18 12 61 K24 K* 2xOEG diacid gGlu- C18 13 LGDIWCDINPFDDSITCSRWVK* 62 K22 2xOEG diacid GGLGDIWCDINPFDDSITCSRWV gGlu- C18 14 63 K24 K* 2xOEG diacid GGPGGLGDIWCDINPFDDSITCS gGlu- C18 15 64 K27 RWVK* 2xOEG diacid GSLGDIWCDINPFDDSITCSRWV gGlu- C18 16 65 K30 EEGAQPK* 2xOEG diacid GEPGEQPEGDIWCDINPFDDSIT gGlu- C20 17 29 K36 CSRWVEGEGEQPK*E 2xOEG diacid GAQPPEGDIWCDINPFDDSITCS gGlu- C20 18 30 K33 RWVEEGAQPK* 2xOEG diacid GPEGDIWCDINPFDDSITCSRWV gGlu- C18 19 31 K38 GEPGEGGPEGGPEGK* 2xOEG diacid GAQPK*GEQPEGDIWCDINPFDD gGlu- C18 20 32 K5 SITCSRWVEEGEQPE 2xOEG diacid GEGDIWCDINPFDDSITCSRWVE gGlu- C18 21 33 K33 EGEQPGEQPK* 2xOEG diacid GAQPEGDIWCDINPFDDSITCSR gGlu- C16 22 34 K32 WVEEGAQPK* 2xOEG diacid GAQPEGDIWCDINPFDDSITCSR gGlu- C18 23 34 K32 WVEEGAQPK* 2xOEG diacid GAQPGGDIWCDINPFDDSITCSR gGlu- C18 24 35 K32 WVEEGAQPK* 2xOEG diacid P-Selectin peptide ligands and antagonists A peptide as described herein above comprises at least one binding motif. If more peptides each comprising a binding motif are linked multivalent molecules are obtained, such molecules may also be considered dimers, trimer, tetramers, etc. depending on the number of binding motifs included. Multivalent can be obtained by methods known in the art. In one embodiment two or more peptides are linked forming a multimeric peptide ligand. When referring to the length of the peptide, the length refers to the monomer and not the multimeric molecules unless specified. In one embodiment two peptides are linked forming a dimeric peptide ligand. In one embodiment the peptide is a dimer. In some embodiments the peptide comprises two peptides as defined in any of the previous embodiments. A dimeric peptide has two ligand binding sites and is a bivalent peptide. In one embodiment the peptide comprises two peptides covalently linked. In one embodiment the two peptides are identical. In one embodiment the two peptides are different. In one embodiment the two peptides are not identical. Such multimeric peptide molecules may include one or more peptide linkers facilitating the covalent binding of the amino acid sequences, which may be beneficial to avoid interfering with the functionality of the sequences comprising the binding motifs. Two or more peptides may be linked by a linking peptide or by a chemical moiety. When the two peptides are linked by a peptide linker the peptide can conveniently be produced as a single polypeptide. Alternatively, one or more peptides can be covalently linked by using an alternative linker, such as a chemical moiety. Depending on which part of the peptides and the amino acid residues in scope various linking techniques can be used. Using a chemical moiety for linking of the peptides allows for a higher degree of flexibility as the peptides may be linked via either the N-terminal, the C-terminal or an internal residue in either of the peptides. In one embodiment two peptides are linked via amino groups. In one embodiment two peptides are linked via the N-terminal amino acid residues. In one embodiment the two peptides are linked by a chemical moiety -L-. In one embodiment -L- is a radical of a diacid, such as -CO-(CH2)n-CO-, wherein n= 2-8, providing a linker that includes a carbon chain of 4, 5, 6,7, 8, 9 or 10 carbon atoms. In one embodiment n is 4, 6 or 8. In one embodiment n is 5, 7 or 9. In one embodiment n is 5. In on embodiment n is 6. Exemplary dimeric peptide comprising a substituent In one embodiment the peptide is selected from the group of substituted peptides identified below indicating the amino acid sequence, the linker and albumin binding moiety of the substituent and the amino acid residue of the peptide serving as attachment site for the substitution. In one embodiment the peptide selected from the group of dimeric peptide derivatives # 25-45. In one embodiment the peptide is selected from the group of dimeric peptide derivatives # 37-45. In one embodiment the peptide is selected from the group of dimeric peptide derivatives # 37-42. In one embodiment the peptide is selected from the group of dimeric peptide derivatives # 38, # 39 and 44. Dimeric SEQ Albumin Attach peptide Peptide amino acid sequence ID linker binding ment derivatives NO moiety [LGDIWCDINPFK*DSITCSRWVEE]x gGlu- C18 25 50x2 2xK12 2 2xOEG diacid [LGDIWCDINPFDK*SITCSRWVEE]x gGlu- C18 26 51x2 2xK13 2 2xOEG diacid [LGDIWCDINPFDDK*ITCSRWVEE]x gGlu- C18 27 52x2 2xK14 2 2xOEG diacid [LGDIWCDINPFDDSK*TCSRWVEE] gGlu- C18 28 53x2 2xK15 x2 2xOEG diacid [LGDIWCDINPFDDSIK*CSRWVEE]x gGlu- C18 29 54x2 2xK16 2 2xOEG diacid [LGDIWCDINPFDDSITCSRWVEEK* gGlu- C18 30 61x2 2xK24 ]x2 2xOEG diacid gGlu- C18 31 [LGDIWCDINPFDDSITCSRWVK*]x2 62x2 2xK22 2xOEG diacid [GGLGDIWCDINPFDDSITCSRWVK gGlu- C18 32 63x2 2xK24 *]x2 2xOEG diacid [GGPGGLGDIWCDINPFDDSITCSR gGlu- C18 33 64x2 2xK27 WVK*]x2 2xOEG diacid [GSLGDIWCDINPFDDSITCSRWVG gGlu- C18 34 58x2 2xK28 EQPK*]x2 2xOEG diacid [GSGSGSLGDIWCDINPFDDSITCS gGlu- C18 35 60x2 2xK29 RWVGK*]x2 2xOEG diacid Dimeric SEQ Albumin Attach peptide Peptide amino acid sequence ID linker binding ment derivatives NO moiety [GSLGDIWCDINPFDDSITCSRWVE gGlu- C18 36 65x2 2xK30 EGAQPK*]x2 2xOEG diacid [GEPGEQPEGDIWCDINPFDDSITC gGlu- C20 37 29x2 2xK36 SRWVEGEGEQPK*E]x2 2xOEG diacid [GAQPPEGDIWCDINPFDDSITCSR gGlu- C20 38 30x2 2xK33 WVEEGAQPK*]x2 2xOEG diacid [GPEGDIWCDINPFDDSITCSRWVG gGlu- C18 39 31x2 2xK38 EPGEGGPEGGPEGK*]x2 2xOEG diacid [GAQPK*GEQPEGDIWCDINPFDDS gGlu- C18 40 32x2 2xK5 ITCSRWVEEGEQPE]x2 2xOEG diacid [GEGDIWCDINPFDDSITCSRWVEE gGlu- C18 41 33x2 2xK33 GEQPGEQPK*]x2 2xOEG diacid [GAQPEGDIWCDINPFDDSITCSRW gGlu- C14 42 34x2 2xK32 VEEGAQPK*]x2 2xOEG diacid [GAQPEGDIWCDINPFDDSITCSRW gGlu- C16 43 34x2 2xK32 VEEGAQPK*]x2 2xOEG diacid [GAQPEGDIWCDINPFDDSITCSRW gGlu- C18 44 34x2 2xK32 VEEGAQPK*]2 2xOEG diacid [GAQPGGDIWCDINPFDDSITCSRW gGlu- C18 45 35x2 2xK32 VEEGAQPK*]x2 2xOEG diacid Lysine (K) residues including a substituent (C20 diacid-gGlu-2xAdo- or C18 diacid-gGlu- 2xAdo- or C16 diacid-gGlu-2xAdo or C14 diacid-gGlu-2xAdo-) are marked with a * (K*). Pharmaceutical composition In one aspect the invention relates to a pharmaceutical composition comprising a peptide according to the invention, and pharmaceutically acceptable excipients. Pharmaceutical compositions containing a peptide according to the present invention may be prepared by conventional techniques, e.g. as described in Remington’s Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19thedition, 1995. In one embodiment the composition is a liquid formulation. In one embodiment the composition is an aqueous formulation. Medical uses In a further aspect the invention relates to medical uses of a peptide according to the invention. In one embodiment the peptide is for use as a medicament. In one embodiment the peptide is for use in a method of treatment. The term “treatment”, as used herein, refers to the medical treatment of any human subject in need thereof. The timing and purpose of said treatment may vary from one individual to another, according to the status of the subject’s health. Said treatment may be prophylactic, palliative, symptomatic and / or curative. In one embodiment the peptide is for use in a method of treatment of a disorder or disease mediated by P-selectin. In one embodiment the peptide is for use in a method of treatment of an inflammatory disease or disorder. In one embodiment the peptide is for use in a method of treatment of a thrombotic disorder or condition which involve platelet, sickled red blood cell, leukocyte, lymphocyte, and / or endothelial cell adhesion, such as vaso- occlusive crisis and sickle cell disease-related conditions. In one embodiment the peptide is for use in a method of treatment or prevention of sickle cell disease (SCD). In one embodiment the peptide is for use in a prophylactic treatment of a disorder or disease mediated by P-selectin. In one embodiment the peptide is for use in a prophylactic treatment of sickle cell disease (SCD). In one embodiment the peptide is for use in a method of treating vaso-occlusive crisis (VOC) either as acute crisis treatment or as prophylaxis. As described herein (Example 7) the peptides and ligands display a fast uptake following subcutaneous administration leading to fast high plasma exposure as well as long half-lives supporting the use of such peptides and ligands for both prophylaxis and acute treatment. Additionally, subcutaneous