NZ615710B2 - Antagonists of the interleukin- 1 receptor - Google Patents
Antagonists of the interleukin- 1 receptor Download PDFInfo
- Publication number
- NZ615710B2 NZ615710B2 NZ615710A NZ61571012A NZ615710B2 NZ 615710 B2 NZ615710 B2 NZ 615710B2 NZ 615710 A NZ615710 A NZ 615710A NZ 61571012 A NZ61571012 A NZ 61571012A NZ 615710 B2 NZ615710 B2 NZ 615710B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- seq
- peptide
- disease
- amino acid
- present
- Prior art date
Links
- 102000019223 Interleukin-1 receptor family Human genes 0.000 title claims abstract description 26
- 108050006617 Interleukin-1 receptor family Proteins 0.000 title claims abstract description 26
- 230000003042 antagnostic Effects 0.000 title description 3
- 239000005557 antagonist Substances 0.000 title description 3
- 150000001413 amino acids Chemical class 0.000 claims abstract description 122
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 55
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 55
- 102000003777 Interleukin-1 beta Human genes 0.000 claims abstract description 53
- 108090000193 Interleukin-1 beta Proteins 0.000 claims abstract description 53
- 230000027455 binding Effects 0.000 claims abstract description 31
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 27
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 23
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 68
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 66
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 66
- 210000004027 cells Anatomy 0.000 claims description 46
- 201000010099 disease Diseases 0.000 claims description 40
- 102000000589 Interleukin-1 Human genes 0.000 claims description 39
- 108010002352 Interleukin-1 Proteins 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 37
- 206010012601 Diabetes mellitus Diseases 0.000 claims description 26
- 206010061218 Inflammation Diseases 0.000 claims description 26
- 230000004054 inflammatory process Effects 0.000 claims description 26
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 25
- 210000002569 neurons Anatomy 0.000 claims description 25
- 206010001897 Alzheimer's disease Diseases 0.000 claims description 22
- 238000006467 substitution reaction Methods 0.000 claims description 22
- 200000000018 inflammatory disease Diseases 0.000 claims description 19
- 201000006417 multiple sclerosis Diseases 0.000 claims description 19
- 239000000412 dendrimer Substances 0.000 claims description 18
- 229920000736 dendritic polymer Polymers 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 206010053643 Neurodegenerative disease Diseases 0.000 claims description 17
- 206010003246 Arthritis Diseases 0.000 claims description 16
- 201000001971 Huntington's disease Diseases 0.000 claims description 16
- 230000001684 chronic Effects 0.000 claims description 15
- 201000005569 gout Diseases 0.000 claims description 15
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 13
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 13
- 206010061536 Parkinson's disease Diseases 0.000 claims description 13
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims description 13
- 230000014511 neuron projection development Effects 0.000 claims description 13
- 230000004913 activation Effects 0.000 claims description 12
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 11
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 10
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 claims description 10
- 230000001154 acute Effects 0.000 claims description 9
- 239000000969 carrier Substances 0.000 claims description 9
- 230000004083 survival Effects 0.000 claims description 9
- 206010003816 Autoimmune disease Diseases 0.000 claims description 7
- 206010052779 Transplant rejections Diseases 0.000 claims description 6
- 230000001404 mediated Effects 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 230000004044 response Effects 0.000 claims description 6
- 208000006673 Asthma Diseases 0.000 claims description 5
- 108090001123 antibodies Proteins 0.000 claims description 5
- 102000004965 antibodies Human genes 0.000 claims description 5
- 230000001363 autoimmune Effects 0.000 claims description 5
- 239000000539 dimer Substances 0.000 claims description 5
- 125000005647 linker group Chemical group 0.000 claims description 5
- 230000002314 neuroinflammatory Effects 0.000 claims description 5
- 201000004681 psoriasis Diseases 0.000 claims description 5
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 5
- 108010047814 Antigen-Antibody Complex Proteins 0.000 claims description 4
- 206010009839 Coeliac disease Diseases 0.000 claims description 4
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 claims description 4
- 229940049954 Penicillin Drugs 0.000 claims description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 4
- 206010046736 Urticarias Diseases 0.000 claims description 4
- 229960000626 benzylpenicillin Drugs 0.000 claims description 4
- 201000004624 dermatitis Diseases 0.000 claims description 4
- 230000000626 neurodegenerative Effects 0.000 claims description 4
- 201000008827 tuberculosis Diseases 0.000 claims description 4
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 3
- 208000003455 Anaphylaxis Diseases 0.000 claims description 3
- 208000009094 Anemia, Hemolytic, Autoimmune Diseases 0.000 claims description 3
- 208000008637 Anti-Glomerular Basement Membrane Disease Diseases 0.000 claims description 3
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 208000005783 Autoimmune Thyroiditis Diseases 0.000 claims description 3
- 208000009137 Behcet Syndrome Diseases 0.000 claims description 3
- 201000008335 Behcet's disease Diseases 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 206010011401 Crohn's disease Diseases 0.000 claims description 3
- 206010018620 Goodpasture's syndrome Diseases 0.000 claims description 3
- 208000003807 Graves Disease Diseases 0.000 claims description 3
- 201000004779 Graves' disease Diseases 0.000 claims description 3
- 208000006454 Hepatitis Diseases 0.000 claims description 3
- 206010028640 Myopathy Diseases 0.000 claims description 3
- 241000721454 Pemphigus Species 0.000 claims description 3
- 208000005987 Polymyositis Diseases 0.000 claims description 3
- 208000002098 Purpura, Thrombocytopenic, Idiopathic Diseases 0.000 claims description 3
- 206010043207 Temporal arteritis Diseases 0.000 claims description 3
- 206010047115 Vasculitis Diseases 0.000 claims description 3
- 230000036783 anaphylactic response Effects 0.000 claims description 3
- 201000001320 atherosclerosis Diseases 0.000 claims description 3
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 3
- 230000002949 hemolytic Effects 0.000 claims description 3
- 201000010770 muscular disease Diseases 0.000 claims description 3
- 201000000306 sarcoidosis Diseases 0.000 claims description 3
- 201000006704 ulcerative colitis Diseases 0.000 claims description 3
- 206010000496 Acne Diseases 0.000 claims description 2
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 2
- 208000002205 Allergic Conjunctivitis Diseases 0.000 claims description 2
- 206010001890 Alveolitis allergic Diseases 0.000 claims description 2
- 206010002425 Angioedemas Diseases 0.000 claims description 2
- 208000000104 Arthus Reaction Diseases 0.000 claims description 2
- 206010003645 Atopy Diseases 0.000 claims description 2
- 208000009361 Bacterial Endocarditis Diseases 0.000 claims description 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 2
- 208000010247 Contact Dermatitis Diseases 0.000 claims description 2
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
- 206010012442 Dermatitis contact Diseases 0.000 claims description 2
- 208000005679 Eczema Diseases 0.000 claims description 2
- 206010014666 Endocarditis bacterial Diseases 0.000 claims description 2
- 206010014950 Eosinophilia Diseases 0.000 claims description 2
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 claims description 2
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims description 2
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 2
- 206010024229 Leprosy Diseases 0.000 claims description 2
- 102000003945 NF-kappa B Human genes 0.000 claims description 2
- 108010057466 NF-kappa B Proteins 0.000 claims description 2
- 206010034695 Pernicious anaemia Diseases 0.000 claims description 2
- 206010063837 Reperfusion injury Diseases 0.000 claims description 2
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 2
- 208000003385 Rhinitis, Allergic, Seasonal Diseases 0.000 claims description 2
- 206010040400 Serum sickness Diseases 0.000 claims description 2
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 2
- 208000003441 Transfusion Reaction Diseases 0.000 claims description 2
- 206010053614 Type III immune complex mediated reaction Diseases 0.000 claims description 2
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 claims description 2
- 201000009961 allergic asthma Diseases 0.000 claims description 2
- 201000010105 allergic rhinitis Diseases 0.000 claims description 2
- 230000002052 anaphylactic Effects 0.000 claims description 2
- 201000008937 atopic dermatitis Diseases 0.000 claims description 2
- 150000001780 cephalosporins Chemical class 0.000 claims description 2
- 230000001419 dependent Effects 0.000 claims description 2
- 231100000406 dermatitis Toxicity 0.000 claims description 2
- 231100000080 dermatitis contact Toxicity 0.000 claims description 2
- 201000001981 dermatomyositis Diseases 0.000 claims description 2
- 231100001003 eczema Toxicity 0.000 claims description 2
- 201000005703 farmer's lung Diseases 0.000 claims description 2
- 231100000283 hepatitis Toxicity 0.000 claims description 2
- 201000008319 inclusion body myositis Diseases 0.000 claims description 2
- 230000001524 infective Effects 0.000 claims description 2
- 230000000302 ischemic Effects 0.000 claims description 2
- 230000000527 lymphocytic Effects 0.000 claims description 2
- 201000004792 malaria Diseases 0.000 claims description 2
- 201000006518 pelvic inflammatory disease Diseases 0.000 claims description 2
- 201000006292 polyarteritis nodosa Diseases 0.000 claims description 2
- 201000007094 prostatitis Diseases 0.000 claims description 2
- 201000003068 rheumatic fever Diseases 0.000 claims description 2
- 201000009594 systemic scleroderma Diseases 0.000 claims description 2
- 201000003067 thrombocytopenia due to platelet alloimmunization Diseases 0.000 claims description 2
- 230000005951 type IV hypersensitivity Effects 0.000 claims description 2
- 230000004071 biological effect Effects 0.000 claims 1
- 230000000052 comparative effect Effects 0.000 claims 1
- 235000001014 amino acid Nutrition 0.000 description 121
- 235000018102 proteins Nutrition 0.000 description 53
- 230000000694 effects Effects 0.000 description 47
- 239000003795 chemical substances by application Substances 0.000 description 38
- 239000000203 mixture Substances 0.000 description 34
- 102000004125 Interleukin-1alpha Human genes 0.000 description 26
- 108010082786 Interleukin-1alpha Proteins 0.000 description 26
- 230000035492 administration Effects 0.000 description 23
- 239000008194 pharmaceutical composition Substances 0.000 description 22
- 102100005027 IL1RN Human genes 0.000 description 21
- -1 His Chemical compound 0.000 description 18
- 230000000975 bioactive Effects 0.000 description 18
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 18
- 229920001184 polypeptide Polymers 0.000 description 17
- 230000002401 inhibitory effect Effects 0.000 description 16
- 229940079593 drugs Drugs 0.000 description 15
- 210000003169 Central Nervous System Anatomy 0.000 description 14
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 14
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 description 14
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 13
- MTCFGRXMJLQNBG-REOHCLBHSA-N L-serine Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 13
- 210000002540 Macrophages Anatomy 0.000 description 13
- 230000001225 therapeutic Effects 0.000 description 13
- 210000004369 Blood Anatomy 0.000 description 12
- 206010010904 Convulsion Diseases 0.000 description 12
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 12
- 239000008280 blood Substances 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- 210000001519 tissues Anatomy 0.000 description 12
- 210000001218 Blood-Brain Barrier Anatomy 0.000 description 11
- 210000004556 Brain Anatomy 0.000 description 11
- 108010023402 Interleukin 1 Receptor Antagonist Protein Proteins 0.000 description 11
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 11
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- 241000700159 Rattus Species 0.000 description 11
- 206010039911 Seizure Diseases 0.000 description 11
- 230000001965 increased Effects 0.000 description 11
- 239000003407 interleukin 1 receptor blocking agent Substances 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 210000002683 Foot Anatomy 0.000 description 10
- 102100018955 IL1A Human genes 0.000 description 10
- 101700006191 IL1A Proteins 0.000 description 10
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 230000002522 swelling Effects 0.000 description 10
- 206010015150 Erythema Diseases 0.000 description 9
- 101710007852 IL1RN Proteins 0.000 description 9
- 102000004877 Insulin Human genes 0.000 description 9
- 108090001061 Insulin Proteins 0.000 description 9
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N Kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 9
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 9
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 9
- 229950006874 kainic acid Drugs 0.000 description 9
- 239000002609 media Substances 0.000 description 9
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 8
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 8
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 8
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 7
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 7
- 239000000178 monomer Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- HMLGSIZOMSVISS-ONJSNURVSA-N (7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 6
- 102100004839 IL1R1 Human genes 0.000 description 6
- 101700060164 IL1R1 Proteins 0.000 description 6
- 102000015696 Interleukins Human genes 0.000 description 6
- 108010063738 Interleukins Proteins 0.000 description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 6
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 6
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 description 6
- 229960004238 anakinra Drugs 0.000 description 6
- 230000003110 anti-inflammatory Effects 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 108010018704 ilantide Proteins 0.000 description 6
- 230000001976 improved Effects 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reduced Effects 0.000 description 6
- 230000011664 signaling Effects 0.000 description 6
- 230000002194 synthesizing Effects 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 102000008186 Collagen Human genes 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 5
- 229960001031 Glucose Drugs 0.000 description 5
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 5
- 210000000265 Leukocytes Anatomy 0.000 description 5
- DAZSWUUAFHBCGE-KRWDZBQOSA-N N-[(2S)-3-methyl-1-oxo-1-pyrrolidin-1-ylbutan-2-yl]-3-phenylpropanamide Chemical compound N([C@@H](C(C)C)C(=O)N1CCCC1)C(=O)CCC1=CC=CC=C1 DAZSWUUAFHBCGE-KRWDZBQOSA-N 0.000 description 5
- 102000007079 Peptide Fragments Human genes 0.000 description 5
- 108010033276 Peptide Fragments Proteins 0.000 description 5
- 210000002381 Plasma Anatomy 0.000 description 5
- 102000001708 Protein Isoforms Human genes 0.000 description 5
- 108010029485 Protein Isoforms Proteins 0.000 description 5
- 238000000692 Student's t-test Methods 0.000 description 5
- 230000002378 acidificating Effects 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 230000001413 cellular Effects 0.000 description 5
- 230000002490 cerebral Effects 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 229960005188 collagen Drugs 0.000 description 5
- 230000002209 hydrophobic Effects 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 5
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 206010012289 Dementia Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 210000000987 Immune System Anatomy 0.000 description 4
- 206010021425 Immune system disease Diseases 0.000 description 4
- 229940047122 Interleukins Drugs 0.000 description 4
- 210000001503 Joints Anatomy 0.000 description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 210000004400 Mucous Membrane Anatomy 0.000 description 4
- 210000003491 Skin Anatomy 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 125000000511 arginine group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 230000002354 daily Effects 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 201000009910 diseases by infectious agent Diseases 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 230000002068 genetic Effects 0.000 description 4
- 230000028709 inflammatory response Effects 0.000 description 4
- 230000002025 microglial Effects 0.000 description 4
- 230000004770 neurodegeneration Effects 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 230000000770 pro-inflamatory Effects 0.000 description 4
- 239000003380 propellant Substances 0.000 description 4
- 230000002685 pulmonary Effects 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 201000010874 syndrome Diseases 0.000 description 4
- 230000000699 topical Effects 0.000 description 4
- 101710027066 ALB Proteins 0.000 description 3
- 210000003423 Ankle Anatomy 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- 210000001130 Astrocytes Anatomy 0.000 description 3
- 210000003050 Axons Anatomy 0.000 description 3
- 210000001175 Cerebrospinal Fluid Anatomy 0.000 description 3
- 210000002889 Endothelial Cells Anatomy 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- 125000000773 L-serino group Chemical group [H]OC(=O)[C@@]([H])(N([H])*)C([H])([H])O[H] 0.000 description 3
- 210000004072 Lung Anatomy 0.000 description 3
- 210000000274 Microglia Anatomy 0.000 description 3
- 125000000534 N(2)-L-lysino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C([H])([H])C(C([H])([H])N([H])[H])([H])[H] 0.000 description 3
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 3
- 102100015381 PTGS2 Human genes 0.000 description 3
- 241000700157 Rattus norvegicus Species 0.000 description 3
- 210000000278 Spinal Cord Anatomy 0.000 description 3
- 210000001744 T-Lymphocytes Anatomy 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 230000002730 additional Effects 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000000240 adjuvant Effects 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 201000009596 autoimmune hypersensitivity disease Diseases 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000003008 brain-resident macrophage Anatomy 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 230000001086 cytosolic Effects 0.000 description 3
- 230000003247 decreasing Effects 0.000 description 3
- 230000004059 degradation Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000002708 enhancing Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000002757 inflammatory Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 230000001537 neural Effects 0.000 description 3
- 230000003959 neuroinflammation Effects 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 3
- 230000003287 optical Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000001575 pathological Effects 0.000 description 3
- 238000007747 plating Methods 0.000 description 3
- 230000034190 positive regulation of NF-kappaB transcription factor activity Effects 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 230000000750 progressive Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000007492 two-way ANOVA Methods 0.000 description 3
- 102100001249 ALB Human genes 0.000 description 2
- 208000002552 Acute Disseminated Encephalomyelitis Diseases 0.000 description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 2
- 208000007502 Anemia Diseases 0.000 description 2
- 206010002556 Ankylosing spondylitis Diseases 0.000 description 2
- 206010059512 Apoptosis Diseases 0.000 description 2
- 229960001230 Asparagine Drugs 0.000 description 2
- 210000004204 Blood Vessels Anatomy 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
- 102100006374 CASP1 Human genes 0.000 description 2
- 108090000426 Caspase 1 Proteins 0.000 description 2
- 210000000349 Chromosomes Anatomy 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N Colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- 102000020504 Collagenase family Human genes 0.000 description 2
- 108060005980 Collagenase family Proteins 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 206010072224 Deficiency of the interleukin-1 receptor antagonist Diseases 0.000 description 2
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 2
- 210000003714 Granulocytes Anatomy 0.000 description 2
- 210000001255 Hallux Anatomy 0.000 description 2
- 102100014231 IGF1 Human genes 0.000 description 2
- 101700074337 IGF1 Proteins 0.000 description 2
- 102100004838 IL1R2 Human genes 0.000 description 2
- 101700043314 IL1R2 Proteins 0.000 description 2
- 229960000310 ISOLEUCINE Drugs 0.000 description 2
- 208000007924 IgA Deficiency Diseases 0.000 description 2
- 206010022114 Injury Diseases 0.000 description 2
- 206010022489 Insulin resistance Diseases 0.000 description 2
- 102000003814 Interleukin-10 Human genes 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 125000003338 L-glutaminyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 125000003290 L-leucino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- 210000001821 Langerhans Cells Anatomy 0.000 description 2
- 210000004698 Lymphocytes Anatomy 0.000 description 2
- 210000001259 Mesencephalon Anatomy 0.000 description 2
- 230000036740 Metabolism Effects 0.000 description 2
- 210000001616 Monocytes Anatomy 0.000 description 2
- 210000003205 Muscles Anatomy 0.000 description 2
- 208000009025 Nervous System Disease Diseases 0.000 description 2
- 210000002682 Neurofibrillary Tangles Anatomy 0.000 description 2
- 210000000440 Neutrophils Anatomy 0.000 description 2
- 208000005225 Opsoclonus-Myoclonus Syndrome Diseases 0.000 description 2
- 108091005771 Peptidases Proteins 0.000 description 2
- 102000035443 Peptidases Human genes 0.000 description 2
- 229960005190 Phenylalanine Drugs 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 206010037162 Psoriatic arthropathy Diseases 0.000 description 2
- 206010039915 Selective IgA immunodeficiency Diseases 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M Sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229960005322 Streptomycin Drugs 0.000 description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 210000003371 Toes Anatomy 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Trioxopurine Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- 229940116269 Uric Acid Drugs 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive Effects 0.000 description 2
- 229940050528 albumin Drugs 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 239000003435 antirheumatic agent Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 230000002238 attenuated Effects 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 230000000903 blocking Effects 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229960002424 collagenase Drugs 0.000 description 2
- 239000003636 conditioned culture media Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000000254 damaging Effects 0.000 description 2
- 230000003412 degenerative Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000002988 disease modifying antirheumatic drug Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000002919 epithelial cells Anatomy 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000009650 gentamicin protection assay Methods 0.000 description 2
- 230000003394 haemopoietic Effects 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000004295 hippocampal neuron Anatomy 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 201000007156 immunoglobulin alpha deficiency Diseases 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 230000002452 interceptive Effects 0.000 description 2
- 102000014909 interleukin-1 receptor activity proteins Human genes 0.000 description 2
- 108040006732 interleukin-1 receptor activity proteins Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 230000000366 juvenile Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 150000002605 large molecules Chemical class 0.000 description 2
- 230000003902 lesions Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 102000006240 membrane receptors Human genes 0.000 description 2
- 230000003923 mental ability Effects 0.000 description 2
- 230000002503 metabolic Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000035786 metabolism Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 230000000926 neurological Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- 230000001717 pathogenic Effects 0.000 description 2
- 244000052769 pathogens Species 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 230000036231 pharmacokinetics Effects 0.000 description 2
- INAAIJLSXJJHOZ-UHFFFAOYSA-N pibenzimol Chemical compound C1CN(C)CCN1C1=CC=C(N=C(N2)C=3C=C4NC(=NC4=CC=3)C=3C=CC(O)=CC=3)C2=C1 INAAIJLSXJJHOZ-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 230000002335 preservative Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 230000001681 protective Effects 0.000 description 2
- 201000001263 psoriatic arthritis Diseases 0.000 description 2
- 230000000384 rearing Effects 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000004936 stimulating Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002459 sustained Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- PWJWZDWOBMKJJV-BYPYZUCNSA-N (2R)-2-[ethyl(hydroxy)amino]-3-sulfanylpropanoic acid Chemical compound CCN(O)[C@@H](CS)C(O)=O PWJWZDWOBMKJJV-BYPYZUCNSA-N 0.000 description 1
- WNICGTIQUHHISW-SSDOTTSWSA-N (2S)-2,6-diamino-2-(difluoromethyl)hexanoic acid Chemical group NCCCC[C@@](N)(C(F)F)C(O)=O WNICGTIQUHHISW-SSDOTTSWSA-N 0.000 description 1
