TWI640632B - 抗發炎胜肽及包含其之成分(三) - Google Patents
抗發炎胜肽及包含其之成分(三) Download PDFInfo
- Publication number
- TWI640632B TWI640632B TW102115617A TW102115617A TWI640632B TW I640632 B TWI640632 B TW I640632B TW 102115617 A TW102115617 A TW 102115617A TW 102115617 A TW102115617 A TW 102115617A TW I640632 B TWI640632 B TW I640632B
- Authority
- TW
- Taiwan
- Prior art keywords
- peptide
- pep
- inflammatory
- composition
- amino acid
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 175
- 239000000203 mixture Substances 0.000 title claims abstract description 53
- 230000003110 anti-inflammatory effect Effects 0.000 title abstract description 32
- 102000004196 processed proteins & peptides Human genes 0.000 title description 30
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 108010017842 Telomerase Proteins 0.000 claims description 16
- 241000282414 Homo sapiens Species 0.000 claims description 13
- 235000013305 food Nutrition 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 3
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 3
- 201000009906 Meningitis Diseases 0.000 claims description 3
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims description 3
- 206010029240 Neuritis Diseases 0.000 claims description 3
- 206010033799 Paralysis Diseases 0.000 claims description 3
- 208000020339 Spinal injury Diseases 0.000 claims description 3
- 206010046851 Uveitis Diseases 0.000 claims description 3
- 210000003169 central nervous system Anatomy 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 206010014599 encephalitis Diseases 0.000 claims description 3
- 201000010849 intracranial embolism Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 208000004296 neuralgia Diseases 0.000 claims description 3
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 abstract description 35
- 230000004054 inflammatory process Effects 0.000 abstract description 34
- 230000000694 effects Effects 0.000 abstract description 29
- 208000027866 inflammatory disease Diseases 0.000 abstract description 19
- 239000012634 fragment Substances 0.000 abstract description 15
- 239000002537 cosmetic Substances 0.000 abstract description 10
- 230000003449 preventive effect Effects 0.000 abstract description 2
- 108010088535 Pep-1 peptide Proteins 0.000 description 94
- 210000004027 cell Anatomy 0.000 description 75
- 235000001014 amino acid Nutrition 0.000 description 45
- 229940024606 amino acid Drugs 0.000 description 44
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 43
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 43
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 42
- 150000001413 amino acids Chemical class 0.000 description 42
- 210000001178 neural stem cell Anatomy 0.000 description 38
- 108090000623 proteins and genes Proteins 0.000 description 34
- 102000004169 proteins and genes Human genes 0.000 description 33
- 230000014509 gene expression Effects 0.000 description 30
- 238000004458 analytical method Methods 0.000 description 27
- 102100037907 High mobility group protein B1 Human genes 0.000 description 25
- 101001025337 Homo sapiens High mobility group protein B1 Proteins 0.000 description 25
- 238000002474 experimental method Methods 0.000 description 24
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 23
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 23
- 235000018102 proteins Nutrition 0.000 description 21
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 20
- 239000002158 endotoxin Substances 0.000 description 19
- 102000004127 Cytokines Human genes 0.000 description 18
- 108090000695 Cytokines Proteins 0.000 description 18
- 230000001965 increasing effect Effects 0.000 description 18
- 229920006008 lipopolysaccharide Polymers 0.000 description 18
- 108020004414 DNA Proteins 0.000 description 17
- 230000004083 survival effect Effects 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 230000002401 inhibitory effect Effects 0.000 description 12
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 11
- 102000040430 polynucleotide Human genes 0.000 description 11
- 108091033319 polynucleotide Proteins 0.000 description 11
- 239000002157 polynucleotide Substances 0.000 description 11
- 108010033276 Peptide Fragments Proteins 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 108010057466 NF-kappa B Proteins 0.000 description 9
- 102000003945 NF-kappa B Human genes 0.000 description 9
- 102000007079 Peptide Fragments Human genes 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 230000002757 inflammatory effect Effects 0.000 description 9
- 230000028709 inflammatory response Effects 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- -1 FITC-TAT Proteins 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 102000039446 nucleic acids Human genes 0.000 description 8
- 108020004707 nucleic acids Proteins 0.000 description 8
- 150000007523 nucleic acids Chemical class 0.000 description 8
- 230000037361 pathway Effects 0.000 description 8
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 8
- 239000002953 phosphate buffered saline Substances 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 238000006467 substitution reaction Methods 0.000 description 8
- 108090001030 Lipoproteins Proteins 0.000 description 7
- 102000004895 Lipoproteins Human genes 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 239000013642 negative control Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 108700010013 HMGB1 Proteins 0.000 description 6
- 102000055207 HMGB1 Human genes 0.000 description 6
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 230000036252 glycation Effects 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 210000004940 nucleus Anatomy 0.000 description 6
- 230000000770 proinflammatory effect Effects 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 108091035539 telomere Proteins 0.000 description 6
- 102000055501 telomere Human genes 0.000 description 6
- 210000003411 telomere Anatomy 0.000 description 6
- 201000004624 Dermatitis Diseases 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 239000012980 RPMI-1640 medium Substances 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 210000000805 cytoplasm Anatomy 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 210000002540 macrophage Anatomy 0.000 description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000007704 transition Effects 0.000 description 5
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 4
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 102000004889 Interleukin-6 Human genes 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000005054 agglomeration Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 230000001640 apoptogenic effect Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 210000001616 monocyte Anatomy 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 230000015607 signal release Effects 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin 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
- 238000000539 two dimensional gel electrophoresis Methods 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 208000018522 Gastrointestinal disease Diseases 0.000 description 3
- 208000024781 Immune Complex disease Diseases 0.000 description 3
- 125000000570 L-alpha-aspartyl group Chemical group [H]OC(=O)C([H])([H])[C@]([H])(N([H])[H])C(*)=O 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- 206010029350 Neurotoxicity Diseases 0.000 description 3
- 239000000020 Nitrocellulose Substances 0.000 description 3
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 3
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 3
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 3
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 3
- 206010040047 Sepsis Diseases 0.000 description 3
- 206010040070 Septic Shock Diseases 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 206010044221 Toxic encephalopathy Diseases 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 206010047115 Vasculitis Diseases 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 208000038016 acute inflammation Diseases 0.000 description 3
- 230000006022 acute inflammation Effects 0.000 description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 150000001720 carbohydrates Chemical group 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- 208000037976 chronic inflammation Diseases 0.000 description 3
- 230000006020 chronic inflammation Effects 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000011278 co-treatment Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000009585 enzyme analysis Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 230000007135 neurotoxicity Effects 0.000 description 3
- 231100000228 neurotoxicity Toxicity 0.000 description 3
- 229920001220 nitrocellulos Polymers 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 244000045947 parasite Species 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 206010034674 peritonitis Diseases 0.000 description 3
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 238000003757 reverse transcription PCR Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 2
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 2
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 2
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 description 2
- 206010001889 Alveolitis Diseases 0.000 description 2
- 208000004881 Amebiasis Diseases 0.000 description 2
- 206010001980 Amoebiasis Diseases 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 206010003011 Appendicitis Diseases 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 2
- 108090001008 Avidin Proteins 0.000 description 2
- 208000031729 Bacteremia Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010006448 Bronchiolitis Diseases 0.000 description 2
- 206010006895 Cachexia Diseases 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- 206010007134 Candida infections Diseases 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 description 2
- 206010009895 Colitis ischaemic Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 208000001490 Dengue Diseases 0.000 description 2
- 206010012310 Dengue fever Diseases 0.000 description 2
- 101100396994 Drosophila melanogaster Inos gene Proteins 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- 206010014561 Emphysema Diseases 0.000 description 2
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 206010016228 Fasciitis Diseases 0.000 description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 description 2
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101001074035 Homo sapiens Zinc finger protein GLI2 Proteins 0.000 description 2
- 206010020843 Hyperthermia Diseases 0.000 description 2
- 208000029523 Interstitial Lung disease Diseases 0.000 description 2
- 102000002397 Kinins Human genes 0.000 description 2
- 108010093008 Kinins Proteins 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 2
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 206010069698 Langerhans' cell histiocytosis Diseases 0.000 description 2
- 102000003820 Lipoxygenases Human genes 0.000 description 2
- 108090000128 Lipoxygenases Proteins 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 208000009525 Myocarditis Diseases 0.000 description 2
- 241000243985 Onchocerca volvulus Species 0.000 description 2
- 206010031252 Osteomyelitis Diseases 0.000 description 2
- 239000012828 PI3K inhibitor Substances 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 208000031481 Pathologic Constriction Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 description 2
- 201000007100 Pharyngitis Diseases 0.000 description 2
- 108010003541 Platelet Activating Factor Proteins 0.000 description 2
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 2
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 206010041969 Steatorrhoea Diseases 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 206010042496 Sunburn Diseases 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 208000025609 Urogenital disease Diseases 0.000 description 2
- 208000024780 Urticaria Diseases 0.000 description 2
- 206010046914 Vaginal infection Diseases 0.000 description 2
- 201000008100 Vaginitis Diseases 0.000 description 2
- 102100035558 Zinc finger protein GLI2 Human genes 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 206010003230 arteritis Diseases 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 201000003984 candidiasis Diseases 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 208000003167 cholangitis Diseases 0.000 description 2
- 201000001352 cholecystitis Diseases 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 208000025729 dengue disease Diseases 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 238000001378 electrochemiluminescence detection Methods 0.000 description 2
- 206010014665 endocarditis Diseases 0.000 description 2
- 208000003401 eosinophilic granuloma Diseases 0.000 description 2
- 210000002409 epiglottis Anatomy 0.000 description 2
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 2
- 208000024326 hypersensitivity reaction type III disease Diseases 0.000 description 2
- 230000036031 hyperthermia Effects 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 201000008222 ischemic colitis Diseases 0.000 description 2
- 150000002617 leukotrienes Chemical class 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000002493 microarray Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 208000002042 onchocerciasis Diseases 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 208000008494 pericarditis Diseases 0.000 description 2
- 208000028169 periodontal disease Diseases 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 2
- 206010035653 pneumoconiosis Diseases 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 201000007094 prostatitis Diseases 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- 206010039083 rhinitis Diseases 0.000 description 2
- 201000009890 sinusitis Diseases 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 208000001162 steatorrhea Diseases 0.000 description 2
- 230000036262 stenosis Effects 0.000 description 2
- 208000037804 stenosis Diseases 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 201000004595 synovitis Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 201000005060 thrombophlebitis Diseases 0.000 description 2
- 206010043778 thyroiditis Diseases 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 2
- 208000025883 type III hypersensitivity disease Diseases 0.000 description 2
- 238000010798 ubiquitination Methods 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 208000000143 urethritis Diseases 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 description 1
- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 description 1
- ADOHASQZJSJZBT-SANMLTNESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C12=CC=CC=C2N(C(=O)OC(C)(C)C)C=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ADOHASQZJSJZBT-SANMLTNESA-N 0.000 description 1
- JAUKCFULLJFBFN-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound C1=CC(OC(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JAUKCFULLJFBFN-VWLOTQADSA-N 0.000 description 1
- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 description 1
- CBPJQFCAFFNICX-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(C)C)C(O)=O)C3=CC=CC=C3C2=C1 CBPJQFCAFFNICX-IBGZPJMESA-N 0.000 description 1
- BUBGAUHBELNDEW-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylsulfanylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCSC)C(O)=O)C3=CC=CC=C3C2=C1 BUBGAUHBELNDEW-SFHVURJKSA-N 0.000 description 1