administration will render home treatment / patient administered treatment feasible, which is very attractive for the patient group in question. In one embodiment the peptide is for intra venous administration. In one embodiment the peptide is for subcutaneous administration. In one embodiment the peptide is for use in a method of treating vaso-occlusive crisis (VOC). In one embodiment the peptide is for use in a method of treating vaso-occlusive crisis (VOC) by subcutaneous administration. In one embodiment the peptide is for use in a patient administered treatment. In one embodiment the peptide is for use as a home treatment. In one embodiment the peptide is administered daily, every second day, bi-weekly or weekly. In an aspect the invention relates to a method of treatment of a disease or disorder comprising administering a peptide as described herein to a subject in need. In a further embodiment a therapeutical effective amount of said peptide is administered. In a further embodiment the subject is a human. In a further embodiment the disease or disorder is mediated by P-selectin. In a further embodiment the disease or disorder is an inflammatory disease or disorder. In a further embodiment the disease or disorder is a thrombotic disorder or condition which involve platelet, sickled red cell, leukocyte, lymphocyte, and / or endothelial cell adhesion, such as vaso-occlusive crisis and sickle cell disease-related conditions. In one embodiment the peptide is administered for the prevention of sickle cell disease (SCD). In a further embodiment the method is for prophylactic treatment of sickle cell disease (SCD). In a further embodiment the peptide is administered by intra-venous administration. In a further embodiment the peptide is administered by subcutaneous administration. In one embodiment the method is for treating vaso-occlusive crisis (VOC). In one embodiment the method is for treating vaso-occlusive crisis (VOC) by subcutaneous administration. In one embodiment the peptide is administered by the patient. In one embodiment the method is a home treatment. In one embodiment the peptide is administered daily, every second day, bi-weekly or weekly. EMBODIMENTS 1. A peptide comprising the amino acid sequence -W-C2-X3-X4-X5-X6-X7-D-D-X10-X11-X12- C13- (SEQ ID NO.: 3), wherein X3is S or D, X4is I or V, X5is S, D, N or H, X6is S or P, X7is any amino acid residue except P, X10is A, S, T, D, E, Q, N or K, X11is A, S, T, I, V or H and X12is A, S, T, G, D, E, Q, N, L, V, K, R or H. 2. The peptide according to embodiment 1, where C2and C13are covalently linked by a disulfide bridge. 3. The peptide according to any of the previous embodiments, wherein X3is D. 4. The peptide according to any of the previous embodiments, wherein X4is I. 5. The peptide according to any of the previous embodiments, wherein X4is V. 6. The peptide according to any of the previous embodiments, wherein X5is S or N. 7. The peptide according to any of the previous embodiments, wherein X5is N. 8. The peptide according to any of the previous embodiments, wherein X6is P. 9. The peptide according to any of the previous embodiments, wherein X7is S, T, L, I, W, Y, F, K, R or H. 10. The peptide according to any of the previous embodiments, wherein X7 is I, W, F or R. 11. The peptide according to any of the previous embodiments, wherein X7is W or F. 12. The peptide according to any of the previous embodiments, wherein X7is W. 13. The peptide according to any of the previous embodiments, wherein X7is F. 14. The peptide according to any of the previous embodiments, wherein X10is S, T, D, E or Q. 15. The peptide according to any of the embodiments, wherein X10is S. 16. The peptide according to any of the previous embodiments, wherein X11is A, S, T, I, V or H. 17. The peptide according to any of the previous embodiments, wherein X11is S, I, V or H. 18. The peptide according to any of the previous embodiments, wherein X11is I, V or H. 19. The peptide according to any of the previous embodiments, wherein X11is I. 20. The peptide according to any of the previous embodiments, wherein X12is A, S, T, G, D, E, Q, N, L, V, K, R or H. 21. The peptide according to any of the previous embodiments, wherein X12is A, S, T, G, D, E, Q, N or H. 22. The peptide according to any of the previous embodiments, wherein X12is A, S, T, D, E, Q or N. 23. The peptide according to any of the previous embodiments, wherein X12is S or T. 24. The peptide according to any of the previous embodiments, wherein the peptide comprises the amino acid sequence -WCDINPWDDSITC- (SEQ ID NO.: 4) or a variant hereof comprising at most 4 amino acid substitutions, such as at most 3 amino acid substitutions, such as at most 2 amino acid substitutions or such as at most 1 amino acid substitutions. 25. The peptide according to any of the previous embodiments, wherein the peptide comprises the amino acid sequence -WCDINPFDDSITC- (SEQ ID NO.: 4). 26. The peptide according to any of the previous embodiments, wherein the peptide comprises the amino acid sequence -WCDINPWDDSITC- (SEQ ID NO.: 5). 27. The peptide according to any of the embodiments, wherein the peptide comprises the amino acid sequence - (SEQ ID NO.: 6). 28. The peptide according to any of the previous embodiments, wherein the peptide comprises amino acids extensions at the N-terminal and / or C-terminal, providing a peptide of 20- 50 amino acid residues in length. 29. The peptide according to any of the previous embodiments, wherein the peptide comprise amino acids extensions referred to as N-terminal flanking sequence (Nflank), C- Terminal flanking sequence, N-terminal extension sequence (Next) and C-Terminal extension sequence (Cext. 30. The peptide according to any of the previous embodiments, wherein the peptide has the structure Next-Nflank-binding motif-Cflank-Cext, and wherein in the binding motif is the amino acid sequence defined as in any of the embodiments 1-27. 31. The peptide according to any of the previous embodiments, wherein the peptide comprises an N-terminal flanking sequence (Nflank) and / or a C-Terminal flanking sequence (Cflank). 32. The peptide according to any of the previous embodiments, wherein the peptide comprises an N-terminal flanking sequence (Nflank) and a C-Terminal flanking sequence (Cflank) 33. The peptide according to any of the embodiments 27-32, wherein the Nflank is an extension of 1-10 amino acid residues, such as 2-8 amino acid residue, such as 2-6, amino acid residues, such as 3-5 amino acid residues. 34. The peptide according to any of the embodiments 27-29, wherein the Cflank is an extension of 1-10 amino acid residues, such as 2-8 amino acid residue, such as 2-6, amino acid residues, such as 3-5 amino acid residues. 35. The peptide according to any of the embodiments 27-34, wherein the Nflank is selected from the group consisting of: LGD, EGDI (SEQ ID NO.: 7), LGDI (SEQ ID NO.: 8) and GGDI (SEQ ID NO.: 9). 36. The peptide according to any of the embodiments 27-32, wherein the Nflank is EGDI (SEQ ID NO.: 7). 37. The peptide according to any of the embodiments 27-32, wherein the Cflank is selected from the group consisting of: SRWV (SEQ ID NO.: 10), SRWL (SEQ ID NO.: 11) and TRWV (SEQ ID NO.: 12). 38. The peptide according to any of the embodiments 270-32, wherein the Cflank is SRWV (SEQ ID NO.: 10). 39. The peptide according to any of the previous embodiments wherein the peptide comprises an N-terminal extension sequence (Next) and / or a C-Terminal extension sequence (Cext). 40. The peptide according to any of the previous embodiments wherein the peptide comprises an N-terminal extension sequence (Next) and a C-Terminal extension sequence (Cext). 41. The peptide according to any of the embodiments 39-40, wherein the Next is an extension of 1-10 amino acid residues, such as 2-8 amino acid residue, such as 2-6, amino acid residues, such as 3-5 amino acid residues. 42. The peptide according to any of the embodiments 39-40, wherein the Next is selected from the group consisting of: G, GE, GG, GS, GP, GPE, EGE, GAQP (SEQ ID NO.: 13), GEQP (SEQ ID NO.: 14), GAQPP (SEQ ID NO.: 15), GGPGG (SEQ ID NO.: 17), GGSGG (SEQ ID NO.: 18), GSGSGS (SEQ ID NO.: 19), GEPGEQP (SEQ ID NO.: 20), GAQPGAQPG (SEQ ID NO.: 21) and GAQPKGEQP (SEQ ID NO.: 22). 