- UJXJZOCXEZPHIE-YFKPBYRVSA-N (2S)-2-(2-hydroxyethylamino)-4-sulfanylbutanoic acid Chemical compound OCCN[C@H](C(O)=O)CCS UJXJZOCXEZPHIE-YFKPBYRVSA-N 0.000 description 1
- SAAQPSNNIOGFSQ-LURJTMIESA-N (2S)-2-(pyridin-4-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=NC=C1 SAAQPSNNIOGFSQ-LURJTMIESA-N 0.000 description 1
- PDRJLZDUOULRHE-ZETCQYMHSA-N (2S)-2-amino-3-pyridin-2-ylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=N1 PDRJLZDUOULRHE-ZETCQYMHSA-N 0.000 description 1
- DFZVZEMNPGABKO-ZETCQYMHSA-N (2S)-2-amino-3-pyridin-3-ylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CN=C1 DFZVZEMNPGABKO-ZETCQYMHSA-N 0.000 description 1
- JQFLYFRHDIHZFZ-RXMQYKEDSA-N (2S)-3,3-dimethylpyrrolidine-2-carboxylic acid Chemical compound CC1(C)CCN[C@@H]1C(O)=O JQFLYFRHDIHZFZ-RXMQYKEDSA-N 0.000 description 1
- YZJSUQQZGCHHNQ-BYPYZUCNSA-N (2S)-6-amino-2-azaniumyl-6-oxohexanoate Chemical compound OC(=O)[C@@H](N)CCCC(N)=O YZJSUQQZGCHHNQ-BYPYZUCNSA-N 0.000 description 1
- CCAIIPMIAFGKSI-DMTCNVIQSA-N (2S,3R)-3-hydroxy-2-(methylazaniumyl)butanoate Chemical compound CN[C@@H]([C@@H](C)O)C(O)=O CCAIIPMIAFGKSI-DMTCNVIQSA-N 0.000 description 1
- OHMHBGPWCHTMQE-UHFFFAOYSA-N 2,2-Dichloro-1,1,1-trifluoroethane Chemical compound FC(F)(F)C(Cl)Cl OHMHBGPWCHTMQE-UHFFFAOYSA-N 0.000 description 1
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1H-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N 2-stearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-Tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- XEVFXAFXZZYFSX-UHFFFAOYSA-N 3-azabicyclo[2.1.1]hexane-4-carboxylic acid Chemical compound C1C2CC1(C(=O)O)NC2 XEVFXAFXZZYFSX-UHFFFAOYSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N 3-hydroxy-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- UHDGCWIWMRVCDJ-STUHELBRSA-N 4-amino-1-[(3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-STUHELBRSA-N 0.000 description 1
- XWHHYOYVRVGJJY-QMMMGPOBSA-N 4-fluorophenyl-L-alanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(F)C=C1 XWHHYOYVRVGJJY-QMMMGPOBSA-N 0.000 description 1
- 101710006356 ACTI Proteins 0.000 description 1
- 101710016959 ALPG Proteins 0.000 description 1
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 description 1
- 210000001015 Abdomen Anatomy 0.000 description 1
- 206010058994 Acute haemorrhagic leukoencephalitis Diseases 0.000 description 1
- 102000011767 Acute-Phase Proteins Human genes 0.000 description 1
- 108010062271 Acute-Phase Proteins Proteins 0.000 description 1
- 201000004304 Addison's disease Diseases 0.000 description 1
- 208000008190 Agammaglobulinemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- SITWEMZOJNKJCH-UHFFFAOYSA-N Alanyl-Arginine Chemical group CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N Allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 206010001767 Alopecia universalis Diseases 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 206010002026 Amyotrophic lateral sclerosis Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010063023 Analgesic asthma syndrome Diseases 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 208000008822 Ankylosis Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 206010002967 Aplastic anaemia Diseases 0.000 description 1
- 229940009098 Aspartate Drugs 0.000 description 1
- 229960005261 Aspartic Acid Drugs 0.000 description 1
- 206010003594 Ataxia telangiectasia Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000006424 Autoimmune oophoritis Diseases 0.000 description 1
- 206010003830 Automatism Diseases 0.000 description 1
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 description 1
- 210000003719 B-Lymphocytes Anatomy 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004161 Basedow's disease Diseases 0.000 description 1
- 210000002469 Basement Membrane Anatomy 0.000 description 1
- 210000003651 Basophils Anatomy 0.000 description 1
- 206010004661 Biliary cirrhosis primary Diseases 0.000 description 1
- 230000037177 Biodistribution Effects 0.000 description 1
- 229940088623 Biologically Active Substance Drugs 0.000 description 1
- 210000001772 Blood Platelets Anatomy 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- 208000001183 Brain Injury Diseases 0.000 description 1
- 210000001217 Buttocks Anatomy 0.000 description 1
- 101700007238 CASP1 Proteins 0.000 description 1
- 102100003729 CD40LG Human genes 0.000 description 1
- 101710003804 CD40LG Proteins 0.000 description 1
- 101700072812 COX2 Proteins 0.000 description 1
- 101700046715 CSTI Proteins 0.000 description 1
- 102100014446 CYBB Human genes 0.000 description 1
- 102000007590 Calpain Human genes 0.000 description 1
- 108010032088 Calpain Proteins 0.000 description 1
- 210000001736 Capillaries Anatomy 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 210000001188 Cartilage, Articular Anatomy 0.000 description 1
- 210000000170 Cell Membrane Anatomy 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 206010051290 Central nervous system lesion Diseases 0.000 description 1
- 210000003710 Cerebral Cortex Anatomy 0.000 description 1
- 201000003884 Chagas disease Diseases 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 208000002691 Choroiditis Diseases 0.000 description 1
- 210000003483 Chromatin Anatomy 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 208000009863 Chronic Kidney Failure Diseases 0.000 description 1
- 206010008909 Chronic hepatitis Diseases 0.000 description 1
- 210000003703 Cisterna Magna Anatomy 0.000 description 1
- 206010009346 Clonus Diseases 0.000 description 1
- 206010057668 Cognitive disease Diseases 0.000 description 1
- 102000000503 Collagen Type II Human genes 0.000 description 1
- 108010041390 Collagen Type II Proteins 0.000 description 1
- 206010010099 Combined immunodeficiency Diseases 0.000 description 1
- 208000003611 Congenital Autoimmune Diabetes Mellitus Diseases 0.000 description 1
- NKLPQNGYXWVELD-UHFFFAOYSA-M Coomassie Brilliant Blue Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=C1 NKLPQNGYXWVELD-UHFFFAOYSA-M 0.000 description 1
- 206010010947 Coordination abnormal Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 206010068271 Cystic fibrosis related diabetes Diseases 0.000 description 1
- 210000000805 Cytoplasm Anatomy 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical group 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 101700020566 DEFA4 Proteins 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N DL-aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N DL-threonine Chemical compound CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 229960000640 Dactinomycin Drugs 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 208000000398 DiGeorge Syndrome Diseases 0.000 description 1
- 208000001380 Diabetic Ketoacidosis Diseases 0.000 description 1
- 229940052760 Dopamine agonists Drugs 0.000 description 1
- 208000001187 Dyskinesias Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010014551 Emotional disease Diseases 0.000 description 1
- 210000002472 Endoplasmic Reticulum Anatomy 0.000 description 1
- 210000003979 Eosinophils Anatomy 0.000 description 1
- 241001492222 Epicoccum Species 0.000 description 1
- 210000002615 Epidermis Anatomy 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- 210000003414 Extremities Anatomy 0.000 description 1
- 102000027757 FGF receptors Human genes 0.000 description 1
- 108091008101 FGF receptors Proteins 0.000 description 1
- 241000272184 Falconiformes Species 0.000 description 1
- 206010016207 Familial mediterranean fever Diseases 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N Fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
- 210000000245 Forearm Anatomy 0.000 description 1
- 210000003194 Forelimb Anatomy 0.000 description 1
- 108010055434 GAP-43 Protein Proteins 0.000 description 1
- 102100008940 GAP43 Human genes 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000004104 Gestational Diabetes Diseases 0.000 description 1
- 208000007465 Giant Cell Arteritis Diseases 0.000 description 1
- 229940065521 Glucocorticoid inhalants for obstructive airway disease Drugs 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- 229940049906 Glutamate Drugs 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- UHUSDOQQWJGJQS-UHFFFAOYSA-N Glycerol 1,2-dioctadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCC UHUSDOQQWJGJQS-UHFFFAOYSA-N 0.000 description 1
- 240000007842 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 210000001126 Granulation Tissue Anatomy 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 210000004326 Gyrus Cinguli Anatomy 0.000 description 1
- 208000005721 HIV Infections Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 210000003128 Head Anatomy 0.000 description 1
- 208000002557 Hidradenitis Diseases 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 102000016252 Huntingtin Human genes 0.000 description 1
- 108050004784 Huntingtin family Proteins 0.000 description 1
- 206010066130 Hyper IgM syndrome Diseases 0.000 description 1
- 208000003352 Hyper-IgM Immunodeficiency Syndrome Diseases 0.000 description 1
- 208000009451 Hyperglycemic Hyperosmolar Nonketotic Coma Diseases 0.000 description 1
- 206010020710 Hyperphagia Diseases 0.000 description 1
- 206010020718 Hyperplasia Diseases 0.000 description 1
- 206010020983 Hypogammaglobulinaemia Diseases 0.000 description 1
- 206010020993 Hypoglycaemia Diseases 0.000 description 1
- 101710006353 IP3R Proteins 0.000 description 1
- 101700035656 ISOTI Proteins 0.000 description 1
- 101700035039 ITI Proteins 0.000 description 1
- 101700052013 ITR2 Proteins 0.000 description 1
- 101700068039 ITRP Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 208000002370 Immune Complex Disease Diseases 0.000 description 1
- 206010021449 Immunodeficiency common variable Diseases 0.000 description 1
- 208000007746 Immunologic Deficiency Syndromes Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 102000004218 Insulin-like growth factor I Human genes 0.000 description 1
- 108090000723 Insulin-like growth factor I Proteins 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 210000004153 Islets of Langerhans Anatomy 0.000 description 1
- 206010023198 Joint ankylosis Diseases 0.000 description 1
- 206010023203 Joint destruction Diseases 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 201000007313 Kawasaki disease Diseases 0.000 description 1
- 210000002510 Keratinocytes Anatomy 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 210000000822 Killer Cells, Natural Anatomy 0.000 description 1
- 229940054136 Kineret Drugs 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid zwitterion Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical group 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical compound OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 description 1
- KKJQZEWNZXRJFG-UHFFFAOYSA-N L-trans-4-Methyl-2-pyrrolidinecarboxylic acid Chemical compound CC1CNC(C(O)=O)C1 KKJQZEWNZXRJFG-UHFFFAOYSA-N 0.000 description 1
- 101710015344 LNPEP Proteins 0.000 description 1
- 201000010743 Lambert-Eaton myasthenic syndrome Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 210000004558 Lewy Bodies Anatomy 0.000 description 1
- 210000004185 Liver Anatomy 0.000 description 1
- 208000000185 Localized Scleroderma Diseases 0.000 description 1
- 210000003141 Lower Extremity Anatomy 0.000 description 1
- 206010025135 Lupus erythematosus Diseases 0.000 description 1
- 206010025169 Lyme disease Diseases 0.000 description 1
- 210000001165 Lymph Nodes Anatomy 0.000 description 1
- 206010061232 Lymphoproliferative disease Diseases 0.000 description 1
- 102100002485 MAPT Human genes 0.000 description 1
- 101710028108 MAPT Proteins 0.000 description 1
- 102100018200 MMP1 Human genes 0.000 description 1
- 101700019781 MMP1 Proteins 0.000 description 1
- 101710034449 MT-CO2 Proteins 0.000 description 1
- 101700036939 MTI Proteins 0.000 description 1
- 229920002521 Macromolecule Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 210000000138 Mast Cells Anatomy 0.000 description 1
- 240000004119 Melissa officinalis Species 0.000 description 1
- 235000010654 Melissa officinalis Nutrition 0.000 description 1
- 210000004379 Membranes Anatomy 0.000 description 1
- 210000002418 Meninges Anatomy 0.000 description 1
- 210000003584 Mesangial Cells Anatomy 0.000 description 1
- 208000008466 Metabolic Disease Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 210000000878 Metatarsophalangeal Joint Anatomy 0.000 description 1
- 102000028664 Microtubules Human genes 0.000 description 1
- 210000004688 Microtubules Anatomy 0.000 description 1
- 108091022031 Microtubules Proteins 0.000 description 1
- 208000003250 Mixed Connective Tissue Disease Diseases 0.000 description 1
- 206010027951 Mood swings Diseases 0.000 description 1
- 206010027982 Morphoea Diseases 0.000 description 1
- 210000000214 Mouth Anatomy 0.000 description 1
- 208000002430 Multiple Chemical Sensitivity Diseases 0.000 description 1
- 206010028417 Myasthenia gravis Diseases 0.000 description 1
- 206010028424 Myasthenic syndrome Diseases 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 229940010383 Mycobacterium tuberculosis Drugs 0.000 description 1
- 210000003007 Myelin Sheath Anatomy 0.000 description 1
- 210000000066 Myeloid Cells Anatomy 0.000 description 1
- 208000003067 Myocardial Ischemia Diseases 0.000 description 1
- 108010082739 NADPH Oxidase 2 Proteins 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 108010008267 Nerve Growth Factors Proteins 0.000 description 1
- 102000001068 Neural Cell Adhesion Molecules Human genes 0.000 description 1
- 108010069196 Neural Cell Adhesion Molecules Proteins 0.000 description 1
- 206010029305 Neurological disorder Diseases 0.000 description 1
- 206010060860 Neurological symptom Diseases 0.000 description 1
- 206010072359 Neuromyotonia Diseases 0.000 description 1
- 210000001331 Nose Anatomy 0.000 description 1
- 210000004940 Nucleus Anatomy 0.000 description 1
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 description 1
- 229920000272 Oligonucleotide Polymers 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 101710040930 PTGS2 Proteins 0.000 description 1
- 210000000496 Pancreas Anatomy 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 210000001152 Parietal Lobe Anatomy 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000008223 Pemphigoid Gestationis Diseases 0.000 description 1
- 210000003516 Pericardium Anatomy 0.000 description 1
- 210000003800 Pharynx Anatomy 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- HXEACLLIILLPRG-UHFFFAOYSA-N Pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
- 210000004011 Plasma Cells Anatomy 0.000 description 1
- 210000004224 Pleura Anatomy 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 206010036067 Polydipsia Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 208000003971 Posterior Uveitis Diseases 0.000 description 1
- 208000001775 Primary Dysautonomias Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N Probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M Propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 210000002307 Prostate Anatomy 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- ZFOMKMMPBOQKMC-KXUCPTDWSA-N Pyrrolysine Chemical compound C[C@@H]1CC=N[C@H]1C(=O)NCCCC[C@H]([NH3+])C([O-])=O ZFOMKMMPBOQKMC-KXUCPTDWSA-N 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102000007312 Recombinant Proteins Human genes 0.000 description 1
- 108010033725 Recombinant Proteins Proteins 0.000 description 1
- 210000000664 Rectum Anatomy 0.000 description 1
- 206010038294 Reiter's syndrome Diseases 0.000 description 1
- 206010038444 Renal failure chronic Diseases 0.000 description 1
- 206010057430 Retinal injury Diseases 0.000 description 1
- 102100019388 SOAT1 Human genes 0.000 description 1
- 101700025022 SOAT1 Proteins 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- 206010039580 Scar Diseases 0.000 description 1
- 210000003786 Sclera Anatomy 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010057863 Selective IgG subclass deficiency Diseases 0.000 description 1
- 229940055619 Selenocysteine Drugs 0.000 description 1
- ZKZBPNGNEQAJSX-REOHCLBHSA-N Selenocysteine Chemical compound [SeH]C[C@H](N)C(O)=O ZKZBPNGNEQAJSX-REOHCLBHSA-N 0.000 description 1
- FDKWRPBBCBCIGA-UWTATZPHSA-N Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 208000008842 Sick Building Syndrome Diseases 0.000 description 1
- 231100000597 Sick building syndrome Toxicity 0.000 description 1
- 206010040767 Sjogren's syndrome Diseases 0.000 description 1
- 206010040984 Sleep disease Diseases 0.000 description 1
- 229940054269 Sodium Pyruvate Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 210000004304 Subcutaneous Tissue Anatomy 0.000 description 1
- 210000003523 Substantia Nigra Anatomy 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 210000000225 Synapses Anatomy 0.000 description 1
- 210000001179 Synovial Fluid Anatomy 0.000 description 1
- 229940037128 Systemic Glucocorticoids Drugs 0.000 description 1
- 101700062451 TI Proteins 0.000 description 1
- 108060008444 TPR Proteins 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- 210000003478 Temporal Lobe Anatomy 0.000 description 1
- 210000002435 Tendons Anatomy 0.000 description 1
- 206010043458 Thirst Diseases 0.000 description 1
- 206010043778 Thyroiditis Diseases 0.000 description 1
- 210000001578 Tight Junctions Anatomy 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010046337 Urate nephropathy Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 210000001215 Vagina Anatomy 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 208000003728 Vulvodynia Diseases 0.000 description 1
- 206010069055 Vulvovaginal pain Diseases 0.000 description 1
- 102100002531 WAS Human genes 0.000 description 1
- 208000006110 Wiskott-Aldrich Syndrome Diseases 0.000 description 1
- 108010093528 Wiskott-Aldrich Syndrome Protein Proteins 0.000 description 1
- LQESELFHCSJUQN-VIFPVBQESA-N [4-[(2S)-2,6-diaminohexanoyl]oxy-3-nitrophenyl]arsonic acid Chemical compound NCCCC[C@H](N)C(=O)OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O LQESELFHCSJUQN-VIFPVBQESA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 210000001642 activated microglia Anatomy 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 231100000494 adverse effect Toxicity 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- 102000003802 alpha-Synuclein Human genes 0.000 description 1
- 108090000185 alpha-Synuclein Proteins 0.000 description 1
- 230000001668 ameliorated Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 230000000844 anti-bacterial Effects 0.000 description 1
- 230000003466 anti-cipated Effects 0.000 description 1
- 230000002555 anti-neurodegenerative Effects 0.000 description 1
- 230000003356 anti-rheumatic Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 230000002917 arthritic Effects 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000003140 astrocytic Effects 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 230000003190 augmentative Effects 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 230000003376 axonal Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 231100000871 behavioral problem Toxicity 0.000 description 1
- 230000003542 behavioural Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960000074 biopharmaceuticals Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004781 brain capillaries Anatomy 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-N calcium;sulfuric acid Chemical compound [Ca+2].OS(O)(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000001889 chemoattractant Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- 201000001973 choreatic disease Diseases 0.000 description 1
- 230000002759 chromosomal Effects 0.000 description 1
- 201000009446 chronic granulomatous disease Diseases 0.000 description 1
- 231100000749 chronicity Toxicity 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- PMMYEEVYMWASQN-IMJSIDKUSA-N cis-L-hydroxyproline Chemical compound O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 230000001149 cognitive Effects 0.000 description 1
- 231100000870 cognitive problem Toxicity 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 201000003874 common variable immunodeficiency Diseases 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000002860 competitive Effects 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000003436 cytoskeletal Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002939 deleterious Effects 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 229950008597 drug INN Drugs 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 230000002774 effect on peptide Effects 0.000 description 1
- 235000021406 elemental diet extra Nutrition 0.000 description 1
- 230000001804 emulsifying Effects 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 201000009273 endometriosis Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000001815 facial Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000001497 fibrovascular Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 102000037240 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 201000002406 genetic disease Diseases 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 230000036252 glycation Effects 0.000 description 1
- 201000010238 heart disease Diseases 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 201000007162 hidradenitis suppurativa Diseases 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 230000000640 hydroxylating Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000002218 hypoglycaemic Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000266 injurious Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 108040001669 interleukin-1 receptor antagonist activity proteins Proteins 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000003522 irritant Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 150000001455 metallic ions Chemical class 0.000 description 1
- 210000001872 metatarsal bones Anatomy 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 210000000452 mid-foot Anatomy 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000037230 mobility Effects 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000004255 neuroglia Anatomy 0.000 description 1
- 239000000712 neurohormone Substances 0.000 description 1
- 230000003962 neuroinflammatory response Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000004031 neuronal differentiation Effects 0.000 description 1
- 230000005015 neuronal process Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 230000000324 neuroprotective Effects 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000001584 occupational therapy Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 201000008125 pain agnosia Diseases 0.000 description 1
- 238000009116 palliative therapy Methods 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000002085 persistent Effects 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative Effects 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000003169 placental Effects 0.000 description 1
- 210000004180 plasmacyte Anatomy 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229920000023 polynucleotide Polymers 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000002516 postimmunization Effects 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000002728 primary biliary cirrhosis Diseases 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000000306 recurrent Effects 0.000 description 1
- 230000012121 regulation of immune response Effects 0.000 description 1
- 230000004625 regulation of water loss via skin Effects 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000717 retained Effects 0.000 description 1
- 201000001949 retinal vasculitis Diseases 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine zwitterion Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 1
- 101710028406 satA Proteins 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 229930000044 secondary metabolites Natural products 0.000 description 1
- 235000016491 selenocysteine Nutrition 0.000 description 1
- 230000001953 sensory Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003616 serine group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 230000001568 sexual Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- NAFSTSRULRIERK-UHFFFAOYSA-M sodium;7,9-dihydro-3H-purin-1-ide-2,6,8-trione Chemical compound [Na+].N1C([O-])=NC(=O)C2=C1NC(=O)N2 NAFSTSRULRIERK-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000002739 subcortical Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000011191 terminal modification Methods 0.000 description 1
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 200000000020 tissue injury Diseases 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N trans-L-hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- 102000027575 transmembrane receptors Human genes 0.000 description 1
- 108091007901 transmembrane receptors Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000007279 water homeostasis Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/545—IL-1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Disclosed is a peptide consisting of a peptide sequence of 7 to 14 contiguous amino acid residues derived from IL-1 receptor antagonist protein (IL1RA), said peptide comprising the amino acid sequence of SEQ ID NO: 1 (SGRKSSKMQA), or consisting of a fragment of 7 to 9 consecutive amino acids of SEQ ID NO:1, or comprising a variant of SEQ ID NO:1 having at least 75% sequence identity to SEQ ID NO:1, or consisting of a variant of a fragment of SEQ ID NO:1, said variant consisting of an amino acid sequence of 7 to 9 consecutive amino acids of SEQ ID NO:1 having at least 75% sequence identity to any one of SEQ ID NO:1, wherein said peptide binds to IL-1 receptor type 1 (IL1RI), and interferes with the binding of IL-1 beta to IL1RI. ID NO:1, or comprising a variant of SEQ ID NO:1 having at least 75% sequence identity to SEQ ID NO:1, or consisting of a variant of a fragment of SEQ ID NO:1, said variant consisting of an amino acid sequence of 7 to 9 consecutive amino acids of SEQ ID NO:1 having at least 75% sequence identity to any one of SEQ ID NO:1, wherein said peptide binds to IL-1 receptor type 1 (IL1RI), and interferes with the binding of IL-1 beta to IL1RI.