- KJYAFJQCGPUXJY-UMSFTDKQSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-(tritylamino)butanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KJYAFJQCGPUXJY-UMSFTDKQSA-N 0.000 description 1
- OTKXCALUHMPIGM-FQEVSTJZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 OTKXCALUHMPIGM-FQEVSTJZSA-N 0.000 description 1
- WDGICUODAOGOMO-DHUJRADRSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-(tritylamino)pentanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)CC(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WDGICUODAOGOMO-DHUJRADRSA-N 0.000 description 1
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 description 1
- VCFCFPNRQDANPN-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCC)C(O)=O)C3=CC=CC=C3C2=C1 VCFCFPNRQDANPN-IBGZPJMESA-N 0.000 description 1
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 1
- HNICLNKVURBTKV-NDEPHWFRSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C HNICLNKVURBTKV-NDEPHWFRSA-N 0.000 description 1
- KYBXNPIASYUWLN-WUCPZUCCSA-N (2s)-5-hydroxypyrrolidine-2-carboxylic acid Chemical compound OC1CC[C@@H](C(O)=O)N1 KYBXNPIASYUWLN-WUCPZUCCSA-N 0.000 description 1
- LZOLWEQBVPVDPR-VLIAUNLRSA-N (2s,3r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]butanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@H](OC(C)(C)C)C)C(O)=O)C3=CC=CC=C3C2=C1 LZOLWEQBVPVDPR-VLIAUNLRSA-N 0.000 description 1
- QXVFEIPAZSXRGM-DJJJIMSYSA-N (2s,3s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@@H](C)CC)C(O)=O)C3=CC=CC=C3C2=C1 QXVFEIPAZSXRGM-DJJJIMSYSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical class C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 description 1
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 1
- 229940117976 5-hydroxylysine Drugs 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 description 1
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 230000006974 Aβ toxicity Effects 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101100496968 Caenorhabditis elegans ctc-1 gene Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 101100298350 Clostridioides difficile (strain 630) zmp1 gene Proteins 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102100030497 Cytochrome c Human genes 0.000 description 1
- 108010075031 Cytochromes c Proteins 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 238000003718 Dual-Luciferase Reporter Assay System Methods 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- 102100032606 Heat shock factor protein 1 Human genes 0.000 description 1
- 101710190344 Heat shock factor protein 1 Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000620009 Homo sapiens Polyunsaturated fatty acid 5-lipoxygenase 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
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 108030003815 Inositol 3-kinases Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 125000001176 L-lysyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])C(N([H])[H])([H])[H] 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 description 1
- 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 125000003798 L-tyrosyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- BFVQTKQTUCQRPI-YYEZTRBPSA-N LPS with O-antigen Chemical compound O([C@@H]1[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@@H]4[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]5[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O5)O)O4)O)[C@@H](O)[C@@H](CO)O3)NC(C)=O)[C@@H](O)[C@@H](CO[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)NC(C)=O)O2)NC(C)=O)[C@H](O)[C@@H](CO)OC1O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)OC([C@@H]1O)O[C@H]1[C@H](O)[C@@H]([C@@H](O)COC2[C@H]([C@@H](O)[C@H](OP(O)(O)=O)[C@@H]([C@@H](O)CO)O2)O)OC([C@H]1O)O[C@H]1[C@H](OP(O)(=O)OP(O)(=O)OCCN)[C@@H]([C@@H](O)CO)OC([C@H]1O)O[C@H]1[C@H](O[C@]2(O[C@@H]([C@@H](O)[C@H](O[C@]3(O[C@@H]([C@@H](O)[C@H](OP(O)(=O)OCCN)C3)[C@@H](O)CO)C(O)=O)C2)[C@@H](O)CO)C(O)=O)C[C@](O[C@@H]1[C@@H](O)CO)(OC[C@H]1O[C@@H](OC[C@@H]2[C@H]([C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O2)O)[C@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@H]([C@@H]1OP(O)(O)=O)OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)C(O)=O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O BFVQTKQTUCQRPI-YYEZTRBPSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 1
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 101100221647 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cox-1 gene Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108010047956 Nucleosomes Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 101150062589 PTGS1 gene Proteins 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 102100022364 Polyunsaturated fatty acid 5-lipoxygenase Human genes 0.000 description 1
- 102100031950 Polyunsaturated fatty acid lipoxygenase ALOX15 Human genes 0.000 description 1
- 101710164073 Polyunsaturated fatty acid lipoxygenase ALOX15 Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 239000013614 RNA sample Substances 0.000 description 1
- 108010052090 Renilla Luciferases Proteins 0.000 description 1
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010038687 Respiratory distress Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000242583 Scyphozoa Species 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 108020004688 Small Nuclear RNA Proteins 0.000 description 1
- 102000039471 Small Nuclear RNA Human genes 0.000 description 1
- 108020003224 Small Nucleolar RNA Proteins 0.000 description 1
- 102000042773 Small Nucleolar RNA Human genes 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 108091060271 Small temporal RNA Proteins 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 108010006785 Taq Polymerase Proteins 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 102100033138 Tyrosine-protein phosphatase non-receptor type 22 Human genes 0.000 description 1
- 208000027207 Whipple disease Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001166 anti-perspirative effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003213 antiperspirant Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 108010030694 avidin-horseradish peroxidase complex Proteins 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 102000055102 bcl-2-Associated X Human genes 0.000 description 1
- 108700000707 bcl-2-Associated X Proteins 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003181 biological factor Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229930189065 blasticidin Natural products 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- HLCGVCZVBXKAMT-UHFFFAOYSA-N butane-2,2-dithiol Chemical compound CCC(C)(S)S HLCGVCZVBXKAMT-UHFFFAOYSA-N 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000012997 ficoll-paque Substances 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229940044680 immune agonist Drugs 0.000 description 1
- 239000012651 immune agonist Substances 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000003455 independent Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000001023 inorganic pigment Substances 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
- 230000009545 invasion Effects 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 238000012775 microarray technology Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 210000002433 mononuclear leukocyte Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000012740 non-selective inhibitor Substances 0.000 description 1
- 210000001623 nucleosome Anatomy 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012860 organic pigment Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000863 peptide conjugate Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 230000009979 protective mechanism Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 102000037983 regulatory factors Human genes 0.000 description 1
- 108091008025 regulatory factors Proteins 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 108010004034 stable plasma protein solution Proteins 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- IWISVGQUKNSOCC-UHFFFAOYSA-K tetramethylazanium;phosphate Chemical compound C[N+](C)(C)C.C[N+](C)(C)C.C[N+](C)(C)C.[O-]P([O-])([O-])=O IWISVGQUKNSOCC-UHFFFAOYSA-K 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 230000009452 underexpressoin Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000024883 vasodilation Effects 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
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
- C12N9/1241—Nucleotidyltransferases (2.7.7)
- C12N9/1276—RNA-directed DNA polymerase (2.7.7.49), i.e. reverse transcriptase or telomerase
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/45—Transferases (2)
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P19/00—Drugs for skeletal disorders
-
- 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
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- 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
- A61P25/28—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
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- 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
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
- A61P37/02—Immunomodulators
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4702—Regulators; Modulating activity
- C07K14/4703—Inhibitors; Suppressors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0815—Tripeptides with the first amino acid being basic
- C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0819—Tripeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1019—Tetrapeptides with the first amino acid being basic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1021—Tetrapeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0069—Oxidoreductases (1.) acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
- C12N9/0083—Miscellaneous (1.14.99)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y113/00—Oxidoreductases acting on single donors with incorporation of molecular oxygen (oxygenases) (1.13)
- C12Y113/11—Oxidoreductases acting on single donors with incorporation of molecular oxygen (oxygenases) (1.13) with incorporation of two atoms of oxygen (1.13.11)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y114/00—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14)
- C12Y114/99—Miscellaneous (1.14.99)
- C12Y114/99001—Prostaglandin-endoperoxide synthase (1.14.99.1), i.e. cyclooxygenase
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
- C12Y207/07—Nucleotidyltransferases (2.7.7)
- C12Y207/07049—RNA-directed DNA polymerase (2.7.7.49), i.e. telomerase or reverse-transcriptase
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Neurosurgery (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Birds (AREA)
Abstract
本發明關於具有抗發炎活性的胜肽,其中該胜肽包含:序列編號:1;與上述序列具有80以上之胺基酸序列同源性的胜肽;或該胜肽為上述胜肽的片段。本發明也關於包含上述胜肽的抗發炎組成物。根據本發明,包含序列編號:1的胜肽對抑制發炎及以預防性手段抑制發炎二者皆具有優異的功效。因此,包含此發明之胜肽的組成物可被用作抗發炎醫藥組成物或用作化妝品組成物,從而治療或防止多種不同類型的發炎疾病。
Description
本發明係有關於抗發炎胜肽及包含抗發炎胜肽的組成物。
發炎是一種生物防禦的型態,作為保護身體不受到可能由外部物理性刺激、化學性刺激(如暴露在多種過敏原下,或包括細菌、黴菌及病毒等微生物的入侵)所造成的生物組織損傷的手段。
產生前列腺素、血栓素等的環氧化酶(Cyclooxygenase;COX)路徑或脂氧化酶(Lipoxygenase;LOX)路徑可用來傳遞發炎訊息。一旦發炎訊號被傳遞,身體所發生的諸多改變之一是血管擴張,以增加發炎周邊的血液供給,集中發炎反應所需的諸如嗜中性白血球等血液細胞。然而,當不正常的生物防禦過度反應發生時,可能導致發炎疾病。為了防止這種情況,目前正在發展可藉由壓制發炎訊號傳遞路徑中所用的酵素(如,COX-1、COX-2、5-LOX、12-LOX等)來抑制過度發炎反應的藥物。
根據反應時間,發炎可分為急性發炎(即時反應、非專一性反應、數天至數周)、慢性發炎(延遲的反應、專一性反應、數周
或更久)、亞急性發炎(急性發炎與慢性發炎之間的中間階段、特徵在於混合產生單核及多型核)。
並且,除了胜肽因子之外,諸如前列腺素、白三烯、脂質因子(包括血小板活化因子(platelet activating factor;PAF))、發炎因子的合成酵素、諸如NO(一氧化氮)等自由基、多種細胞黏著分子、免疫系統及凝血因子等因子皆可導致發炎。
一旦細胞因為已知的致發炎物質而受損時,將釋出組織胺及激肽,所述致發炎物質諸如外部生物因子(微生物、病毒、寄生蟲)、物理因子(機械性刺激、熱、輻射、電流)及化學因子。釋出的組織胺及激肽將造成血管擴張、毛細血管滲透性增加及發炎處的巨噬細胞濃度增加,並導致血液流速增加、浮腫、免疫細胞及抗體遷移及產生疼痛與熱。
目前使用諸如異布洛芬(ibuprofen)、抗組織胺、類固醇、皮質醇(cortisone)、免疫抑制劑及免疫促效劑(immune agonist)等合成藥物來治療發炎;但這些藥物僅能暫時性緩解發炎。這些藥物無法從根本上治療發炎,且該等藥物具有諸如高敏感性反應(hypersensitivity reaction)及免疫系統退化等副作用。
因此,為了有效緩解發炎,已開始進行研究以開發能抑制上述發炎蛋白表現的物質。然而,先前開發的抗發炎物質具有若干問題。已開發出包括非類固醇類抗發炎藥物(Non-steroidal Anti-Inflammatory Drugs;NSAIDs)及類固醇類抗發炎藥物(Steroidal Anti-Inflammatory Drugs;SAIDs)等許多類型的抗發炎藥物;但這些藥物不但時常在服用時產生副作用,且該等藥物無法從根本上治療發炎。因此,目前需要在身體上及經濟上皆可行的
抗發炎藥物。就急性或慢性發炎(如慢性類風濕性關節炎)的例子而言,非類固醇類抗發炎藥物不僅會抑制COX-2酵素的活性,也已知此類藥物會抑制COX-1的活性,導致如腸胃道失調等副作用。
本案發明人發現從端粒酶所衍生的胜肽可具有抗發炎特性而完成本發明。
因此,此發明的目的在於提供新穎胜肽。
本發明的另一個目的在於提供編碼該新穎胜肽的聚核苷酸。
本發明的另一個目的在於提供具有抗發炎活性的胜肽。
本發明的另一個目的在於提供使用此胜肽作為活性成分的抗發炎組成物。
本發明的另一個目的在於提供使用此胜肽作為活性成分的化妝品組成物。
本發明的另一個目的在於提供使用此胜肽作為活性成分的醫藥組成物。
在本發明的一個實施例中,茲提供一種具抗發炎活性的胜肽,其中該胜肽包含序列編號:1之胺基酸序列,或其中該胜肽與序列編號:1之胺基酸序列具有至少80%的同源性,或該胜肽為上述胜肽的片段。
在另一個實施例中,上述片段可由3個或更多個胺基酸所組成。舉例而言,所述片段可由4、5、6、7、8、9、10、11、12、13、14或15、16、17、18、19、20、21、22、23、24、25或26個胺基酸殘基所組成。
在另一個實施例中,上述胜肽可由30個或更少個胺基酸所組成。
在另一個實施例中,上述胜肽可由序列編號:1之胺基酸序列所組成。舉例而言,所述胜肽可由29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9或8個胺基酸殘基所組成。
在另一個實施例中,上述胜肽可源自人類端粒酶。
在本發明的一個實施例中,茲提供一種聚核苷酸,其編碼具抗發炎活性的胜肽,其中該胜肽包含序列編號:1之胺基酸序列,或該胜肽與序列編號:1具有至少80%的序列相同度,或該胜肽為上述胜肽之片段。
在所述聚核苷酸的另一個實施例中,上述片段可由至少3個胺基酸所組成。舉例而言,所述片段可由4、5、6、7、8、9、10、11、12、13、14或15、16、17、18、19、20、21、22、23、24、25或26個胺基酸殘基所組成。
在所述聚核苷酸的另一個實施例中,上述胜肽可由30個或更少個胺基酸所組成。舉例而言,上述胜肽可由29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9或8個胺基酸殘基所組成。
在所述聚核苷酸的另一個實施例中,上述胜肽可由序列編號:1之胺基酸序列所組成。
在所述聚核苷酸的另一個實施例中,上述胜肽源自人類端粒酶。
在本發明的一個實施例中,茲提供抗發炎組成物,其包含作為活性成分的胜肽,其中該胜肽包含序列編號:1之胺基酸序列,該胜肽具有與序列編號:1的同源性為80%以上之胺基酸序列,或該胜肽為上述胜肽的片段。
在所述組成物的另一個實施例中,上述胜肽可由至少3個胺基酸組成,參照上文。
在所述組成物的另一個實施例中,上述胜肽可由30個或更少個胺基酸組成,參照上文。
在所述組成物的另一個實施例中,上述胜肽可由序列編號:1之胺基酸序列組成。
在所述組成物的另一個實施例中,上述胜肽可源自人類端粒酶。
在所述組成物的另一個實施例中,上述組成物可用於治療或預防發炎疾病。
在所述組成物的另一個實施例中,上述組成物為用於改善或防止皮膚發炎之化妝品組成物。
在所述組成物的另一個實施例中,上述組成物為用於治療或預防發炎疾病之醫藥組成物。
在所述組成物的另一個實施例中,上述組成物為用於治療或預防發炎之食品組成物。
在所述組成物的另一個實施例中,上述發炎疾病的特徵在於其選自由下列疾病所組成之群組:(1)普遍的或局部的發炎疾病(例如,過敏症;免疫複合體疾病(immune-complex disease);乾草熱(hayfever);過敏性休克(hypersensitive shock);內毒素
休克(endotoxin shock);惡病質(cachexia)、體溫過高(hyperthermia);肉芽腫(granulomatosis);或類肉瘤病(sarcoidosis));(2)腸胃相關疾病(例如,闌尾炎;胃潰瘍;十二指腸潰瘍;腹膜炎;胰臟炎;潰瘍性結腸炎、急性結腸炎或缺血性結腸炎;膽管炎;膽囊炎、脂肪痢(steatorrhea)、肝炎、克隆氏症(Crone’s disease);或惠氏症(Whipple’s Disease));(3)皮膚相關疾病(例如,牛皮癬;燒傷;曬傷;皮膚炎;蕁痲疹性疣或水皰);(4)血管相關疾病(例如,脈管炎(angiitis);血管炎(vasculitis);心內膜炎;動脈炎(arteritis);動脈硬化;血栓靜脈炎;心包炎;充血性心臟衰竭;心肌炎;心肌缺血;結節性動脈周圍炎(periarteritis nodosa);週期性狹窄症(recurrent stenosis);柏格氏症(Buerger's disease);或風濕熱);(5)呼吸道疾病(例如,氣喘;會厭炎;支氣管炎;肺氣腫;鼻炎;囊性織維化;間質性肺炎;COPD(慢性阻塞性肺病);成人呼吸窘迫症候群;肺塵病(coniosis);肺泡炎;細支氣管炎;咽炎;肋膜炎;或鼻竇炎);(6)骨骼、關節、肌肉及結締組織相關疾病(例如,嗜伊紅性肉芽腫;關節炎;關節痛;骨髓炎;皮肌炎;筋膜炎;柏哲氏症(Paget's disease);痛風;牙周病;類風濕性關節炎;重症肌無力症;僵直性脊椎炎;或滑膜炎);(7)泌尿生殖器失調(例如,附睪炎;陰道炎;前列腺炎;或尿道炎);(8)中樞或周邊神經系統相關疾病(例如,阿茲海默氏症(Alzheimer’s diease);腦膜炎;腦炎;多發性硬化症;腦梗塞(cerebral infarction);腦栓塞(cerebral embolism);格林-巴利症候群(Guillain-Barre syndrome);神經炎;神經痛;脊椎損傷;麻痺;或葡萄膜炎);(9)病毒(例如,流
行性感冒;呼吸道融合病毒;HIV;B型肝炎;C型肝炎;或皰疹病毒)、感染症(例如,登革熱;或敗血症)、黴菌感染(例如,念珠菌症);或細菌、寄生蟲及類似微生物感染(例如,瀰漫性菌血症(disseminated bacteremia);瘧疾;蟠尾絲蟲病(onchocerciasis);或阿米巴症);(10)自體免疫疾病(例如,甲狀腺炎;紅斑性狼瘡;古巴士德氏症候群(Goodpasture's syndrome);移植體排斥(allograft rejection);移植體對抗宿主疾病(graft versus host disease);或糖尿病);及(11)癌症或腫瘤疾病(例如,何杰金氏病(Hodgkin's disease))。
在本發明的一個實施例中,茲提供藉由給予所述抗發炎組成物來治療或防止發炎疾病的方法。
在本發明的一個實施例中,茲提供用於預防或治療發炎疾病的套組,包含:具抗發炎活性之胜肽或包含所述胜肽之組成物,其中該胜肽包含序列編號:1之胺基酸序列,該胜肽與序列編號:1具有80%以上之胺基酸序列同源性,或該胜肽為上述胜肽的片段;以及包括給藥劑量、給藥途徑、給藥頻率及該胜肽或組成物之標示中之至少一者的說明書。
產業利用性
根據本發明,具有序列編號:1之序列的胜肽對抑制發炎及以預防性手段抑制發炎二者皆具有優異的功效。因此,包含此發明之胜肽的組成物可被用作抗發炎醫藥組成物或用作化妝品組成物,從而治療或防止多種不同類型的發炎疾病。
參考
KR2012-0130996A
KR2012-0133661A
KR2011-0060940A
US2011-0150873A1
Bonaldi T et al., EMBO J, (22)5551-60, 2003
Yankner BA et al, Science (New York, N.Y.) [1990, 250(4978):279-282]
Dahlgren KN et al, J. Biol. Chem. 277:32046-32053, 2002.