43. The peptide according to any of the embodiments 39-42, wherein the Cext is an extension of 1-20 amino acid residues, such as 2-18 amino acid residue, such as 5-15, amino acid residues, such as 8-12 amino acid residues. 44. The peptide according to any of the embodiments 39-42, , wherein the Cext is selected from the group consisting of: K, E, GK, EEK, EEGAQPK (SEQ ID NO.: 23), EEGEQPE (SEQ ID NO.: 24), EGEGEQPKE (SEQ ID NO.: 25), EEGEQPGEQPK (SEQ ID NO.: 26), GEPGEGGPEGGPEGK (SEQ ID NO.: 27), EEGEQPGEQPGEQPK (SEQ ID NO.: 28), EEGSK (SEQ ID NO.: NO.: 67), GSEEK (SEQ ID NO.: 68), GSGSGSEEK (SEQ ID (SEQ ID NO.: 70). 45. The peptide according to any wherein the peptide sequence is selected from the group consisting of: GEPGEQPEGDIWCDINPFDDSITCSRWVEGEGEQPKE (SEQ ID NO.: 29), GAQPPEGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 30), GPEGDIWCDINPFDDSITCSRWVGEPGEGGPEGGPEGK (SEQ ID NO.: 31), GAQPKGEQPEGDIWCDINPFDDSITCSRWVEEGEQPE (SEQ ID NO.: 32), GEGDIWCDINPFDDSITCSRWVEEGEQPGEQPK (SEQ ID NO.: 33), GAQPEGDIWCDINPFDDSITCSRWVEEGAQPK (SEQ ID NO.: 34) and GAQPGGDIWCDINPFDDSITCSRWVEEGAQP (SEQ ID NO.: 35). 46. The peptide according to any of the previous embodiments, wherein the peptide is a dimer comprising two sequences as defined in any of the previous embodiments. 47. The peptide according to embodiment 42, wherein the two peptide sequences are identical. 48. The peptide according to embodiment 42, wherein the two peptide sequences are not identical. 49. The peptide according to embodiments 42-44, wherein the two peptides are linked by a peptide linker. 50. The peptide according to embodiments 42-44, wherein the two peptides are linked by a chemical moiety -L-. 51. The peptide according to embodiment 46, wherein -L- is an alkyl chain connecting two carboxylic groups, such as -CO-(CH2)n-CO-, wherein n is 2-10, such as 2-8, such as 4-8, such as 6. 52. The peptide according to embodiments 42-47, wherein the peptides are linked via the N- terminal amino acid resides. 53. The peptide according to any of the embodiments, wherein the N-terminal amino acid residue(s) comprise(s) a regular amino group (NH2-), an acylation (-CH2-CO- NH-) or an alkylation (-CH2-NH-). 54. The peptide according to any of the previous embodiments, wherein the C-terminal amino acid residue(s) comprise(s) a regular carboxyl acid group (COOH) or an amide (CONH2). 55. The peptide according to any of the previous embodiments, wherein the peptide comprises a substituent. 56. The peptide according to any of the previous embodiments, wherein the peptide comprises a substituent providing a longer plasma half-life. 57. The peptide according to any of the previous embodiments, wherein the peptide comprises a substituent comprising an albumin binding moiety. 58. The peptide according to any of the embodiments 55-57, wherein the substituent is covalently attached to the peptide. 59. The peptide according to any of the embodiments 55-57, wherein the substituent is covalently attached to the N-terminal amino acid residue. 60. The peptide according to any of the embodiments 55-57, wherein the substituent is covalently attached to a lysine residue. 61. The peptide according to embodiment 55-57, wherein the substituent is covalently attached to the peptide via an epsilon nitrogen of a lysine residue. 62. The peptide according to any of the embodiments 55-0, wherein the substituent is covalently attached to a lysine residue out-side the amino acid sequence defined in embodiments 1-27. 63. The peptide according to embodiment 55-57, wherein the substituent is covalently attached to the peptide via an amino acid residue in Nflank, Next, Cflank or Cext. 64. The peptide according to embodiment wherein the substituent is selected from the group consisting of: HOOC-(CH2)18-CO-gGlu-2xAdo- HOOC-(CH2)18-CO-NH-CH2-(C6H10)-CO-gGlu-2xAdo- HOOC-(CH2)16-CO-gGlu-2xAdo- HOOC-(CH2)16-CO-gGlu-2xAdo-NH-CH2-(C6H4)-CH2- HOOC-(CH2)16-CO-gGlu- HOOC-(CH2)16-CO-NH-CH2-(C6H10)-CO-gGlu-2xAdo- HOOC-(CH2)14-CO-gGlu-2xAdo- HOOC-(CH2)14-CO-gGlu- HOOC-(CH2)12-CO-gGlu-2xAdo- Tetrazolyl-(CH2)15-CO-NH-SO2-(CH2)3-CO-Ado-Ado-NH-CH2-(C6H4)-CH2- Tetrazolyl-(CH2)12-CO-gGlu-2xAdo- Tetrazolyl-(CH2)15-CO-gGlu-2xAdo- MeS(O)2NH(CO)NH-(CH2)12-CO-gGlu-2xAdo HOOC-(CH2)14-CO-gGlu-2xεLys- HOOC-(CH2)16-CO-gGlu-2xεLys- HOOC-(CH2)18-CO-gGlu-2xεLys- 65. The peptide according to embodiment 64, wherein the substituent is selected from the group consisting of: HOOC-(CH2)12-CO-gGlu-2xAdo-, HOOC-(CH2)14-CO-gGlu-2xAdo-, HOOC-(CH2)16-CO-gGlu-2xAdo- and HOOC-(CH2)18-CO-gGlu-2xAdo-. 66. The peptide according to any of the previous embodiments, wherein the peptide is selected from the group consisting of peptide derivatives 1-24. 67. The peptide according to embodiment 61, wherein the peptide is selected from the group consisting of: dimeric peptide derivatives 25-46. 68. The peptide according to embodiment 61, wherein the peptide is selected from the group consisting of: dimeric peptide derivatives 37-46. 69. The peptide according to embodiment 61, wherein the peptide is selected from the group consisting of: dimeric peptide derivatives 38-41 and 42-46. 70. The peptide according to embodiment 61, wherein the peptide is selected from the group consisting of: dimeric peptide dimeric peptide derivatives 39, dimeric peptide derivatives 44 and dimeric peptide derivatives 46. 71. The peptide according to embodiment 61, wherein the peptide is selected from the group consisting of: dimeric peptide derivatives 25-45. 72. The peptide according to embodiment 61, wherein the peptide is selected from the group consisting of: dimeric peptide derivatives 37-45. 73. The peptide according to embodiment 61, wherein the peptide is selected from the group consisting of: dimeric peptide derivatives 37-42. 74. The peptide according to embodiment 61, wherein the peptide is selected from the group consisting of: dimeric peptide derivatives 38, dimeric peptide derivatives 39 and dimeric peptide derivatives 44. 75. The peptide according to any of the previous embodiments, wherein the peptide binds P- selectin. 76. The peptide according to any of the previous embodiments, wherein the peptide antagonises binding of P-selectin to P-selectin glycoprotein ligand 1 (PSGL-1). 77. The peptide according to any of the previous embodiments, wherein the peptide inhibits binding of P-selectin to P-selectin glycoprotein ligand 1 (PSGL-1). 78. The peptide according to any of the previous embodiments, wherein the peptide inhibits binding of activated platelets or endothelia cells to immune cells or sickled red blood cells or platelets. 79. The peptide according to any of the previous embodiments, wherein the peptide inhibits platelets leukocyte aggregation. 80. The peptide according to any of the previous embodiments, wherein the peptide inhibits platelets leukocyte aggregation on par or better than Crizanlizumab. 81. The peptide according to any of the previous embodiments, wherein the peptide has a plasma half-life above 24 hours. 82. The peptide according to embodiment 81, wherein the plasma half-life is determined in pigs as described in Example 7 after iv administration. 83. The peptide according to any of the previous embodiments, wherein the peptide reaches Cmax within 12 hours after subcutaneous administration. 84. The peptide according to embodiment 83, wherein Cmax is determined in pigs as described in Example 7. 85. A pharmaceutical composition comprising a peptide according to any of the previous embodiments. 86. The pharmaceutical composition according to embodiment 85, wherein the composition comprises one or more pharmaceutically acceptable excipients. 87. The pharmaceutical composition according to embodiment 85, wherein the composition is a liquid formulation. 88. The pharmaceutical composition according to embodiment 85, wherein the composition is an aqueous formulation. 89. A peptide or composition according to any of the previous embodiments for use in a method of treatment. 90. The peptide or composition according to embodiment 89, where in the peptide or composition is for use in treatment of a disease or disorder mediated by P-selectin. 91. The peptide or composition according to embodiment 89, where in the peptide or composition is for use in treatment of an inflammatory disease or disorder. 