Description
Antagonists of the interleukin-1 receptor
Field of invention
The present invention relates to novel compounds comprising short peptides derived
from the IL-1 receptor antagonist protein (IL1RA), capable of binding to the cell surface
IL-1 receptor 1 to antagonise the inflammatory effects of IL-1 throughout the human
body. Also disclosed is the use of said peptides as anti-inflammatory agents for
treatment of pathological conditions wherein IL-1 plays a prominent role, such as
inflammatory conditions of the body and the central nervous system.
Background of invention
Interleukin 1 (IL-1) is a general name for two distinct proteins, IL-1 alpha and IL-1 beta,
which are major pro-inflammatory cytokines. IL-1 exerts its effects by binding to specific
transmembrane receptors (IL-1RI) on multiple cell types. The effects of IL-1 are
counteracted by natural inhibitors such as soluble IL-1 receptors and IL-1R antagonist
protein (IL1RA or IL1Ra). IL1RA inhibits the effect of IL-1 by blocking its interaction with
the cell surface receptors.
Therapeutic approaches for targeting IL-1 for anti-inflammatory purposes have been
addressed in the art. These include administration of recombinant IL-1R antagonist
protein, IL-1 trap fusion proteins, anti-IL-1 antibodies, anti-IL-1RI and soluble IL-1RI
and II in experimental models of arthritis (reviewed in Gabay C et al. 2010).
Peptides with IL-1R antagonist activity are disclosed in e.g. US20060094663A1. These
sequences are derived from IL-1RAcP (IL-1RI accessory protein).
Recombinant IL-1R antagonist protein for use as an anti-inflammatory drug has been
commercialised: Anakinra, sold under the trade name ‘Kineret’ (See US5075222). It
has been approved for treatment of rheumatoid arthritis. The drawbacks of anakinra is
that (1) it is delivered as an injection concentrate with 100 mg in each dose; (2) it is
prepared from genetically modified E. coli using recombinant DNA technology; and (3)
it has a high molecular weight (corresponding to full-length IL-1RA)
Thus, identification of shorter and potent peptides derived from IL1RA may address
these disadvantages, in that (1) a lower concentration of the present peptides may be
used, (2) the smaller peptides are stable in solution and can be more easily chemically
synthesised with a lower associated cost, and (3) the lower molecular weight of the
small mimetic peptides enable them to more easily pass the blood-brain barrier,
meaning a lower peptide amount is needed to reach working concentrations in the
brain - this makes them particularly useful also for treatment of neuroinflammatory
diseases. Specific targeting also has the potential of fewer side-effects and improved
efficacy.
The WO05086695A2 patent family discloses specific peptide fragments of the IL-1R
antagonist protein. These fragments are capable of inhibiting tissue destruction in
inflammatory disorders, and may be used to treat chronic inflammatory disorders and
rheumatoid arthritis (US2007027082; patent application of issued US7674464). No
effect on neurodegenerative disorders is addressed.
According to US2007027082, the disclosed peptide fragments preferably comprise the
subsequence LVAGY (“SEQ ID NO:42”); being present in “SEQ ID NOs:13, 18, 21, 23,
24 and 43” of US2007027082. Reversal of IL-1 induced effects were observed for
“SEQ ID NO:13, 15, 23 and 24” in vitro (Example 3), and “SEQ ID NO:18 and 43” in
vivo (Example 10).
“SEQ ID NOs:13, 18 and 19” of US2007027082 further comprise the subsequence
SGRKSSKMQA of ILR1A (present SEQ ID NO:1). The shortest peptide comprising the
subsequence SGRKSSKMQA of ILR1A having an effect according to US2007027082
is 35 amino acids long (“SEQ ID NO:13”), being 42 amino acids long when a nuclear
localisation signal is added for optimisation (“SEQ ID NO:18”). When examined as
short as 15 amino acids – excluding the LVAGY subsequence (“SEQ ID NO:19”), no
effect is observed on inhibiting the collagenase production stimulated by IL-1 in vitro
(Example 3). It is thus concluded in US2007027082 that all peptides active in inhibiting
MMP-1 (a collagenase) by IL-1beta contain residues LVAGY of IL1RA; being common
to all 4 isoforms of IL1RA (US2007027082 [0115]).
The present invention discloses further peptide fragments of IL-1RA; in one
embodiment being as short as 10 amino acids and in one embodiment comprising or
consisting of SGRKSSKMQA (SEQ ID NO:1). Such fragments are shown herein to
directly bind to IL-1RI and interfere with the binding of IL-1R to IL-1beta; which is in
contrast to the 35-amino acid long peptide fragment (“SEQ ID NO:13”) of
US2007027082 that does not bind IL1R1.
Short peptides according to the present invention may comprise or consist of
SGRKSSKMQA (SEQ ID NO:1) or variants, fragments, or variants of fragments
thereof. They have the advantage over both full-length IL1RA (anakinra) and the 35
and 42 amino-acid long peptides of US2007027082 (both comprising the subsequence
SGRKSSKMQA) that they are very stable, has a high solubility and also have a low
cost of synthesis. These effects occur with a retained ability of the peptides to bind
IL1R1 and antagonise the effect of IL-1.
Further short peptides of the present invention derived from IL1RA invention comprise
or consist of RIWDVNQKT (SEQ ID NO:29), TAMEADQPVS (SEQ ID NO:35) or
GPNAKLEEKA (SEQ ID NO:36) or variants, fragments, or variants of fragments
thereof; having the same advantages as outlined for SEQ ID NO:1 herein.
Furthermore, peptides of a certain short length; such as the 10-amino acid peptide of
SEQ ID NO:1, have an increased capability of passing the blood-brain-barrier (BBB) to
elicit an effect on cells of the central nervous system (CNS); thus enabling use of said
short peptides on neuroinflammatory disorders associated with IL-1. An effect on
neurons of IL1RA or peptide fragments thereof has not been addressed in the art
previously, nor has passing the BBB. A positive effect on neurite outgrowth and
neuronal cell survival is shown herein.
Summary of invention
The present invention relates to truncated forms of IL1RA having improved properties
over the full-length IL1RA protein and anakinra.
The peptides are shown herein by the present inventors to bind to IL-1R1, and interfere
with the binding of IL-1R1 to the cytokine IL-1beta, thus having an inhibitory effect on
IL-1 downstream signalling including inhibition of NF-κB activation and reduced TNF-
alpha increase. Also, a positive effect on neurite outgrowth and cell survival is
observed in neurons, and signs of rheumatoid arthritis are ameliorated in vivo.
In a first aspect the invention provides a peptide consisting of a peptide sequence of 7
to 14 contiguous amino acid residues derived from IL-1 receptor antagonist protein
(IL1RA), said peptide
comprising the amino acid sequence of SEQ ID NO:1 (SGRKSSKMQA), or
consisting of a fragment of 7 to 9 consecutive amino acids of SEQ ID NO:1, or
comprising a variant of SEQ ID NO:1 having at least 75% sequence identity to SEQ ID
NO:1, or
consisting of a variant of a fragment of SEQ ID NO:1, said variant consisting of an
amino acid sequence of 7 to 9 consecutive amino acids of SEQ ID NO:1 having at least
75% sequence identity to any one of SEQ ID NO:1,
wherein said peptide binds to IL-1 receptor type 1 (IL1RI), and interferes with the
binding of IL-1 beta to IL1RI.
In a second aspect the invention provides a multimeric compound comprising two or
more peptides, wherein each of said two or more peptides consists of a peptide
according to the first aspect.
In a third aspect the invention provides use of a peptide or compound according to the
first or second aspect 16 in the manufacture of a medicament for the treatment of an
inflammatory disease.
In a fourth aspect the invention provides use of a peptide or compounds according to
the first or second aspect in the manufacture of a medicament for the treatment of a
neurodegenerative disease.
Disclosed herein is an isolated peptide consisting of a peptide sequence of 5 to 20
contiguous amino acid residues derived from IL-1 receptor antagonist protein (IL1RA),
said peptide consisting of
the amino acid sequence of any one of SEQ ID NO:1, SEQ ID NO:29, SEQ ID NO:35
or SEQ ID NO:36; or
a fragment consisting of 5 or more consecutive amino acids of any one of SEQ ID
NO:1, SEQ ID NO:29, SEQ ID NO:35 or SEQ ID NO:36; or
a variant of any one of SEQ ID NO:1, SEQ ID NO:29, SEQ ID NO:35 or SEQ ID
NO:36, said variant consisting of an amino acid sequence of 5 to 20 amino acids
having at least 50% identity to any one of SEQ ID NO:1, SEQ ID NO:29, SEQ ID
NO:35 or SEQ ID NO:36,
wherein said peptide is capable of binding to IL-1 receptor type 1 (IL1RI), and capable
of interfering with the binding of IL-1 to IL1RI.
Also disclosed herein is a compound comprising at least one peptide according to the
present invention. Said compound may be formulated as a monomer consisting of a
single copy of the peptide, or may be formulated as a multimeric compound comprising
two or more peptides according to the invention. Said two or more peptides may be
identical or not, with respect to each other. Said multimer may in a particular
embodiment be a dimer or a tetrameric dendrimer.
Also disclosed herein is a composition, such as a pharmaceutical composition or
formulation, comprising a peptide or a compound according to the invention.
Herein, the peptides, compounds and compositions according to the invention are
provided for use as a medicament.
Said use may comprise the treatment of a subset of inflammatory disorders, especially
those wherein IL-1 plays a prominent role. These include rheumatoid arthritis,
diabetes mellitus, such as diabetes mellitus type I, neurodegenerative disorder
wherein said neurodegenerative disorder has a neuro-inflammatory component,
including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Multiple
Sclerosis.
Description of Drawings
Figure 1 shows a tertiary structure model of the complex between IL1Ra (space filling
presentation) and IL1RI (backbone secondary structures). The location of the Ilantafin
(aka. Ilantide) peptide sequence (SEQ ID NO:1) is shown in black.
Figure 2 shows binding of IL1β (A), IL1Ra (B) and the Ilantafin peptide (SEQ ID NO:1)
to the immobilized on a sensor chip IL1RI employing surface plasmon resonance
(SPR) analysis. RU – resonance units.
Figure 3 shows affinity and rate constants for interaction between Ilantafin (SEQ ID
NO:1), IL1β and IL1Ra, and IL1RI.
Figure 4 shows competition between soluble IL1RI (SILR1) and the Ilantafin peptide
(SEQ ID NO:1) for binding to the immobilized IL1β. * p < 0.05, when compared to the
binding of SILR1 alone.
Figure 5 shows the inhibitory effect of Ilantafin (SEQ ID NO:1) on NF-KB activated by
IL1β. The Ilantafin peptide was synthesized as tetrameric dendrimer (Ilantafin-d)
attached to a lysine backbone. * p < 0.05. ** p < 0.01, when compared to the black bar.
Figure 6 shows the inhibitory effect of Ilantafin (SEQ ID NO:1) on NF-KB activated by
IL1β. The Ilantafin peptide was synthesized as a monomer (Ilantafin-m). * p < 0.05, ** p
< 0.01, when compared to the black bar.
Figure 7 shows the inhibitory effect of the ILRa (A) and SILR1 (B) proteins on NF-KB
activated by IL1β. * p < 0.05, ** p < 0.01, *** p < 0.001, when compared to the black
bar.
Figure 8 shows that the effect of the Ilantafin-d peptide (tetrameric dendrimer of SEQ
ID NO:1) is sequence-specific, since neither two peptides with scrambled sequences,
Ilantafin scr-d1 (KQSAGKRSMS), Ilantafin scr-d2 (KASQKGMSRS), nor a peptide with
the reverseequence, Ilantafin rev-d (AQMKSSKRGS) inhibit the activation of NF-KB
induced by IL1β.
Figure 9 shows that the effect of the Ilantafin-d peptide (tetrameric dendrimer of SEQ
ID NO:1) is target (IL1RI)-specific, since the peptide does not affect the activation of
STAT signalling induced by IL6.
Figure 10 shows the inhibitory effect of Ilantafin (SEQ ID NO:1) on TNFα secretion by
IL1β-activated AMJ2-C8 macrophage cells. The Ilantafin peptide was synthesized as
tetrameric dendrimer (Ilantafin-d) attached to a lysine backbone. * p < 0.05, when
compared to the black bar.
Figure 11 shows the inhibitory effect of Ilantafin (SEQ ID NO:1) on TNFα secretion by
IL1β-activated AMJ2-C8 macrophage cells. The Ilantafin peptide was synthesized as a
monomer (Ilantafin-m). * p < 0.05, when compared to the black bar.
Figure 12 shows the inhibitory effect of ILRa (A) and SIL1R1 on TNFα secretion by
IL1β-activated AMJ2-C8 macrophage cells. * p < 0.05, ** p < 0.01, when compared to
the black bar.
Figure 13 shows the effect of Ilantafin (SEQ ID NO:1), IL1Ra (B), SIL-1R1 (C) and IL1β
(D) on neurite outgrowth in primary cultures of cerebellar granule neurons. * p < 0.05,
** p < 0.01, when compared to untreated controls.
Figure 14 shows that IL1β competes with Ilantafin (SEQ ID NO:1) and IL1Ra thereby
inhibiting Ilantafin (A) - and IL1Ra (B) -induced neurite outgrowth. * p < 0.05, when
compared to the black bar.
Figure 15 shows that Ilantafin (SEQ ID NO:1), both as a dendrimer (Ilantafin-d, A) and
a monomer (Ilantafin-m, B), promotes survival of cerebellar granule neurons induced to
undergo apoptosis by lowering potassium concentration. IGF – insulin-like growth
factor-1. Results from the two independent experiments are shown.
Figure 16 shows the results of an in vivo study employing the collagen-induced
rheumatoid arthritis model in rats. Treatment with Ilantafin-d (tetrameric dendrimer of
SEQ ID NO:1) abrogated an increase in clinical manifestations of the disease, when
compared with the untreated control group.
Figure 17 shows how Ilantafin reduces morbidity of animals with CIA. Morbidity was
expressed as a percentage of animals reached clinical index 7 and therefore sacrificed
by the test day. Ilantafin significantly reduced morbidity by dpi 12. * - P<0.05 (unpaired
t-test with Welch’s correction).
Figure 18 shows how Ilantafin attenuates severity of CIA (clinical evaluation). Two-way
ANOVA revealed significant effect of treatment on clinical score of animals with CIA
[F(1, 238)=18.05, P<0.0001]. Ilantafin attenuated severity of CIA on dpi 13-15. * -
P<0.05 (unpaired t-test with Welch’s correction).
Further details on the figures may be found in the Examples herein below.
Definitions and abbreviations
IL1RA or IL1Ra: IL-1 receptor antagonist protein, may also be denoted IL-1 receptor
antagonist herein.
IL1R1 or IL1RI: IL1 receptor type 1.
Affinity: the strength of binding between receptors and their ligands.
Ilantafin/Ilantide: Used interchangeably herein to denote fragments of IL1RA; Ilantafin-8
has been examined mostly and given the sequence identifier SEQ ID NO:1. SEQ ID
NO:1 may also be denoted simply as ‘Ilantafin’ or ‘Ilantide’ herein.
The term “Individual” refers to vertebrates, particular members of the mammalian
species, preferably primates including humans. As used herein, ‘subject’ and
‘individual’ may be used interchangeably.
A "polypeptide" or “protein” is a polymer of amino acid residues preferably joined
exclusively by peptide bonds, whether produced naturally or synthetically. The term
“polypeptide” as used herein covers proteins, peptides and polypeptides, wherein said
proteins, peptides or polypeptides may or may not have been post-translationally
modified. A peptide is usually shorter in length than a protein.
An "isolated polypeptide" is a polypeptide that is essentially free from contaminating
cellular components, such as carbohydrate, lipid, or other proteinaceous impurities
associated with the polypeptide in nature. Typically, a preparation of isolated poly-
peptide contains the polypeptide in a highly purified form, i.e., at least about 80% pure,
at least about 90% pure, at least about 95% pure, greater than 95% pure, or greater
than 99% pure. One way to show that a particular protein preparation contains an
isolated polypeptide is by the appearance of a single band following sodium dodecyl
sulfate (SDS)-polyacrylamide gel electrophoresis of the protein preparation and
Coomassie Brilliant Blue staining of the gel. However, the term "isolated" does not
exclude the presence of the same polypeptide in alternative physical forms, such as
dimers or alternatively glycosylated or derivatised forms.
An “amino acid residue” can be a natural or non-natural amino acid residue linked
peptide bonds or bonds different from peptide bonds. The amino acid residues can be
in D-configuration or L-configuration. An amino acid residue comprises an amino
terminal part (NH ) and a carboxy terminal part (COOH) separated by a central part
comprising a carbon atom, or a chain of carbon atoms, at least one of which comprises
at least one side chain or functional group. NH refers to the amino group present at
the amino terminal end of an amino acid or peptide, and COOH refers to the carboxy
group present at the carboxy terminal end of an amino acid or peptide. The generic
term amino acid comprises both natural and non-natural amino acids. Natural amino
acids of standard nomenclature as listed in J. Biol. Chem., 243:3552-59 (1969) and
adopted in 37 C.F.R., section 1.822(b)(2) belong to the group of amino acids listed in
Table 1 herein below. Non-natural amino acids are those not listed in Table 1. Also,
non-natural amino acid residues include, but are not limited to, modified amino acid
residues, L-amino acid residues, and stereoisomers of D-amino acid residues.
______________________________________
Symbols Amino acid
1-Letter 3-Letter
______________________________________
Y Tyr tyrosine
G Gly glycine
F Phe phenylalanine
M Met methionine
A Ala alanine
S Ser serine
I Ile isoleucine
L Leu leucine
T Thr threonine
V Val valine
P Pro proline
K Lys lysine
H His histidine
Q Gln glutamine
E Glu glutamic acid
W Trp tryptophan
R Arg arginine
D Asp aspartic acid
N Asn asparagine
C Cys cysteine
______________________________________
Table 1. Natural amino acids and their respective codes.
An “equivalent amino acid residue” refers to an amino acid residue capable of replacing
another amino acid residue in a polypeptide without substantially altering the structure
40 and/or functionality of the polypeptide. Equivalent amino acids thus have similar
properties such as bulkiness of the side-chain, side chain polarity (polar or non-polar),
hydrophobicity (hydrophobic or hydrophilic), pH (acidic, neutral or basic) and side chain
organization of carbon molecules (aromatic/aliphatic). As such, “equivalent amino acid
residues” can be regarded as “conservative amino acid substitutions”.