第1圖為顯示以PBMC演生之單核球培養進行TNF-α ELISA的結果之作圖。以LPS(10ng/ml)刺激單核球達2小時,接著分別與胜肽、FITC、FITC-TAT、PEP 1-FITC及FITC-胜肽反應2小時(** P<0.01,相較於陰性對照組(FITC及FITC-TAT))。
第2圖為顯示以NF-kB螢光酵素轉染HEK293/缺失及HEK293/TLR2細胞株,接著與脂蛋白(10ng/ml)及FITC及FITC-PEP1(4μM)進行反應,並培育18小時後,進行螢光酵素分析的結果之作圖。藉由使用校正而獲得螢光酵素的結果(** P<0.01,相較於陰性對照組(未處理)且將較於脂蛋白處理樣本)。
第3圖代表未經處理、以LPS處理、以PEP 1處理,及以LPS+PEP 1處理之THP1細胞株中的細胞激素之抑制程度。第4圖代表以0、2.5、5.0、10、20及40μM之類澱粉-β蛋白處理之神經幹細胞的存活比例。
第5圖代表以0、2.5、5.0、10、20及40μM之類澱粉-β蛋白處理之神經幹細胞的增生。
第6圖代表以0、1、10、50、100及200μM的PEP 1處理之神經幹細胞的存活比例。
第7圖代表以0、1、10、50、100及200μM的PEP 1處理之神經幹細胞的增生。
第8圖代表以1、10、50及100μM的PEP 1處理之神經幹細胞的存活比例;神經幹細胞受到20μM的類澱粉β蛋白之損傷,且接著在以不同濃度的PEP1處理後測量細胞的存活比例(對照組未以類澱粉β蛋白及端粒酶系胜肽處理)。
第9圖代表以1、10、50及100μM的PEP 1處理之神經幹細胞的毒性;神經幹細胞受到20μM的類澱粉β蛋白之損傷,且接著在以不同濃度的PEP1處理後測量細胞毒性(對照組未以類澱粉β蛋白及端粒酶系胜肽處理)。
第10圖代表以1、10、50及100μM的PEP 1處理之神經幹細胞的增生;神經幹細胞受到20μM的類澱粉β蛋白之損傷,且接著在以不同濃度的PEP1處理後測量細胞增生(對照組未以類澱粉β蛋白及端粒酶系胜肽處理)。
第11圖代表以1、10、50及100μM的PEP 1處理之神經幹細胞的遷移;神經幹細胞受到20μM的類澱粉β蛋白之損傷,且接著在以不同濃度的PEP1處理後測量細胞遷移(對照組未以類澱粉β蛋白及端粒酶系胜肽處理)。
第12圖代表以1、10、50及100μM的PEP 1處理之神經幹細胞的凋亡;神經幹細胞受到20μM的類澱粉β蛋白之損傷,且接著在以不同濃度的PEP1處理後測量細胞凋亡(對照組未以類澱粉β蛋白及端粒酶系胜肽處理)。
第13圖代表PEP1在受到類澱粉β蛋白損傷之神經幹細胞中的ROS(活性氧化物)抑制功效;神經幹細胞受到20μM的類澱粉β蛋白之損傷,且接著在以不同濃度的PEP1(1、10、50及100μM)處理後測量ROS的抑制(對照組未以類澱粉β蛋白及PEP1處理)。
第14圖代表以(A)2D電泳及(B)抗體陣列所分析之蛋白質表現量的結果;神經幹細胞受到20μM的類澱粉β蛋白之損傷,且接著在以不同濃度的PEP1(1、10及50μM)處理後測量蛋白質表現量(對照組未以類澱粉β蛋白及PEP1處理)。
第15圖代表西方墨點法的結果,其顯示了發炎相關蛋白質的表現量:神經幹細胞受到20μM的類澱粉β蛋白之損傷,且接著以不同濃度的PEP1(1、10及50μM)處理細胞。
第16圖代表PEP 1對類澱粉β蛋白聚結的抑制功效;(A)顯示當以1μM的類澱粉β蛋白與PEP 1(0.1、1及10μM)共同處理時,減少的類澱粉β蛋白寡聚化;(B)顯示以PEP-1處理已經被誘導聚結的類澱粉-β蛋白的例子。
第17圖代表PI3K-抑制劑,LY294002,對以PEP 1處理之細胞的存活比例的影響。以PEP 1處理後所增加的細胞存活比例因LY294002的處理而減少。
由於本發明可適應各種轉型及實務應用實例,以下是對本發明的更詳細描述。然而,這不意味著對實務應用形式的限制;應理解的是,本發明的意圖在於包括所有轉型中之技術概念及延伸、等效例及替代例。在描述本發明時,若有關於先前技術的任何
細節描述被認為會使本發明的基本原則變質的話,則將省略該描述。
已知端粒為染色體端部的遺傳材料之反覆序列,端粒可防止染色體受損或與其它染色體合併。端粒的長度會在每次細胞分裂時縮短,且在細胞分裂若干次後,端粒的長度會縮得非常短而使細胞停止分裂並死亡。另一方面,已知端粒的延長可延續細胞的壽命。舉例而言,癌細胞分泌一種稱為端粒酶的酵素,其可防止端粒縮短,因而導致癌細胞的增生。本發明是基於發現具抗發炎功效的端粒酶衍生之胜肽而完成。
在本發明的一個實施例中,茲提供具抗發炎活性的胜肽。所述胜肽包含序列編號:1之至少一個胺基酸序列,所述胜肽與上述序列具有80%以上的同源性,或所述胜肽為上述胜肽的片段。
本發明中具抗發炎活性的胜肽為具有序列編號:1之胺基酸序列的胜肽。序列編號:1之胜肽為由端粒酶-[611-626]的位置中的16個胺基酸所組成的胜肽。
序列編號:1 EARPALLTSRLRFIPK
在本發明的一個實施例中,茲提供一種聚核苷酸,該聚核苷酸編碼具抗發炎活性之胜肽。該聚核苷酸可編碼:包含序列編號:1之至少一個胺基酸序列的胜肽、與上述序列具有80%以上之同源性的胜肽,或為上述胜肽之片段的胜肽。上述聚核苷酸能大量製造該等胜肽。例如,培育包括有編碼胜肽之聚核苷酸的載體可容許大量製造該等胜肽。
本文所揭示的胜肽可包括:包含80%以上、85%以上、90%以上、95%以上、96%以上、97%以上、98%以上或99%以上之同源性的胺基酸序列之胜肽。並且,本發明所揭示之胜肽可包括:包含序列編號:1或序列編號:1的片段的胜肽,及具有超過1個轉型胺基酸(transformed amino acid)、超過2個轉型胺基酸、超過3個轉型胺基酸、超過4個轉型胺基酸、超過5個轉型胺基酸、超過6個轉型胺基酸或超過7個轉型胺基酸的胜肽。
在本案說明書及申請專利範圍中,術語「同源性(homology)」及「序列相同度(sequence identity)」被用來可互換地指示兩個胺基酸(或若有關的話:核酸)序列之間的序列重疊程度。
除非另外陳述,本文所用針對胜肽之術語「序列相同度」指的是依(n ref -n dif ).100/n ref 計算之序列相同度,其中n dif 是指當兩個序列對齊使得相等胺基酸的數目最大時,所述兩個序列中不相等殘基(non-identical residue)的數目,且其中n ref 是指該等序列中最短者的殘基數目。因此,DNA序列agtcagtc與序列aatcaatc將具有75%的序列相同度(n dif =2且n ref =8)。
在某些實施例中,可藉由習用方法決定序列相同度,習用方法如:Smith與Waterman,1981,Adv.Appl.Math.2:482;藉由相似度尋找方法(Pearson & Lipman,1988,Proc.Natl.Acad.Sci.USA 85:2444);使用CLUSTAL W演算法(Thompson等人,1994,核酸s Res 22:467380);藉由電腦化執行這些演算法(威斯康辛遺傳學軟體包(Wiseonsin Genetics Software Package)中的GAP、BESTFIT、FASTA及TFASTA,
遺傳學電腦集團(Genetics Computer Group))等。也可使用BLAST演算法(Altschul等人,1990,Mol.Biol.215:403-10),可透過國家生物技術資訊中心(National Center for Biotechnology Information)(www.ncbi.nlm.nih.gov/)獲得用於BLAST演算法的軟體。當使用任何上述演算法時,就「視窗(Window)」長度、間隔扣分(gap penalty)等使用預設參數。
在本發明的一個實施例中,胺基酸序列的改變屬於胜肽之物理及化學特性的修飾。例如,可藉由增進胜肽的熱穩定性、改變基材特異性及改變最適pH來進行胺基酸轉型(transformation)。
在本發明的一個實施例中,包含序列編號:1之胺基酸序列的胜肽、包含與上述序列具有80%以上的同源性之胺基酸序列的胜肽,或上述胜肽的胜肽片段較佳地由30個或更少個胺基酸所形成。
在本發明的一個實施例中,包含序列編號:1之胺基酸序列的胜肽、包含與上述序列具有80%以上的同源性的胺基酸序列之胜肽,或上述胜肽的胜肽片段包含源自端粒酶(更特定言之,智人(Homo sapiens)的端粒酶)的胜肽。
本文之術語「胺基酸(amino acid)」不僅包括可自然地整合成胜肽的22種標準胺基酸,也包括D-異構物及轉型的胺基酸。因此,在本發明之一特定實施例中,本文之胜肽包括具有D-胺基酸的胜肽。另一方面,胜肽可包括非標準胺基酸,諸如那些經轉譯後修飾的胺基酸。轉譯後修飾的例子包括磷酸化、醣化(glycosylation)、醯化(包括乙醯化、肉荳蔻酸酯化
(myristorylation)、棕櫚酸酯化(plamitoylation))、烷化、羧化、羥化、糖化(glycation)、生物素化、泛素化(ubiquitinylation)、化學特性的變性(例如,β-移除去亞醯胺作用(β-removing deimidation)、去醯胺作用(deamidation))及結構變型(例如,雙硫鍵得形成)。並且,也包括胺基酸的改變,胺基酸發生改變是起因於在以用於形成胜肽共軛物(peptide conjugate)的交聯劑進行的結合過程期間的化學反應。
本文所揭示之胜肽可為已被辨識並從自然界來源分離出來的原生型(wild-type)胜肽。另一方面,當與序列編號:1的胜肽片段比較時,本文所揭露的胜肽可為人工突變體,其包含一或多個被取代、被刪除及/或被插入的胺基酸。原生型多胜肽中的胺基酸變動-不僅在人工突變體-包含了不會影響蛋白質摺疊及/或活性的胺基酸保留性取代(conservative substitution)。保留性取代的例子屬於由以下胺基酸所組成之群組:鹼性胺基酸(精胺酸、離胺酸及組胺酸)、酸性胺基酸(麩胺酸及天門冬胺酸)、極性胺基酸(麩醯胺酸及天門冬醯胺酸)、疏水性胺基酸(白胺酸、異白胺酸、纈胺酸及甲硫胺酸)、芳香族胺基酸(苯丙胺酸、色胺酸及酪胺酸),及小型胺基酸(甘胺酸、丙胺酸、絲胺酸及蘇胺酸)。通常不會改變特定活性的胺基酸取代已為本發明所屬技術領域所知。最常發生的取代為Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Tyr/Phe、Ala/Pro、Lys/Arg、Asp/Asn、Leu/Ile、Leu/Val、Ala/Glu、Asp/Gly,及相反的取代。保留性取代的另外實例列示於下表1中。
表1
可藉由依據下列功效選擇顯著不同的取代基來進行胜肽的生物特性之實質轉變:(a)在取代區域中維持多胜肽基幹結構(如
片狀或螺旋狀三維結構)之功效;(b)維持目標區域中之分子的電荷或疏水性之功效;或(c)維持側鏈主體之功效。可藉由一般的側鏈特性將天然殘基分為以下群組:(1)疏水性:正白胺酸、met、ala、val、leu、ile;(2)中性親水性:cys、ser、thr;(3)酸性:asp、glu;(4)鹼性:asn、gln、his、lys、arg;(5)影響鏈取向(chain orientation)的殘基:gly、pro;及(6)芳香性:trp、tyr、phe。可藉由將以上分組的一員交換成不同的分組來進行非保留性取代。與維持胜肽的合適三維結構無關的任何半胱胺酸殘基典型地可被取代為絲胺酸,因而增加了分子的氧化穩定性,並可預防不適當的交聯。相反的,可藉由將(多個)半胱胺酸鍵結加入胜肽來增進穩定性。
胜肽的胺基酸變異的型態變更屬於抗體醣化態樣改變。本文的術語「改變(change)」與碳水化合物殘基的刪除及/或不存在於胜肽內之至少一個經醣化殘基的加入有關。
胜肽中的醣化為典型的N-連結型(N-connected)或O-連結型醣化。本文之術語「N-連結型(N-connected)」與碳水化合物殘基接附至天門冬醯胺酸殘基的側鏈有關。作為三胜肽序列,天門冬醯胺酸-X-絲胺酸及天門冬醯胺酸-X-蘇胺酸(其中X為除了脯胺酸之外的任何胺基酸)為碳水化合物殘基經由酵素作用而附接至天門冬醯胺酸側鏈之辨識序列。因此,有這些三胜肽序列中之一者存在於多胜肽中,便可創造出潛在的醣化位置。「O-連結型醣化」
意指將糖N-乙醯半乳糖胺(N-acetylgalactosamine)、半乳糖或木糖中之一者附接至羥基胺基酸(hydroxyl amino acid)。最典型的羥基胺基酸為絲胺酸或蘇胺酸,但也可使用5-羥基脯胺酸或5-羥基離胺酸。
通常藉由改變胺基酸序列以含有上述三胜肽序列(用於N-連結的醣化位置)來將醣化位置加入胜肽。可藉由將至少一個絲胺酸或蘇胺酸殘基加入至第一抗體序列,或藉由以彼等殘基取代(用於O-連結的醣化位置),來完成這些改變。
在本發明的一個實施例中,聚核苷酸為核酸分子,所述核酸分子可為自然發生的或人工的DNA或RNA分子,無論是單股或雙股。核酸分子可為相同類型(例如,具有相同的核苷酸序列)的一或多個核酸,或不同類型的核酸。核酸分子包含一或多個DNA、cDNA、誘導DNA、RNA、siRNA、miRNA shRNA、stRNA、snoRNA、snRNA PNA、反意寡聚物、質體及其它經修飾的核酸,但不限於彼等核酸。
已知HMGB1蛋白為細胞激素。HMGB1蛋白首先進行乙醯化並藉由外部刺激而移位至細胞質。接著HMGB1被分泌至細胞外,因而扮演著致炎細胞激素(inflammation-causing cytokine)的角色。因為當此作用導致一個人發炎時,HMGB1蛋白自細胞分泌,且發炎疾病(如Churg strauss症候群、類風濕性關節炎及修格蘭氏症候群(Sjogren’s syndrome))的患者將呈現升高的HMGB1血中濃度。因此,若即使在致炎刺激存在的情況下細胞核仍含有大量HMGB1時,暗示著HMGB1未被分泌離開細胞的事實,這意味著發炎受到抑制。
在本發明的一個實施例中,當以包含序列編號:1之胺基酸序列的胜肽處理細胞;以具有與上述序列有80%以上的同源性之胺基酸序列的胜肽處理細胞;或以上述胜肽的片段處理細胞時,會增加細胞核內的HMGB1量。這代表上述胜肽具有卓越的發炎預防或抑制功效。
並且,在本發明的特定實施例中,包含序列編號:1之胺基酸序列的胜肽、具有與上述序列有80%以上的同源性之胺基酸序列的胜肽,或上述胜肽的片段的優點在於:因為在細胞內的低毒性而具有高度可行性。