92. The peptide or composition according to embodiment 89, where in the peptide or composition is for use in treatment of a thrombotic disorder or condition which involve platelet, sickled red cell, leukocyte, lymphocyte, and / or endothelial cell adhesion, such as vaso-occlusive crisis and sickle cell disease-related conditions. 93. The peptide or composition according to embodiment 89, where in the peptide or composition is for use in treatment or of sickle cell disease. 94. The peptide or composition according to embodiment 89, wherein the peptide or composition is for use in treatment of vaso-occlusive crisis. 95. The peptide or composition according to any of the embodiments 89-93, wherein the peptide or composition is for intra venous administration. 96. The peptide or composition according to embodiment 89-93, wherein the peptide or composition is for subcutaneous administration. 97. A method of treatment a disease or disorder comprising administering a peptide or composition according to any of the previous embodiments 1-70, to a subject in need. 98. The method according to embodiment 94, wherein the disease or disorder is an inflammatory disease or disorder. 99. The method according to embodiment 94, wherein the disease or disorder is a thrombotic disorder or condition which involve platelet, sickled red cell, leukocyte, lymphocyte, and / or endothelial cell adhesion, such as vaso-occlusive crisis and sickle cell disease- related conditions. 100. The method according to embodiment 94, wherein the disease or disorder is sickle cell disease. 101. The method according to embodiment 94, wherein the disease or disorder is vaso- occlusive crisis . 102. The method according to embodiments 94, wherein the subject is a human. 103. The method according to embodiments 94, wherein a therapeutical effective amount of said peptide or said composition is administered. 104. The method according to any of the embodiments 94-103, wherein the peptide or composition is administered intra venously. 105. The method according to any of the embodiments 94-103, wherein the peptide or composition is administered subcutaneously. EXAMPLES Materials and Methods General Methods and reagents A. Peptide synthesis, purification, and analysis All solvents and chemicals were used without any further purification. Materials. N,N-dimethylformamide (DMF) peptide grade (Biosolve). Diisopropylcarbodiimide and collidine (Sigma). The following L-amino acids were used: Fmoc-Glu-(Otbu), Fmoc- Lys(Mtt)-OH, Boc-Gly-OH, Fmoc-Ala-OH, Fmoc-Arg(pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc- Asp(Otbu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(Otbu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Val-OH, Fmoc-Met-OH, Fmoc-Pro- OH, Fmoc-Lys(boc)-OH, Fmoc-Ser(Otbu)-OH, Fmoc-Thr(Otbu)-OH, Fmoc-Tyr(Otbu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Phe-OH, and OxymaPure (Protein Technologies / Merck Millipore Novabiochem / IRIS). Preloaded resin (Merck Millipore Novabiochem). Fmoc-8-amino-3,6- dioxaoctanoic acid (Fmoc-Ado-OH) (Flamma Group, Italy).20-(tert-Butoxy)-20- oxooctadecanoic acid (C20-diacid) ,18-(tert-Butoxy)-18-oxooctadecanoic acid (C18-diacid), (16-(tert-Butoxy)-16-oxooctadecanoic acid (C16-diacid) and 14-(tert-Butoxy)-14- oxooctadecanoic acid (C14-diacid) (Solvias). Peptides for in vitro experiments were synthesized using Prelude or Prelude X with heating. Instruments were equipped with 0,3M solutions of Fmoc-amino acids that were solubilized with either 0,3M HOBt or 0,3M Oxyma Pure in NMP or DMF. In situ activation was done by adding 1 / 10 volume (relative to amino acid volume) of 3M DIC in NMP and 1 / 10 volume 3M collidine in NMP. A final excess of 6-8-fold activated amino acid relative to resin substitution was typically used and coupling time was 60-90 min without heating whereas 10- 15 min was used with heating at 60 °C. Removal of the Fmoc-group was done by adding 2x resin volume 25% piperidine in NMP (4 + 4 min.) but only 1+2 min with heating. The N- terminal Gly was coupled as Boc-Gly-OH using conditions as described for the Fmoc-amino acids. The Mtt protecting group on lysine was removed with 4x washing with 3% triisopropylsilane (TIPS) in 75% HFIP in 25% DCM and a total of 30 min of cleavage time. The fatty acid albumin binder C18diacid-gGlu-2xAdo and other substituents were synthesized by step-wise assembly using the procedures as described for backbone synthesis. Fatty diacids were used as mono-tert-butyl protected fatty acids (Solvias). After synthesis the peptidyl-resins were washed with DCM and dried. Peptides were cleaved with TFA (92%) containing 2% (DTT) and 3% triisopropylsilane (TIPS) and 3% H2O for 2-4 hours. The crude peptide was precipitated in diethylether and washed several times with diethylether. The dried peptides were dissolved in 20% DMSO, 1% NaHCO3(or NH4CO3), pH 8 to 1-10 mg / ml and cyclized for 1-2 days. The peptides were purified by preparative HPLC using a linear gradient: 20-50% ACN with 0.1% TFA (buffer B) (alternatively 10-30% buffer B) over 40 min on a SymmetryPrep C1819 × 300 mm, 7 µm column (Waters Corporation, Milford, USA) eluting at 20 ml / min. Analysis of purity of the peptides was performed using Waters Acquity UPLC system, with Waters Acquity TUV detector 214 nm and 254 nm. Alternatively, characterization was performed by UPLC–MS on a setup consisting of a Waters Acquity UPLC system connected to an LCT Premier XE mass spectrometer from Micromass, or by HPLC–MS on an Agilent 1200 series HPLC connected to an Agilent 6230 time-of-flight (TOF) system using solvent A 0.1% formic acid (FA) in H2O and solvent B 0.1% FA in acetonitril (CAN). All peptide stocks for in vitro assays were quantified to a final concentration close to 200 µM by using a chemiluminescent nitrogen detector (Thermo Scientific Vanquish) or charged aerosol detector (Thermo Scientific Ultimate 3000) before performing the in vitro assay. The measured concentration was used in data analysis. B. Peptide dimerization and purification Purified monomer peptide was dissolved in DMSO 30-50 mg / ml and more than 10 eq of diisopropylethylamine (DIPEA) was added. Suberic acid N-hydroxysuccinimide ester was dissolved in DMSO and 0,5 equivalent relative to peptide content (1 equivalent) was added gradually to the DMSO peptide solution and dimerisation proceeded overnight. After the dimerization the dimer peptide was purified. Purification acidic method Column: Waters XBridge Protein BEH C4; Prep Column, 300Å, 5µm 10mm x 150 mm A-buffer: 0.1% TFA in MQ-water B-buffer: 0.1% TFA in CH3CN The column is pre-equilibrated with 3 column volume (CV) MQ-water. Reaction mixture (DMSO / DIPEA) carefully diluted with MQ-water 1:3 and loaded onto the pre-equilibrated HPLC-column.this was followed by 3 column volumes (CV) 100% MQ-water followed by 3 CV of A-buffer and a gradient 10->35%B- over 2 CV followed by 35->55%B over 9 CV. Purification neutral method Column: Waters XSelect Peptide CSH C18; Prep Column OBD, 130Å, 5µm, 10mm x 150 mm or Waters XSelect Peptide CSH C18; Prep Column, 5µm OBD, 30mm x 150 mm C-buffer: 1% NH4HCO3D-buffer: 80% CH3CN in MQ-water The column is pre-equilibrated with 3 CV MQ-water. The pooled fractions are carefully diluted with MQ-water just before loading to the HPLC-column. Following the loading of the peptide to the column 3 CV 100% MQ-water followed by 3 CV of 100% C-buffer, followed by a gradient 10->50%D over 9 CV. Recombinant expression of antibody (Crizanlizumab) The antibody was prepared using transient transfection of HEK293 suspension cells (293Expi, Invitrogen) essentially following manufacturer’s instructions.293Expi cells were typically subcultivated every 3-4 days in Expi293F expression medium (Invitrogen, catalogue number A1435104) supplemented with 1% P / S (GIBCO catalogue number 15140-122). Expi293F cells were transfected at a cell density of 2.5-3 mill / mL using Expifectamine. For each litre of Expi293F cells, the transfection was performed by diluting a total of 1 mg of plasmid DNA (VH-CH1 (for Fab) or VH-CH1-CH2-CH3 (for mAb) and LC plasmids) into 50 mL Optimem (GIBCO, cat. no.51985-026, dilution A) and by diluting 2.7 mL Expifectamine into 50 mL Optimem (dilution B). For Fab and mAb producing co-transfections, VH-CH1 and LC plasmids (Fab) and VH-CH1-CH2-CH3 and LC plasmids (mAb), respectively, were used in a 1:1 ratio. Dilution A and B were mixed and incubated at room temperature for 10-20 minutes. The transfection mix was