The classification of equivalent amino acids refers in one embodiment to the following
classes: 1) HRK, 2) DENQ, 3) C, 4) STPAG, 5) MILV and 6) FYW
Within the meaning of the term “equivalent amino acid substitution” as applied herein,
one amino acid may be substituted for another, in one embodiment, within the groups
of amino acids indicated herein below:
i) Amino acids having polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gln, Ser,
Thr, Tyr, and Cys,)
ii) Amino acids having non-polar side chains (Gly, Ala, Val, Leu, Ile, Phe, Trp, Pro,
and Met)
iii) Amino acids having aliphatic side chains (Gly, Ala Val, Leu, Ile)
iv) Amino acids having cyclic side chains (Phe, Tyr, Trp, His, Pro)
v) Amino acids having aromatic side chains (Phe, Tyr, Trp)
vi) Amino acids having acidic side chains (Asp, Glu)
vii) Amino acids having basic side chains (Lys, Arg, His)
viii) Amino acids having amide side chains (Asn, Gln)
ix) Amino acids having hydroxy side chains (Ser, Thr)
x) Amino acids having sulphur-containing side chains (Cys, Met),
xi) Neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr)
xii) Hydrophilic, acidic amino acids (Gln, Asn, Glu, Asp), and
xiii) Hydrophobic amino acids (Leu, Ile, Val)
A “Bioactive agent” (i. e., biologically active substance/agent) is any agent, drug,
compound, composition of matter or mixture which provides some pharmacologic,
often beneficial, effect that can be demonstrated in-vivo or in vitro. It may refer to the
Ilantafin/Ilantide peptide sequences, or compounds comprising these. As used herein,
this term further includes any physiologically or pharmacologically active substance
that produces a localized or systemic effect in an individual. Further examples of
bioactive agents include, but are not limited to, agents comprising or consisting of an
oligosaccharide, agents comprising or consisting of a polysaccharide, agents com-
prising or consisting of an optionally glycosylated peptide, agents comprising or
consisting of an optionally glycosylated polypeptide, agents comprising or consisting of
a nucleic acid, agents comprising or consisting of an oligonucleotide, agents com-
prising or consisting of a polynucleotide, agents comprising or consisting of a lipid,
agents comprising or consisting of a fatty acid, agents comprising or consisting of a
fatty acid ester and agents comprising or consisting of secondary metabolites. It may
be used either prophylactically, therapeutically, in connection with treatment of an
individual, such as a human or any other animal.
The terms "drug", "medicament" as used herein includes biologically, physiologically, or
pharmacologically active substances that act locally or systemically in the human or
animal body.
The terms "treating", "treatment" and "therapy" as used herein refer equally to curative
therapy, prophylactic or preventative therapy and ameliorating or palliative therapy. The
term includes an approach for obtaining beneficial or desired physiological results,
which may be established clinically. For purposes of this invention, beneficial or desired
clinical results include, but are not limited to, alleviation of symptoms, diminishment of
extent of disease, stabilized (i.e., not worsening) condition, delay or slowing of pro-
gression or worsening of condition/symptoms, amelioration or palliation of the condition
or symptoms, and remission (whether partial or total), whether detectable or
undetectable. The term "palliation", and variations thereof, as used herein, means that
the extent and/or undesirable manifestations of a physiological condition or symptom
are lessened and/or time course of the progression is slowed or lengthened, as
compared to not administering compositions of the present invention.
A "treatment effect" or "therapeutic effect" is manifested if there is a change in the
condition being treated, as measured by the criteria constituting the definition of the
terms "treating" and "treatment." There is a "change" in the condition being treated if
there is at least 5% improvement, preferably 10% improvement, more preferably at
least 25%, even more preferably at least 50%, such as at least 75%, and most
preferably at least 100% improvement. The change can be based on improvements in
the severity of the treated condition in an individual, or on a difference in the frequency
of improved conditions in populations of individuals with and without treatment with the
bioactive agent, or with the bioactive agent in combination with a pharmaceutical
composition of the present invention.
A treatment according to the invention may be prophylactic, ameliorating or curative.
"Pharmacologically effective amount", “pharmaceutically effective amount” or "physio-
logically effective amount” of a “bioactive agent" is the amount of an active agent
present in a pharmaceutical composition as described herein that is needed to provide
a desired level of active agent in the bloodstream or at the site of action in an individual
(e.g. the lungs, the gastric system, the colorectal system, prostate, etc.) to be treated to
give an anticipated physiological response when such composition is administered.
The precise amount will depend upon numerous factors, e.g., the active agent, the
activity of the composition, the delivery device employed, the physical characteristics of
the composition, intended patient use (i.e. the number of doses administered per day),
patient considerations, and the like, and can readily be determined by one skilled in the
art, based upon the information provided herein. An “effective amount” of a bioactive
agent can be administered in one administration, or through multiple administrations of
an amount that total an effective amount, preferably within a 24-hour period. It can be
determined using standard clinical procedures for determining appropriate amounts
and timing of administration. It is understood that the "effective amount" can be the
result of empirical and/or individualized (case-by-case) determination on the part of the
treating health care professional and/or individual.
The terms "enhancing" and “improving” a beneficial effect, and variations thereof, as
used herein, refers to the therapeutic effect of the bioactive agent against placebo, or
an increase in the therapeutic effect of a state-of-the-art medical treatment above that
normally obtained when a pharmaceutical composition is administered without the
bioactive agent of this invention. "An increase in the therapeutic effects" is manifested
when there is an acceleration and/or increase in intensity and/or extent of the thera-
peutic effects obtained as a result of administering the bioactive agent(s). It also
includes extension of the longevity of therapeutic benefits. It can also manifest where a
lower amount of the pharmaceutical composition is required to obtain the same
benefits and/or effects when it is co-administered with bioactive agent(s) provided by
the present invention as compared to the administration in a higher amount of the
pharmaceutical composition in the absence of bioactive agent. The enhancing effect
preferably, but not necessarily, results in treatment of acute symptoms for which the
pharmaceutical composition alone is not effective or is less effective therapeutically.
Enhancement is achieved when there is at least a 5% increase in the therapeutic
effects, such as at least 10% increase in the therapeutic effects when a bioactive agent
of the present invention is co-administered with a pharmaceutical composition com-
pared with administration of the pharmaceutical composition alone. Preferably the
increase is at least 25%, more preferably at least 50%, even more preferably at least
75%, most preferably at least 100%.
"Co-administering" or "co-administration" of bioactive agents and state-of-the-art
medicaments, as used herein, refers to the administration of one or more bioactive
agents of the present invention, or administration of one or more bioactive agents of
the present invention and a state-of-the-art pharmaceutical composition within a certain
time period. The time period is preferably less than 72 hours, such as 48 hours, for
example less than 24 hours, such as less than 12 hours, for example less than 6 hours,
such as less than 3 hours. However, these terms also mean that the bioactive agent
and a therapeutic composition can be administered together.
An “individual in need thereof” refers to an individual who may benefit from the present
invention. In one embodiment, said individual in need thereof is a diseased individual,
wherein said disease may be an immune disease wherein IL-1 plays a prominent role.
The term “Kit of parts” as used in the present invention provides the one or more
peptides, compounds or compositions according to the present invention and a second
bioactive agent for administration in combination. The parts of the kit are meant to be
for simultaneous, separate or sequential use. The use may be a therapeutic use, such
as the treatment of inflammation wherein IL-1 plays a prominent role.
Due to the imprecision of standard analytical methods, molecular weights and lengths
of polymers are understood to be approximate values. When such a value is expressed
as "about" X or "approximately" X, the stated value of X will be understood to be
accurate to +/- 20%, such as +/- 10%, for example +/- 5%.
Detailed description of the invention
Inflammation
Inflammation (Latin, inflammare, to set on fire) is part of the complex biological
response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or
irritants. Inflammation is a protective attempt by the organism to remove the injurious
stimuli and to initiate the healing process. Inflammation is not a synonym for infection,
even in cases where inflammation is caused by infection. Although infection is caused
by a microorganism, inflammation is one of the responses of the organism to the
pathogen.
Inflammation can be classified as either acute or chronic. Acute inflammation is the
initial response of the body to harmful stimuli and is achieved by the increased
movement of plasma and leukocytes (especially granulocytes) from the blood into the
injured tissues. A cascade of biochemical events propagates and matures the
inflammatory response, involving the local vascular system, the immune system, and
various cells within the injured tissue. Prolonged inflammation, known as chronic
inflammation, leads to a progressive shift in the type of cells present at the site of
inflammation and is characterized by simultaneous destruction and healing of the
tissue from the inflammatory process
Interleukins
Interleukins are a group of cytokines (secreted proteins/signaling molecules) that were
first seen to be expressed by white blood cells (leukocytes). The term interleukin
derives from (inter-) "as a means of communication", and (-leukin) "deriving from the
fact that many of these proteins are produced by leukocytes and act on leukocytes".
The name is something of a relic though as it has since been found that interleukins
are produced by a wide variety of cells.
The function of the immune system depends in a large part on interleukins, and rare
deficiencies of a number of them have been described, all featuring autoimmune
diseases or immune deficiency. The majority of interleukins are synthesized by helper
CD4+ T lymphocytes, as well as through monocytes, macrophages, and endothelial
cells. They promote the development and differentiation of T, B, and hematopoietic
cells.
Interleukin-1 (IL-1)
Interleukin 1 (IL-1) is a general name for two distinct proteins, IL-1 alpha (IL1A) and IL-
1 beta (IL1B), which are major pro-inflammatory cytokines. They participate in the
regulation of immune responses, inflammatory reactions, tissue injury and
hematopoiesis.
The IL1 gene family consists of three members, IL1α, IL1β, and IL1RA (IL-1 receptor
antagonist protein, also IL1Ra). IL1RA consists of a six-stranded β-barrel closed on
one side by three β-hairpin loops. Although IL1α and IL1β are agonists of the IL1
receptor, the naturally occurring IL1RA functions as a specific antagonist of the
receptor (Hallegua and Weisman, 2002).
IL-1 alpha
Interleukin-1 alpha (IL-1α) is a protein that in humans is encoded by the IL1A gene.
The protein encoded by this gene is a cytokine of the interleukin-1 family. Interleukin-1
alpha possesses a wide spectrum of metabolic, physiological, haematopoietic
activities, and plays one of the central roles in the regulation of the immune responses.
It binds to the interleukin-1 receptor. IL-1α is a unique member in the cytokine family in
the sense that the structure of its initially synthesized precursor does not contain a
signal peptide fragment (same is known for IL-1β and IL-18). After processing by the
removal of N-terminal amino acids by specific proteases, the resulting peptide is called
"mature" form. Calpain, a calcium-activated cysteine protease, associated with the
plasma membrane, is primarily responsible for the cleavage of the IL-1α precursor into
a mature molecule. Both the 31 kDa precursor form of IL-1α and its 18 kDa mature
form are biologically active.
The 31 kDa IL-1α precursor is synthesized in association with cytoskeletal structures
(micro-tubules), unlike most proteins, which are translated in the endoplasmic
reticulum.
The three-dimensional structure of the IL-1α contains an open-ended barrel composed
entirely of beta-pleated strands. Crystal structure analysis of the mature form of IL-1α
shows that it has two sites of binding to IL-1 receptor. There is a primary binding site
located at the open top of its barrel, which is similar, but not identical to that of IL-1β.
IL-1α is constitutively produced by epithelial cells and is found in substantial amounts in
normal human epidermis, where it has an essential role in maintenance of skin barrier
function. With the exception of skin keratinocytes, some epithelial cells and certain cells
in central nervous system, IL-1α is not observed in health in most of cell types, tissues
and in blood. A wide variety of other cells only upon stimulation can be induced to
transcribe the IL-1α genes and produce the precursor form of IL-1α. Among them are
fibroblasts, macrophages, granulocytes, eosinophils, mast cells and basophils,
endothelial cells, platelets, monocytes and myeloid cell lines, blood T-lymphocytes and
B-lymphocytes, astrocytes, kidney mesangial cells, Langerhans cells, dermal dendritic
cells, natural killer cells, large granular lymphocytes, microglia, blood neutrophils,
lymph node cells, maternal placental cells and several other cell types.
The most important regulatory molecule for IL-1α activity is IL-1RA, which is usually
produced in a 10fold molar excess. In addition, the soluble form of the IL-1R type I
has a high affinity for IL-1α and is produced in a 5-10 molar excess. IL-10 also inhibits
IL-1α synthesis.
IL-1 beta
Interleukin-1 beta (IL-1β) also known as catabolin, is a cytokine protein that in humans
is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 (interleukin 1
beta convertase). Cytosolic thiol protease cleaves the product to form mature IL-1β.
IL-1β is a member of the interleukin 1 cytokine family. This cytokine is produced by
activated macrophages as a proprotein, which is proteolytically processed to its active
form by caspase 1. This cytokine is an important mediator of the inflammatory
response, and is involved in a variety of cellular activities, including cell proliferation,
differentiation, and apoptosis. The induction of cyclooxygenase-2 (PTGS2/COX2) by
this cytokine in the central nervous system (CNS) is found to contribute to inflammatory
pain hypersensitivity. This gene and eight other interleukin 1 family genes form a
cytokine gene cluster on chromosome 2.
IL-1 receptor antagonist protein (IL1RA)
The interleukin-1 receptor antagonist protein (IL1RA) is a protein that in humans is
encoded by the IL1RN gene. It is a member of the IL-1 cytokine family that inhibits the
activities of IL1A and IL1B, and modulates a variety of IL-1 related immune and
inflammatory responses. This gene and five other closely related cytokine genes form a
gene cluster spanning approximately 400 kb on chromosome 2. Four alternatively
spliced transcript variants encoding distinct isoforms have been reported.
Mutations in the IL1RN gene results in a rare disease called deficiency of the
interleukin-1–receptor antagonist (DIRA). Variants of the IL1RN gene are also
associated with risk of schizophrenia.
In terms of protein similarities, IL-1β is more closely related to IL-1RA than it is to IL-
1α. The amino acids that are identical between mature human IL-1α and mature IL-1β
is 22% while it is 26% when comparing IL-1β to IL-1RA and only 18% when comparing
IL-1α to IL-1RA.
The sequence of IL1RA is disclosed herein below (‘sequences’), for all 4 isoforms of
IL1RA.
IL-1 receptors
IL1 has two distinct receptors, IL1RI and IL1RII (IL-1 receptor type I and II, or 1 and 2,
respectively). IL1RI comprises an extracellular portion with three immunoglobulin-like
modules for IL1 binding and a long cytoplasmic domain, whereas IL1RII contains the
same ectodomain but a shorter cytoplasmic domain.
The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1
receptors are thought to be post-translationally derived from cleavage of the extra-
cellular portion of the membrane receptors. Both IL-1 receptors (CD121a/IL1R1,
CD121b/IL1R2 ) appear to be well conserved in evolution, and map to the same
chromosomal location. The receptors can both bind all three forms of IL-1 (IL-1 alpha,
IL-1 beta and IL-1RA).
IL1 associates with IL1RI with low affinity, and the binding of the IL1R accessory
protein (IL1R-AcP) to the complex results in high-affinity binding that forms an
asymmetric tertiary complex composed of IL1, IL1RI, and IL1R-AcP, resulting in
receptor activation and subsequent intracellular signal transduction and cellular
responses. IL1RA binds primarily to IL1RI but does not induce signal transduction
because it lacks a second binding site. IL1RII is a decoy receptor because the binding
of IL1 to ILRII is unable to trigger intracellular signals. The naturally occurring IL1RA
and the decoy receptor attenuate the effects of IL1, and thus appears to be a unique
phenomenon in cytokine biology (Dinarello, 1996).
Peptide fragments of the present invention
The present invention discloses truncated forms of IL1RA having improved properties
over the full-length IL1RA protein and anakinra. The improved properties of the short
peptides of the present invention relate to increased solubility, increased stability and
lower cost of synthesis. Furthermore, the peptide of the present invention retains its
ability to bind to IL-1R1 and interfere with binding of IL-1beta to this receptor; in
addition to several desirable downstream effects addressed herein elsewhere.
The provision of a short peptide according to the present invention also allow for better
passage of said short peptide across the blood-brain barrier. This is especially
interesting in that the peptide of the present invention (SEQ ID NO:1) of 10 amino acid
residues, has been shown by the present inventors to have a positive effect on neurite
outgrowth and neuronal cell survival.
The blood-brain barrier (BBB) is a separation of circulating blood and the cerobrospinal
fluid (CSF) in the central nervous system (CNS), provided to maintain homeostasis. It
occurs along all brain capillaries and consists of tight junctions around the capillaries
that do not exist in normal circulation. Endothelial cells restrict the diffusion of micro-
scopic objects (e.g. bacteria) and large or hydrophilic molecules into the cerebrospinal
fluid, while allowing the diffusion of small hydrophobic molecules (O , hormones, CO ).
Cells of the barrier actively transport metabolic products such as glucose across the
barrier with specific proteins. This barrier also includes a thick basement membrane
and astrocytic endfeet. The BBB thus effectively blocks entry into the brain of most
molecules. This means that many drugs, which would otherwise be capable of treating
disorders of the CNS, are denied access to the very regions where they would be
affective.
While most peptides may be able to penetrate the BBB to some extent, there is a clear
correlation between the molecular weight (MW) of the protein and the degree of
penetration – shorter, unbranched peptides with a low MW thus have a better degree of
penetration, meaning that a lower amount of peptide is needed for small MW peptides
to reach working concentrations in the brain.
A peptide according to the invention comprises a short fragment of the IL1RA protein.
In one embodiment, said peptide comprises or consists of SGRKSSKMQA (SEQ ID
NO:1), or a functional fragment or variant thereof.
A ‘fragment or variant thereof’ as used herein refer to fragments of SEQ ID NO:1
(length), variants of SEQ ID NO:1 (identity), and variants of fragments of SEQ ID NO:1
(identity and length). The latter may be denoted ‘variant fragment’.
Both fragments and variants of amino acid sequences according to the invention are
meant to be the functional equivalents of said sequences, i.e. retaining their ability to
bind to IL1R1.
Further short peptides of the present invention derived from IL1RA invention comprise
or consist of RIWDVNQKT (SEQ ID NO:29), TAMEADQPVS (SEQ ID NO:35) or
GPNAKLEEKA (SEQ ID NO:36) or variants, fragments, or variants of fragments
thereof; as outlined for SEQ ID NO:1 herein.
In a preferred embodiment, the peptides according to the present invention are
specific, in that the peptide sequence have no or substantially reduced effect when the
amino acid sequence is scrambled or reversed. Also, the peptides are preferably
specific to antagonising the effect of IL-1, and not other proteins and interleukins.
A functional fragment or variant of e.g. SEQ ID NO:1 is a fragment or variant (or variant
of a fragment) which retain its ability to bind to IL-1R1 and interfere with the binding of
IL-1 beta to said receptor, and/or retain the ability to affect downstream effects to a
comparable level as SEQ ID NO:1 with respect to inhibition of IL-1 induced NF-kB
activation, reduction of IL-1 induced TNF-alpha release from macrophages, induction of
neurite outgrowth and/or promotion of neuronal cell survival. The same applies to SEQ
ID NOs:29, 35 and 36.
In the present context the standard one-letter code for amino acid residues as well as
the standard three-letter code is applied. Abbreviations for amino acids are in
accordance with the recommendations in the IUPAC-IUB Joint Commission on
Biochemical Nomenclature Eur. J. Biochem, 1984, vol. 184, pp 9-37. Throughout the
application either the three letter code or the one letter code for natural amino acids are
used. Where the L or D form (optical isomers) has not been specified it is to be
understood that the amino acid in question has the natural L form, cf. Pure & Appl.
Chem. Vol. (56(5) pp 595-624 (1984) or the D form, so that the peptides formed may
be constituted of amino acids of L form, D form, or a sequence of mixed L forms and D
forms.
Where nothing is specified it is to be understood that the C-terminal amino acid of a
peptide according to the invention exists as the free carboxylic acid, this may also be
specified as “-OH”. However, the C-terminal amino acid of a peptide for use according
to the invention may in another embodiment be the amidated derivative, which is
indicated as “-NH ”. Where nothing else is stated the N-terminal amino acid of the
peptide comprises a free amino-group, this may also be specified as “H-“. However, the
N-terminal amino acid of a peptide according to the invention may in another
embodiment be the acetylated derivative, which is indicated as “-Acetyl” or “COCH ”.
A peptide according to the invention in one embodiment comprises at least 5 of the
twenty-two amino acids naturally incorporated into polypeptides, called proteinogenic
or natural amino acids. Of these, 20 are encoded by the universal genetic code. The
remaining 2; selenocysteine and pyrrolysine, are incorporated into proteins by unique
synthetic mechanisms. A peptide according to the invention can also comprise one or
more unnatural, non-proteinogenic or non-standard amino acids.
In a preferred embodiment, the peptide of the present invention consists of or
comprises SGRKSSKMQA (SEQ ID NO:1), or a fragment or a variant, or a variant
fragment thereof.
In another embodiment, the peptide of the present invention consists of or comprises
SEQ ID NOs:29, 35 or 36, or a fragment or a variant, or a variant fragment thereof.
In one embodiment, the peptide comprises a contiguous amino acid sequence of at
most 14 amino acids, such as at most 13 amino acids, for example at most 12 amino
acids, for example at most 11 amino acids, such as at most 10 amino acids derived
from IL1RA which comprises SEQ ID NO:1, or a fragment or a variant, or a variant
fragment thereof.
The peptide of the present invention in one embodiment consists of 10 contiguous
amino acid residues of IL1RA consisting of SEQ ID NO:1. In another embodiment, the
peptide of the invention has a total length of less than or equal to 5, 6, 7, 8, 9, 10, 11,
12 13 or 14 contiguous amino acid residues derived from IL1RA and comprises SEQ
ID NO:1 or a variant or a fragment, or a variant fragment, thereof.