在本發明中,「發炎疾病(inflammatory disease)」泛指以發炎為主因的任何疾病或因疾病所造成的發炎。詳言之,發炎疾病包括,但不限於:(1)普遍的或局部的發炎疾病(例如,過敏症;免疫複合體疾病;乾草熱;過敏性休克;內毒素休克;惡病質、體溫過高;肉芽腫;或類肉瘤病);(2)腸胃相關疾病(例如,闌尾炎;胃潰瘍;十二指腸潰瘍;腹膜炎;胰臟炎;潰瘍性結腸炎、急性結腸炎或缺血性結腸炎;膽管炎;膽囊炎、脂肪痢、肝炎、克隆氏症;或惠氏症);(3)皮膚相關疾病(例如,牛皮癬;燒傷;曬傷;皮膚炎;蕁痲疹性疣或水皰);(4)血管相關疾病(例如,脈管炎;血管炎;心內膜炎;動脈炎;動脈硬化;血栓靜脈炎;心包炎;充血性心臟衰竭;心肌炎;心肌缺血;結節性動脈周圍炎;週期性狹窄症;柏格氏症;或風濕熱);(5)呼吸道疾病(例如,氣喘;會厭炎;支氣管炎;肺氣腫;鼻炎;囊性織維化;間質性肺炎;COPD(慢性阻塞性肺病);成人呼吸窘迫症候群;肺塵病;肺泡炎;細支氣管炎;咽炎;肋膜炎;或鼻竇炎);(6)骨骼、關節、
肌肉及結締組織相關疾病(例如,嗜伊紅性肉芽腫;關節炎;關節痛;骨髓炎;皮肌炎;筋膜炎;柏哲氏症;痛風;牙周病;類風濕性關節炎;重症肌無力症;僵直性脊椎炎;或滑膜炎);(7)泌尿生殖器失調(例如,附睪炎;陰道炎;前列腺炎;或尿道炎);(8)中樞或周邊神經系統相關疾病(例如,阿茲海默氏症;腦膜炎;腦炎;多發性硬化症;腦梗塞;腦栓塞;格林-巴利症候群;神經炎;神經痛;脊椎損傷;麻痺;或葡萄膜炎);(9)病毒(例如,流行性感冒;呼吸道融合病毒;HIV;B型肝炎;C型肝炎;或皰疹病毒)、感染症(例如,登革熱;或敗血症)、黴菌感染(例如,念珠菌症);或細菌、寄生蟲及類似微生物感染(例如,瀰漫性菌血症;瘧疾;蟠尾絲蟲病;或阿米巴症);(10)自體免疫疾病(例如,甲狀腺炎;紅斑性狼瘡;古巴士德氏症候群;移植體排斥;移植體對抗宿主疾病;或糖尿病);及(11)癌症或腫瘤疾病(例如,何杰金氏病)。
數十年來,治療這些疾病的發炎成分已成為國際製藥工業的主要目標,且已開發出多種有用的治療劑。例子包括皮質類固醇(被設計來模擬皮質醇的功效之各種自然、半合成及合成的製劑,包括培尼皮質醇(prednisolone)、甲基培尼皮質醇(methylprednisolone)、地塞米松(dexamethasone)、貝他每松(betamethasone)、氟替卡松(fluticasone)等等)、環氧化酶抑制劑(非選擇性抑制劑或cox-1選擇性抑制劑二者,如吲哚美辛(indomethacin)、磺胺塞拉金(sulfasalzine)及乙醯水楊酸(aspirin),且更近的還有cox-2選擇性抑制劑,如塞來考昔(celecoxib))、白三烯(leukotriene)阻斷劑(如孟魯司特
(monteleukast))及抗-TNF(如經修飾的單株中和抗體,包括英夫利昔單抗(infliximab)(RemicadeTM)及阿達木單抗(adalimumab)(HumiraTM)、TNF受器融合蛋白,如依那西普(etanercept)(EnbrelTM),還有小分子TNF-α合成抑制劑如沙利竇邁(thalidomide))。
在本發明的一個實施例中,茲提供一種包含胜肽作為活性成分的抗發炎組成物。所述胜肽包含序列編號:1之胺基酸序列;所述胜肽與上述序列具有80%以上的同源性;或所述胜肽為上述胜肽的片段。
在本發明的一個實施例中,抗發炎組成物可含有0.1μg/mg至1mg/mg,特別地1μg/mg至0.5mg/mg,更特別地10μg/mg至0.1mg/mg的包含序列編號:1之胺基酸序列的胜肽、包含與上述序列具有80%以上的同源性之胺基酸序列的胜肽,或上述胜肽的胜肽片段。當含有上述範圍的胜肽時,可滿足該組成物的所有安全性及穩定性,且就成本效益而言為適當的。
在本發明的一個實施例中,所述組成物可應用在所有動物,包括人類、狗、雞、豬、牛、羊、天竺鼠及猴子。
在本發明的一個實施例中,茲提供用於以活性成分治療或預防發炎疾病的醫藥組成物,所述活性成分包含:由選自序列編號:1之胺基酸所組成之胜肽、包含與上述序列具有80%以上的同源性之胺基酸序列的胜肽,或序列編號:1的胜肽片段。在本發明的一個實施例中,所述醫藥組成物可透過如口服、直腸、經皮、靜脈內、肌肉內、腹膜內、骨髓內、硬膜上或皮下等方式給藥。
口服給藥的形式可為,但不限於,錠劑、丸劑、軟式或硬式膠囊、顆粒、粉末、溶液或乳化液。非口服給藥的形式可為,但不限於,注射劑、滴劑、乳液、軟膏、凝膠、乳霜、懸浮液、乳化液、栓劑、貼片或噴劑。
在本發明的一個實施例中,若有需要的話,醫藥組成物可含有添加劑,如稀釋劑、賦形劑、潤滑劑、結合劑、崩解劑、緩衝劑、分散劑、表面活性劑、著色劑、芳香劑或甜味劑。在本發明的一個實施例中,可由本案技術領域中的工業之習用方法來製造醫藥組成物。
在本發明的一個實施例中,可根據患者的年齡、性別、體重、病理及狀態、給藥途徑或開處方者的判斷來改變醫藥組成物的活性成分。可在本案所屬技術領域中之習知技藝者的水平內根據這些因素來決定劑量,舉例而言,每日劑量可為,但不限於,每日每公斤0.1μg至每日每公斤1g,特別為每日每公斤1μg至每日每公斤10mg,更特別為每日每公斤10μg至每日每公斤1mg,更特別為每日每公斤50μg至每日每公斤100μg。在本發明的一個實施例中,可以,但不限於,每日1至3次給予醫藥組成物。
在本發明的一個實施例中,茲提供用於改善或防止皮膚發炎的皮膚外用組成物。皮膚外用組成物可含有活性成分,該活性成分可為:包含序列編號:1之胺基酸序列的胜肽、包含與上述序列具有80%以上之同源性的胺基酸序列之胜肽,或上述胜肽之胜肽片段。
在本發明的另一個實施例中,茲提供用以改善或防止皮膚發炎的化妝品組成物。化妝品組成物可含有活性成分,該活性成
分可為:包含序列編號:1之胺基酸序列的胜肽、包含與上述序列具有80%以上之同源性的胺基酸序列之胜肽,或上述胜肽之胜肽片段。
在本發明的一個實施例中,可提供適於局部施用(topical application)的所有型式之外用組成物或化妝品組成物。例如,可提供溶液、藉由將油相分散於水中所獲得的乳液、藉由將水分散於油相中所獲得的乳液、懸浮液、固體、凝膠、粉末、糊劑(paste)、泡沫或氣溶膠等型式。這些形式可藉由本技術領域中之產業的習用法來製造。
在本發明的一個實施例中,在無損於主要功效的程度內,化妝品組成物可包括可如預期般增進主要功效的其它成分。在本發明的一個實施例中,化妝品組成物可額外地包括:保濕劑、軟化劑、表面活性劑、UV吸收劑、防腐劑、殺真菌劑、抗氧化劑、pH調節劑、有機或無機色素、芳香劑、冷卻劑或止汗劑。所屬領域中的習知技術者可在無損本發明的目的及功效的程度內決定上述成份的配方比例,且基於化妝品組成物的總重量的配方比例可為0.01至5重量%,特別是0.01至3重量%。
在本發明的一個實施例中,茲提供用於預防或抑制發炎的食品組成物。食品組成物可含有活性成分,該活性成分可為:包含序列編號:1之胺基酸序列的胜肽、包含與上述序列具有80%以上之同源性的胺基酸序列之胜肽,或上述胜肽之胜肽片段。
在本發明的一個實施例中,食品組成物可形成,例如,但不限於,顆粒、粉末、液體及固體型式。除了活性成分之外,可
用由本案所屬技術領域中的習知技藝者適當地選擇的相關工業中常用的成分來形成上述各型式,且可用其它成分來增加功效。
本案所屬技術領域中的習知技藝者可決定上述活性成分之劑量,且每日劑量的例子可為每日每公斤1μg至每日每公斤10mg,更特別地為每日每公斤10μg至每日每公斤1mg,更特別地為每日每公斤50μg至每日每公斤100μg,但不限於這些數量而可依照年齡、健康狀態、併發症及其它多種因素而改變。
在本發明的一個實施例中,茲提供以包含序列編號:1之胺基酸序列的胜肽、包含與上述序列具有80%以上的同源性的胺基酸序列之胜肽,或上述胜肽的胜肽片段來預防或治療發炎疾病的用途。
在本發明的一個實施例中,茲提供以施用上述胜肽至患者來預防或治療發炎疾病的方法。
在本發明的一個實施例中,茲提供用於預防或治療發炎疾病的套組。該套組可含有:具抗發炎活性的胜肽或包含該胜肽之組成物,其中該胜肽包含序列編號:1之胺基酸序列、與上述序列具有80%以上之同源性的胜肽,或者該胜肽為上述胜肽的片段;以及包括給藥劑量、給藥途徑、給藥頻率及該胜肽或組成物之標示中之至少一者的說明書。
本文所用的術語意在用來描述實施例,而非用來限制本發明。在前面沒有數字的術語並非用來限制量,而是用來顯示所使用的術語可能超過一項。術語「包括」、「具有」、「由…構成」及「包含」應作開放性解釋(即,「包括但不限於」)。
提及數字範圍是用來代替指名該範圍內的個別數字,因此除非特別指明,各個數字可被解讀為本文所整合之個別的數字。所有範圍的終值皆包括在該範圍內,且可被單獨結合。
除非在內容中有另外註記或明顯牴觸,否則可以合適的順序進行本文所述的所有方法。除非包括於申請專利範圍中,否則任一個實施例及所有實施例,或範例語言(如,使用「類~(like~)」者)的使用是為了更清楚地描述本發明,而非限制本發明的範疇。在申請專利範圍以外的本文的任何語言不應被解讀為本發明的必然。除非另外界定,本文所用的技術性及科學性術語的意思應該普遍為本發明所屬技術領域中的習知技藝者所了解。
本發明的較佳實施例為本案發明人已知用於進行本發明的最佳模式。在閱讀前文對較佳實施例中之變化例的陳述後,所屬技術領域中的習知技藝者應能清楚本發明。本案發明人希望所屬技術領域中的習知技藝者可充分使用該等變化例,且本發明可以本文所列的方式以外的其它方式實施。因此,本發明,在專利法允許下,包括本發明的等效例及變化例,而本發明的重點陳述於隨附申請專利範圍中。此外,除非另有清楚陳述或於內文中產生牴觸,否則上述組成分的任何組合內的所有可能變化例皆包括在本發明中。儘管藉由示範性實施例來說明並示意本發明,所屬技術領域中的習知技藝者將可充分了解在不悖離本發明之精神及範疇下,可有由以下申請專利範圍所界定的多種形式及細節上的變化。
已知會從發炎細胞釋出腫瘤壞死因子(Tumor necrosis factor;TNF),特別是TNF-α,並造成多種細胞毒性反應、免疫反應及發炎反應。已知TNF-α涉及許多發炎與自體免疫疾病的發
生及延長,且當TNF-α被釋出而進入血液並同步作用時,會進一步導致嚴重的敗血症和敗血性休克。因為TNF-α為與活體的免疫系統廣泛相關的因子,所以目前積極進行抑制TNF-α之製劑的開發。可藉由生物性合成不活化形式的TNF-α,且受到蛋白酶的剪切而變成活化形式;負責上述活動的酵素稱作腫瘤壞死因子轉化酵素(tumor necrosis factor-converting enzyme;TACE)。因此,抑制此TACE的物質可治療、改善或防止歸因於TNF-α的疾病、病理狀態、異常狀態、疑難、不利的症狀等(KR2011-0060940A)。
高遷移率族1(High-mobility group box 1;HMGB1)蛋白以高濃度存在於胸腺、淋巴結、睪丸中,且存在胎兒肝臟中,且不存在於肝臟及腦細胞中,通常存在於細胞核內。所述HMGB1蛋白具有由A-box、B-box及C-端部所組成的3個域段(domain)。
Tracey等人於1999年報導指出HMGB1蛋白扮演著可誘導發炎的細胞激素的角色,且所述HMGB1的發炎誘導機制是藉由外部刺激導致HMGB1的乙醯化,並接著自細胞核移動進入細胞質。此後,已知HMGB1會被分泌至細胞外,或被分泌至壞死的細胞外(Bonaldi T等人,EMBO J,(22)5551-60,2003)。
可藉由圖式、以下的實例及實驗來進一步描述本發明,所述圖式、實例及實驗僅為闡明本發明的特定實施例之目的,且無論如何都不應被解釋為對本發明之範疇的限制。
實例1
PEP-1的合成及PEP-1(序列編號:1)的抗發炎活性之測量
實驗1:合成PEP-1(序列編號:1)
合成由16個胺基酸組成的具有如下所示之化學結構1的胜肽,該胜肽具有源自人類端粒酶的序列,即序列編號:1(PEP-1):
可根據現有的固相胜肽合成方法來合成序列編號:1(PEP-1)。詳言之,可透過Fmoc固相胜肽合成、SPPS、使用ASP48S(Peptron,Inc.,Daejeon,ROK),藉由從C-端耦合
各胺基酸來合成胜肽。所使用的該些胜肽(該等胜肽位於C-端的第一個胺基酸被附接至樹脂)如下:NH2-Lys(Boc)-2-chloro-三苯甲基樹脂
NH2-Ala-2-chloro-三苯甲基樹脂
NH2-Arg(Pbf)-2-chloro-三苯甲基樹脂
用於合成胜肽的所有胺基酸材料的N-端受到Fmoc保護,且胺基酸殘基受到可溶解於酸中的Trt、Boc、t-Bu(三級丁酯(t-butylester))、Pbf(2,2,4,6,7-五甲基二氫-苯并呋喃-5-磺醯基(2,2,4,6,7-pentamethyl dihydro-benzofuran-5-sulfonyl))保護。例如:Fmoc-Ala-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Pro-OH、Fmoc-Leu-OH、Fmoc-Ile-OH、Fmoc-Phe-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-Lys(Boc)-OH、Fmoc-Gln(Trt)-OH、Fmoc-Trp(Boc)-OH、Fmoc-Met-OH、Fmoc-Asn(Trt)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ahx-OH、Trt-巰乙酸(Trt-Mercaptoacetic acid)。
可使用HBTU[2-(1H-苯并三唑-1-基)-1,1,3,3-六氟化磷酸四甲銨(2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetamethylaminium hexafluorophosphate)]/HOBt[N-羥苯并三唑(N-Hydroxybenzotriazole)]/NMM[4-甲基嗎啉(4-Methylmorpholine)]作為耦合試劑。在20%的DMF中,使用哌啶(piperidine)移除Fmoc。為了從殘基移除保護或為了將合成的胜肽從樹脂分離,可使用切割雞尾酒配方(cleavage cocktail)
[TFA(三氟乙酸)/TIS(三異丙基矽烷(triisopropylsilane))/EDT(乙二硫醇(ethanedithiol))/H2O=92.5/2.5/2.5/2.5]。
可藉由使用固相鷹架(solid phase scaffold)結合以下製程來合成胜肽:以胺基酸保護成分所保護的胺基酸起始、分別使對應的胺基酸反應、以溶劑洗滌並去保護,及重複該製程。在從樹脂切下合成的胜肽之後,以HPLC純化合成的胜肽,並以MS驗證合成狀況,並接著冷凍乾燥。
PEP 1的特定合成製程描述如下。
1)耦合將NH2-Lys(Boc)-2-氯-三苯甲基樹脂所保護的胺基酸(8當量)融化,且耦合劑HBTU(8當量)/HOBt(8當量)/NMM(16當量)加入DMF內,接著使反應在室溫下進行2小時,接著依序以DMF、MeOH及DMF洗滌。
2)Fmoc去保護將20%的哌啶加入DMF中並於室溫下進行5分鐘的反應2次,接著依序以DMF、MeOH及DMF洗滌。