hereafter added to the Expi293F cells and cells were incubated at 37^C in a humidified incubator with orbital rotation (85-125 rpm). One day post-transfection, transfected cells were supplemented with 5 ml of ExpiFectamine 293 Transfection Enhancer 1 and 50 ml of ExpiFectamine 293 Transfection Enhancer 2. Cell culture supernatants were typically harvested 4-5 days post-transfection by centrifugation followed by filtration. The sequence of the antibody used is provide by SEQ ID NO.: 71 and 72. Antibody purification setup: Resin: MabSelect Sure, pre-packed column cat. no.11-0034-95) Column type: HiTrap Mabselect Sure 5 ml Diameter (cm): 1.6 Length (cm): 2.5 Volume (ml): 5 Resin: Superdex 200 (GEH cat. no.28-9893-36) Column type: Superdex 20026 / 60 pre-packed Diameter (cm): 2.6 Length (cm): 60 Volume (ml): 320 LC analysis setup: Column Waters MassPREP Desalt (cat. no.186004032) Flow 0.4 ml / min Tempereture 20 °C A-buffer Water / 0.1% FA B-buffer ACN / 0.1% FA UV detection 280 / 254 / 214nm Program 0 min: 5% B, MS waste 3 min: 5% B, MS inject 3-6 min: 5-60% B, MS inject 6 min: 95% B, MS inject 8.5 min: 5% B, MS inject 12.5 min + 4 min post time: 5% B, MS inject Mass obs: 145900.72 Mass calc: 146266,38 Assays P-selectin binding assay Estimation of binding affinity to human P-selectin by surface plasmon resonance (SPR assay).P-selectin is immobilized the surface of a chip and peptides are passed through on the top of the chip and binding association rate (konrate) to the P-selectin is recorded. After binding the chip is flushed with solvent and the dissociation rate is recorded (koffrate). The dissociation contant Kdis then calculated from the Koff / Kon. Binding studies were performed on a Biacore T200 instrument (Cytiva) at 25˚C.P- selectin (R&D systems; cat# 137-PS) were on the sensor surface of a CM5 sensor chip (Cytiva; cat#BR100530) using standard amine coupling chemistry. In brief, P-selectin were injected at 10 ug / ml in 10 mM Acetate buffer pH 5.0 over an N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC) / N-Hydroxysuccinimide (NHS) activated surface (contact time 420 sec; flow rate 10 µl / min) resulting in immobilization levels between 10000 – 15000 response units (RUs). As the final step of the immobilization procedure unreacted NHS-ester groups were blocked by injection of 1M ethanolamine. Test peptide (9.8 nM – 2500 nM) was injected sequentially in a single cycle without dissociation or regeneration between each injection (contact time: 120 sec; flow rate: 30 µl / min) followed by 600 sec dissociation (running buffer: 10 mM Hepes; 150 mM NaCl; 5 mM CaCl2; 0.05% v / v Surfactant P20; flow rate: 30 µl / min). Binding curves were subjected to double referencing by subtraction of reference surface signals as well as a buffer injection over a blank sensor surface. From the binding sensorgrams kinetic parameters ka (association rate) and kd (dissociation rate) were determined using the Biacore evaluation software applying a 1:1 Langmuir binding model. Platelet Leukocyte Aggregates Assay (PLA) assay The inhibitory function of P-selectin ligands is measured in a Platelet Leukocyte Aggregates (PLA) assay, wherein concentration dependent inhibition of aggregation by the P-selectin ligands is measured. Platelet-leukocyte aggregates (PLA) are defined as the interaction between at least one platelet and one leukocyte through cell surface receptors. During a typical protocol, blood is drawn from healthy / disease individuals by venipuncture into sodium citrate containing collection tubes. For optimal sample collection, the first 2 to 5mL of blood should be discarded and a smooth free-flowing blood pattern should be ensured. To generate the PLAs, a platelet agonist (eg TRAP-6, ADP) is used to ensure appropriate levels of activation and leukocyte binding. Following activation, samples are stained with a platelet-specific fluorescent-conjugated antibody (eg CD41a-PE) and a leukocyte-specific fluorescent- conjugated antibody (eg CD45-APC). Following an incubation period, samples are fixed, and red blood cells are lysed. Data acquisition and analysis may then be performed on any flow cytometry system allowing for measurements of the selected fluorophores / stains. Platelet- leukocyte aggregates are identified by positive signal for a platelet-specific marker (eg CD41a) and positive signal for a pan-leukocyte marker (eg. CD45).   The results provided herein are from before as follows: Test compounds were serially diluted in assay buffer at pH HEPES, 137mM NaCl, 270μM MgCl2, 40μM NaH2PO4, 500μM glucose, 2% FBS, and 10μM CaCl2) and transferred to 96 Deepwell assay plates (Thermo, Cat. no.260251) with a final volume of 17μL.23μL of stabilized whole blood (2mM GPRP, 1.29μg / mL rTAP, and 0.57μg / mL rHirudine) from healthy individuals was added at room temperature for 10mins.20μL assay buffer mixed with 60μM of the platelet agonist TRAP6, anti-CD41a PE (1:50) (BD Bioscience, cat. no.557297) and anti-CD45 AF488 (1:50) (BioLegend, Cat. no.304017) was added to the wells and incubated in the dark at room temperature for 20mins.900μL of 1X RBC lysis buffer (Invitrogen™ (eBioscience™), Cat. no.422401) was added to each well and incubated for 10mins. Staining was quantified by simultaneously scanning the Deepwell plates with 488nm and 566nm lasers on a NovoCyte Quanteon cytometer. Data was analysed in Prism, using a four-parameter nonlinear regression with variable slope to generate IC50 and IC90 values. LC-MS analysis LC-MS analysis was done on a TurboFlow High Performance Liquid Chromatography system coupled to a Q Exactive Plus mass spectrometer (Thermo Fisher Scientific). Plasma samples underwent sample preparation by addition of three volumes of methanol to one volume of plasma sample. Following centrifugation, the supernatant was diluted with one volume of water. Precipitated plasma samples were first cleaned up and concentrated on a TurboFlow Cyclone column (Thermo Fisher Scientific) operated at 30 °C and then transferred to an analytical column. The analytical column was an XBridge Peptide BEH C18 column from Waters for 0586-2088, and a Jupiter C4 column from Phenomenex for 0586-2014. Both analytical separations were conducted with a linear gradient at 60 °C. Mobile phase A was water with 5% organic solvent (acetonitrile / methanol (1:1, by volume)) and 1% formic acid, and mobile phase B was water with 95% organic solvent (acetonitrile / methanol (1:1, by volume)) and 1% formic acid. The mass spectrometer was operated in selected ion monitoring mode, and positive electro spray ionization was used. Examples Example 1A - Identification of P-selectin peptide ligands. A series of cyclic peptides selected as binders to human P-selectin were identified. Initially, binders having an affinity < 500 nM determined as Kd in a SPR assay were selected from mRNA display library. After several rounds of selection, peptides with affinities < 25 nM were obtained. Table 1.1 summarizes peptide structures and SPR results of a representative group of peptides made by solid phase peptide synthesis and Table 1.2 includes a summary of the quality analysis. A lysine with an azide functional group at a lysine side chain was incorporated in some of the monomer peptide derivates. This was done to enable conjugation to a peptide monomer having an alkyne functional group by cobber catalyzed click-chemistry, if of interest. The lysine and azide per se did not have any other function and did not interfere with the binding to P-slelctin protein. From table 1.1 it is observed that the core peptides -WCDINPWDDSITC- (SEQ ID NO.: 4), -WCDINPFDDSITC- (SEQ ID NO.: 5), and -WCDINPRDDSITC-(SEQ ID NO.: 6), which only differ by one amino acid residue (W / P / R in position 7), are shared among peptides with high binding affinity. Furthermore, adding some additional amino acid residues in the flanking region towards the N- and C-terminus, further improved binding affinity as measured by SPR. Peptide # Sequence SEQ Kd ID (nM) NO.: A Ac-MW-CTLHLWELVHEC-TGS-NH236 436 B Ac-MW-CDIIPFYDMIKC-NGSGSGSDYKDDDDK*-NH237 214 C Ac-MEW-CDINPWDHSSSC-LGSGSGSDYKDDDDK*-NH238 147 D Ac-MEW-CDIDPWYHFSTC-NGSGSGSDYKDDDDK*-NH239 144 Ac-MW-CTLHLWDTVHEC-VPETYGSGGGSDYKDDDDK*- E 40 68.6 NH2F LW-CDINPWDDSITC-NGSGSGSDYKDDDDK*-NH241 21.3 G Ac-MW-CDINPWDDSITC-VFDDFGAQPGAQPEEK 42 14.0 H Ac-MW-CDINPWDDSITC-VFDDFGAQPEEK 