A peptide of the present invention may consist of 5-10 contiguous amino acids, such as
6-10 amino acids contiguous, for example 8-10 contiguous amino acids. In one
embodiment, the peptide of the invention consists of 5-6, such as 6-7, for example 7-8,
such as 8-9, for example 9-10, such as 10-11, for example 11-12, such as 12-13, for
example 13-14 contiguous amino acids comprising any of SEQ ID NOs:1, 29, 35 or 36,
or a variant, a fragment or a variant fragment thereof.
In one embodiment, the peptide of the invention consists of 5-6, such as 6-7, for
example 7-8, such as 8-9, for example 9-10, such as 10-11, for example 11-12, such
as 12-13, for example 13-14, such as 14-15, for example 15-16, such as 16-17, for
example 17-18, such as 18-19, for example 19-20 contiguous amino acids comprising
any of SEQ ID NOs:29, 35 or 36, or a variant, a fragment or a variant fragment thereof.
The peptide of the present invention in another embodiment comprises a contiguous
amino acid sequence having a total length of less than or equal to 5, 6, 7, 8, 9, 10, 11,
12 13, 14, 15, 16, 17, 18, 19 or 20 contiguous amino acid residues derived from IL1RA
comprising SEQ ID NOs:29, 35 or 36, or a fragment or a variant, or a variant fragment
thereof.
In yet another embodiment, the peptide of the invention comprises or consists of a
fragment of SEQ ID NOs:1, 29, 35 or 36 comprising at least 5 contiguous amino acids
of said peptide sequence(s); such as 5 contiguous amino acids, for example 6
contiguous amino acids, such as 7 contiguous amino acids, for example 8 contiguous
amino acids, such as 9 contiguous amino acids of said peptide sequence(s).
A fragment of a peptide is thus defined herein as a peptide comprising at least 5
contiguous amino acids of SEQ ID NOs:1, 29, 35 or 36; such as 5 contiguous amino
acids, for example 6 contiguous amino acids, such as 7 contiguous amino acids, for
example 8 contiguous amino acids, such as 9 contiguous amino acids of SEQ ID
NOs:1, 29, 35 or 36. A fragment of SEQ ID NOs:1, 35 or 36 may thus comprise
between 5 and 9 amino acids of said sequences, and a fragment of SEQ ID NO:29
may thus comprise between 5 and 8 amino acids of said sequence.
A variant of a peptide of the invention, or a variant of a fragment of said peptides, may
be an amino acid sequence which has at least 40% sequence identity with SEQ ID
NOs:1, 29, 35 or 36 or a fragment thereof, such as at least 50%, 60%, 65%, 70%, 75%,
80%, 85%, 90% or 95% identity to SEQ ID NOs:1, 29, 35 or 36 or a fragment thereof,
or an amino acid which has 40-50% identity, for example 50-60% identity, such as 60-
70% identity, for example 70-80% identity, such as 80-90%, for example 95-99%
sequence identity to SEQ ID NOs:1, 29, 35 or 36 or a fragment thereof, wherein the
identity is defined as a percentage of identical amino acids in said variant sequence
when it is collated with SEQ ID NOs:1, 29, 35 or 36 or a fragment thereof.
The identity between amino acid sequences may be calculated using well known
algorithms such as BLOSUM 30, BLOSUM 40, BLOSUM 45, BLOSUM 50, BLOSUM
55, BLOSUM 60, BLOSUM 62, BLOSUM 65, BLOSUM 70, BLOSUM 75, BLOSUM 80,
BLOSUM 85, or BLOSUM 90, or by simple comparison of the specific amino acids
present at corresponding positions in two peptide sequences to be compared.
Homology may be used as a synonym to identity / sequence identity.
A variant of a peptide of the invention may also be an amino acid sequence which has
about 10% positive amino acid matches with SEQ ID NOs:1, 29, 35 or 36 or a fragment
thereof, such as about 20% positive amino acid matches, for example about 30%
positive amino acid matches, such as about 40% positive amino acid matches, for
example about 50% positive amino acid matches, such as about 60% positive amino
acid matches, for example about 70% positive amino acid matches, such as about 80%
positive amino acid matches, for example about 90% positive amino acid matches,
wherein a positive amino acid match is defined as the presence at the same position in
two compared sequences of amino acid residues which has similar physical and/or
chemical properties. Particular positive amino acid matches of the present invention
are K to R, E to D, L to M, Q to E, I to V, I to L, A to S, Y to W, K to Q, S to T, N to S
and Q to R.
Variants include sequences wherein an alkyl amino acid is substituted for an alkyl
amino acid, wherein an aromatic amino acid is substituted for an aromatic amino acid,
wherein a sulfur-containing amino acid is substituted for a sulfur-containing amino acid,
wherein a hydroxy-containing amino acid is substituted for a hydroxy-containing amino
acid, wherein an acidic amino acid is substituted for an acidic amino acid, wherein a
basic amino acid is substituted for a basic amino acid, or wherein a dibasic mono-
carboxylic amino acid is substituted for a dibasic monocarboxylic amino acid.
In another embodiment, a variant of the peptide sequences according to the invention,
or a variant of a fragment of the peptide sequence, may comprise at least one sub-
stitution, such as a plurality of substitutions introduced independently of one another. In
one embodiment, the peptide variant comprises 1, 2, 3, 4, 5 or 6 amino acid sub-
stitutions with respect to the amino acid sequence of SEQ ID NOs:1, 29, 35 or 36 or a
fragment thereof.
Variants of SEQ ID NOs:1, 29, 35 or 36, or of fragments thereof, may comprise one or
more conservative substitutions independently of one another, that is the substitution of
amino acids whose side chains have similar biochemical properties and thus do not
affect the function of the peptide.
Among the common amino acids, for example, a "conservative amino acid substitution"
can also be illustrated by a substitution among amino acids within each of the following
groups: (1) glycine, alanine, valine, leucine, and isoleucine, (2) phenylalanine, tyrosine,
and tryptophan, (3) serine and threonine, (4) aspartate and glutamate, (5) glutamine
and asparagine, and (6) lysine, arginine and histidine.
The polypeptides according to the present invention can also comprise non-naturally
occurring amino acid residues. Non-naturally occurring amino acids include e.g.,
without limitation, transmethylproline, 2,4-methanoproline, cishydroxyproline,
transhydroxyproline, N-methylglycine, allo-threonine, methylthreonine, hydroxyl-
ethylcysteine, hydroxyethylhomocysteine, nitroglutamnine, homoglutamine, pipecolic
acid, thiazolidine carboxylic acid, dehydroproline, 3- and 4-methylproline, 3,3-dimethyl-
proline, tert-leucine, norvaline, 2-azaphenylalanine, 3-azaphenylalanine, 4-azaphenyl-
alanine, and 4-fluorophenylalanine.
Conservative substitutions (or synonymous substitutions) may be introduced in any one
or more positions of a peptide according to the invention or a fragment thereof, as long
as the variant, or variant of a fragment, remains functional. It may however also be
desirable to introduce non-conservative substitutions in one or more positions (non-
synonymous substitutions).
A non-conservative substitution leading to the formation of a variant of the peptide
according to the invention would for example differ substantially in polarity, for example
a residue with a non-polar side chain (Ala, Leu, Pro, Trp, Val, Ile, Leu, Phe or Met)
substituted for a residue with a polar side chain such as Gly, Ser, Thr, Cys, Tyr, Asn, or
Gln or a charged amino acid such as Asp, Glu, Arg, or Lys, or substituting a charged or
a polar residue for a non-polar one; and/or ii) differ substantially in its effect on peptide
backbone orientation such as substitution of or for Pro or Gly by another residue;
and/or iii) differ substantially in electric charge, for example substitution of a negatively
charged residue such as Glu or Asp for a positively charged residue such as Lys, His
or Arg (and vice versa); and/or iv) differ substantially in steric bulk, for example
substitution of a bulky residue such as His, Trp, Phe or Tyr for one having a minor side
chain, e.g. Ala, Gly or Ser (and vice versa).
Substitution of amino acids may in one embodiment be made based upon their
hydrophobicity and hydrophilicity values and the relative similarity of the amino acid
side-chain substituents, including charge, size, and the like.
In one embodiment, 1, 2 or 3 serine residues (Ser) of SEQ ID NO:1, or a fragment
thereof, is substituted with an amino acid selected from the group consisting of Gln,
Asn and Thr (all amino acids with polar uncharged side chains); and independently
thereof, glycine (Gly) is substituted with an amino acid selected from the group
consisting of Ala, Val, Leu, and Ile; and independently thereof, at least one arginine
(Arg) is substituted with an amino acid selected from the group consisting of Lys and
His (all have positively charged side shains); and independently thereof, 1 or 2 lysine
residues (Lys) are substituted with an amino acid selected from the group consisting of
Arg and His; and independently thereof, methionine (Met) is substituted with an amino
acid selected from the group consisting of Leu, Pro, Ile, Val, Phe, Tyr and Trp (all have
hydrophobic side chains); and independently thereof, at least one glutamine (Gln) is
substituted with an amino acid selected from the group consisting of Asp, Glu, and Asn;
and independently thereof, at least one alanine (Ala) is substituted with an amino acid
selected from the group consisting of Gly, Val, Leu, and Ile.
SEQ ID NO:1 consists of 10 amino acids, referred to as positions 1 to 10. In one
embodiment, Ser at position 1 of SEQ ID NO:1 is unchanged, deleted or substituted
with Gly; Gly at position 2 is unchanged, deleted or substituted with Ala, Ser or Arg; Arg
at position 3 is unchanged, deleted or substituted with Lys; Lys at position 4 is
unchanged or substituted with Arg, Thr, Gln, Met, Gly or Ser; Ser at position 5 is
unchanged or substituted with Pro, AlaArg, Leu, Gln, Asn, Gly or Lys; Ser at position 6
is unchanged or substituted with His, Gln, Trp, Asn, Glu, Pro, Ala, Thr, Cys, Gly or Arg;
Lys at position 7 is unchanged or substituted with Arg, His, Glu or Ser; Met at position 8
is unchanged or substituted with Leu, Thr or Ser; Gln at position 9 is unchanged,
deleted or substituted with Glu, His or Lys; and/or Ala at position 10 is unchanged,
deleted or substituted with Leu or Met.
Furthermore, a functional variant of SEQ ID NOs:1, 29, 35 or 36 may comprise one or
more amino acid additions within or at either end of said sequence, such as 1, 2, 3, 4
or 5 amino acids added within or at either end of SEQ ID NOs:1, 29, 35 or 36, or a
variant, a fragment or a variant fragment thereof.
Examples of variants, fragments and variants of fragments of SEQ ID NO:1 according
to the present invention include (identical amino acids compared to SEQ ID NO:1 are
underlined, and ‘missing’ or omitted amino acids compared to SEQ ID NO:1 are
indicated with an “-“; the overall identity score is indicated; as compared to SEQ ID
NO:1):
SEQ ID NO:1 SGRKSSKMQA (‘Ilantafin’/’Ilantide’)
SEQ ID NO:2 SGRKPSKMQA Identity: 9/10 (90%)
SEQ ID NO:3 SGRKSQKM-- Identity: 7/8 (87.5%)
SEQ ID NO:4 --RKASKLQA Identity: 6/8 (75%)
SEQ ID NO:5 SARKSEKM-- Identity: 6/8 (75%)
SEQ ID NO:6 SGRQSPKM-- Identity: 6/8 (75%)
SEQ ID NO:7 SGRKSPHSKLPA Identity: 5/10 (50%)
SEQ ID NO:8 SSRQSSKM-- Identity: 6/8 (75%)
SEQ ID NO:9 SGKRPCKMQA Identity: 6/10 (60%)
SEQ ID NO:10 --RMNSKMQ- Identity: 5/7 (71.4%)
SEQ ID NO:11 ---KSPKMQ- Identity: 5/6 (83.3%)
SEQ ID NO:12 --RKGGKMQ- Identity: 5/7 (71.4%)
SEQ ID NO:13 SGRGKSSSKM Identity: 4/10 (40%)
SEQ ID NO:14 GRRSSRKMPA Identity: 5/10 (50%)
SEQ ID NO:15 --RKANKLQA Identity: 5/8 (62.5%)
SEQ ID NO:16 SGRKSHRLQ- Identity: 6/9 (66.6%)
SEQ ID NO:17 --RKAWKMQ- Identity: 5/7 (71.4%)
SEQ ID NO:18 --RKANKLQA Identity: 5/8 (62.5%)
SEQ ID NO:19 -GRRSSKTEA Identity: 6/9 (66.6%)
SEQ ID NO:20 --RTSSRMQ- Identity: 5/7 (71.4%)
SEQ ID NO:21 -GRKRSRMH- Identity: 5/8 (62.5%)
SEQ ID NO:22 -GRKRSKTQ- Identity: 6/8 (75%)
SEQ ID NO:23 SGRKLAKLQ- Identity: 6/9 (66.6%)
SEQ ID NO:24 --RKSTEMEA Identity: 5/8 (62.5%)
SEQ ID NO:25 --RKQNKMEA Identity: 5/8 (62.5%)
SEQ ID NO:26 --RRSSRLQA Identity: 5/8 (62.5%)
40 SEQ ID NO:27 --RTSSRMQ- Identity: 5/7 (71.4%)
A variant of a peptide of the invention may also mean that the peptide sequence may
be modified. A modification may be any modification known to the skilled person, such
as those referred to as posttranslational modifications. These include acetylation,
phosphorylation, methylation, glucosylation, glycation, amidation, hydroxylation,
deimination, deamidation, carbamylation and sulfation of one or more amino acid
residues.
In one embodiment, the peptide of the present invention does not comprise or consist
of the amino acid sequence RPSGRKSSKMQAFRI (SEQ ID NO:37), and/or does not
comprise or consist of the amino acid sequence LVAGY (SEQ ID NO:38).
In one embodiment, the peptide according to the invention is an isolated peptide.
In one embodiment, the peptide according to the invention is a non-naturally occurring
peptide; being derived from a naturally occurring protein (IL1RA). It is in one embodi-
ment synthetically made.
In a particular embodiment, the peptides according to the present invention have a
molecular weight in the range from 100 Da to 5000 Da, such as from 100 Da to 250
Da, for example 250 Da to 500 Da, such as from 500 Da to 750 Da, for example 750
Da to 1000 Da, such as from 1000 Da to 1500 Da, for example 1500 Da to 2000 Da,
such as from 2000 Da to 3000 Da, for example 3000 Da to 4000 Da, such as from
4000 Da to 5000 Da.
It is an aspect of the present invention to provide a peptide according to the present
invention for use as a medicament.
Synthetic preparation
The methods for synthetic production of peptides are well known in the art. Detailed
descriptions as well as practical advice for producing synthetic peptides may be found
in Synthetic Peptides: A User's Guide (Advances in Molecular Biology), Grant G. A.
ed., Oxford University Press, 2002, or in: Pharmaceutical Formulation: Development of
Peptides and Proteins, Frokjaer and Hovgaard eds., Taylor and Francis, 1999.
Peptides according to the invention may be synthesized as monomers, dimers or
tetramers (>80%purity, Schafer-N, Copenhagen, Denmark). Dimers and tetramers
consist of two and four chains, respectively, in one embodiment coupled to a lysine
backbone.
In one embodiment the peptide sequences of the invention are produced synthetically,
in particular, by the Sequence Assisted Peptide Synthesis (SAPS) method or Solid-
phase peptide synthesis (SPPS). These are well-known to the skilled person.
Peptides may be synthesised either batch wise on a fully automated peptide synthe-
siser using 9-fluorenylmethyloxycarbonyl (Fmoc) or tert-Butyloxycarbonyl (Boc) as N-a-
amino protecting group and suitable common protection groups for side-chain
functionalities.
After purification by reversed phase HPLC, peptides may be further processed to
obtain for example cyclic or C- or N-terminal modified isoforms. The methods for
cyclization and terminal modification are well-known in the art.
Compound of the present invention
It is an aspect of the present invention to provide a compound comprising or consisting
of a peptide according to the present invention. In one embodiment, said peptide is
formulated as a monomer (i.e. comprising 1 copy of the peptide), whereas in another
embodiment, said peptide is formulated as a multimer.
It is an aspect of the present invention to provide a compound according to the present
invention for use as a medicament.
Multimeric compound
A peptide sequence of the present invention may be connected to another (identical or
non-identical) peptide sequence of the present invention by a chemical bond or through
a linker group. In some embodiments a peptide of the invention may be formulated as
an oligomer or multimer of monomers, wherein each monomer is as a peptide
sequence as defined herein above.
Thus, according to the invention a multimeric compound may be a polymer comprising
two or more peptide sequences of the invention, said peptide sequences being
identical or non-identical, wherein at least one of the two or more peptide sequences is
a peptide according to the present invention. Preferably, both peptide sequences are a
peptide according to the present invention.
In one embodiment the multimeric compound is a dimer, comprising two peptides
according to the present invention, said two peptides being identical or non-identical
with respect to each other.
In another embodiment the multimeric compound is a trimer or a tetramer, comprising
three or four peptides according to the present invention, respectively, said peptides
being identical or non-identical with respect to each other.
In one embodiment the multimeric compound is a dendrimer, such as a tetrameric
dendrimer. Dendrimers are repeatedly branched, roughly spherical large molecules,
typically symmetric around the core, and often adopts a spherical three-dimensional
morphology. Dendrimers according to the present invention may comprise 4 peptides,
8 peptides, 16 peptides, or 32 peptides; preferably four peptides (i.e. tetrameric
dendrimer).
In some particular embodiments, the multimeric compound may comprise two identical
amino acid sequences of the present invention (dimer) or the compound may comprise
four identical copies of an amino acid sequence of the present invention (tetrameric
dendrimer).
The multimers according to the invention may be made by linking two or more peptide
monomers via a peptide bond or a linker group. They may be linked to a lysine back-
bone, such as a lysine residue (a single lysine residue), or coupled to a polymer carrier,
for example a protein carrier. Said linker group in one embodiment comprises a
plurality of lysine residues, such as a core moiety having a plurality of lysine residues.
However, any other linking of peptide monomers known to the skilled person may be
envisioned.
The linking may in one embodiment occur at the N-terminal or C-terminal end of the
peptide monomers.
Methods
It is also an aspect of the present invention to provide a method for stimulating neurite
outgrowth and/or promoting survival of neurons, said method comprising administering
an effective amount of a peptide, of a compound, or of a composition according to the
present invention, to an individual in need thereof.
Also disclosed in a method for interfering with the binding of IL1RI to IL-1, said method
comprising administering an effective amount of a peptide, of a compound, or of a
composition according to the present invention, to an individual in need thereof.
In a preferred embodiment, said individual in a human being, such as a human being
having a neurodegenerative condition.
The invention also relates to a method for identifying binding partners for peptides
described herein, said method comprising the steps of extracting the polypeptide and
isolating said binding partners.
Pharmaceutical formulation
Whilst it is possible for the peptides or compounds of the present invention to be
administered as the raw chemical (or peptide), it is sometimes preferred to present
them in the form of a pharmaceutical formulation. Such a pharmaceutical formulation
may be referred to as a pharmaceutical composition or pharmaceutically acceptable or
safe composition.
Accordingly, the present invention further provides a pharmaceutical formulation, which
comprises a peptide or compound of the present invention, or a pharmaceutically
acceptable salt or ester thereof, and a pharmaceutically acceptable carrier and/or
diluent. The pharmaceutical formulations may be prepared by conventional techniques,
e.g. as described in Remington: The Science and Practice of Pharmacy 2005,
Lippincott, Williams & Wilkins.
The pharmaceutically acceptable carriers can be either solid or liquid. Solid form
preparations include powders, tablets, pills, capsules, cachets, suppositories, and
dispersible granules. A solid carrier can be one or more excipients which may also act
as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders,
preservatives, wetting agents, tablet disintegrating agents, or an encapsulating
material.
Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin,
agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids,
fatty acid amines, polyoxyethylene, water, saline or a glucose solution. Similarly, the
carrier or diluent may include any sustained release material known in the art, such as
glycerol monostearate or glycerol distearate, alone or mixed with a wax.
Also included are solid form preparations which are intended to be converted, shortly
before use, to liquid form preparations. Such liquid forms include solutions, suspen-
sions, and emulsions. These preparations may contain, in addition to the active
component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners,
dispersants, thickeners, solubilizing agents, and the like.
The compounds of the present invention may be formulated for parenteral administra-
tion and may be presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers, optionally with an added preservative. The
compositions may take such forms as suspensions, solutions, or emulsions in oily or
aqueous vehicles, for example solutions in aqueous polyethylene glycol.
Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include
propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable
organic esters (e.g., ethyl oleate), and may contain agents such as preserving, wetting,
emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active
ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by
lyophilisation from solution for constitution before use with a suitable vehicle, e.g.,
sterile, pyrogen-free water.
The compounds of the invention may also be formulated for topical delivery. Regions
for topical administration include the skin surface and also mucous membrane tissues
of the vagina, rectum, nose, mouth, and throat. The topical formulation may include a
pharmaceutically acceptable carrier adapted for topical administration. Thus, the
composition may take the form of a suspension, solution, ointment, lotion, sexual
lubricant, cream, foam, aerosol, spray, suppository, implant, inhalant, tablet, capsule,
dry powder, syrup, balm or lozenge, for example.