3)藉由重覆進行反應1及2來製造胜肽的基本架構。
4)切割:將切割雞尾酒(Cleavage Cocktail)加入完全合成的胜肽,並自樹脂分離胜肽。
5)將冷卻的乙醚加入所獲得的混合物內,並接著使用離心來沉澱聚集的胜肽。
6)在藉由Prep-HPLC純化之後,藉由LC/MS確認分子量,並冷凍乾燥以產生粉末形式的胜肽。
實驗2:PEP 1的抗發炎活性測量
細胞株培養
於37℃下,伴隨著5%的CO2,將來自韓國細胞庫(Korea Cell Bank)的Raw 264.7巨噬細胞(KCBL,40071)維持在含有10%的胎牛血清(FBS;Gibco Laboratories)、100單位/mL的鏈黴素及青黴素(Gibco Laboratories)的杜貝可氏改良之伊格氏培養基(Dulbecco’s modified Eagle’s medium(DMEM);PAA,奧地利)中。以1×106個細胞/mL的密度將Raw 264.7細胞播種至96孔盤內並隔夜培育。
翌日,以新鮮培養基取代上述培養基,並將5ug/mL的胜肽(以實例1的實驗1所述方式獲得)加入細胞。在以胜肽進行30分鐘的細胞培育後,加入50uL的LPS(達1ug/mL的最終濃度),且培育細胞達額外的24小時。以1ug/mL脂多醣(LPS;Sigma,USA)處理誘導發炎反應的實驗樣本,並以磷酸緩衝鹽水(PBS;pH 7.2)處理對照樣本。將來自各實驗條件的上清液樣本收集於eppendorf管中,並執行進一步分析。
實驗2-1:分析NO量
可使用格里斯試劑系統(Griess reagent system)(Promega,USA)測量Raw 264.7細胞(1×106個細胞/ml)中之一氧化氮(NO)的量。50μl的培養基加入96孔盤,接著加入相同量的Griess試劑I(NED)溶液及Griess試劑II(苯磺胺(Sulfaniliamide)溶液)。在以該等試劑培育細胞10分鐘之後,在30分鐘內使用微盤分析儀(Molecular Devices,USA)測量540
nm波長下的光學密度。可使用亞硝酸鈉的標準曲線(0~100μM)來計算NO的濃度。
如以下表2所示,以LPS刺激細胞會增加NO的表現,但在以LPS與Pep1共同處理的情況中,上述NO的表現量降低了。NO是在發炎期間所產生的,且這樣的結果顯示出Pep1降低達對照組的65%之NO量,因而有力地支持了Pep1的抗發炎功效。
實驗2-2:細胞激素抑制功效的分析
為了研究PEP1對產生促發炎細胞激素的抑制功效,以濃度5μg/mL的PEP 1預先處理受濃度1μg/mL的LPS所刺激的RAW 264.7細胞,並進一步培育細胞達24小時。收集含有細胞培養基的上清液樣本,並使用ELISA套組(eBioscience,San Diego)分析細胞激素的量。
以100uL的捕捉抗體(在塗佈緩衝液中稀釋至製造商的科學實驗計劃所建議的濃度)塗佈96孔盤在4℃下隔夜。接著,在洗滌該盤5次之後,將200uL的分析稀釋劑加入各孔,
並於室溫下培育1小時以進行阻斷。在以洗滌緩衝液洗滌各孔5次之後,將細胞培養樣本或各細胞激素標準蛋白質樣本稀釋,並將100uL的各細胞培養樣本或各細胞激素標準蛋白質樣本加入各孔內。在4℃下隔夜培育含有該等樣本的該盤。接著,在以洗滌緩衝液洗滌該盤5次之後,加入100uL與抗生物素(avidin)共軛的二次抗體,並在室溫下培育1小時。
在以二次抗體培育之後,洗滌該盤5次,並在室溫下以100uL的抗生物素-HRP(BD Bioscience)培育30分鐘。在洗滌該盤7次之後,加入100uL的TMB溶液(Pierce)並在室溫下培育15分鐘。藉由在各孔中加入50μl的2N H2SO4來停止反應。使用微盤分析儀測量450nm波長下的光學密度。可藉由使用SPSS程式的ANOVA程序之差異分析來進行統計分析,並使用鄧肯氏多變域測試(Duncan’s multiple range test)來驗證分析之間的顯著性。
實驗2-3:IL-6分泌測量
如下表3所示,單獨以LPS處理會增加細胞激素IL-6(介白素-6)分泌。然而,以LPS與PEP-1共同處理顯示出促發炎細胞激素IL-6分泌量的減少。更重要地,在以PEP-1處理之後,促發炎細胞激素分泌的量減少超過70%,這象徵著Pep1的強大抗發炎功效。
實驗2-4:HMGB1、TNF-α、COX-2表現抑制
可藉由西方墨點法分析來測定蛋白質表現量。以PBS洗滌在含PEP-1培養基中所生長的細胞,以0.05%的胰蛋白-EDTA處理,並藉由離心來收集。將收集的細胞溶解在適當體積的分解緩衝液中。藉由離心來丸粒化細胞內的碎屑,並藉由SDS-聚丙烯醯胺凝膠電泳分離來自各樣本的等量蛋白質。將分離出來的蛋白質轉移至硝化纖維膜(Schleicherand Schuell,Keene,NH,USA),接著對各種蛋白質進行抗體專一性測試。以ECL(增強的化學發光)溶液(Amersham Life Science Corp.,Arlington Heights,IL,USA)培育硝化纖維膜;將硝化纖維膜暴露於X光;並根據X光膜上顯示的曝光程度分析蛋白質表現量。
進行西方墨點法分析來測定Ppep1對細胞激素蛋白質表現的抑制功效。如下表4所示,以LPS刺激細胞會增加細胞激素(HMGB1、TNF-α及COX)的表現。然而,若以LPS和Pep1二者處理細胞的話,可減少上述促發炎細胞激素的表現量。結果顯示以Pep1進行處理可減少超過70%的促發炎細胞激素量,因而提供了有力的證據支持Pep1的抗發炎功效。
表4:Pep1對促發炎細胞激素表現量的抑制功效測量
實驗3:Pep1對HepG2細胞中之TNF-α量的抑制功效之研究
實驗3-1:細胞培養
使用Ficoll-PaqueTM PLUS(GE Healthcare Life Sciences,Piscataway,NJ,USA)從收集自健康對象的血液樣本(50ml)中分離出PBMC(周邊血液單核細胞)。在含有20%的人類血清之完整RPMI 1640培養基中滋養PBMC,接著將PBMC轉移到塗佈有人類血清的100mm聚苯乙烯細胞培養盤達30分鐘。在37℃及5%的CO2下培育2小時後,使用冷卻的PBS(磷酸緩衝鹽水)(Gibco/Life Technologies,Carlsbad,CA,USA)使單核球自細胞培養盤底部脫離,且在96孔盤的各個孔中,於RPMI 1640培養基(補充有青黴素-鏈黴素;100mg/ml,及人類血清;20%)中隔夜培養1×105個細胞。
針對螢光酵素分析,使用從首爾國立大學(Seoul National University)牙醫學院(School of Dental Medicine)獲得的HEK293/缺失(null)(人類胚胎腎臟)細胞及穩定
表現TLR2(類鐸受體2)的HEK293/TRL細胞。在螢光酵素實驗前一天,將2.5×105個細胞播種至12孔盤的各孔內,並在DMEM(杜貝可氏改良之伊格氏培養基)培養基(補充有保米黴素(blasticidin);10μg/ml,胎牛血清;10%)(Invitrogen/Life Technologies,Carlsbad,CA,USA)中隔夜培養。
實驗3-2:細胞激素分析
為了從蛋白質表現量的關點觀察PEP-1對TNF-α量的影響,可進行ELISA(酵素連結免疫吸附分析)。在96孔盤中隔夜培養1×105個PBMC-衍生的單核球。接著,以LPS(脂多醣;10ng/ml,Sigma)處理2小時,隨後以PBS洗滌3次。接著以OPTI-MEM培養基(Invitrogen/Life Technologies,Carlsbad,CA,USA)處理1小時,以誘導飢餓,且在測量TNF-α量之前,以4uM的FITC(異硫氰酸螢光素)、FITC-TAT、PEP-1-FITC及FITC-PEP-1處理2小時。在培養後,收及細胞湯(cell soup),並使用ELISA套組(R&D,Minneapolis,MN,USA)測量TNF-α的量,如下:TNF測量使用三明治ELISA方法。將100ul的TNF-α初級抗體加入預先塗佈的96孔盤的各個孔內,並於4℃下隔夜培育該盤。翌日,以0.5%的Tween20洗滌溶液洗滌該盤3次,每次5分鐘,並接著加入100ul的各樣本及標準溶液,並置於室溫2小時。以如上述方式洗滌該盤之後,將100ul之HRP-共軛的次級抗體加入各孔中,並置於室溫2小時。再次洗滌96孔盤,並加入卵白素/生物素進行吸光度測量。使用從標準溶液的吸光度所計算的標準圖形來定量各樣本的TNF-α量。
以內毒素LPS(10ng/ml)刺激PBMC-衍生的單核球達2小時,用OPTI-MEM使PBMC-衍生的單核球飢餓達1小時,並接著以4uM的FITC、FITC-TAT、PEP 1-FITC及FITC-PEP 1處理達2小時。在培育之後,使用ELISA測量伴隨著細胞培養基的TNF-α量。結果,在FITC及FITC-TAT的例子中,因LPS(分別為6.2及6.7ng/ml)之故而使TNF-α量增加,但在PEP-1-FITC及FITC-PEP-1(分別為0.17及0.25ng/ml)的例子中,TNF-α量顯著減少了,且這樣的差異有統計顯著性(P<0.01)(第1圖)。
實驗3-3:螢光酵素分析
為了研究PEP 1在發炎反應中的角色,吾人透過螢光酵素分析來評估NF-kB表現態樣。首先,吾人在12孔盤中培育HEK293/缺失及HEK293/TLR2細胞(首爾國立大學牙醫學研究所)達24小時,以獲得2.5×105個細胞/孔。在以PBS洗滌3次後,將培養基換成OPTI-MEM(Invitrogen/Life Technologies,Carlsbad,CA,USA)並培育4小時,接著將3μl的lipofectamine(Invitrogen/Life Technologies)、1μg的NF-kB螢光酵素與10ng的水母螢光酵素(renilla luciferase)(Promega,Madison,WI,USA)之混合物加入各孔內,並再次培育4小時。將脂蛋白pam3cys(10ng/ml,Sigma-Aldrich,St.Louis,MO,USA)置入除了陰性對照組之外的所有孔內,並以FITC(4μM)及FITC-PEP 1(4μM)處理18小時後以PBS洗滌3次。在藉由將雙螢光酵素報導載體分析系統(dual-luciferase reporter assay system)(Promega)所提供的50μl的被動胞溶緩
衝液(passive lysis buffer)置入各孔以溶解(胞溶)細胞之後,吾人透過TD-20/20光度計(Turner designs,Sunnyvale,CA,USA)來確認NF-kB的活化。藉由pCMV-水母螢光酵素(Promega)的共同轉染可確認轉染效率,且吾人藉由校準螢光酵素值來分析結果。
在將NF-kB螢光酵素轉染至HEK293/缺失及HEK293/TLR2細胞株後,以pam3cys(一種合成脂蛋白)與FITC(4μM)(陰性對照)一起處理,並再次以pam3cys與FITC-PEP 1(4μM)一起處理並培養18小時。透過雙螢光酵素報導載體分析系統(Promega)所提供的被動胞溶緩衝液使細胞產生胞溶,藉由螢光酵素強度測量NF-kB的表現態樣顯示以脂蛋白處理或以FITC-PEP1處理或未處理的HEK293/缺失細胞之間並無差異性。然而,當以脂蛋白(TLR2的促效劑)處理HEK293/TLR2細胞株時,NF-kB表現量相較於未處理的細胞株增加(P<0.01),因而確認了發炎反應的發生。並且,相較於未處理的細胞株,當以FITC-PEP 1一起處理時,NF-kB表現量增加;且相較於以脂蛋白與FITC一起處理的陰性對照組,以FITC-PEP 1一起處理時的NF-kB表現量減少(P<0.01)(第2圖)。最終,吾人能確認當以PEP 1一起處理時能降低可由TLR2所造成的發炎反應。
實驗3.4:胜肽影響THP1細胞株中之細胞激素量的再次分析
使用人類急性單核白血球細胞株,THP-1單核球細胞株(American Type Culture Collection(Manassas,VA,USA))來確認PEP 1的功效。使密度為0.5至7×105個細胞/mL的細胞在RPMI 1640(含有10%的FBS、0.05mM的2-巰基乙
醇、100U/ml的青黴素及100μg/mL的鏈黴素)中生長,並在5%的CO2下維持於37℃。在37℃下,以100ng/mL的佛波豆蔻醚乙酸鹽(phorbol myristate acetate;PMA)處理THP-1細胞24小時,使THP-1細胞分化成巨噬細胞。
所有試劑及培養基皆購自Gibco BRL。PMA、LPS及2-巰基乙醇購自Sigma(St.Louis,MO,USA)。胜肽RIA由Peptron(Daejeon,Republic of Korea)合成。反轉錄PCR套組購自Promega(Madison,WI,USA)。RT2 SYBR® Green qPCR Mastermix試劑及QIAzol購自QIAGEN(Valencia,CA,USA)。
在分化成巨噬細胞後,使用完全RPMI 1640洗滌THP-1細胞2次(每次5分鐘)。接著,在無FBS的RPMI 1640中,以10ng/ml的LPS及/或4μM的胜肽RIA處理細胞4小時。
藉由使用Trizol(QIAzol)試劑從胜肽處理後之THP-1細胞將總體RNA樣本分離,並依照廠商的實驗計劃,使用購自Promega的反轉錄PCR套組進行反轉錄PCR來合成cDNA。
接著,使用CFX96(Bio-Rad)儀器與SYBR Green系統一起進行即時qPCR。本實驗所用的引子可見於表5。PCR循環條件為:95℃達10分鐘以活化HotStart DNA Taq聚合酶,接著進行95℃達10秒、55℃達30秒、及72℃達30秒的45個循環。所有樣本進行三次測量,並使用2-循環閾值法(2-cycle threshold method)計算基因表現的差異。來自至少三次獨立
實驗的所有數據與β肌動蛋白(管家基因)對比進行常態化,並呈現為+/- S.E.的平均值。
如第3圖所示,藉由以PEP 1作治療可顯著減少涉及發炎反應的細胞激素。
實例3
由類澱粉-β蛋白(amyloid-β protein)所誘導之發炎反應的分析
HMGB1首先進行乙醯化並藉由外部刺激而移位至細胞質。接著HMGB1被分泌至細胞外,因而扮演著致炎細
胞激素的角色。因為當此作用導致一個人發炎時,HMGB1蛋白自細胞分泌,且發炎疾病(如Churg strauss症候群、類風濕性關節炎及修格蘭氏症候群)的患者將呈現升高的HMGB1血中濃度。因此,若即使在致炎刺激存在的情況下細胞核仍含有大量HMGB1時,暗示著HMGB1未被分泌離開細胞的事實,這意味著發炎受到抑制。
實驗1:由PEP-1之抗發炎功效所導致之神經幹細胞的存活及增生之分析
首先,根據實例1中所描述的製造方法來製備PEP-1。