43 11.0 Ac-GW-CDINPWDDSITC-VFDDFGGSGSGSDYKDDDDK*- I 44 6.5 NH2J LGDIW-CDINPFDDSITC-SRWVE 45 3.2 K Ac-LGDIW -CDINPFDDSITC-SRWVGSGSGSDYKDDDDK 46 1.0 L Ac-MGDIW-CDINPRDDSITC-SRWVGSGSGS 47 0.8 M Ac-MGDIW-CDINPRDDSITC-SRWV 48 0.3 Table 1.1 Human P-selectin peptide ligands and P-selectin affinity. Peptide modifications are indicated as follows: Ac- signifies an N-terminal acylation (CH3CO- NH2-), K* signifies a lysine residue with an azide modification and -NH2signifies that the C- terminal has an amide modification. The binding affinity was measured in an SPR assay and the Kd provided. Peptide # Purity (%) Calculated MW Found Mw [M+2H]+2 [M+3H]+3 D 95,5 2084,40 2084,94 1043,47 695,65 B 87,0 3512,83 3511,66 1757,33 1171,87 C 83,9 3415,48 3415,36 1708.68 1139,45 D 90,8 3539,62 3539,38 1770,69 1180,78 E 95,9 3768,98 3767,61 1256,87 F 97,4 3245,30 3245,14 1623,57 1082,37 G 90,5 3455,71 3455,54 1728,77 1152,83 H 98,2 3102,34 3101,5 1551,67 1034,76 I 96,4 3797,82 3797,56 1899,78 1266,85 J 90,5 2582,81 2582,12 1292,06 862,05 K 94,9 3923,08 3920,74 1961,37 1307,91 L 90,6 2946,16 2944,3 1473,14 982,42 M 98,7 2522,79 2521,2 1261,6 841,4 Table 1.2 Purity and mass identified by LC-MS for human P-selectin peptide ligands. Example 1B - Identification of P-selectin peptide ligand variants Using a mRNA display library different peptide binders were identified. Among the peptides tested, a peptide MWCDINPWDDSITCVFDDFG (SEQ ID NO.: 49), was identified as a potent ligand to human P-selectin. Therefore, it was decided to analyse the core of this peptide in more detail by variant generation and analysis using spot array. The spot array arranges peptides on a solid support and binding interaction can be visualised by adding the fluorophore-labelled receptor of interest. The fluorescence intensity corresponds to affinity and since each spot (peptide) has the same on the paper the relative fluorescence is a measure of binding strength. A variant analysis of the core peptide was done by replacing each amino acid residue except for the cysteines (C’s) in position 2 and 13 forming a disulfide bridge. The peptide variants were synthesise including an N-terminal methionine (M) and the VFDDFG extension (AA 14-20 of SEQ ID NO.: 49) from the parent peptide. The peptides were synthesised on paper as small spots and all with the same density on the paper (100 nmol / cm2). The array was screened against biotin labelled human P-selectin and streptavidin-Alexa 488 used for detection. The fluorescence intensity corresponding to the binding affinity to P-selectin was determined by quantifying the fluorescence intensity using Amersham typhoon laser scanner. The fluorescence intensity of the core peptide was set to 1. The fluorescence intensity for the peptides variants was evaluated relative to the core peptide and thus a value >1 shows that the peptide including the amino acid substitution has a high binding affinity than the parent peptide and a value <1 shows that the peptide including the amino acid substitution has lower binding affinity than the parent peptide. The data obtained are included in table 1.3. W D I N P W D D S I T Pos 1 3 4 5 6 7 8 9 10 11 12 A 0,62 0,56 0,57 0,61 0,69 0,72 0,57 0,57 0,70 0,74 0,88 S 0,68 0,76 0,56 0,81 0,71 0,83 0,57 0,66 1 0,78 1,07 T 0,56 0,66 0,56 0,57 0,65 0,83 0,60 0,58 0,77 0,74 1 G 0,61 0,54 0,59 0,54 0,59 0,70 0,58 0,60 0,69 0,57 0,79 P 0,57 0,54 0,59 0,50 1 0,60 0,53 0,54 0,51 0,69 0,59 D 0,61 1 0,60 0,78 0,59 0,73 1 1 0,75 0,66 0,86 E 0,55 0,53 0,56 0,61 0,63 0,77 0,54 0,68 0,78 0,65 0,84 Q 0,59 0,54 0,61 0,65 0,60 0,76 0,52 0,59 0,76 0,64 0,82 N 0,62 0,56 0,58 1 0,60 0,78 0,65 0,64 0,70 0,61 0,83 L 0,59 0,50 0,66 0,59 0,53 0,89 0,53 0,57 0,65 0,64 0,72 I 0,60 0,49 1 0,63 0,58 0,90 0,51 0,55 0,63 1 0,67 V 0,58 0,50 0,94 0,66 0,67 0,86 0,53 0,54 0,59 0,8 0,72 W 1 0,52 0,55 0,58 0,54 1 0,5 0,56 0,58 0,54 0,62 Y 0,6 0,58 0,53 0,57 0,52 0,86 0,58 0,52 0,59 0,60 0,63 F 0,71 0,59 0,54 0,56 0,51 0,91 0,57 0,53 0,59 0,59 0,60 K 0,61 0,57 0,54 0,59 0,53 0,81 0,57 0,55 0,72 0,60 0,75 R 0,59 0,59 0,53 0,63 0,54 0,92 0,58 0,54 0,68 0,64 0,71 H 0,62 0,63 0,54 0,72 0,59 0,89 0,57 0,64 0,67 0,82 0,78 Table 1.3: Variant analysis Variant analysis by relative fluorescence compared to the parent peptide. <1) reduced binding. >1) increase binding =1) equal binding. The results of the variant analysis showed that the amino acid in position 7 can be substituted with several different amino acid residues, while only few amino acid residues can substitute the individual amino acid residue in most other positions of the optimized core peptide without significantly reducing P-selectin binding. Example 2A - Identification and characterisation of peptide derivatives as P-selectin peptide ligands To further explore the tolerance for a side chain modification of the peptide, additional peptide derivatives were prepared, including a substituent comprising a fatty diacid placed with-in or adjacent to the optimized core. The binding affinity to the P-selectin receptor were again tested in an SPR assay. Summary tables 2.1 and 2.2 includes information on the sequence and the attachment site for the substituent comprising the diacid of the peptide derivatives together with the Kd obtained from the SPR assay. The structure of each peptide derivative is provided further below. Quality parameters for the generated peptides are included in table 2.3 further below. Peptide / Sequence SEQ Attachment Kd Peptide ID site (nM) derivative NO.: M Ac-MGDIWCDINPRDDSITCSRWV 48 NA 0.3 J LGDIWCDINPFDDSITCSRWVE 45 NA 3,2 1 LGDIWCDINPFK*DSITCSRWVGAQPEE 50 K12 494 2 LGDIWCDINPFDK*SITCSRWVGAQPEE 51 K13 310 3 LGDIWCDINPFDDK*ITCSRWVGAQPEE 52 K14 52 4 LGDIWCDINPFDDSK*TCSRWVGAQPEE 53 K15 321 5 LGDIWCDINPFDDSIK*CSRWVGAQPEE 54 K16 37 6 LGDIWCDINPFDDSITCSRWVGSGSGSEEK* 55 K30 9,7 7 LGDIWCDINPFDDSITCSRWVGSEEK* 56 K26 9,4 8 LGDIWCDINPFDDSITCSRWVEEGSK* 57 K26 7,3 9 GSLGDIWCDINPFDDSITCSRWVGEQPK* 58 K28 14,8 Peptide / Sequence SEQ Attachment Kd Peptide ID site (nM) derivative NO.: 10 GSLGDIWCDINPFDDSITCSRWVGK* 59 K25 12,9 11 GSGSGSLGDIWCDINPFDDSITCSRWVGK* 60 K29 11,9 12 LGDIWCDINPFDDSITCSRWVEEK* 61 K24 6,5 13 LGDIWCDINPFDDSITCSRWVK* 62 K22 4.5 14 GGLGDIWCDINPFDDSITCSRWVK* 63 K24 4.8 15 GGPGGLGDIWCDINPFDDSITCSRWVK* 64 K27 6,9 16 GSLGDIWCDINPFDDSITCSRWVEEGAQPK* 65 K30 12,7 Table 2.1. Human P-selectin peptide derivative ligands and their affinity to P-selectin. Lysine (K) residues including a substituent (C18 diacid-gGlu-2xAdo-) is marked with a * (K*). The affinity to human P-selectin is included as the Kd measured as in SPR assay. From the table it is observed that attaching a substituent in the optimised motif WCDINPFDDSITC (SEQ ID NO.:4) lowers the affinity to the receptor, while a high affinity can be retained when the substituent is attached out-side the optimized motif. Furthermore, adding residues in the flanking region towards the N- and C-terminus, improve binding affinity as measured in the SPR assay. Further adjustments of the flanking amino acids and location of the substituent provided further peptide derivatives with improved binding affinity as measure in SPR assay (table 2.2). Peptide Peptide amino acid sequence SEQ linker albumin Attach Kd derivative ID binding ment (nM) NO moiety 17 GEPGEQPEGDIWCDINPFDD29gGlu-C20 K36 nd SITCSRWVEGEGEQPK*E 2xOEG diacid 18 GAQPPEGDIWCDINPFDDSIT30gGlu-C20 K33 nd CSRWVEEGAQPK* 2xOEG diacid 19 GPEGDIWCDINPFDDSITCSR31gGlu-C18 K38 9,7 WVGEPGEGGPEGGPEGK* 2xOEG diacid 20 GAQPK*GEQPEGDIWCDINPF32gGlu-C18 K5 nd DDSITCSRWVEEGEQPE 2xOEG diacid 21 GEGDIWCDINPFDDSITCSRW33gGlu-C18 K33 nd VEEGEQPGEQPK* 2xOEG diacid 22 GAQPEGDIWCDINPFDDSITC34gGlu-C16 K32 15,6 SRWVEEGAQPK* 2xOEG diacid 23 GAQPEGDIWCDINPFDDSITC34gGlu-C18 K32 11,6 SRWVEEGAQPK* 2xOEG diacid 24 GAQPGGDIWCDINPFDDSITC35gGlu-C18 K32 12,0 SRWVEEGAQPK* 2xOEG diacid Table 2.2. Human P-selectin peptide derivative ligands and their affinity to P-selectin. The peptide derivatives comprise a substituent including a linker (-gGlu-2xAdo-) and a diacid (C16, C18 or C20) attached via a lysine residue as marked with a * (K*). The affinity to human P-selectin as measured as Kd in a SPR assay for the monomeric peptides indicated. Peptide derivatives (monomers) The structure of each peptide derivative # 1-24 is included here below. Peptide derivative # 1 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K12

