Peptide analogues with branched amino acid probe(s)

Abstract

The present invention relates to peptide analogues comprising one or more branched amino acid probes and a peptide, native or variants thereof.

1 - 34 . (canceled) 
     
     
         35 . A peptide analogue comprising a peptide and one or more branched amino acid probes,
 wherein said branched amino acid probe comprises a first amino-alkyl amino acid residue,   said first amino-alkyl amino acid residue optionally being covalently linked to a second amino-alkyl amino acid residue, or to a second and a third amino-alkyl amino acid residue, to form a linear chain of 2 or 3 amino-alkyl amino acid residues,   wherein the side chain of one or more of said first, second and/or third amino-alkyl amino acid residues are each modified by attaching to the side chain amino group a molecule independently selected from the group consisting of AAA q -AAA (SEQ ID NO: 168); (aa 3 ) p -AAA q  (SEQ ID NO: 169-174); AAA q -(aa 3 ) p  (SEQ ID NO: 175-180); [(aa 3 )-AAA] p  (SEQ ID NO: 181) and [AAA-(aa 3 )] p  (SEQ ID NO: 183 and 184);   wherein q is a number selected from 0, 1, 2 and 3; p is a number selected from 1, 2 and 3; AAA is an amino-alkyl amino acid residue; and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala,   wherein said amino-alkyl amino acid residues are optionally acetylated,   wherein said first amino-alkyl amino acid residue is covalently linked to the N-terminus of said peptide, covalently linked to the C-terminus of said peptide, and/or attached to the side chain amino group of an amino-alkyl amino acid residue within said peptide,   with the proviso that said branched amino acid probe consists of 2 to 9 amino acid residues.   
     