The pharmaceutical formulation described herein can be administered transdermally.
Transdermal administration typically involves the delivery of a compound for per-
cutaneous passage of the drug into the systemic circulation of the patient. The skin
sites include anatomic regions for transdermally administering the drug and include the
forearm, abdomen, chest, back, buttock, mastoidal area, and the like.
Transdermal delivery is accomplished by exposing a source of the compound to a
patient's skin for an extended period of time. Transdermal patches have the added
advantage of providing controlled delivery of a pharmaceutical agent-chemical modifier
complex to the body. Such dosage forms can be made by dissolving, dispersing, or
otherwise incorporating the pharmaceutical agent-chemical modifier complex in a
proper medium, such as an elastomeric matrix material. Absorption enhancers can also
be used to increase the flux of the compound across the skin. The rate of such flux can
be controlled by either providing a rate-controlling membrane or dispersing the com-
pound in a polymer matrix or gel. For example, a simple adhesive patch can be
prepared from a backing material and an acrylate adhesive.
Lotions according to the present invention also include those suitable for application to
the eye. An eye lotion may comprise a sterile aqueous solution optionally containing a
bactericide.
Formulations for use in nasal, pulmonary and/or bronchial administration are normally
administered as aerosols in order to ensure that the aerosolized dose actually reaches
the mucous membranes of the nasal passages, bronchial tract or the lung. The term
"aerosol particle" is used herein to describe the liquid or solid particle suitable for nasal,
bronchial or pulmonary administration, i.e., that will reach the mucous membranes.
Typically aerosols are administered by use of a mechanical devices designed for
pulmonary and/or bronchial delivery, including but not limited to nebulizers, metered
dose inhalers, and powder inhalers. With regard to construction of the delivery device,
any form of aerosolization known in the art, including but not limited to spray bottles,
nebulization, atomization or pump aerosolization of a liquid formulation, and
aerosolization of a dry powder formulation, can be used.
Liquid aerosol formulations in general contain a compound of the present invention in a
pharmaceutically acceptable diluent. Pharmaceutically acceptable diluents include but
are not limited to sterile water, saline, buffered saline, dextrose solution, and the like.
Formulations for dispensing from a powder inhaler device will normally comprise a
finely divided dry powder containing pharmaceutical composition of the present
invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol,
sucrose, or mannitol in amounts which facilitate dispersal of the powder from the
device. Dry powder formulations for inhalation may also be formulated using powder-
filled capsules, in particularly capsules the material of which is selected from among
the synthetic plastics.
The formulation is formulated to the type of device employed and may involve the use
of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or
carriers useful in therapy and known to the person skilled in the art. The propellant may
be any propellant generally used in the art. Specific non-limiting examples of such
useful propellants are a chlorofluorocarbon, a hydrofluorocarbon, a hydrochloro-
fluorocarbon, or a hydrocarbon.
The formulations of the present embodiment may also include other agents useful for
pH maintenance, solution stabilization, or for the regulation of osmotic pressure.
Pharmaceutically acceptable salts of the instant compounds, where they can be
prepared, are also intended to be covered by this invention. These salts will be ones
which are acceptable in their application to a pharmaceutical use. By that it is meant
that the salt will retain the biological activity of the parent compound and the salt will
not have untoward or deleterious effects in its application and use in treating diseases.
Pharmaceutically acceptable salts are prepared in a standard manner. If the parent
compound is a base it is treated with an excess of an organic or inorganic acid in a
suitable solvent. If the parent compound is an acid, it is treated with an inorganic or
organic base in a suitable solvent.
The compounds of the invention may be administered in the form of an alkali metal or
earth alkali metal salt thereof, concurrently, simultaneously, or together with a
pharmaceutically acceptable carrier or diluent, especially and preferably in the form of
a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including
subcutaneous) route, in an effective amount.
Examples of pharmaceutically acceptable acid addition salts for use in the present
inventive pharmaceutical composition include those derived from mineral acids, such
as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids,
and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic,
gluconic, succinic, p-toluenesulphonic acids, and arylsulphonic, for example.
Dosage
The dosage requirements will vary with the particular drug composition employed, the
route of administration and the particular subject being treated. It will also be
recognized by one of skill in the art that the optimal quantity and spacing of individual
dosages of a compound will be determined by the nature and extent of the condition
being treated, the form, route and site of administration, and the particular patient being
treated, and that such optimums can be determined by conventional techniques. It will
also be appreciated by one of skill in the art that the optimal course of treatment, i.e.,
the number of doses of a compound given per day for a defined number of days, can
be ascertained using conventional course of treatment determination tests.
The daily parenteral dosage regimen may be in the range of about 0.1 to about 100
mg/kg of total body weight, such as 0.1 to 1 mg/kg, 1 to 5 mg/kg, 5 to 10 mg/kg, 10 to
mg/kg, 15 to 20 mg/kg, 20 to 30 mg/kg, 30 to 40 mg/kg, 40 to 50 mg/kg, 50 to 60
mg/kg, 60 to 70 mg/kg, 70 to 80 mg/kg, 80 to 90 mg/kg and 90 to 100 mg/kg of total
body weight. The dosage may be evaluated using a model as described in Example 7
herein, in which a daily dosage of 3.3 or 10 mg/kg is used in mice.
A dosage may be administered once a day, or at a frequency higher or lower than once
a day. For example, a dosage may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times a
day. Alternatively, a dosage may be administered with intervals of 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13 or 14 days,
The term "unit dosage form" as used herein refers to physically discrete units suitable
as unitary dosages for human and animal subjects, each unit containing a predeter-
mined quantity of a compound, alone or in combination with other agents, calculated in
an amount sufficient to produce the desired effect in association with a pharmaceu-
tically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage
forms of the present invention depend on the particular compound or compounds
employed and the effect to be achieved, as well as the pharmacodynamics associated
with each compound in the host. The dose administered should be an "effective
amount" or an amount necessary to achieve an "effective level" in the individual
patient.
When the "effective level" is used as the preferred endpoint for dosing, the actual dose
and schedule can vary, depending on inter-individual differences in pharmacokinetics,
drug distribution, and metabolism. The "effective level" can be defined, for example, as
the blood or tissue level desired in the patient that corresponds to a concentration of a
compound according to the invention.
Administration
The main routes of administration are oral and parenteral in order to introduce a
compound into the blood stream to ultimately target the sites of desired action. Oral
administration is less preferred for protein compounds of the present invention due to
degradation in the gastrointestinal tract. Parenteral administration is any administration
route not being the oral/enteral route whereby the compound avoids first-pass
degradation in the liver. Accordingly, parenteral administration includes any injections
and infusions, for example bolus injection or continuous infusion, such as intravenous
administration, intramuscular administration and subcutaneous administration.
Furthermore, parenteral administration includes inhalations and topical administration.
As peptides are susceptible to degradation if ingested, parenteral administration is
preferred. The peptide of the present invention has a high solubility that show no
potential for aggregation, allowing it to be formulated for and administered e.g.
intranasally and subcutaneously.
Co-administration
In one embodiment the present invention relates to co-administration of a peptide,
compound or composition according to the present invention, together with one or
more other bioactive agents.
In one embodiment the present invention relates to co-administration of a peptide,
compound or composition according to the present invention, together with one or
more anti-inflammatory drugs.
In one embodiment the present invention relates to co-administration of a peptide,
compound or composition according to the present invention, together with one or
more anti-rheumatoid drugs.
In one embodiment the present invention relates to co-administration of a peptide,
compound or composition according to the present invention, together with one or
more anti-neurodegenerative drugs.
It follows, that co-administration should be targeted so that to optimise treatment of the
patient; i.e. in a patient with rheumatoid arthritis, a drug approved for this specific
purpose may be complemented with the peptide, compound or composition according
to the present invention to optimise and improve treatment outcome for the patient.
This is regardless of whether the approved drug for the specific purpose is
prophylactic, ameliorating or curative.
Kit-of-parts
The present invention also relates to a kit-of-parts comprising one or more of the
peptides, compounds or composition described above, and at least an additional
component. Said additional component may be drugs for treatment of an inflammatory
condition, diabetes mellitus, a neurodegenerative condition etc.
Inflammatory disorders
Abnormalities associated with inflammation comprise a large, unrelated group of
disorders which underlie a variety of human diseases. The immune system is often
involved with inflammatory disorders, demonstrated in both allergic reactions and some
myopathies, with many immune system disorders resulting in abnormal inflammation.
Non-immune diseases with aetiological origins in inflammatory processes are thought
to include cancer, atherosclerosis, and ischaemic heart disease. A large variety of
proteins are involved in inflammation, and any one of them is open to a genetic
mutation which impairs or otherwise deregulates the normal function and expression of
that protein.
Shortly after an onset of an infection into organism, IL-1 activates a set of immune
system response processes. In particular, IL-1 stimulates fibroblasts proliferation;
induces synthesis of proteases, subsequent muscle proteolysis, release of all types of
amino acids in blood and stimulates acute phase proteins synthesis; changes the
metallic ion content of blood plasma by increasing copper and decreasing zinc and iron
concentration in blood; increases blood neutrophils and activates lymphocyte
proliferation and induces fever.
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of inflammatory disorders, especially inflammatory
disorders wherein IL-1 plays a prominent role.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of inflamma-
tory disorders, especially inflammatory disorders wherein IL-1 plays a prominent role.
In a further aspect of the present invention there is provided a method for treatment of
an inflammatory disorder, such as an inflammatory disorder wherein IL-1 plays a
prominent role, comprising administering a peptide according to the present invention
to an individual in need thereof.
In one embodiment of the present invention, an inflammatory disease selected from the
group consisting of Acne vulgaris, Asthma, Atherosclerosis, Autoimmune diseases,
Behçet's disease, Chronic Inflammation, Chronic prostatitis, Dermatitis, Gout,
Glumerulonephritis, Hypersensitives (including type 1 (immediate, or atopic, or
anaphylactic) comprising Allergic asthma, Allergic conjunctivitis, Allergic rhinitis (hay
fever), Anaphylaxis, Angioedema, Urticaria (hives), Eosinophilia, and response to
Penicillin and Cephalosporin; Type 2 (antibody-dependent) comprising Autoimmune
hemolytic anemia, Goodpasture’s syndrome, Hepatitis, IBS (irritable bowel disease),
Juvenile idiopathic arthritis (JIA), Pemphigus, Pernicious anemia (if autoimmune),
Psoriasis, Psoriasis Arthritis, Immune thrombocytopenia, Transfusion reactions,
Hashimoto’s thyroiditis, Interstitial cystitis, Graves disease, Myastenia gravis,
Rheumatic fever, Hemolytic disease of the newborn and Acute transplant rejection;
Type 3 (immune complex) comprising Rheumatoid arthritis, Immune complex
glumerulonephritis, Serum sickness, Subacute, bacterial endocarditis, Symptoms of
malaria, Systemic lupus erythematosus (SLE), Arthus reaction, Farmer’s lung and
Polyarteritis nodosa; Type 4 (cell-mediated or delayed-type hypersensitivity DTH)
comprising Contact dermatitis, Atopic dermatitis (eczema), Temporal arteritis,
Sarcoidosis, Symptoms of leprosy, Symptoms of tuberculosis, Systemic sclerosis,
Mantoux test, Coeliac disease and Chronic transplant rejection), Inflammatory bowel
diseases (including Crohn’s disease, Ulcerative colitis, Collagenous collitis, Lympho-
cytic collitis, Ischaemic collitis, Diversion collitis, Behcet’s syndrome, Infective collitis
and Indeterminate collitis), Myopathies (including dermatomyositis, polymyositis, and
inclusion body myositis), Pelvic inflammatory disease, Podagra, Reperfusion Injury,
Rheumatoid arthritis, Transplant rejection and Vasculitis, may be subject to use or
treatment according to the present invention.
In one embodiment of the present invention, immune diseases selected from the group
consisting of Achlorhydra Autoimmune Active Chronic Hepatitis, Acute disseminated
encephalomyelitis (ADEM), Acute hemorrhagic leukoencephalitis, Addison’s disease,
Agammaglobulinemia, Allergies, Alopecia universalis, Amyotrophic Lateral Sclerosis,
Anaphylaxis, Ankylosing spondylitis, Antiphospholipid Syndrome, Aplastic anemia,
Asthma, Ataxia-Telangiectasia, Autoimmune Diseases, Autoimmune haemolytic
anemia, Autoimmune hepatitis, Autoimmune Oophoritis, Behcet’s disease,
Celiac/Coeliac disease, Chagas’ disease, Crohn’s disease, Chronic fatique syndrome,
Chronic Granulomatous Disease, Common Variable Immunodeficiency, Diabetes
mellitus type 1, DiGeorge Syndrome, Dysautonomia, Electrosensitivity, Endometriosis,
Familial Mediterranean Fever, Gestational pemphigoid, Goodpasture’s syndrome, Graft
vs Host Disease, Graves’ disease, Guillain-Barré syndrome (GBS), Hashimoto’s
disease, Hidradenitis suppurativa, HIV Infections, Hyper-IgM syndrome, Hyper-
sensitivity, IgA Deficiency, Idiopathic thrombocytopenic purpura, IgG Subclass
Deficiency, Immune Complex Diseases, Immune System Diseases, Immunologic
Deficiency Syndromes, Intestinal cystitis, Kawasaki’s disease, Lambert-Eaton
Myasthenic Syndrome, Lyme disease, Lymphoproliferative Disorders, Mixed
connective tissue disease, Morphea, Multiple Chemical Sensitivity, Multiple sclerosis
(MS), Myasthenia gravis, Narcolepsy, Neuromyotonia, Opsoclonus myoclonus
syndrome (OMS), Optic neuritis, Ord’s thyroiditis, Pemphigus, Pernecious anemia,
Polymyositis, polyarticular Arthritis, Primary biliary cirrhosis, Psoriasis, Psoriatic
arthritis, Purpura, Rheumatoid arthritis (RA), Reiter’s syndrome, Samter's Syndrome,
Sarcoidosis, Schizophrenia, Schoenlein-Henoch, Scleroderma, Selective IgA
deficiency, Severe Combined Immunodeficiency (SCID), Sick Building Syndrome,
Sjogren's Syndrome, Systemic lupus erythromatosus (SLE), Takayasu’s arteritis (giant
cell arteritis), Ulcerative colitis, Uveitis, Vitiligo, Vulvodynia, Warm autoimmune
hemolytic anemia, Wegener’s granulomatosis and Wiskott-Aldrich Syndrome, may be
subject to use or treatment according to the present invention.
Rheumatoid arthritis
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of rheumatoid arthritis.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of rheumatoid
arthritis.
In a further aspect of the present invention there is provided a method for treatment of
rheumatoid arthritis, comprising administering a peptide according to the present
invention to an individual in need thereof.
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect
many tissues and organs, but principally attacks synovial joints. The pathological
process produces an inflammatory response of the synovium (synovitis) secondary to
hyperplasia of synovial cells, excess synovial fluid, and the development of pannus
(abnormal layer of fibrovascular tissue or granulation tissue) in the synovium. The
pathology of the disease process often leads to the destruction of articular cartilage
and ankylosis (stiffness) of the joints. Rheumatoid arthritis can also produce diffuse
inflammation in the lungs, pericardium, pleura, and sclera, and also nodular lesions,
most common in subcutaneous tissue. Although the cause of rheumatoid arthritis is
unknown, autoimmunity plays a pivotal role in both its chronicity and progression, and
RA is considered a systemic autoimmune disease.
About 1% of the world's population is afflicted by rheumatoid arthritis, women three
times more often than men. Onset is most frequent between the ages of 40 and 50, but
people of any age can be affected. It can be a disabling and painful condition, which
can lead to substantial loss of functioning and mobility if not adequately treated. It is a
clinical diagnosis made on the basis of symptoms, physical examination, radiographs
(X-rays) and labs.
Various treatments are available today. Non-pharmacological treatment includes
physical therapy, orthoses, occupational therapy and nutritional therapy but do not stop
progression of joint destruction. Analgesia and anti-inflammatory drugs, including
steroids, are used to suppress the symptoms, while disease-modifying antirheumatic
drugs (DMARDs) are required to inhibit or halt the underlying immune process and
prevent long-term damage. In recent times, the newer group of biologics has increased
treatment options.
Gout/Podagra
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of gout and/or podagra.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of gout and/or
podagra.
In a further aspect of the present invention there is provided a method for treatment of
gout and/or podagra, comprising administering a peptide according to the present
invention to an individual in need thereof.
Gout (also known as podagra when it involves the big toe) is a medical condition
usually characterized by recurrent attacks of acute inflammatory arthritis - a red,
tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is
the most commonly affected (~50% of cases). However, it may also present as tophi
(deposit of monosodium urate crystals), kidney stones, or urate nephropathy. It is
caused by elevated levels of uric acid in the blood which crystallize and are deposited
in joints, tendons, and surrounding tissues. Diagnosis is confirmed clinically by the
visualization of the characteristic crystals in joint fluid.
Gout has increased in frequency in recent decades affecting approximately 1–2% of
the Western population at some point in their lives. The increase is believed to be due
to increasing risk factors in the population, such as metabolic syndrome, longer life
expectancy and changes in diet.
Current treatment modalities include nonsteroidal anti-inflammatory drugs (NSAIDs),
steroids, or colchicine to improve symptoms. Once the acute attack has subsided,
levels of uric acid are usually lowered via lifestyle changes, and in those with frequent
attacks allopurinol or probenicid provide long-term prevention.
JIA (juvenile idiopathic arthritis)
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of JIA.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of JIA.
In a further aspect of the present invention there is provided a method for treatment of
JIA, comprising administering a peptide according to the present invention to an
individual in need thereof.
Juvenile idiopathic arthritis (JIA) is the most common form of persistent arthritis in
children. Juvenile in this context refers to an onset before age 16, idiopathic refers to a
condition with no defined cause, and arthritis is the inflammation of the synovium of a
joint. JIA is a subset of arthritis seen in childhood, which may be transient and self-
limited, or chronic. It differs significantly from arthritis commonly seen in adults
(osteoarthritis, rheumatoid arthritis), and other types of arthritis that can present in
childhood which are chronic conditions (e.g. psoriatic arthritis and ankylosing
spondylitis). JIA is an autoimmune disease.
Diabetes Mellitus
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of diabetes mellitus.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of diabetes
mellitus.
In a further aspect of the present invention there is provided a method for treatment of
diabetes mellitus, comprising administering a peptide according to the present
invention to an individual in need thereof.
In one embodiment, said diabetes mellitus is diabetes mellitus type I. In another
embodiment, said diabetes mellitus is diabetes mellitus type II.
Diabetes mellitus is a group of metabolic diseases in which a person has high blood
sugar, either because the body does not produce enough insulin, or because cells do
not respond to the insulin that is produced. This high blood sugar produces the
classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and
polyphagia (increased hunger).
• Type 1 diabetes: results from the body's failure to produce insulin, and presently
requires the person to inject insulin. (Also referred to as insulin-dependent
diabetes mellitus, IDDM for short, and juvenile diabetes.)
Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta
cells of the islets of Langerhans in the pancreas leading to insulin deficiency.
This type of diabetes can be further classified as immune-mediated or
idiopathic. The majority of type 1 diabetes is of the immune-mediated nature,
where beta cell loss is a T-cell mediated autoimmune attack.
• Type 2 diabetes: results from insulin resistance, a condition in which cells fail to
use insulin properly, sometimes combined with an absolute insulin deficiency.
(Formerly referred to as non-insulin-dependent diabetes mellitus, NIDDM for
short, and adult-onset diabetes.)
Type 2 diabetes mellitus is characterized by insulin resistance which may be
combined with relatively reduced insulin secretion. The defective
responsiveness of body tissues to insulin is believed to involve the insulin
receptor. Type 2 diabetes is due primarily to lifestyle factors and genetics.
• Gestational diabetes: is when pregnant women, who have never had diabetes
before, have a high blood glucose level during pregnancy. It may precede
development of type 2 DM.
Other forms of diabetes mellitus include congenital diabetes, which is due to genetic
defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by
high doses of glucocorticoids, and several forms of monogenic diabetes.
Diabetes without proper treatments can cause many complications. Acute complica-
tions include hypoglycemia, diabetic ketoacidosis, or nonketotic hyperosmolar coma.
Serious long-term complications include cardiovascular disease, chronic renal failure
and retinal damage. Adequate treatment of diabetes is thus important, as well as blood
pressure control and lifestyle factors such as smoking cessation and maintaining a
healthy body weight.
As of 2000 at least 171 million people worldwide suffer from diabetes, or 2.8% of the
population. Type 2 diabetes is by far the most common, affecting 90 to 95% of the U.S.
diabetes population
Behçet's disease
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of Behçet's disease.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of Behçet's
disease.
In a further aspect of the present invention there is provided a method for treatment of
Behçet's disease, comprising administering a peptide according to the present
invention to an individual in need thereof.
Behçet's disease is a rare, systemic, form of vasculitis (or inflammation of the blood
vessels) that often presents with mucous membrane ulceration, and ocular involve-
ments (involvement of the eyes). Ocular involvement can be in the form of posterior
uveitis, anterior uveitis, or retinal vasculitis. As a systemic disease, it also involves
visceral organs such as the gastrointestinal tract, pulmonary, musculoskeletal, and
neurological systems. This syndrome can be fatal; death can be caused by
complicated rupture of the vascular aneurysms, or severe neurological complications,
and therefore immediate medical treatment is necessary.