實驗1-1:神經幹細胞培養及類澱粉-β毒性評估
在從懷胎13天的胚胎大鼠的頭部移出皮質後,以鹼性纖維母細胞生長因子(Basic Fibroblast Growth Factor;bFGF)培養皮質一周,以獲得神經幹細胞。為了分析類澱粉-β蛋白對神經幹細胞的影響,以濃度為0至40μM之預先寡聚化的類澱粉-β蛋白處理神經幹細胞達48小時,接著使用CCK-8分析、BrdU,及TUNEL分析進行細胞毒性評估(參考BA Yankner等人,1990及KN Dahlgren等人,2002)。在吾人確認以20μM的類澱粉-β蛋白處理時,細胞存活比例降至60%(參見第4及5圖)之後,吾人在後續實驗中使用相同濃度的類澱粉-β蛋白。
實驗1-2:以PEP-1處理之細胞毒性評估
為了評估PEP-1對培養的神經幹細胞的影響,首先藉由已知方法(BA Yankner等人,1990及KN Dahlgren等
人,2002)培養神經幹細胞。接著,以不同濃度(0、1、10、50、100、200μM)的PEP-1處理48小時,接下來使用MTT分析、BrdU及TUNEL分析進行細胞存活率及細胞增生評估。自0至200μM的PEP-1濃度在神經系統中顯得穩定,因為該等PEP-1濃度沒有抑制神經幹細胞的生存及增生(參見第6及7圖)。
實驗1-3:以類澱粉-β蛋白與端粒酶胜肽共同處理之細胞毒性評估
為了測定PEP 1是否有抑制類澱粉-β蛋白所造成的神經毒性之功效,以20μM的類澱粉-β蛋白與多種濃度的PEP-1共同處理48小時。使用MMT分析、CCK-8分析、LDH分析及TUNEL分析來測量細胞存活率及細胞凋亡,並藉由BrdU分析來測量神經幹細胞增生。
MMT分析及CCK-8分析的結果確認了10μM的PEP-1開始保護神經幹細胞免於受到類澱粉-β引起之神經毒性的影響,且100μM的PEP-1提供了最有效的保護(參見第8圖)。進行LDH分析作為評估細胞死亡程度的另一種方法,且吾人確認由類澱粉-β所導致的細胞死亡增加程度可被PEP-1減少,從1μM濃度開始可看到這樣的效果(參見第9圖)。
吾人也用BrdU分析確認了當以PEP-1處理時,可恢復歸因於類澱粉-β蛋白的減少的細胞增生(參見第10圖)。
由於神經幹細胞的本質,細胞活動性是一種生存要素(vital matter)。根據細胞活動性的實驗結果,吾人確認了相較於對照組,當以PEP-1處理時,可恢復歸因於類澱粉-β蛋白
的減少的細胞增生,且甚至在PEP-1濃度為10μM時可使細胞活動性更為增加。這暗示著在未來的臨床試驗中,在幹細胞移植之前進行處理可能帶來更有效率的結果(參見第11圖)。
為了確認神經幹細胞損傷的程度,可進行TUNEL分析。在20μM的類澱粉-β蛋白處理組中,可觀察到神經幹細胞死亡顯著增加,且當以1μM至100μM的PEP 1處理時,神經幹細胞死亡減少(參見第12圖)。
PEP-1對類澱粉-β蛋白引起的細胞凋亡起到保護功效的作用機制也被研究。首先,研究PEP-1是否能將類澱粉-β蛋白造成的氧化性損傷降到最小。藉由使用DCF-DA染色(Molecular Probes,Eugene,OR)觀察以類澱粉-β蛋白與PEP-1處理後,活性氧化物生成的改變。在活性氧化物因20μM的類澱粉-β蛋白而增加的組別中,藉由PEP-1(1μM、10μM、50μM)處理可使增加的活性氧化物減少(參見第13圖)。
實驗1-4:以PEP-1處理的組別與未以PEP-1處理的組別之間的蛋白質表現量之比較性分析
藉由2D-電泳技術及抗體微陣列技術分析以PEP-1處理的組別與未以PEP-1處理的組別的蛋白質表現量。製備從實例3的實驗1-1中培養的神經幹細胞所萃取的蛋白質體200ug。此外,使用未以PEP-1處理的組別作為相同條件下的比較組別。
使用12%的丙烯醯胺凝膠進行2D-電泳。首先使用8.5×7cm的凝膠尺寸在P1 4~10N下進行凝膠電泳。在電泳
之後,以膠體考馬斯藍(Colloidal Coomassie Blue)染色,並接著使用PDQuest軟體分析各個點來比較表現量。
使用MALDI-TOF MS(基質輔助雷射脫附離子化-飛行時間質譜儀)辨識表現量的差異超過1.5倍者。其中,辨識出與發炎相關訊號釋放有關的蛋白質,如i-NOS及HMGB-1(參見表6)。無論是增加或減少,類澱粉-β蛋白對蛋白質表現量的改變都超過1.5倍,但可確定的是,當加入PEP-1時,表現量都受到控制而接近陰性對照組(參見第14圖)。
藉由使用細胞發訊套組(CSAA1,PanoramaTM Ab Microarray Cell Signaling kit)來完成抗體微陣列,由GenePix Personal 4100A掃描器(Molecular Devices)掃描陣列載片,並由GenePix Pro 5.0(Molecular Devices)分析數據。
下表6為藉由2D電泳技術所完成之發炎相關蛋白質的表現量分析。對照組呈現的是未以類澱粉-β蛋白處理也未以PEP-1處理之細胞的蛋白質表現量。表6顯示基於對照組的表現量之蛋白質表現的增加或減少倍數。
根據與下表6所示類似的分析結果,吾人可確認發炎相關蛋白質的過量表現或不足量表現可受到PEP-1控制;蛋白質表現量接近陰性對照組。
磷脂醯肌醇3-激酶(PI3K)/AKT訊號釋放路徑在神經幹細胞的生長及存活中扮演著關鍵角色。PI3K路徑可被生長因子及調控因子活化,且PI3K路徑涉及神經幹細胞生長及存活的正常調控。AKT訊號釋放路徑可使多種促凋亡因子(pro-apoptotic factor)失效,包括習知的凋亡訊號釋放分子GSK3β。
由於HMGB1在蛋白質分析中顯示出較大的改變,因此為了進一步研究PEP-1的抗發炎功效,吾人對HMGB1進行西方墨點法分析。結果,PEP-1的處理增加了諸如Ki67、pAKT、PI3K、HSTF-1及Bcl-2等抗凋亡蛋白的蛋白質表現量,並減少了諸如Bax、GSK3β、細胞色素-c及凋亡蛋白酶-3等凋亡訊號因子的蛋白質表現量(參見第15圖)。
HMGB1,一種與DNA結合的非組織蛋白結構蛋白質,在細胞內扮演多種角色;如穩定核小體結構及調控基因表現。作為在發炎反應後期分泌的致發炎物質之一,當發炎反應被刺激時,巨噬細胞及單核球分泌出HMGB1,但當神經顯著受損並導
致細胞壞死時,HMGB1將被分泌至細胞外,導致劇烈的發炎反應。在以類澱粉-β處理使得神經細胞的細胞質中之HMGB1減少之後,藉由PEP-1處理可增加神經細胞的細胞質中之HMGB1,這反映了PEP-1可抑制HMGB1因神經細胞死亡而被分泌至細胞外的事實;因而暗示了PEP-1具有有力的抗發炎功效(參見第15圖)。
此外,吾人研究了PEP-1對類澱粉-β聚結的反應。在誘導類澱粉-β聚結的情況下,當以PEP-1處理時,可抑制蛋白質聚結(參見第16(A)圖),且以PEP-1處理已被誘導而聚結的類澱粉-β蛋白可使蛋白質降解(參見第16(B)圖)。
在PEP-1作用的機制中,先前吾人已確認了對PI3K之細胞存活訊號釋放的增加,以及對PI3K之凋亡訊號釋放的減少。為了研究這些功效是直接還是間接的,吾人以PI3K-抑制劑,LY294002(Promega),進行處理。結果,當以LY294002處理時,在以PEP 1處理後所增加的細胞存活比例降低了。因此,吾人可獲得PI3K與PEP 1的神經保護功效直接有關之結論(參見第17圖)。
PEP-1可抑制因類澱粉-β蛋白所致的神經幹細胞凋亡。並且,也確認了PEP-1可增進神經幹細胞的細胞活動性,因此暗示了臨床應用的各種可能性。對由β-類澱粉蛋白所引起的神經毒性之抑制功效可由PEP 1作用機制的抗發炎功效、增加的神經幹細胞的存活因子及減少的凋亡因子,特別是PI3K訊號釋放路徑的活化及抗氧化功效的活化而獲得證實。
SEQUENCE LISTING
<110> KAEL-GemVax Co.,Ltd. KIM,Sangjae
<120> 抗發炎胜肽及包含其之成分
<130> OF13P082TW
<150> KR 10-2012-0050529
<151> 2012-05-11
<150> KR 10-2012-0050533
<151> 2012-05-11
<150> KR 10-2012-0071989
<151> 2012-07-02
<150> KR 10-2012-0104144
<151> 2012-09-19
<150> KR 10-2012-0104207
<151> 2012-09-19
<160> 13
<170> PatentIn version 3.5
<210> 1
<211> 16
<212> PRT
<213> 智人
<400> 1
<210> 2
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對TNF-alpha的順向引子
<400> 2
<210> 3
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對TNF-alpha的反向引子
<400> 3
<210> 4
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對il-1 beta的順向引子
<400> 4
<210> 5
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對il-1 beta的反向引子
<400> 5
<210> 6
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 針對il-6的順向引子
<400> 6
<210> 7
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對il-6的反向引子
<400> 7
<210> 8
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對il-8的順向引子
<400> 8
<210> 9
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對il-8的反向引子
<400> 9
<210> 10
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對inos的順向引子
<400> 10
<210> 11
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對inos的反向引子
<400> 11
<210> 12
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對beta肌動蛋白的順向引子
<400> 12
<210> 13
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 針對beta肌動蛋白的反向引子
<400> 13
Claims (6)
- 一種將一胜肽用於製造一組成物之用途,該組成物用於治療或改善中樞或周邊神經系統相關疾病,其中該胜肽由序列編號:1之胺基酸序列所構成。
- 如請求項1所述之用途,其中該胜肽源自人類端粒酶。
- 如請求項1所述之用途,其中該組成物為用於治療或改善該疾病之一醫藥組成物。
- 如請求項1所述之用途,其中該組成物為用於改善該疾病之一食品組成物。
- 如請求項1所述之用途,其中該疾病係選自由:阿茲海默氏症(Alzheimer’s disease);腦膜炎;腦炎;多發性硬化症;腦梗塞(cerebral infarction);腦栓塞(cerebral embolism);格林-巴利症候群(Guillain-Barre syndrome);神經炎;神經痛;脊椎損傷;麻痺;葡萄膜炎(uveitis)所組成之群組。
- 如請求項5所述之用途,其中該疾病係阿茲海默氏症。
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
??10-2012-0050529 | 2012-05-11 | ||
KR20120050533 | 2012-05-11 | ||
??10-2012-0050533 | 2012-05-11 | ||
KR20120050529 | 2012-05-11 | ||
KR20120071989 | 2012-07-02 | ||
??10-2012-0071989 | 2012-07-02 | ||
KR20120104207 | 2012-09-19 | ||
??10-2012-0104207 | 2012-09-19 | ||
??10-2012-0104144 | 2012-09-19 | ||
KR20120104144 | 2012-09-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201406959A TW201406959A (zh) | 2014-02-16 |
TWI640632B true TWI640632B (zh) | 2018-11-11 |
Family
ID=47882179
Family Applications (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW102115617A TWI640632B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(三) |
TW106131711A TWI649423B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW111127474A TW202246301A (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW110101563A TWI784394B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW102115616A TWI665304B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW107131413A TWI719344B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW106131665A TWI640320B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(三) |