[0002] Peptide derivative # 2 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K13 Peptide derivative # 3 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K14

[0003] Peptide derivative # 4 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K15 Peptide derivative # 5 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K16

[0004] Peptide derivative # 6 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K30 Peptide derivative # 7 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K26

[0005] Peptide derivative # 8 O O H N Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K26 Peptide derivative # 9 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K28 Peptide derivative # 10 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K25 derivative # 11 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K29 Peptide derivative # 12 O O H N H Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K24 Peptide derivative # 13 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K22 Peptide derivative # 14 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K24 Peptide derivative # 15 O O H N H O OH Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K27 Peptide derivative # 16 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K30 Peptide derivative # 17 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K36 Peptide derivative # 18 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K33 Peptide derivative # 19 HOOC-(CH2)16-CO-gGlu-2xAdo- at K38

[0006] Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K5 Peptide derivative # 21 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K33 Peptide derivative # 22 Substituent: HOOC-(CH2)14-CO-gGlu-2xAdo- at K32

[0007] Peptide derivative # 23 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K32 Peptide derivative # 24 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at K32 Peptide derivate Purity (%) Calc Mw Found Mw [M+3H]3+ 194,6 3794,3 3795,6 1266,2290,3 3794,3 3795,6 1266,2396,7 3822,3 3823,6 1275,6493,1 3796,2 3797,6 1267,2596,3 3808,2 3809,6 1270,9694,7 3988,4 3987,9 1330,3795,7 3700,1 3699,6 1234,2896,8 3700,1 3699,6 1234,21981 3853,3 3852,61285,21073 3498,9 3498,31167,111 83,8 3787,2 3786,6 1263,2 Peptide derivate Purity (%) Calc Mw Found Mw [M+3H]3+ 1296,3 3556,0 3553,8 1185,613 94,3 3297,7 3295,6 1099,5 14 87,1 3411,9 3409,6 853,4 15 85,3 3623,1 3620,8 1207,9 16 89,1 4053,5 4050,9 1351,3 17 nd 4892,3 4892,4 1631,8 18 89,2 4403,8 4403,2 1468 19 90,8 4675 4674,8 1558,4 20 86,6 4877,2 4876 1626,7 21 91,9 4451,8 4451,2 1484,7 22 91,5 4250,6 4250 1418 23 96,6 4278,7 4278 1427,4 24 96,5 4206,6 4206 1403 Table 2.3 List of peptides derivatives with purity and mass identified by LC-MS Example 3 - Identification and characterisation of dimeric peptide derivatives as P-selectin peptide ligands By reacting individual peptide derivatives with Suberic acid N-hydroxysuccinimide ester dimeric P-selectin binding peptide derivatives were prepared having -CO-(CH2)6-CO- as linker between the N-terminals of the two peptides. The dimeric peptide derivatives are described in the summary table 2.4 and the structures of the dimeric peptide derivatives are shown further below and finally table 2.5 includes the quality parameters. Peptide Peptide amino acid sequence Substituent (linker and Attach derivative (SEQ ID NO.:) albumin binding moiety) ment 25 2x[LGDIWCDINPFK*DSITCSRWVGA gGlu-2xOEG C18 diacid K12 QPEE (SEQ ID NO.:50)] 26 2x[LGDIWCDINPFDK*SITCSRWVGA gGlu-2xOEG C18 diacid K13 QPEE (SEQ ID NO.:51)] 27 2x[LGDIWCDINPFDDK*ITCSRWVGA gGlu-2xOEG C18 diacid K14 QPEE (SEQ ID NO.:52)] Peptide Peptide amino acid sequence Substituent (linker and Attach derivative (SEQ ID NO.:) albumin binding moiety) ment 28 2x[LGDIWCDINPFDDSK*TCSRWVGA gGlu-2xOEG C18 diacid K15 QPEE (SEQ ID NO.:53)] 29 2x[LGDIWCDINPFDDSIK*CSRWVGA gGlu-2xOEG C18 diacid K16 QPEE (SEQ ID NO.:54)] 30 2x[LGDIWCDINPFDDSITCSRWVEEK gGlu-2xOEG C18 diacid K24 * (SEQ ID NO.:61)] 31 2x[LGDIWCDINPFDDSITCSRWVK* gGlu-2xOEG C18 diacid K22 (SEQ ID NO.:62)] 32 2x[GGLGDIWCDINPFDDSITCSRWVK gGlu-2xOEG C18 diacid K24 * (SEQ ID NO.:63)] 33 2x[GGPGGLGDIWCDINPFDDSITCSR gGlu-2xOEG C18 diacid K27 WVK* (SEQ ID NO.:64)] 34 2x[GSLGDIWCDINPFDDSITCSRWVG gGlu-2xOEG C18 diacid K28 EQPK* (SEQ ID NO.:58)] 35 2x[GSGSGSLGDIWCDINPFDDSITCS gGlu-2xOEG C18 diacid K29 RWVGK* (SEQ ID NO.:60)] 36 2x[GSLGDIWCDINPFDDSITCSRWVE gGlu-2xOEG C18 diacid K30 EGAQPK* (SEQ ID NO.:65)] 37 2x[GEPGEQPEGDIWCDINPFDDSITC gGlu-2xOEG C20 diacid) K36 SRWVEGEGEQPK*E (SEQ ID NO.: 29)] 38 2x[GAQPPEGDIWCDINPFDDSITCSR gGlu-2xOEG C20 diacid K33 WVEEGAQPK* (SEQ ID NO.: 30)] 39 2x[GPEGDIWCDINPFDDSITCSRWVG gGlu-2xOEG C18 diacid K38 EPGEGGPEGGPEGK* (SEQ ID NO.: 31)] 40 2x[GAQPK*GEQPEGDIWCDINPFDD gGlu-2xOEG C18 diacid K5 SITCSRWVEEGEQPE (SEQ ID NO.: 32)] 41 2x[GEGDIWCDINPFDDSITCSRWVEE gGlu-2xOEG C18 diacid K33 GEQPGEQPK* (SEQ ID NO.: 33)] 42 2x[GAQPEGDIWCDINPFDDSITCSRW gGlu-2xOEG C14 diacid K32 VEEGAQPK* (SEQ ID NO.: 34)] Peptide Peptide amino acid sequence Substituent (linker and Attach derivative (SEQ ID NO.:) albumin binding moiety) ment 43 2x[GAQPEGDIWCDINPFDDSITCSRW gGlu-2xOEG C16 diacid K32 VEEGAQPK* (SEQ ID NO.: 34)] 44 2x[GAQPEGDIWCDINPFDDSITCSRW gGlu-2xOEG C18 diacid K32 VEEGAQPK* (SEQ ID NO.: 34)] 45 2x[GAQPGGDIWCDINPFDDSITCSR gGlu-2xOEG C18 diacid K32 WVEEGAQPK* (SEQ ID NO.: 35)] 46 2x[GPEGDIWCDINPFDDSITCSRWVG gGlu-2xOEG C16 diacid K38 EPGEGGPEGGPEGK*(SEQ ID: 31) Table 3.1 Human P-selectin dimeric peptide derivative ligands. The peptide derivatives comprise a substituent comprising a linker (-gGlu-2xAdo-) and a diacid (C14, C16, C18 or C20) attached to each of the peptide sequences via the lysine residue as indicated. Dimeric peptide derivatives The structure of each of the peptide derivative # 25-46 is included here below.

[0008] Dimeric peptide derivative # 25 16-

[0009] Dimeric peptide derivative # 26 Dimeric peptide derivative # 27 16- Dimeric peptide derivative # 28 16- Dimeric peptide derivative # 29 16- Dimeric peptide derivative # 30 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK24

[0010] Dimeric peptide derivative # 31 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK22

[0011] Dimeric peptide derivative # 32 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK24

[0012] Dimeric peptide derivative # 33 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK27

[0013] Dimeric peptide derivative # 34 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK25 Dimeric peptide derivative # 35 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK29 Dimeric peptide derivative # 36 O H O N H O OH Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK30 Dimeric peptide derivative # 37 O O H N H O OH Substituent: HOOC-(CH2)18-CO-gGlu-2xAdo- at 2xK36 Dimeric peptide derivative # 38 Substituent: HOOC-(CH2)18-CO-gGlu-2xAdo- at 2xK33

[0014] Dimeric peptide derivative # 39 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK38 Dimeric peptide derivative # 40 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK5 Dimeric peptide derivative #41 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK33 Dimeric peptide derivative # 42 Substituent: HOOC-(CH2)12-CO-gGlu-2xAdo- at 2xK32

[0015] Dimeric peptide derivative # 43 Substituent: HOOC-(CH2)14-CO-gGlu-2xAdo- at 2xK32 Dimeric peptide derivative # 44 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK32 Dimeric peptide derivative # 45 Substituent: HOOC-(CH2)16-CO-gGlu-2xAdo- at 2xK32 Dimeric peptide derivative # 46 Substituent: HOOC-(CH2)14-CO-gGlu-2xAdo- at 2xK38 Dimeric peptide derivative Purity (%) Calc MW Found Mw [M+4H]+4 M+5H]+5 25 96,1 7726,7 7725,2 1932,3 Dimeric peptide derivative Purity (%) Calc MW Found Mw [M+4H]+4 M+5H]+5 26 89,5 7726,7 7725,3 1932,3- 27 86,2 7782,7 7781,4 1946,3- 28 87,4 7730,5 7730,1 1933,3- 29 88,1 7754,7 7753,2 1939,3- 30 94,6 7250,1 7249,6 1813,4- 31 86,1 6733,7 6729,3 1683,3- 32 93,7 6961,9 6957,3 1740,4- 33 89,4 7384,3 7384,8 1847,2- 34 80,9 7844,7 7845,2 1962,3- 35 91 7712,5 7711,6 1928,9- 36 86,6 8245,11 8244,8 2062,2- 37 90,2 9922,7 9922 na 1985,4 38 92,6 8945,9 8945 2237,4 - 39 96,7 9488,2 9487 2372,7 - 40 93,7 9892,6 9892,5 2474,1 - 41 95,2 9041,2 9040,4 2261,3 - 42 97,2 8583,3 8582,5 2146,6 - 43 97,3 8639,4 8638,5 2160,4 - 44 95,3 8695,5 8694,5 2174,6 - 45 96,8 8551,4 8550,5 2138,6 - 46 90,0 9432,1 9431,0 na 1887,2 Table 3.3. Purity calculated and measured, molecular weight (MW) for the P-selectin ligands peptides prepared and analysed.