Neurodegenerative disorders
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of a neurodegenerative disorder.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of a
neurodegenerative disorder.
In a further aspect of the present invention there is provided a method for treatment of
a neurodegenerative disorder, comprising administering a peptide according to the
present invention to an individual in need thereof.
Particularly, said neurodegenerative disorder has a neuro-inflammatory component and
is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease and Multiple Sclerosis. Especially, said neurodegenerative
disorder may be those wherein IL-1 has a prominent role.
The brain is an immunologically privileged site under normal conditions. Suppression
factors of the immune response include neurotransmitters, neurohormones, neuro-
trophic factors, anti-inflammatory factors, and cell-cell contacts via adhesion molecules
or CD200. However, no single factor can fully account for immune control. Augmented
cerebral immune responses observed in neurodegenerative diseases probably reflect
stimulatory signals that override suppressive signals. However, the suppression of
immune responses is not always beneficial to neurons in degenerative conditions
(Chang et al., 2009). Thus, therapeutic interventions in neurodegenerative diseases
should help re-establish the appropriate control of immune cells/microglia in the CNS.
Neurodegenerative diseases are a growing cause of disability in the aging community.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder. The annual
incidence of AD worldwide is estimated to be 4.6 million cases, with one new case
every 7 s. By the year 2040, 80 million cases worldwide are expected (Massoud and
Gauthier, 2010). Neurodegeneration; the slow progression of dysfunction with a loss of
neurons and axonal connections in the central nervous system (CNS), is the primary
pathological characteristic of such neurological disorders as AD, Parkinson’s disease
(PD) and Huntington’s disease (HD) (Heneka et al., 2010). In AD, the main charac-
teristics of neuroinflammation include microglial activation in regions associated with
Aβ (amyloid beta) deposition and the expression of a variety of proinflammatory
cytokines, such as IL1β and tumor necrosis factor α (TNFα). The ratio of the pro-
inflammatory IL1β to the anti-inflammatory IL10 is markedly increased in serum in AD
patients. The local inflammatory reaction in AD is sustained by activated microglia and
reactive astrocytes. Microglial activation can either be neuroprotective or damaging. An
acute neuroinflammatory response is generally beneficial to the CNS, minimizing
further injury and contributing to the repair of damaged tissue, whereas chronic
inflammation is detrimental and damaging to the nervous system. The progressive
deposition of Aβ in AD is known to be chemo-attractive for microglia and might
therefore provide a chronic stimulus to microglial cells. A non-steroidal anti-inflamma-
tory drug, ibuprofen, has recently been shown to be protective in AD (Heneka et al.,
2010; Krause and Müller, 2010).
The implication of the IL1 system in neurodegeneration is supported by the following
lines of evidence. Its expression is enhanced dramatically and rapidly following any
type of brain injury. All chronic neurodegenerative diseases are accompanied by an
increase in IL1 expression. Moreover, neuroinflammation mediated by IL1β increases
the susceptibility of neurons to degeneration. Microglial cells are the main source of
IL1β in neuroinflammation, although its production is also induced in astrocytes.
Decreased levels of IL1Ra have been found in AD patients. Blocking IL1 signaling by
increasing the amounts of IL1Ra following brain lesions results in improved outcomes
in many experimental models of neurodegeneration. IL1Ra consistently provides
neuroprotection. IL1Ra has been shown to penetrate the human brain at experimen-
tally therapeutic concentrations, and clinical trials for introducing IL1Ra as a post-stroke
therapy have been designed (Cawthorne et al., 2011; Clark et al., 2008; Koprich et al.,
2008; Spulber et al., 2009; Tarkowski et al., 2001).
Alzheimer’s disease
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of Alzheimer's disease.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of Alzheimer's
disease.
In a further aspect of the present invention there is provided a method for treatment of
Alzheimer's disease, comprising administering a peptide according to the present
invention to an individual in need thereof.
Alzheimer's disease (AD) is the most common form of dementia. Most often, it is
diagnosed in people over 65 years of age, although the less-prevalent early-onset
Alzheimer's can occur much earlier. In 2006, there were 26.6 million sufferers
worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.
Although the course of Alzheimer's disease is unique for every individual, there are
many common symptoms. The earliest observable symptoms are often mistakenly
thought to be 'age-related' concerns, or manifestations of stress. In the early stages,
the most commonly recognised symptom is inability to acquire new memories, such as
difficulty in recalling recently observed facts. As the disease advances, symptoms
include confusion, irritability and aggression, mood swings, language breakdown, long-
term memory loss, and the general withdrawal of the sufferer as their senses decline.
Gradually, bodily functions are lost, ultimately leading to death. The mean life
expectancy following diagnosis is approximately seven years.
Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral
cortex and certain subcortical regions. This loss results in gross atrophy of the affected
regions, including degeneration in the temporal lobe and parietal lobe, and parts of the
frontal cortex and cingulate gyrus. Both amyloid plaques and neurofibrillary tangles are
clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense,
mostly insoluble deposits of amyloid-beta peptide and cellular material outside and
around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-
associated protein tau which has become hyperphosphorylated and accumulate inside
the cells themselves.
Parkinson’s disease
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of Parkinson’s disease.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of Parkinson’s
disease.
In a further aspect of the present invention there is provided a method for treatment of
Parkinson’s disease, comprising administering a peptide according to the present
invention to an individual in need thereof.
Parkinson's disease (PD) is a degenerative disorder of the central nervous system. It
results from the death by unknown causes of the dopamine-containing cells of the
substantia nigra, which is a region of the midbrain. Early in the course of the disease,
the most obvious symptoms are movement-related, including shaking, rigidity, slow-
ness of movement and difficulty with walking and gait. Later, cognitive and behavioral
problems may arise, with dementia commonly occurring in the advanced stages of the
disease. Other symptoms include sensory, sleep and emotional problems. PD is more
common in the elderly with most cases occurring after the age of 50 years.
The pathology of the disease is characterized by the accumulation of a protein called
alpha-synuclein into inclusions called Lewy bodies in neurons, and from insufficient
formation and activity of dopamine produced in certain neurons of parts of the
midbrain.
Modern treatments are effective at managing the early motor symptoms of the disease,
mainly through the use of levodopa and dopamine agonists. As the disease progresses
and dopamine neurons continue to be lost, a point eventually arrives at which these
drugs become ineffective at treating the symptoms, while at the same time produce a
complication called dyskinesia, marked by writhing movements. Medications to treat
other symptoms of PD exist. Diet and some forms of rehabilitation have shown some
effectiveness at alleviating symptoms. Surgery and deep brain stimulation have been
used to reduce motor symptoms as a last resort in severe cases where drugs are
ineffective.
Huntingtons disease
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of Huntington's disease.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of
Huntington's disease.
In a further aspect of the present invention there is provided a method for treatment of
Huntington's disease, comprising administering a peptide according to the present
invention to an individual in need thereof.
Huntington's disease, chorea, or disorder (HD), is a neurodegenerative genetic
disorder that affects muscle coordination and leads to cognitive decline and dementia.
It typically becomes noticeable in middle age. HD is the most common genetic cause of
abnormal involuntary writhing movements called chorea and is much more common in
people of Western European descent than in those from Asia or Africa. The disease is
caused by an autosomal dominant mutation on either of an individual's two copies of a
gene called Huntingtin. Physical symptoms of Huntington's disease can begin at any
age from infancy to old age, but usually begin between 35 and 44 years of age. About
6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they
progress faster and vary slightly. The variant is classified as juvenile, akinetic-rigid or
Westphal variant HD.
The Huntingtin gene (HTT) codes for the protein Huntingtin (Htt). Part of this gene is a
repeated section called a trinucleotide repeat, which varies in length between
individuals and may change length between generations. When the length of this
repeated section reaches a certain threshold, it produces an altered form of the protein,
called mutant Huntingtin protein (mHtt). The differing functions of these proteins are the
cause of pathological changes which in turn cause the disease symptoms as the
mutated protein results in gradual damage to specific areas of the brain.
Symptoms of the disease can vary between individuals and even members of the same
family, but the symptoms progress predictably for most individuals. The earliest
symptoms are a general lack of coordination and an unsteady gait. As the disease
advances, uncoordinated, jerky body movements become more apparent, along with a
decline in mental abilities and behavioral and psychiatric problems. Physical abilities
are gradually impeded until coordinated movement becomes very difficult, and mental
abilities generally decline into dementia. Complications such as pneumonia, heart
disease, and physical injury from falls reduce life expectancy to around twenty years
after symptoms begin.
There is no cure for HD, and full-time care is required in the later stages of the disease,
but there are emerging treatments to relieve some of its symptoms.
Multiple sclerosis
It is an aspect of the present invention to provide a peptide according to the present
invention for use in the treatment of Multiple sclerosis.
It is also an aspect of the present invention to provide a peptide according to the
present invention for the manufacture of a medicament for the treatment of Multiple
sclerosis.
In a further aspect of the present invention there is provided a method for treatment of
Multiple sclerosis, comprising administering a peptide according to the present
invention to an individual in need thereof.
Multiple sclerosis (MS, also known as disseminated sclerosis or encephalomyelitis
disseminata) is an inflammatory disease in which the fatty myelin sheaths around the
axons of the brain and spinal cord are damaged, leading to demyelination and scarring
as well as a broad spectrum of signs and symptoms. Disease onset usually occurs in
young adults, and it is more common in females. It has a prevalence that ranges
between 2 and 150 per 100,000.
MS affects the ability of nerve cells in the brain and spinal cord to communicate with
each other. Nerve cells communicate by sending electrical signals called action
potentials down long fibers called axons, which are wrapped in an insulating substance
called myelin. In MS, the body’s own immune system attacks and damages the myelin.
When myelin is lost, the axons can no longer effectively conduct signals. The name
multiple sclerosis refers to scars (scleroses—better known as plaques or lesions)
particularly in the white matter of the brain and spinal cord, which is mainly composed
of myelin.
Almost any neurological symptom can appear with the disease, and often progresses
to physical and cognitive disability. MS takes several forms, with new symptoms
occurring either in discrete attacks (relapsing forms) or slowly accumulating over time
(progressive forms). Between attacks, symptoms may go away completely, but
permanent neurological problems often occur, especially as the disease advances.
There is no known cure for Multiple sclerosis. Treatments attempt to return function
after an attack, prevent new attacks, and prevent disability. MS medications can have
adverse effects or be poorly tolerated, and many patients pursue alternative
treatments, despite the lack of supporting scientific study. Life expectancy of patients is
to 10 years lower than that of the unaffected population
Sequences
Amino acid sequence of the Interleukin-1 receptor antagonist protein (full-length; SEQ
ID NO:28)
UniProt Accession No.: P18510 (IL1RA_HUMAN)
Short names: IL-1RN, IL1RN, IL-1ra, IRAP, IL1F3, IL1RA.
Alternative name(s): ICIL-1RA, IL1 inhibitor, INN=Anakinra
4 isoforms (1 secreted, 3 cytoplasm).
Isoform 1 (identifier: P18510-1), 177 amino acids long, has been chosen as the
'canonical' sequence:
MEICRGLRSHLITLLLFLFHSETICRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGY
LQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRK
QDKRFAFIRSDSGPTTSFESAACPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQ
EDE (SEQ ID NO:28)
The Sequence of Ilantafin-8 / Ilantafin (SEQ ID NO:1) is underlined.
Isoform 2 (identifier: P18510-2), 159 aa long (Also known as: icIL-1ra)
The sequence of this isoform differs from the canonical sequence as follows:
aa 1-21: MEICRGLRSHLITLLLFLFHS → MAL
Isoform 3 (identifier: P18510-3), 180 aa long (Also known as: icIL-1ra type II)
The sequence of this isoform differs from the canonical sequence as follows:
aa 1-21: MEICRGLRSHLITLLLFLFHS → MALADLYEEGGGGGGEGEDNADSK
Isoform 4 (identifier: P18510-4), 143 aa long
The sequence of this isoform differs from the canonical sequence as follows:
aa 1-34: Missing (deleted).
Further Ilantafin-sequences (fragments of IL1RA)
Ilantafin-1: RIWDVNQKT (SEQ ID NO:29)
Ilantafin-2: AGYLQGPNVN (SEQ ID NO:30) – soluble in water, not soluble in PBS or
medium
Ilantafin-3: NQLVAGYLQGPNVN (SEQ ID NO:31) - not soluble in water
Ilantafin-4: VTKFYFQED (SEQ ID NO:32) - not soluble in water
Ilantafin-5: EGVMVTKFYFQED (SEQ ID NO:33) - completely insoluble when produced
Ilantafin-6: NQKTFYLRNNQL (SEQ ID NO:34) – soluble in water, not soluble in PBS or
medium
Ilantafin-7: TAMEADQPVS (SEQ ID NO:35)
Ilantafin-8: Is Ilantafin, SEQ ID NO:1
Ilantafin-9: GPNAKLEEKA (SEQ ID NO:36)
Examples
Example 1
Location of the Ilantafin (Ilantide) sequence motif (SEQ ID NO:1) in the crystal structure
of the complex of human IL1Ra and human IL1RI (Figure 1).
Method: Mapping of the location of the peptide was performed employing PyMOL
software, based on PyMOL v0.99 (DeLano Scientific LLC, South San Francisco,
California, U.S.A). This was done based on the crystal structure of the complex of
human ILRa and human IL1RI, PDB ID: 1IRA (Schreuder et al., 1997).
Example 2
The Ilantafin peptide (SEQ ID NO:1) interacts with the immobilized ectodomain of IL1RI
with an affinity which is within the same order of magnitude as the binding affinities of
IL1β and IL1Ra to IL1RI (Figures 2 and 3). Moreover the peptide competes with the
receptor for the binding of IL1β (Figure 3).
Method: Binding analysis was performed using a BiaCore 2000 Instrument (BiaCore
AB, Uppsala, Sweden) at 25°C using 10 mM sodium phosphate (pH 7.4), 150 mM
NaCl as running buffer. The flow-rate was 5 µl/min. Data were analysed by nonlinear
curve fitting using the manufacturer’s software. The recombinant protein comprising the
whole extracellular part of IL1RI was immobilised on the surface of a CM5 sensor chip
by means of electrostatic interactions, and the peptide and the IL1β and IL1Ra proteins
were injected at various concentrations. The curves corresponding to the difference
between binding to peptides and a blank chip were used for analysis. In Figure 4, the
IL1β protein was immobilized on a sensor chip and the Ilantafin peptide in various
concentrations and the soluble receptor (SIL1RI) in a concentration of 0.12 µM were
injected.
Example 3
The Ilantafin peptide SEQ ID NO:1 (made as a dendrimer/tetramer and in a monomeric
form) inhibits activation of macrophages, which is induced by treatment with IL1β
(Figure 5, Figure 6 and Figure 7). The Ilantafin effect is sequence-specific, since
various forms of a scrambled sequence of Ilantafin, and Ilantafin with the reverse
sequence, do not inhibit activation of NF-κB by IL1β (Figure 8). The Ilantafin effect is
sequence-specific, since the peptide does not inhibit signaling induced by IL6 (Figure
9).
Method: IL1RI signaling assay: Commercially available Blue Cytokine Reporter Cell
technology from InvivoGen (Denmark distributor: Sigma-Aldrich Denmark) was used. It
is represented by an expanding family of engineered cell lines designed to provide a
simple, rapid, and reliable method of monitoring the activation of signaling pathways
induced by key cytokines. HEK-Blue™ IL1β cells are specifically engineered to
selectively respond to IL1β, and they feature the secreted embryonic alkaline
phosphatase (SEAP) reporter gene under the control of an NF-κB-inducible promoter.
The inhibitory effect of the Ilantafin peptide in various concentrations on IL1β-induced
(1.2 pM) activation of NF-κB was determined and compared with data obtained with
commercial IL1Ra and IL1RI. A target/receptor-specificity of the Ilantafin effect was
verified employing HEK-Blue™ IL6 cells.
Example 4
The Ilantafin peptide (SEQ ID NO:1), both as a dendrimer/tetramer or a monomer, in a
dose dependent manner inhibits the IL1β-induced activation of macrophages as
reflected by TNF-α secretion (Figure10, Figure 11). The IL1Ra and SIL1RI proteins
also inhibit macrophage activation (positive controls, Figure 12).
Method: The Ilantafin peptide or IL1Ra or IL1RI was added to cultures of macrophages
(AMJ2-C8) seeded in 6-well multi-dishes (Nunc) (2.5 × 10 cells/well). After 24 h of
incubation at 37 °C, IL1β (1.2 pM) was added to the cultures to activate the macro-
phages. L929 cells were seeded in a 96-well plate at a density of 2 × 10 cells/mL. Both
cell cultures were incubated for 24 h at 37 °C. Conditioned medium from the macro-
phage cultures was collected and added to the fibroblast cultures together with 0.6
μg/well actinomycin D (Sigma-Aldrich). Finally, after 24 h of incubation at 37°C, 20 µl of
3-(4,5-dimethylthiazolyl)(3-carboxymethoxyphenyl)(4-sulfophenyl)-2H-tetra-
zolium (MTS) (Promega, Madison, WI, USA) was added to each well and the plates
were incubated protected from light, at 37 °C, for ~45 min and the optical density was
measured at 490 nm in a Sunrise absorbance reader (Tecan, Männedorf, Switzerland).
In order to calculate the amount of TNF-α in the conditioned medium, a standard curve
was obtained by treating fibroblasts with different concentrations of TNF-α (R&D
systems, Minneapolis, MN, USA).
Example 5
The Ilantafin peptide (SEQ ID NO:1), the IL1Ra and SIL1RI proteins induce neurite
outgrowth in primary cerebellar neurons in a dose-dependent manner, whereas IL1β
itself does not affect neuritogenesis. Moreover, IL1β inhibits Ilantafin- and IL1Ra-
induced neurite outgrowth. It indicates that the inhibition of IL1RI activation promotes
neuronal differentiation (Figure 13 and Figure 19 (same data recalculated), Figure 14).
Method: Cerebellar granular neurons (CGN) were prepared from 3 or 7 postnatal (P)
day Wistar rats (Charles River, Sulzfeld, Germany or Taconic, Ejby, Denmark). Cere-
bella were cleared of meninges and blood vessels, roughly homogenized by chopping,
and trypsinized with trypsin from Sigma-Aldrich (Brøndby, Denmark). The neurons
were washed in the presence of DNAse 1 and soybean trypsin inhibitor (Sigma-
Aldrich), and cellular debris was pelleted by centrifugation before plating. CGNs were
plated at a density of 10,000 cells/well onto uncoated eight-well Lab-Tek chamber
slides (NUNC, Slangerup, Denmark) in Neurobasal-A medium supplemented with 0.4%
(w/v) BSA. Peptides or proteins at various concentrations were added to the medium
immediately after plating, and cells were maintained at 37°C and 5% CO for 24 h.
Cultures then were fixed, blocked and incubated with polyclonal rabbit antibody against
rat GAP-43 (Chemicon, Temecula, CA, USA) followed by incubation with secondary
Alexa Fluor488 goat anti-rabbit antibody (Molecular Probes, Eugene, OR, USA) as
previously described (Neiiendam et al., 2004). The immunostained cultures were all
recorded by computer-assisted fluorescence microscopy using a Nikon Diaphot in-
verted microscope (Nikon, Japan) equipped with a Nikon Plane 20× objective. Images
were captured with a charge-coupled device video camera (Grundig Electronics, Nurn-
berg, Germany) using the software package Prima developed at the Protein Laboratory
(University of Copenhagen, Copenhagen, Denmark). The length of neuronal processes
per cell was estimated using the software package Process Length developed at the
Protein Laboratory (Ronn et al. 2000). For estimation of neurite outgrowth, at least 200
± 20 cells were processed for each group in each individual experiment.
Example 6
The Ilantafin peptide (SEQ ID NO:1) reduces neuronal cell death (apoptosis), which is
induced by lowering concentrations of potassium chloride. The peptide effect is
comparable with the effect of the neuronal survival factor IGF-1 (Figure 15 and Figure
).
Method: Survival assay: Primary cultures of CGN were plated at a density of 100,000
cells/cm2 on poly-L-lysine coated 8-well permanox slides in Neurobasal-A medium
(Gibco BRL) supplemented with 2% (v/v) B27, 0.5% (v/v) glutamax, 100 units/mL
penicillin, 100 lg/mL streptomycin and KCl, making the final concentration of KCl in the
medium 40 mM. 24 hours after plating, cytosine-b-D-arabinofuranoside (Ara-C; Sigma-
Aldrich) was added to a final concentration of 10 µM to avoid proliferation of glial cells,
after which the neurons were allowed to differentiate for a further 6 days at 37°C.
Apoptotic cell death was induced by washing twice and changing the medium to Basal
Medium Eagle (BME; Gibco BRL) supplemented with 1% (v/v) glutamine, 100 U/mL
penicillin and 100 lg/mL streptomycin, 3.5 g D-glucose/L and 1% (v/v) sodium pyruvate
(Gibco BRL) together with various concentrations of peptide. Thereby the concentration
of potassium in the cultures was reduced to 5 mM KCl (Ditlevsen et al., 2003). Two
days after induction of apoptosis, the cells were fixed with 4% (v/v) formaldehyde and
stained with Hoechst 33258 as described for the survival assay employing
hippocampal neurons.