Family Applications After (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW106131711A TWI649423B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW111127474A TW202246301A (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW110101563A TWI784394B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW102115616A TWI665304B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW107131413A TWI719344B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(二) |
TW106131665A TWI640320B (zh) | 2012-05-11 | 2013-05-01 | 抗發炎胜肽及包含其之成分(三) |
Country Status (8)
Country | Link |
---|---|
US (12) | US9527888B2 (zh) |
EP (2) | EP2850097B1 (zh) |
JP (7) | JP6466833B2 (zh) |
KR (5) | KR20150014483A (zh) |
CN (7) | CN115927242A (zh) |
ES (2) | ES2691070T3 (zh) |
TW (7) | TWI640632B (zh) |
WO (3) | WO2013167298A1 (zh) |
Families Citing this family (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20150014483A (ko) | 2012-05-11 | 2015-02-06 | 주식회사 카엘젬백스 | 항염증 활성을 갖는 펩티드 및 이를 포함하는 조성물 |
US9730984B2 (en) | 2012-05-11 | 2017-08-15 | Gemvax & Kael Co., Ltd. | Composition for preventing or treating rheumatoid arthritis |
KR101799904B1 (ko) | 2012-07-11 | 2017-11-22 | 주식회사 젬백스앤카엘 | 세포 투과성 펩티드, 그를 포함한 컨쥬게이트 및 그를 포함한 조성물 |
US20150125438A1 (en) | 2012-07-20 | 2015-05-07 | Sang Jae Kim | Anti-Inflammatory Peptides and Composition Comprising the Same |
TWI616530B (zh) * | 2012-09-19 | 2018-03-01 | 傑姆維克斯&凱爾有限公司 | 穿膜胜肽以及包含該胜肽之共軛物及組成物(一) |
KR102362341B1 (ko) | 2012-09-19 | 2022-02-14 | 주식회사 젬백스앤카엘 | 세포 투과성 펩티드, 그를 포함한 컨쥬게이트 및 그를 포함한 조성물 |
JP6510410B2 (ja) | 2012-09-19 | 2019-05-08 | ジェムバックス アンド カエル カンパニー,リミティド | 細胞透過性ペプチド、それを含んだコンジュゲート、及びそれを含んだ組成物 |
ES2758451T3 (es) * | 2012-09-19 | 2020-05-05 | Gemvax & Kael Co Ltd | Péptido de penetración celular, conjugado que comprende el mismo y composición que comprende el conjugado |
JP6474786B2 (ja) | 2013-04-19 | 2019-02-27 | ジェムバックス アンド カエル カンパニー,リミティド | 虚血性損傷の治療及び予防用の組成物 |
EP3004883B1 (en) | 2013-06-07 | 2022-09-14 | Gemvax & Kael Co., Ltd. | Gv1001, gemcitabine and capecitabine for use in the treatment of pancreatic cancer in high eotaxin baseline level patients |
TWI539960B (zh) | 2013-06-21 | 2016-07-01 | 凱爾傑姆維克斯有限公司 | 激素分泌調節劑、包括其的組成物以及其用途 |
WO2015060673A1 (ko) | 2013-10-23 | 2015-04-30 | 주식회사 카엘젬백스 | 전립선 비대증 치료 및 예방용 조성물 |
KR102494803B1 (ko) * | 2013-11-22 | 2023-02-06 | 주식회사 젬백스앤카엘 | 혈관 신생 억제 활성을 가지는 펩티드 및 이를 포함하는 조성물 |
KR20230025935A (ko) * | 2013-12-10 | 2023-02-23 | 주식회사 젬백스앤카엘 | 항산화 효과를 가지는 펩티드 및 이를 포함하는 조성물 |
JP6367950B2 (ja) | 2013-12-17 | 2018-08-01 | ジェムバックス アンド カエル カンパニー,リミティド | 前立腺癌治療用組成物 |
EP3130345B9 (en) * | 2014-04-11 | 2022-05-04 | Gemvax & Kael Co., Ltd. | Peptide having fibrosis inhibitory activity and composition containing same |
WO2015167067A1 (ko) * | 2014-04-30 | 2015-11-05 | 주식회사 카엘젬백스 | 장기, 조직 또는 세포 이식용 조성물, 키트 및 이식 방법 |
WO2015170790A1 (ko) * | 2014-05-09 | 2015-11-12 | 주식회사 카엘젬백스 | 허혈성 손상 치료 및 예방용 조성물 |
KR102232319B1 (ko) * | 2014-05-09 | 2021-03-26 | 주식회사 젬백스앤카엘 | 텔로머라제 펩티드를 유효성분으로 포함하는 뇌혈관 질환 예방 또는 치료용 조성물 |
KR102413243B1 (ko) * | 2014-12-23 | 2022-06-27 | 주식회사 젬백스앤카엘 | 안질환 치료 펩티드 및 이를 포함하는 안질환 치료용 조성물 |
CN107405380B (zh) * | 2015-02-27 | 2021-04-20 | 珍白斯凯尔有限公司 | 用于预防听觉损伤的肽及其包含该肽的组合物 |
KR101662438B1 (ko) | 2015-04-07 | 2016-10-04 | 가톨릭대학교 산학협력단 | X형 구조의 dna를 유효성분으로 포함하는 아토피 피부염 예방 또는 치료용 조성물 |
EP3288960B1 (en) * | 2015-04-27 | 2021-01-06 | MacKay Memorial Hospital | Short synthetic peptide for treatment and/or prophylaxis of autoimmune and inflammatory disorders |
WO2016190660A1 (ko) | 2015-05-26 | 2016-12-01 | 주식회사 젬백스앤카엘 | 신규 펩티드 및 이를 포함한 조성물 |
WO2017003267A1 (ko) * | 2015-07-02 | 2017-01-05 | 주식회사 젬백스앤카엘 | 항바이러스 활성 효능을 가지는 펩티드 및 이를 포함하는 조성물 |
CN105061573B (zh) * | 2015-07-20 | 2018-08-21 | 苏州大学 | 姚虻天然抗炎症多肽cecropin-TY1及其应用 |
EP3372613A4 (en) * | 2015-11-03 | 2019-07-10 | Gemvax & Kael Co., Ltd. | PEPTIDE WITH NERVE DAMAGE PREVENTION AND REGENERATION EFFECT AND COMPOSITION THEREOF |
KR20180089440A (ko) * | 2015-12-28 | 2018-08-08 | 주식회사 젬백스앤카엘 | 멜라닌 억제 기능성 펩티드 및 이를 포함하는 조성물 |
CN108431020B (zh) * | 2016-03-09 | 2022-03-29 | 凯恩塞恩斯株式会社 | 用于预防或治疗炎症性疾病的肽及其应用 |
KR101897122B1 (ko) * | 2016-03-09 | 2018-09-10 | 주식회사 바이오펩 | 염증성 질환의 예방 또는 치료용 펩타이드 및 이의 용도 |
US9943566B2 (en) | 2016-03-16 | 2018-04-17 | Geoffrey Brooks Consultants, Llc | NF-κB inhibitor composition for skin health |
JP7114481B2 (ja) * | 2016-04-07 | 2022-08-08 | ジェムバックス アンド カエル カンパニー,リミティド | テロメラーゼ活性の増加及びテロメアの延長の効能を有するペプチド、及びこれを含む組成物 |
KR101831888B1 (ko) * | 2016-04-15 | 2018-04-16 | (주)케어젠 | 항염증 활성을 갖는 펩타이드 및 이의 용도 |
WO2017183942A2 (ko) * | 2016-04-21 | 2017-10-26 | 주식회사 젬백스앤카엘 | 콜라겐 생성 증가 효능을 가지는 펩티드 및 이를 포함하는 조성물 |
WO2018014936A1 (en) * | 2016-07-18 | 2018-01-25 | Nuritas Limited | Topical compositions |
KR102042600B1 (ko) * | 2018-02-13 | 2019-11-08 | 전북대학교산학협력단 | 항산화 및 항염증 활성을 갖는 홍갯지렁이 유래 신규 펩타이드 및 이의 이용 |
JP2021525242A (ja) * | 2018-05-28 | 2021-09-24 | ジャンイン ユスン ファーマシューティカル カンパニー,リミテッド | 新たな医薬品使用 |
CN112824428B (zh) * | 2019-11-21 | 2022-08-16 | 上海医药工业研究院 | 一种治疗肺疾病的生物肽及其应用 |
KR102354916B1 (ko) * | 2020-02-11 | 2022-01-26 | 주식회사 쓰리빅스 | 신규 펩타이드 3ps_i014 및 이의 용도 |
KR102266613B1 (ko) * | 2020-09-21 | 2021-06-18 | 자안바이오 주식회사 | 항염증 활성을 갖는 신규한 펩티드 및 이의 용도 |
KR102302984B1 (ko) * | 2021-06-16 | 2021-09-17 | 주식회사 쓰리빅스 | 염증성 피부 질환 예방 또는 치료용 약학조성물 |
WO2022270478A1 (ja) * | 2021-06-21 | 2022-12-29 | 国立大学法人北海道大学 | 抗ウイルス剤 |
CN113461776B (zh) * | 2021-07-08 | 2023-05-16 | 南京财经大学 | 一种具有预防及治疗肠炎功能的小肽及其应用 |
US11724077B2 (en) * | 2021-07-28 | 2023-08-15 | Subhash Dhawan | Therapeutic swabs for treating upper respiratory infections |
CN114349821B (zh) * | 2021-12-08 | 2024-01-16 | 南方医科大学珠江医院 | 蛙皮抗氧化肽及其基因在制药和抗皱化妆品的应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010003520A2 (en) * | 2008-06-16 | 2010-01-14 | Genovax S.R.L. | Anti-tumor immunotherapy |
Family Cites Families (90)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR930001915B1 (ko) | 1990-06-27 | 1993-03-20 | 포항종합제철 주식회사 | 저온 소결 압전요업재료 제조방법 |
HU207799B (en) | 1991-07-24 | 1993-06-28 | Beres Export Import Rt | Process for producing pharmaceutical composition for influencing the reticuloendothelial system, for treating chronic pain symptomes of degenerative locomotor disorders or tumors, and for treating mucoviscidosis |
DE69731302T3 (de) | 1996-07-22 | 2011-01-20 | Renovo Ltd. | Verwendung von substanzen, die die östrogen wirkung fördern, zur behandlung von wunden |
DE69739675D1 (de) * | 1996-10-01 | 2010-01-07 | Geron Corp | Oter |