[0016] Example 4 - Estimation of binding affinities monomeric peptide binding to human L-, E-, and P-selectin by surface plasmon resonance (SPR) SPR Binding studies were performed on a Biacore T200 instrument (Cytiva) at 25˚C. L-selectin (R&D systems; cat# 728-LS), E-selectin (R&D systems; cat# 724-ES), and P- selectin (R&D systems; cat# 137-PS) were immobilized on the sensor surface of a CM5 sensor chip (Cytiva; cat#BR100530) using standard amine coupling chemistry. In brief, L-, E-, and P-selectin were injected at 10 ug / ml in 10 mM Acetate buffer pH 5.0 over an N-(3- Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC) / N-Hydroxysuccinimide (NHS) activated surface (contact time 420 sec; flow rate 10 µl / min) resulting in immobilization levels between 10000 – 15000 response units (RUs). As the final step of the immobilization procedure unreacted NHS-ester groups were blocked by injection of 1M ethanolamine. Monomeric peptide (9.8 nM – 2500 nM) was injected sequentially in a single cycle without dissociation or regeneration between each injection (contact time: 120 sec; flow rate: 30 µl / min) followed by 600 sec dissociation (running buffer: 10 mM Hepes; 150 mM NaCl; 5 mM CaCl2; 0.05% v / v Surfactant P20; flow rate: 30 µl / min). Binding curves were subjected to double referencing by subtraction of reference surface signals as well as a buffer injection over a blank sensor surface. From the binding sensorgrams kinetic parameters ka (association rate) and kd (dissociation rate) were determined using the Biacore evaluation software applying a 1:1 Langmuir binding model. The results are provided in Table 3. Ligand Analyte ka×105M-1s-1kd×10-3 s-1KD(nM) P-selectin Peptide derivative 1.1 1.1 10 19 E-selectin Peptide derivative N.A. N.A. >2500 19 L-selectin Peptide derivative N.A. N.A. >2500 19 Table 4. Selective binding of Peptide derivative 19 to P-selectin. The monomeric peptide ligand binds human P-selectin with an estimated affinity of 10 nM. No or low binding signals were observed at the highest tested concentration (2500 nM) to human L-, and E-selectin and hence the equilibrium dissociation constant (KD) is reported as >2500 nM. Example 5 – Inhibitory activity of P-Selectin peptide ligands Platelet Leukocyte Aggregates Assay (PLA) assay was performed by as described herein above Peptide samples and Crizanlizumab were analysed in parallel and Crizanlizumab relative values were calculated by dividing the selected peptide value with the Crizanlizumab value of the same experiment. Selected peptides were tested and the results (IC50 and IC90 data relative to Crizanlizumab) are shown in tables 5.1 (monomeric peptides) and 5.2 (dimeric peptides), All data displayed is the mean of n≥3. PLA PLA [IC50 relative (fold)] [IC90 relative (fold)] Crizanlizumab 1,00 1,00 Peptide derivative 17 10,0 6,28 18 4,50 15,56 19 3,61 4,49 20 4,09 4,44 21 12,7 5,86 22 6,53 9,08 23 5,93 294,20 24 16,64 39,6 Table 5.1 Activity of monomeric peptide ligands relative to Crizanlizumab. A value >1 means that the peptide binds P-Selectin with a lower affinity than crizanlizumab. A value <1 means the peptide binds P-Selectin with a higher affinity than crizanlizumab. PLA PLA [IC50 relative (fold)] [IC90 relative (fold)] Crizanlizumab 1,00 1,00 Dimeric peptide derivative 25 442 159 26 2,2 197 27 9,4 18 28 5,7 9,8 PLA PLA [IC50 relative (fold)] [IC90 relative (fold)] 29 5,3 8,8 30 7,4 14,1 31 18,6 12,1 32 11,4 18,8 33 9,4 15,1 34 21 92 35 9,3 8,3 36 15,2 20,7 37 0,51 0,66 38 0,98 0,93 39 0,97 0,91 40 0,84 0,63 41 1,27 0,98 42 0,93 0,56 43 1,06 1,55 44 1,31 1,16 45 1,16 1,39 46 0,98 1,71 Table 5.2 Activity of dimeric peptide ligands relative to Crizanlizumab. A value >1 means that the peptide binds P-Selectin with a lower affinity than crizanlizumab. A value <1 means the peptide binds P-Selectin with a higher affinity than crizanlizumab. All monomeric peptides tested bind with a lower affinity than crizanlizumab, whereas some of the dimeric peptides display an efficacy on par or even better than crizanlizumab. Based on the PLA assay the dimeric peptide derivatives 37-45 displayed an affinity increase around 4-5 fold compared to the monomeric peptide derivatives 1-8, which is more than the expected 2-fold increase due to the presence of two binding domains present in a dimeric molecule. As the peptides are much smaller than antibody molecules a substantially higher concentration can be reach when administering the same amount of peptide or protein on a milligram scale. As an example,10 mg antibody with a molecular weight of 149000 Da will correspond to 67 nmol, whereas 10 mg of peptide with a molecular weight of 9000 Da will correspond to 1100 nmol. Example 6 - Physical stability of P-Selectin To test the stability of the P-selectin binding peptides in liquid compositions suitable for pharmaceutical use, a series of aqueous compositions where prepared. The physical stability and solubility of dimeric peptide derivatives 38, 39 and 44 at 5, 10 and 30 or 40 and 60 mg / ml in a 8 mM Phosphate buffer pH 7.4 with 250 mM Sorbitol were evaluated after incubation of up to 4 weeks at 37 C. High Molecular weight species formation At time zero, one week, two weeks and four weeks, 2 µl of samples diluted at 1 mg / ml from each concentration were analysed with a denaturing reverse phase UPLC (Acquity UPLC, Waters), on a Protein BEH SEC Column 20 (Waters) using as eluent 10.0 mM phosphoric acid, 20.0 mM sodium dihydrogen phosphate monobasic, 600 mM sodium chloride at pH 2.4, in isopropanol and acetonitrile 10:3:7 v / v / v. Absorbance at 215nm was recorded for each experiment. Chromatograms were analysed through a proprietary software (BayesChrom), where main peak was defined as the one with largest area, HMWP as all peaks eluting earlier than main peaks. The results shown in figure 2, demonstrate a high level of stability as the content of HMWP remains below 2,5 % through-out the study for all concentration ranges tested. Content of P-Selectin binding peptide To measure the peptide content in sample after up to 4 weeks, samples from the compositions described in example 6, where analysed as follows. Samples of 10 µl from each composition were taken at time zero, after 1 week, 2 weeks and four weeks and centrifuged for 10 minutes at 20000 g to remove any insoluble material formed during storage. The supernatants were quantified with UV detection at 280 nm (Lunatic, Unchained Labs) for each concentration. The results demonstrate that over the four week of study all concentrations tested show a low propensity of the peptides to form irreversible aggregates (figure 3). Example 7 – Pharmacokinetics of intra venous (iv) and subcutaneous (sc) administration in minipigs. The aim of these studies was to measure the pharmacokinetic profile after intra venous (iv) and subcutaneous (sc) administration. The studies were done in female Göttingen minipigs (Ellegaard Minipigs A / S, Dalmose, Denmark) with a body weight of approximately 25 kg. The minipigs were administered either intravenously or subcutaneously, n=3 per group. A dose of 10-20 nmol / kg were administered in a vehicle comprising 50 mM phosphate and 70 mM sodium chloride at pH 7.4. Blood was sampled for up to 312 hours through an indwelling permanent venous catheter and collected in EDTA tubes (Sarstedt, Germany). Plasma was separated and analysed for compound concentration using Liquid chromatography mass spectrometry (LC- MS). Non-compartmental (NCA) pharmacokinetic analysis was done in Phoenix® WinNonlin® v.8.1 (Certara L.P. Princeton, NJ, USA). The AUC were calculated using the “Linear Up Log Down” method. The terminal elimination phase was fitted via linear regression with uniform weighting. Nominal sampling times and actual doses were used for NCA. A series of dimeric peptide derivatives were administered intravenously to mini pigs and the half-life measured and provided in table 7.1 below. The half-life of the derivatives was above 36 hours for all. Derivative # Dose (nmol / kg) T½ (hr) 32 15 67 33 15 65 38 15 42 39 15 37 43 15 44 44 15 38 45 15 51 Table 7.1 Half-life of the derivatives as measured after iv administration to minipigs. Further studies were done using derivative # 39 and # 44 which were also administered subcutaneously to mini pigs. observed plasma exposure profiler is provided in Figure 4, showing a sustained exposure (4A) and a fast uptake (4B).   Derivative # Body weight Dose Tmax (hr) Cmax (pM) T½ (hr) (nmol / kg) median median Harmonic mean 39 22,8 15 8 86000 65 44 22,8 16 6 123000 68 Table 7.2 Pharmacokinetic parameters of derivative # 39 and # 44 as measured following subcutaneous administration in minipigs. The half-life estimated based on subcutaneous administration are notably longer than from the iv study, which is likely due to a sustained release from site of injection. The extended half-life and the good subcutaneous absorption demonstrate that these derivatives are very well suitable for pharmaceutical use. While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

CLAIMS 1. A peptide comprising the amino acid sequence -W-C2-X3-X4-X5-X6-X7-D-D-X10-X11-X12- C13- defined by SEQ ID NO.: 3, where C2and C13are covalently linked by a disulfide bridge and wherein X3is S or D, X4is I or V, X5is S, D, N or H, X6is S or P, X7is any amino acid residue except P, X10is A, S, T, D, E, Q, N or K, X11is A, S, T, I, V or H and X12is A, S, T, G, D, E, Q, N, L, V, K, R or H.

2. The peptide according to any of the previous claims, wherein the amino acid sequence is -WCDINPFDDSITC- (SEQ ID NO.: 4) or -WCDINPWDDSITC- (SEQ ID NO.: 5).

3. The peptide according to any of the previous claims, wherein the peptide comprises amino acids extensions at the N-terminal and / or C-terminal, providing a peptide of 20- 50 amino acid residues in length.

4. The peptide according to claim 3, wherein the peptide comprise amino acids extensions referred to as N-terminal flanking sequence (Nflank), C-Terminal flanking sequence, N- terminal extension sequence (Next) and C-Terminal extension sequence (Cext), providing a peptide of the structure Next-Nflank-binding motif-Cflank-Cext, wherein the binding motif is the amino acid sequence defined in claim 1 or claim 2.

5. The peptide according to claim 4, wherein the Nflank is selected from the group consisting of: LGD, EGDI (SEQ ID NO.: 7), LGDI (SEQ ID NO.: 8) and GGDI (SEQ ID NO.: 9) and the Cflank is selected from the group consisting of SRWV (SEQ ID NO.: 10), SRW (SEQ ID NO.: 11) and TRWV (SEQ ID NO.: 12).

6. The peptide according to claim 4 or claim 5, wherein the Next is selected from the group consisting of: G, GP, GAQP (SEQ ID 13), GAQPP (SEQ ID NO.: 15), GEGDI (SEQ ID NO.: 16) and GAQPKGEQP (SEQ ID NO.: 22) and the Cext is selected from the group consisting of: EEGAQPK (SEQ ID NO.: 23), EEGEQPE (SEQ ID NO.: 24), EGEGEQPKE (SEQ ID NO.: 25), EEGEQPGEQPK (SEQ ID NO.: 26), GEPGEGGPEGGPEGK (SEQ ID NO.: 27), and EEGEQPGEQPGEQPK (SEQ ID NO.: 28).

7. The peptide according to any of the previous claims, wherein the peptide sequence is selected from SEQ ID NO.: 29-35 and 55-65.

8. The peptide according to any of the previous claims, wherein the peptide comprises a substituent comprising an albumin binding moiety, such as a fatty diacid.

9. The peptide according to any of the previous claims, wherein the peptide comprises a substituent attached to a lysine (K) residue outside the amino acid sequence defined in claim 1.

10. The peptide according to any of the previous claims, wherein the peptide is a dimer comprising two peptides as defined in any of the previous claims.

11. The peptide according to claim 11, wherein the two peptides are covalently linked via a linker having the structure -CO-(CH2)n-CO)- wherein n= 2-8, such as n=5 or 6.

12. A peptide selected from the group consisting of dimeric peptide derivatives 25-46 or 37- 46.

13. A peptide selected from the group consisting of dimeric peptide derivatives 38, 39, 44 and 46 having the following structures:Dimeric peptide derivative 38OHO H O N OH O NH OH 31)Dimeric peptide derivative 4434) Dimeric peptide derivative # 46.

14. A pharmaceutical composition comprising a peptide according to any of the previous claims.

15. The composition according to claim 14, for medical use, such as for use in treatment or prevention of sickle cell disease (SCD).

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