Example 7
The Ilantafin peptide (SEQ ID NO:1) abrogates an increase in clinical manifestations of
CIA in rats (Figure 16).
Method: Rheumatoid arthritis is a chronic, inflammatory, systemic autoimmune disease
that affects about 1% of the general population in Western countries. Collagen-induced
arthritis (CIA) in rats is a widely employed animal model for the screening of anti-
inflammatory compounds. Collagen bovine, type II (CII, Cat.no.20021, Lot 090209,
Chondrex, USA), Complete Freund’s Adjuvant, containing 0.1% of Mycobacterium
tuberculosis (CFA, Cat.no. F5581, Lot 049K8700, Sigma-Aldrich), Incomplete Freund’s
Adjuvant (IFA, Cat.no. F5506, Lot 058K8702, Sigma). PBS (Panum Institute, Copen-
hagen University). Isofluran (Baxter). Animals were immunized twice: on day 0
(CII+CFA) and on day 10 (CII+IFA, booster). On day 15 the mean clinical score
reached a value of 5.0 and all animals were divided into 3 groups so that the severity of
disease (mean clinical score) in all groups was almost equal. The peptide (two doses,
3.3 and 10 mg/kg) was administered subcutaneously daily starting at day 15. The
clinical evaluation of the arthritis severity was assessed using the following grading
system: 0 - no redness or swelling in foot and palm; 1 - slight swelling or redness in
metatarsophalangeal joint and ankle joint foot or palm; 2 - progressed swelling/inflam-
mation and redness from ankle to mid foot or in entire palm; 3 - swelling/inflammation
of entire foot except toes; 4 - swelling and inflammation of entire foot including toes.
Example 8
Detection of Ilantafin peptides (such as SEQ ID NO:1) in plasma and cerebrospinal
fluid.
Blood samples are collected from the orbital plexus of anaesthetized 200 g Wistar rats
at 15min, 30min, 1, 2, 4, 8 and 24 h after single subcutaneous Ilantafin (SEQ ID NO:1)
administration (10mg/kg) as described in Secher et al. (2006). Cerebrospinal fluid is
sampled from the cisterna magna at 2 h, as previously described (Secher et al., 2006).
Ilantafin concentrations in plasma samples were measured using a competitive
enzyme-linked immunosorbent assay. Ninety-six-well AminoTM plates (Nunc) are
coated with 30 mg/ml biotinylated albumin (Sigma-Aldrich) diluted in 100mM carbonate
buffer (pH 9.6). Plates are incubated for 2 h and washed three times with 0.05% v/v
Tween 20 in phosphate buffered saline (PBST). One sample volume is mixed with
three volumes of peroxidase-labelled streptavidin diluted 1:5000 in PBST and
incubated for 30min. A quantity of 100 ml/well of the mixture is then added to
biotinylated albumin-coated plates. Plates are incubated for 1 h, washed three times
with PBST and developed with TMB plus (Kem-En-Tec, Taastrup, Denmark). The
enzymatic reaction is stopped with 0.2M sulphuric acid. Optical density is recorded at
450 nm using a Sunrise absorbance reader (Tecan, Männedorf, Switzerland). All
samples are preferably run in duplicate.
To investigate whether SEQ ID NO:1 penetrates the blood-brain barrier in rats, biotin-
Ilantafin is detected in plasma and the CSF after subcutaneous administration. If the
peptide is present in both the plasma and the CSF, it suggests that systemically
administered Ilantafin crosses the blood–brain barrier.
Example 9
The effect of the Ilantafins, such as SEQ ID NO:1 in reversing neuronal cytotoxicity
may be evaluated by the following method: “Kainic acid-induced cytotoxicity”
Hippocampal neurons are plated at a density of 5x10 cells per well in poly-L-lysine-
coated eight-well LabTek Permanox slides (Nunc) as previously described (Soroka et
al., 2002). After 7 days in culture, neurons are treated with Ilantafin (0.001–3 mM) or
full-length IL1RA for 1 h followed by the addition of 300 mM freshly reconstituted kainic
acid (Sigma, Brøndby, Denmark). Cells are further cultured for 24 h. The cells are fixed
in 4% v/v formaldehyde and stained with 5 mg/ml Hoechst 33258 (Invitrogen, Copen-
hagen, Denmark) or 5 mg/ml propidium iodide (Sigma). At least 1000 cells/condition
are recorded in a systematic series of view fields, with the position of the first field
chosen randomly as described in Ronn et al. (2000). Cell viability is estimated based
on nuclear morphology (dead cells displaying condensed chromatin or fragmented
nuclei) in a semi-automatic mode using software developed at the laboratory to
minimize bias. Results are presented as the mean of the live cell ratio [n live cells/(n
live cells + n dead cells) +/- SEM].
Example 10
The effect of the Ilantafins, such as SEQ ID NO:1 in attenuating seizures, decrease
mortality and decreasing neurodegeneration may be evaluated by the following
method: “Kainic acid-induced seizures”.
Male C57BL/6J mice, 28–32 g, are injected subcutaneously with Ilantafin (10mg/kg),
full-length IL1RA or vehicle 48, 24 and 2 h prior to kainic acid treatment. Based on
preliminary dose-adjustment experiments, two doses of kainic acid (intraperitoneal) are
chosen to perform two sets of experiments to induce either low-grade seizures
(20mg/kg kainic acid) or high-grade seizures and mortality (30mg/kg kainic acid).
Measured parameters included latency of seizure onset, seizure severity and mortality.
Seizure activity is recorded for 2 h following kainic acid administration by an observer
blind to treatment and assessed according to a modified Racine scale (0 = immobility;
1 = facial automatism; 2 = head nodding; 3 = forelimb clonus; 4 = rearing; 5 =
generalized convulsions; 6 = death; Racine, 1972). Seizure grades 1–3 are regarded
as low-grade seizures, and seizure grades 4–5 were regarded as high-grade seizures.
The latency of immobility is measured as the time between kainic acid injection and the
appearance of immobility. The control group of animals received a vehicle injection.
Example 11
Peptides were synthesized using the Fmoc protection strategy on TentaGel resin
(Rapp Polymere, Tübingen, Germany) using Fmoc- (Calbiochem-Novabiochem)
protected amino acids. Dendrimers were composed of four monomers coupled to a
lysine backbone. Dimers were composed of two monomers coupled to a lysine residue.
Peptides were at least 95% pure as estimated by high performance liquid chromato-
graphy and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy
(VG TOF Spec E, Fisons Instruments, Beverly, MA).
Example 12
Peptide solubility.
Upon receiving the peptides from the synthesizing company (as powder), they were
reconstituted in water, in PBS or in medium. Thus it is immediately apparent whether a
peptide is soluble or not.
Example 13
Peptide stability.
A method for evaluating peptide stability is that the peptide amount in solution is
measured spectrophotometrically or by MS (mass spectrometry; measures the mass-
to-charge ratio of charged particles) as a function of time (1, 2, 3 etc days) when
keeping the peptide in solution at 4 C and at room temperature.
Example 14
Effect of Ilantafin SEQ ID NO:1 (SGRKSSKMQA) in a rat model of collagen-induced
arthritis (CIA).
Method:
Collagen-induced arthritis in rats (CIA).
Induction of CIA. The CIA study was performed on a total of 40 male Wistar rats with
an average weight of 150 g at the beginning of the experiment. CIA was induced by
subcutaneous (s.c.) injection of bovine collagen type II (CII, Sigma-Aldrich) solubilised
in 0.05 M acetic acid (2 mg/ml), and then emulsified 1:1 with CFA (Sigma-Aldrich)
containing 1.0 mg/ml heat-inactivated M. tuberculosis. Under inhalation anaesthesia
(Isofluran, 3%) 250 μl of the emulsion containing 250 µg of CII and 125 µg of M.
tuberculosis was injected (s.c.) at the tail base (post-immunization day, dpi 0).
Treatment design. At dpi 8, before onset of clinical signs, all animals were randomly
divided into two groups, 20 rats per group, and were dosed daily during 8 days (dpi 8 -
) with Ilantafin (10.0 mg/kg, s.c.) or vehicle (PBS, 1.0 ml/kg, s.c.). Clinical evaluation
was carried out on dpi 7 – 16, and was continued in the period without treatment on dpi
29-33.
Clinical scores. An observer blinded to treatment groups evaluated the severity of
arthritis employing the following grading system: 0 - no redness or swelling in foot; 1 –
slight redness in foot or redness and swelling in single interfalangeal joints; 2 -
moderate swelling and redness in ankle and metatarsal part of foot; 3 – marked
swelling and redness of entire foot, restricted usage of foot in locomotion; 4 - marked
swelling and redness of entire foot, impossibility of usage foot in locomotion and
rearing. Since CIA typically involves only the hind limbs, the arthritic index of a rat was
defined as the sum of the 2 limb scores. Animals were sacrificed when severity of the
arthritis reached score 7.
Statistical analysis was performed employing two- way ANOVA and t-test.
Results:
Ilantafin reduces morbidity of animals with CIA, see figure 17. Morbidity was expressed
as a percentage of animals reached clinical index 7 and therefore sacrificed by the test
day. Ilantafin significantly reduced morbidity by dpi 12. * - P<0.05 (unpaired t-test with
Welch’s correction).
Furthermore, Ilantafin attenuates severity of CIA (clinical evaluation), see figure 18.
Two-way ANOVA revealed significant effect of treatment on clinical score of animals
with CIA [F(1, 238)=18.05, P<0.0001]. Ilantafin attenuated severity of CIA on dpi 13-15.
* - P<0.05 (unpaired t-test with Welch’s correction).
References
Cawthorne C, Prenant C, Smigova A, Julyan P, Maroy R, Herholz K, Rothwell N,
Boutin H (2011) Biodistribution, pharmacokinetics and metabolism of inter-
leukin-1 receptor antagonist (IL-1RA) using [ F]-IL1RA and PET imaging in
rats. Br J Pharmacol 162:659-672.
Chang RC, Chiu K, Ho YS, So KF (2009) Modulation of neuroimmune responses on
glia in the central nervous system: implication in therapeutic intervention against
neuroinflammation. Cell Mol Immunol 6:317-326.
Clark SR. McMahon CJ, Gueorguieva I, Rowland M, Scarth S, Georgiou R, Tyrrell PJ,
Hopkins SJ, Rothwell NJ (2008) Interleukin-1 receptor antagonist penetrates
human brain at experimentally therapeutic concentrations. J Cereb Blood Flow
Metab 28:387-394.
Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095-2147.
Ditlevsen DK, Køhler LB, Pedersen MV, Rissel M, Kolkova K, Meyer M, Berezin V and
Bock E. The role of phosphatidylinositol 3-kinase in neural cell adhesion
molecule-mediated neuronal differentiation and survival. J. Neurochem. 2003,
84:546-556.
Hallegua DS, Weisman MH (2002) Potential therapeutic uses of interleukin 1 receptor
antagonists in human diseases. Ann Rheum Dis 61:960-967.
Heneka MT, O'Banion MK, Terwel D, Kummer MP (2010) Neuroinflammatory
processes in Alzheimer’s disease. J Neural Transm 117:919-947.
Koprich JB, Reske-Nielsen C, Mithal P, Isacson O (2008) Neuroinflammation mediated
by IL-1β increases susceptibility of dopamine neurons to degenertion in an
animal model of Parkinson’s disease. J Neuroinflammation 5:8.
Krause DL, Müller N (2010) Neuroinflammation, microglia and implications for anti-
inflammatory treatment in Alzheimer’s disease. Int J Alzheimers Dis pii:732806.
Massoud F, Gauthier S (2010) Update on the pharmacological treatment of Alzheimer’s
disease. Curr Neuropharmacol 8:69-80.
Neiiendam JL, Køhler LB, Christensen C, Li S, Pedersen MV, Ditlevsen DK, Kornum
MK, Kiselyov VV, Berezin V and Bock E. An NCAM-derived FGF-receptor
agonist, the FGF-peptide, induces neurite outgrowth and neuronal survival in
primary rat neurons. J. Neurochem. 2004, 91:920-935.
Rønn LC, Ralets I, Hartz B, Beck M, Berezin A, Berezin V, Møller A and Bock E. A
simple procedure for quantification of neurite outgrowth based on stereological
principles. J. Neurosci. Meth. 2000, 100:25-32.
Schreuder H, Tardif C, Trump-Kallmeyer S, Soffientini A, Sarubbi E, Akeson A, Bowlin
T, Yanofsky S, Barrett RW (1997) A new cytokine-receptor binding mode
revealed by the crystal structure of the IL-1 receptor with an antagonist. Nature
386:194-200.
Secher T, Novitskaia V, Berezin V, Bock E, Glenthoj B, Klementiev B. A neural cell
adhesion molecule-derived fibroblast growth factor receptor agonist, the FGL-
peptide, promotes early postnatal sensorimotor development and enhances
social memory retention. Neuroscience 2006; 141: 1289–99.
Spulber S, Bartfai T, Schultzberg M (2009) IL-1/IL-1ra balance in the brain revisited:
evidence from transgenic mouse models. Brain Behav Immun 23:573-579.
Soroka V, Kiryushko D, Novitskaya V, Ronn LC, Poulsen FM, Holm A, et al. Induction
of neuronal differentiation by a peptide corresponding to the homophilic binding
site of the second Ig module of the neural cell adhesion molecule. J Biol Chem
2002; 277: 24676–83.
Tarkowski E, Liljeroth AM, Nilsson A, Minthon L, Blennow K (2001) Decreased levels of
intrathetical interleukin 1 receptor antagonist in Alzheimer’s disease. Dement
Geriatr Cogn Disord 12:314-317.
Claims (23)
1. A peptide consisting of a peptide sequence of 7 to 14 contiguous amino acid residues derived from IL-1 receptor antagonist protein (IL1RA), said peptide 5 comprising the amino acid sequence of SEQ ID NO:1 (SGRKSSKMQA), or consisting of a fragment of 7 to 9 consecutive amino acids of SEQ ID NO:1, or comprising a variant of SEQ ID NO:1 having at least 75% sequence identity to SEQ ID NO:1, or consisting of a variant of a fragment of SEQ ID NO:1, said variant consisting of 10 an amino acid sequence of 7 to 9 consecutive amino acids of SEQ ID NO:1 having at least 75% sequence identity to any one of SEQ ID NO:1, wherein said peptide binds to IL-1 receptor type 1 (IL1RI), and interferes with the binding of IL-1 beta to IL1RI. 15
2. The peptide according to claim 1, wherein said peptide stimulates neurite outgrowth, promoties survival of neurons, inhibits IL-1 induced biological effects, inhibits NF-kB activation and/or inhibits TNF-alpha increase.
3. The peptide according to claim 1, wherein said variant of SEQ ID NO:1has at 20 least 85% identity to SEQ ID NO:1.
4. The peptide according to claim 1, wherein said peptide consists of SEQ ID NO:1. 25
5. The peptide according to claim1, wherein said peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:11 and SEQ ID NO:22. 30
6. The peptide according to claim 1, wherein said variant of SEQ ID NO:1 comprises one amino acid substitution.
7. The peptide according to claim 6, wherein said variant of SEQ ID NO:1 comprises two amino acid substitutions.
8. The peptide according to claim 6 or claim 7, wherein said one or more amino acid substitution is a conservative amino acid substitution.
9. A multimeric compound comprising two or more peptides, wherein each of said 5 two or more peptides consists of a peptide according to any one of claims 1 to
10. The compound according to claim 9, wherein the two or more peptides are linked via a peptide bond or a linker group.
11. The compound according to claim 10, wherein said linker group comprises one or more lysine residues, a lysine backbone or a polymer carrier.
12. The compound according to claim 9, wherein said compound is selected from 15 the group consisting of a dimer, a trimer, a tetramer, a dendrimer comprising 4, 8, 16 or 32 peptides and a tetrameric dendrimer.
13. The compound according to claim 12, wherein said compound is a dimer. 20
14. The compound according to claim 12, wherein said compound is a tetramer.
15. The compound according to any one of claims 9 to 14, wherein said two or more peptides are identical with respect to each other. 25
16. The compound according to claim 15, wherein each of said two or more peptides consist of SEQ ID NO:1.
17. Use of a peptide or compound according to any one of claims 1 to 16 in the manufacture of a medicament for the treatment of an inflammatory disease.
18. The use according to claim 17, wherein said inflammatory disease is selected from the group consisting of Acne vulgaris, Asthma, Atherosclerosis, Autoimmune diseases, Behçet's disease, Chronic Inflammation, Chronic prostatitis, Dermatitis, Gout, Glumerulonephritis, Hypersensitives (including type 35 1 (immediate, or atopic, or anaphylactic) comprising Allergic asthma, Allergic conjunctivitis, Allergic rhinitis (hay fever), Anaphylaxis, Angioedema, Urticaria (hives), Eosinophilia, and response to Penicillin and Cephalosporin; Type 2 (antibody-dependent) comprising Autoimmune hemolytic anemia, Goodpasture’s syndrome, Hepatitis, IBS (irritable bowel disease), Juvenile idiopathic arthritis (JIA), Pemphigus, Pernicious anemia (if autoimmune), 5 Psoriasis, Psoriasis Arthritis, Immune thrombocytopenia, Transfusion reactions, Hashimoto’s thyroiditis, Interstitial cystitis, Graves disease, Myastenia gravis, Rheumatic fever, Hemolytic disease of the newborn and Acute transplant rejection; Type 3 (immune complex) comprising Rheumatoid arthritis, Immune complex glumerulonephritis, Serum sickness, Subacute, bacterial endocarditis, 10 Symptoms of malaria, Systemic lupus erythematosus (SLE), Arthus reaction, Farmer’s lung and Polyarteritis nodosa; Type 4 (cell-mediated or delayed-type hypersensitivity DTH) comprising Contact dermatitis, Atopic dermatitis (eczema), Temporal arteritis, Sarcoidosis, Symptoms of leprosy, Symptoms of tuberculosis, Systemic sclerosis, Mantoux test, Coeliac disease and Chronic 15 transplant rejection), Inflammatory bowel diseases (including Crohn’s disease, Ulcerative colitis, Collagenous collitis, Lymphocytic collitis, Ischaemic collitis, Diversion collitis, Behcet’s syndrome, Infective collitis and Indeterminate collitis), Myopathies (including dermatomyositis, polymyositis, and inclusion body myositis), Pelvic inflammatory disease, Podagra, Reperfusion Injury, 20 Rheumatoid arthritis, Transplant rejection and Vasculitis.
19. The use according to claim 17, wherein said inflammatory disease is rheumatoid arthritis. 25
20. The use according to claim 17, wherein said inflammatory disease is diabetes mellitus, diabetes mellitus type I or diabetes mellitus type II.
21. Use of a peptide or compounds according to any one of claims 1 to16 in the manufacture of a medicament for the treatment of a neurodegenerative 30 disease.
22. The use according to claim 21, wherein said neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Multiple Sclerosis and neurodegenerative diseases with a 35 neuro-inflammatory component.
23. A peptide according claim 1 substantially as hereinbefore defined with reference to the Examples, excluding any comparative Examples. 1 /33
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA201170120 | 2011-03-14 | ||
DKPA201170120 | 2011-03-14 | ||
PCT/DK2012/000022 WO2012122985A1 (en) | 2011-03-14 | 2012-03-14 | Antagonists of the interleukin- 1 receptor |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ615710A NZ615710A (en) | 2015-10-30 |
NZ615710B2 true NZ615710B2 (en) | 2016-02-02 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2012228769B2 (en) | Antagonists of the interleukin- 1 receptor | |
JP6403062B2 (en) | Tissue repair active composition and use thereof | |
CN109718363B (en) | Peptide for preventing, relieving or treating Alzheimer disease and application thereof | |
JP6529606B2 (en) | Short synthetic peptides for treating and / or preventing autoimmune and inflammatory disorders | |
WO2013097748A1 (en) | Uses of interleukin-22(il-22) in treating and preventing nerve damage diseases or neurodegenerative diseases | |
CN107629114B (en) | Polypeptide, derivative thereof and application thereof in preparation of anti-pulmonary fibrosis drugs | |
CN110799547B (en) | Compounds for treating, ameliorating or preventing neurological-related disorders and uses thereof | |
JP6262661B2 (en) | A therapeutic agent for amyotrophic lateral sclerosis | |
CN110809579B (en) | Pharmaceutically acceptable salts of polypeptides and uses thereof | |
US7608589B2 (en) | Peptidyl diacylglycerides | |
JP2020509061A (en) | Polypeptides, polypeptide fragments and derivatives thereof, and applications | |
Class et al. | Patent application title: Antagonists of the Interleukin-1 Receptor Inventors: Vladimir Berezin (Copenhagen N, DK) Vladimir Berezin (Copenhagen N, DK) Elisabeth Bock (Charlottenlund, DK) Assignees: SERODUS ASA | |
NZ615710B2 (en) | Antagonists of the interleukin- 1 receptor | |
WO2016160576A1 (en) | Human leucine zipper/trail recombinant polypeptides | |
KR20170069997A (en) | Myristoylated leptin-related peptides and uses thereof | |
CN118252913A (en) | Polypeptide conjugate and application thereof in heart failure with ejection fraction reserved | |
US20050256039A1 (en) | Novel fibroblast growth factors and methods of use thereof | |
WO2004100892A2 (en) | Novel fibroblast growth factors and methods of use thereof |