     
         36 . The peptide analogue according to  claim 35 , wherein said peptide is selected from the group consisting of VIP (Vasoactive Intestinal Peptide; PHM27), PACAP (Pituitary Adenylate Cyclase Activating Peptide), Peptide PHI 27 (Peptide Histidine Isoleucine 27), GHRH 1-24 (Growth Hormone Releasing Hormone 1-24), Glucagon, Secretin, glicentin precursor, GIP (gastric inhibitory peptide), prealbumin or transthyretin (TTR), peptide HI-27 and growth hormone releasing factor (GHRF or GHRH), incretins, glucagon-like peptide-2 (GLP-2), of somatotrophins (such as somatotropin or growth hormone (GH)), Thyrotrophins (such as Thyroid-stimulating hormone (TSH), Corticotropins (such as Adrenocorticotropic hormone (ACTH), and Beta-endorphin), Lactotrophins (such as Prolactin (PRL), Gonadotropins (such as Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH)), Antidiuretic hormone (ADH or vasopressin) Oxytocin, growth hormone-releasing hormone (GHRH), somatostatin, thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH) Gonadotropin-Releasing Hormone (GnRH), CREB (cAMP response element-binding protein), Lactotripeptides, Isoleucine-Proline-Proline (IPP), Valine-Proline-Proline (VPP), NPY (NeuroPeptide Y), PYY (Peptide YY), APP (Avian Pancreatic Polypeptide) and PPY/PP (Pancreatic Polypeptide), Proopiomelanocortin (POMC) peptides (including N-Terminal Peptide of Proopiomelanocortin (NPP, or pro-γ-MSH)), Corticotropin (Adrenocorticotropic Hormone, or ACTH), Corticotropin-like Intermediate Peptide (CLIP), β-Lipotropin (β-LPH), Lipotropin Gamma (γ-LPH), β-MSH, β-Endorphin and [Met]Enkephalin); Enkephalin pentapeptides (Met-enkephalin and Leu-enkephalin), Prodynorphin peptides, dynorphins (dynorphin A, dynorphin B, α-neo-endorphin, β-neo-endorphin, and Big dynorphin), endorphins (beta-endorphin, Alpha-endorphin, Gamma-endorphin, α-neo-endorphin and 3-neo-endorphin), Adrenorphin, Amidorphin, Leumorphin, Nociceptin, Opiorphin, Spinorphin, kinins, tachykinin neuropeptides (including substance P, kassinin, neurokinin A (NKA), neurokinin B (NKB), eledoisin and physalaemin), Bradykinin, Neuromedins/Bombesin-related peptides (including Neuromedin B (NMB), Neuromedin N, Neuromedin S and Neuromedin U (NmU)); Angiotensin, Bombesin, Calcitonin gene-related peptide (CGRP), α-CGRP, β-CGRP, Carnosine, Cocaine and amphetamine regulated transcript (CART), Delta sleep-inducing peptide (DSIP), FMRFamide, FMRFamide-related peptides (FaRPs), Galanin, Galanin-like peptide (GALP), Gastrin releasing peptide (GRP), Neuropeptide S, Neuropeptide Y, Neurophysins (Neurophysin I and Neurophysin II), Neurotensin, Pancreatic polypeptide, Pituitary adenylate cyclase activating peptide (PACAP), RVD-Hpα, hemopressin, VGF (VGF nerve growth factor inducible), VGF-derived peptides (TLQP-21), Calcitonin, Amylin (or Islet Amyloid Polypeptide (IAPP)), AGG01, Adrenomedullin (AM), Angiopoietin (Ang), Autocrine motility factor, Bone morphogenetic proteins (BMPs) (BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP15), Brain-derived neurotrophic factor (BDNF), Epidermal growth factor (EGF), Erythropoietin (EPO), Fibroblast growth factor (FGF), Glial cell line-derived neurotrophic factor (GDNF), Granulocyte colony-stimulating factor (G-CSF), Granulocyte macrophage colony-stimulating factor (GM-CSF), Growth differentiation factor-9 (GDF9), Hepatocyte growth factor (HGF), Hepatoma-derived growth factor (HDGF), Insulin-like growth factors (IGF), IGF-1, IGF-2, Migration-stimulating factor, Myostatin (GDF-8), neurotrophins, Neurotrophin-3 (NT-3), Neurotrophin-4 (NT-4), Nerve growth factor (NGF), Platelet-derived growth factor (PDGF), Thrombopoietin (TPO), Transforming growth factor alpha (TGF-α), Transforming growth factor beta (TGF-β), Tumor necrosis factor-alpha (TNF-α), Vascular endothelial growth factor (VEGF), Wnt proteins, Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt9A, Wnt9B, Wnt10A, Wnt10B, Wnt11, Wnt16, placental growth factor (PGF), Foetal Bovine Somatotrophin (FBS), insulin and insulin-like growth factors, IGF-1, IGF-2, IGF-binding proteins, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGFBP7, Relaxin family peptide hormones, relaxin-like (RLN) peptides, insulin-like (INSL) peptides, RLN1 (relaxin 1), RLN2 (relaxin 2), RLN3 (relaxin 3), INSL3 (insulin-like peptide 3, Leydig cell-specific insulin-like peptide), INSL4 (insulin-like peptide 4, early placenta insulin-like peptide, ELIP), INSL5 (insulin-like peptide 5), INSL6 (insulin-like peptide 6), Gastrin, gastrin-34, gastrin-17, gastrin-14, pentagastrin, thyroid hormone (T4), Thyrotropin-releasing hormone (TRH), vasopressin, protein hormones, glycoprotein hormones, growth hormone (GH), insulin, LH, FSH, Thyroid-stimulating hormone (thyrotropin, TSH), Angiotensin (AGT), Angiotensin I, Angiotensin II, Angiotensin III, Angiotensin IV, Atrial natriuretic peptide (ANP), NT-proBNP, B-type Natriuretic Peptide (BNP), Atrial natriuretic peptide (ANP), and annexin A-II (annexin II), or variants thereof. 
     
     
         37 . The peptide analogue according to  claim 35 , with the proviso that the peptide is not glucagon-like peptide-1 (GLP-1), GLP-1 (7-37), GLP-1 (7-33), exendin-4, or annexin A1; and/or with the proviso that the peptide is not α-MSH, or γ-MSH. 
     
     
         38 . The peptide analogue according to  claim 35 , wherein said amino-alkyl amino acid residue is an amino acid with a side chain comprising an amino-alkyl group (—C n H 2n NH 2 ). 
     
     
         39 . The peptide analogue according to  claim 35 , wherein said amino-alkyl amino acid residue comprises a side chain amino-alkyl group selected from the group consisting of methylamine (—CH 2 NH 2 ), ethylamine (—C 2 H 4 NH 2 ), propylamine (—C 3 H 6 NH 2 ), n-butylamine (—C 4 H 8 NH 2 ), pentylamine (—C 5 H 10 NH 2 ), n-hexylamine (—C 6 H 12 NH 2 ), heptylamine (—C 7 H 14 NH 2 ), octylamine (—C 8 H 16 NH 2 ), nonylamine (—C 9 H 18 NH 2 ), decylamine (—C 10 H 20 NH 2 ), undecylamine (—C 11 H 22 NH 2 ) and dodecylamine (—C 12 H 24 NH 2 ). 
     
     
         40 . The peptide analogue according to  claim 35 , wherein the side chain amino group of said amino-alkyl amino acid residue is selected from the group consisting of the β-amino group (methylamine); the γ-amino group (ethylamine); the δ-amino group (propylamine), the ε-amino group (n-butylamine); the ζ-amino group (pentylamine); the η-amino group (n-hexylamine); the θ-amino group (heptylamine); the ι-amino group (octylamine); the κ-amino group (nonylamine); the λ-amino group (decylamine); the μ-amino group (undecylamine); and the ν-amino group (dodecylamine). 
     
     
         41 . The peptide analogue according to  claim 35 , wherein the branched amino acid probe comprises a first amino-alkyl amino acid residue, said first amino-alkyl amino acid residue being optionally acetylated,
 wherein the side chain amino group of said first amino-alkyl amino acid residue is modified by attaching a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) p -AAA q ; AAA q -(aa 3 ) p ; [(aa 3 )-AAA] p  and [AAA-(aa 3 )] p ; wherein q is a number selected from 0, 1, 2 and 3; p is a number selected from 1, 2 and 3; AAA is an amino-alkyl amino acid residue (optionally acetylated); and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala.   
     
     
         42 . The peptide analogue according to  claim 35 , wherein the branched amino acid probe comprises a first amino-alkyl amino acid residue covalently linked to a second amino-alkyl amino acid residue, to form a linear chain of 2 amino-alkyl amino acid residues,
 said first and/or second amino-alkyl amino acid residues optionally acetylated,   wherein the side chain amino group of said first and/or said second amino-alkyl amino acid residue is modified by attaching a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) p -AAA q ; AAA q -(aa 3 ) p ; [(aa 3 )-AAA] p  and [AAA-(aa 3 )] p ; wherein q is a number selected from 0, 1, 2 and 3; p is a number selected from 1, 2 and 3; AAA is an amino-alkyl amino acid residue (optionally acetylated); and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala.   
     
     
         43 . The peptide analogue according to  claim 35 , wherein said amino-alkyl amino acid residues are individually selected from the group consisting of L-lysine, D-lysine, L-ornithine and D-ornithine. 
     
     
         44 . The peptide analogue according to  claim 35 , wherein each of the first, second and/or third amino-alkyl amino acids of the branched amino acid probe are individually selected from the group consisting of L-lysine, D-lysine, L-ornithine and D-ornithine. 
     
     
         45 . The peptide analogue according to  claim 35 , wherein each AAA of the molecules AAA q -AAA; (aa 3 ) p -AAA q ; AAA q -(aa 3 ) p ; [(aa 3 )-AAA] p  and [AAA-(aa 3 )] p  are individually selected from the group consisting of L-lysine, D-lysine, L-ornithine and D-ornithine. 
     
     
         46 . The peptide analogue according to  claim 35 , wherein said side chain amino group is individually selected from the δ-amino group (ornithine) and the ε-amino group (lysine). 
     
     
         47 . The peptide analogue according to  claim 35 , wherein the molecule to be attached to said side chain amino group(s) is independently selected from the group consisting of Lys q -Lys; (aa 3 ) p -Lys q ; Lys q -(aa 3 ) p ; [(aa 3 )-Lys] p ; [Lys-(aa 3 )] p ; Orn q -Orn; (aa 3 ) p -Orn q ; Orn q -(aa 3 ) p ; [(aa 3 )-Orn] p  and [Orn-(aa 3 )] p ; Orn p -Lys p ; Lys p -Orn p ; [Orn-Lys] p  and [Lys-Orn] p , wherein q is a number selected from 0, 1, 2 and 3; p is a number selected from 1, 2 and 3; (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala; and each of said Lys, Orn and (aa) 3  amino acid residues are optionally acetylated. 
     
     
         48 . The peptide analogue according to  claim 35 , wherein the branched amino acid probe consist of 2 to 3 amino acid residues, such as 3 to 4 amino acid residues, for example 4 to 5 amino acid residues, such as 5 to 6 amino acid residues, for example 6 to 7 amino acid residues, such as 7 to 8 amino acid residues, for example 8 to 9 amino acid residues. 
     
     
         49 . The peptide analogue according to  claim 35 , wherein the molecule to be attached to the side chain amino group(s) of one or more of the first, second and/or third amino-alkyl amino acid residues is selected from the group consisting of Lys, Ac-Lys, Lys-Lys, Ac-Lys-Lys, Lys-Lys-Lys, Ac-Lys-Lys-Lys, Lys-Lys-Lys-Lys, Ac-Lys-Lys-Lys-Lys, Lys-Gly-Lys, Ac-Lys-Gly-Lys, Lys-Lys-Gly, Ac-Lys-Lys-Gly, Lys-Gly, Ac-Lys-Gly, Lys-Ala-Lys, Ac-Lys-Ala-Lys, Lys-Lys-Ala, Ac-Lys-Lys-Ala, Lys-Ala, Ac-Lys-Ala, Lys-His-Lys, Ac-Lys-His-Lys, Lys-Lys-His, Ac-Lys-Lys-His, Lys-His, Ac-Lys-His, Lys-Arg-Lys, Ac-Lys-Arg-Lys, Lys-Lys-Arg, Ac-Lys-Lys-Arg, Lys-Arg and Ac-Lys-Arg. 
     
     
         50 . The peptide analogue according to  claim 35 , wherein the branched amino acid probe comprises a first amino-alkyl amino acid residue covalently linked to a second and a third amino-alkyl amino acid residue to form a linear chain of 3 amino-alkyl amino acid residues,
 said first, second and/or third amino-alkyl amino acid residues optionally acetylated,   wherein the side chain amino group of said first, second and/or third amino-alkyl amino acid residues is modified by attaching a molecule independently selected from the group consisting of AAA q -AAA; (aa 3 ) p -AAA q ; AAA q -(aa 3 ) p ; [(aa 3 )-AAA] p  and [AAA-(aa 3 )] p ; wherein q is a number selected from 0, 1, 2 and 3; p is a number selected from 1, 2 and 3; AAA is an amino-alkyl amino acid residue (optionally acetylated); and (aa 3 ) is an amino acid residue independently selected from Arg, His, Gly and Ala.   
     
     
         51 . The peptide analogue according to  claim 35 , wherein the side chain of i) one of said first, second and/or third amino-alkyl amino acid residues, ii) two of said first, second and/or third amino-alkyl amino acid residues, or iii) three of said first, second and third amino-alkyl amino acid residues, are modified by attaching a molecule to the side chain amino group. 
     
     
         52 . The peptide analogue according to  claim 35 , wherein said amino-alkyl amino acid residues are individually selected from the group consisting of L-lysine and L-ornithine. 
     
     
         53 . The peptide analogue according to  claim 35 , wherein the molecule to be attached to said side chain amino group(s) is independently selected from the group consisting of Lys q -Lys; Orn q -Orn; Orn p -Lys p ; Lys p -Orn p ; [Orn-Lys] p  and [Lys-Orn] p , wherein q is a number selected from 0, 1, 2 and 3; p is a number selected from 1, 2 and 3; and each of said Lys and Orn amino acid residues are optionally acetylated. 
     
     
         54 . A method of treating a patient suffering from a disease or condition, said method comprising administering to said patient the peptide analogue according to  claim 35 , said disease or condition selected from the group comprising stroke, injury, septic shock, systemic hypotension, cardiac arrest due to heart attack, cardiac arrhythmia, atheromatous disease with thrombosis, embolism from the heart or from blood vessel from any organ, vasospasm, aortic aneurysm or aneurisms in other organs, coronary stenosis, myocardial infarction, angina pectoris, pericarditis, myocarditis, myxodemia, or endocarditis, ischemic and/or inflammatory condition, be associated with surgery, such as major surgery, cardiothoracic surgery, abdominal surgery, surgery on the aorta and/or other major blood vessels, repair of one or more cardiac valves, cardiac artery bypass grafting (CABG), surgery on the aortic root or the aortic branch including the common carotic arteries, and combined cardiac surgery such as valve(s) replacement and CABG and/or aortic root surgery, ischemic and/or inflammatory condition may in one embodiment be associated with organ transplantation, such as solid organ transplantation, including heart transplantation, lung transplantation, combined heart and lung transplantation, liver transplantation and kidney transplantation, post-surgical systemic inflammatory response syndrome (SIRS) or post-surgical organ dysfunction, including post-surgical renal failure such as acute kidney injury (AKI), neprotoxicity and/or chronic renal failure (CRF), reperfusion injury, arthropathy (joint disease), rheumatoid arthritis (RA), gout, inflammatory diseases of the gastrointestinal system, and multiple sclerosis, diabetes mellitus, prediabetic conditions including glucose intolerance, obesity, overweight, metabolic syndrome, gestational diabetes mellitus, or metabolic disease associated with polycystic ovarian syndrome, wherein said treatment may be prophylactic, ameliorative or curative.