US6475789B1 (en) * | 1996-10-01 | 2002-11-05 | University Technology Corporation | Human telomerase catalytic subunit: diagnostic and therapeutic methods |
US6610839B1 (en) * | 1997-08-14 | 2003-08-26 | Geron Corporation | Promoter for telomerase reverse transcriptase |
BR9809629A (pt) | 1997-05-15 | 2000-07-04 | Chugai Pharmaceutical Co Ltd | Agente terapêutico para caquexia |
JP2002514928A (ja) | 1997-07-01 | 2002-05-21 | キャンビア バイオシステムス リミティド ライアビリティー カンパニー | 脊椎動物テロメラーゼ遺伝子およびタンパク質ならびにその使用 |
US7030211B1 (en) * | 1998-07-08 | 2006-04-18 | Gemvax As | Antigenic peptides derived from telomerase |
US6378526B1 (en) | 1998-08-03 | 2002-04-30 | Insite Vision, Incorporated | Methods of ophthalmic administration |
IL132406A0 (en) | 1998-10-21 | 2001-03-19 | Pfizer Prod Inc | Treatment of bph with cgmp elevators |
US6815426B2 (en) | 2001-02-16 | 2004-11-09 | E. I. Du Pont De Nemours And Company | Angiogenesis-inhibitory tripeptides, compositions and their methods of use |
RU2282446C2 (ru) | 2001-04-10 | 2006-08-27 | Ниппон Синяку Ко., Лтд. | Лекарственное средство для хронического суставного ревматизма |
SI1425028T1 (sl) | 2001-05-16 | 2010-02-26 | Yeda Res & Dev | Uporaba inhibitorjev za il-18 za zdravljenje ali prepreäśevanje sepse |
US20030143228A1 (en) | 2001-10-29 | 2003-07-31 | Baylor College Of Medicine | Human telomerase reverse transcriptase as a class-II restricted tumor-associated antigen |
US7786084B2 (en) | 2001-12-21 | 2010-08-31 | Biotempt B.V. | Treatment of burns |
WO2003064447A2 (en) * | 2002-01-29 | 2003-08-07 | Posco | Immune-modulating peptide |
RS89204A (en) | 2002-04-10 | 2006-12-15 | Applied Research Systems Ars Holding N.V. | Use of osteoprotegerin for the treatment and/or prevention of fibrotic disease |
KR20050020987A (ko) | 2002-06-12 | 2005-03-04 | 바이오겐 아이덱 엠에이 인코포레이티드 | 아데노신 수용체 길항제를 사용하여 허혈 재관류 손상을치료하는 방법 |
US20080025986A1 (en) | 2003-06-06 | 2008-01-31 | Ozes Osman N | Methods of Treating Tnf-Mediated Disorders |
CA2530900A1 (en) | 2003-06-25 | 2004-12-29 | Canbas Co., Ltd. | Peptides and peptidomimetics having immune-modulating, anti-inflammatory, and anti-viral activity |
KR20050040517A (ko) | 2003-10-29 | 2005-05-03 | 주식회사 오리엔트 | 허혈성 질환에 대한 저항성을 나타내는 형질전환 생쥐 |
SI1530965T1 (sl) | 2003-11-11 | 2006-06-30 | Mattern Udo | Formulacija za nasalno aplikacijo z nadzorovanim sproscanjem spolnih hormonov |
GB0426146D0 (en) | 2004-11-29 | 2004-12-29 | Bioxell Spa | Therapeutic peptides and method |
JP5273721B2 (ja) | 2005-03-21 | 2013-08-28 | ビカス セラピューティクス,エルエルシー | 悪液質を緩和するための組成物および方法 |
JPWO2007061029A1 (ja) | 2005-11-25 | 2009-05-07 | 学校法人慶應義塾 | 前立腺癌治療剤 |
WO2007069068A2 (en) | 2005-12-16 | 2007-06-21 | Diatos | Cell penetrating peptide conjugates for delivering nucleic acids into cells |
CA2634818A1 (en) * | 2005-12-23 | 2007-06-28 | Sienna Cancer Diagnostics Ltd | Assay for detection of telomerase activity |
WO2007097561A1 (en) | 2006-02-20 | 2007-08-30 | Ewha University - Industry Collaboration Foundation | Peptide having cell membrane penetrating activity |
WO2008015580A2 (en) | 2006-07-24 | 2008-02-07 | Forhumantech. Co., Ltd. | Pharmaceutical composition for alleviation and treatment of ischemic conditions and method for delivering the same |
CA2676797C (en) | 2007-01-29 | 2014-04-22 | Dae Woong Jo | Novel macromolecule transduction domains and methods for identification and uses thereof |
JP2010532484A (ja) | 2007-06-29 | 2010-10-07 | コレロジック システムズ,インコーポレイテッド | 卵巣癌のための予測マーカー |
EP2185701A4 (en) | 2007-08-15 | 2011-03-02 | Amunix Operating Inc | COMPOSITIONS AND METHODS FOR ENHANCING THE PRODUCTION OF RECOMBINANT POLYPEPTIDES |
WO2009025871A1 (en) * | 2007-08-23 | 2009-02-26 | University Of Medicine And Dentistry Of Nj | Telomerase reverse transcriptase variant |
EP2212696B1 (en) | 2007-10-25 | 2013-12-04 | Genelux Corporation | Systems and methods for viral therapy |
GB2455539B (en) | 2007-12-12 | 2012-01-18 | Cambridge Entpr Ltd | Anti-inflammatory compositions and combinations |
TW200946541A (en) | 2008-03-27 | 2009-11-16 | Idenix Pharmaceuticals Inc | Solid forms of an anti-HIV phosphoindole compound |
US8252282B2 (en) | 2008-06-19 | 2012-08-28 | University Of Medicine & Dentistry Of New Jersey | Nuclear telomerase reverse transcriptase variant |
ES2334315B1 (es) | 2008-07-29 | 2011-02-28 | Universitat Pompeu Fabra | Peptidos con capacidad de penetracion celular y sus usos. |
TW201020245A (en) | 2008-08-20 | 2010-06-01 | Schering Corp | Ethynyl-substituted pyridine and pyrimidine derivatives and their use in treating viral infections |
US20110183925A1 (en) | 2008-09-22 | 2011-07-28 | Nisshin Pharma Inc. | Anti-inflammatory peptide |
EP2337795A2 (en) * | 2008-10-01 | 2011-06-29 | Dako Denmark A/S | Mhc multimers in cancer vaccines and immune monitoring |
KR101169030B1 (ko) | 2009-01-21 | 2012-07-26 | 애니젠 주식회사 | 신규한 세포막 투과 도메인 및 이를 포함하는 세포내 전달 시스템 |
JP5654569B2 (ja) | 2009-04-20 | 2015-01-14 | オーチス エレベータ カンパニーOtis Elevator Company | 乗用コンベヤ用の欄干アセンブリ |
CN102421440B (zh) | 2009-05-07 | 2017-06-09 | 东国制药(株) | 用于预防或治疗神经病理性疼痛的药学组合物 |
EP2251028A1 (en) | 2009-05-12 | 2010-11-17 | Biocompatibles Uk Ltd. | Treatment of eye diseases using encapsulated cells encoding and secreting an anti-angiogenic factor and/or a neuroprotective factor |
US7928067B2 (en) | 2009-05-14 | 2011-04-19 | Ischemix Llc | Compositions and methods for treating ischemia and ischemia-reperfusion injury |
JP5653214B2 (ja) | 2009-05-20 | 2015-01-14 | 東レ株式会社 | 細胞膜透過性ペプチド |
KR20110057049A (ko) | 2009-11-23 | 2011-05-31 | 박의신 | 기능성 전립선염 치료제 |
KR20110062943A (ko) | 2009-12-04 | 2011-06-10 | 주식회사종근당 | 퀴나졸린 유도체를 유효성분으로 하는 전립선 비대증 예방 또는 치료제 |
JP6027893B2 (ja) | 2010-01-11 | 2016-11-16 | カッパーアールエヌエー,インコーポレイテッド | 性ホルモン結合グロブリン(shbg)に対する天然アンチセンス転写物の阻害による性ホルモン結合グロブリン(shbg)関連疾患の治療 |
RS59462B1 (sr) * | 2010-02-16 | 2019-11-29 | Ultimovacs As | Polipeptidi |
FR2960542B1 (fr) | 2010-05-27 | 2012-08-17 | Esther Suzy Arlette Fellous | Peptide en tant que medicament, en particulier pour le traitement du cancer |
KR101263212B1 (ko) | 2010-05-28 | 2013-05-10 | 성신여자대학교 산학협력단 | 신규한 세포막 투과성 펩타이드 및 그의 용도 |
WO2011150494A1 (en) | 2010-05-30 | 2011-12-08 | The Governing Council Of The University Of Toronto | Mitochondrial penetrating peptides as carriers for anticancer compounds |
KR101388372B1 (ko) | 2010-06-11 | 2014-04-23 | 한국화학연구원 | 청각보호 작용을 하는 신규 화합물 |
KR101348284B1 (ko) | 2010-09-09 | 2014-01-03 | 주식회사 나이벡 | 인간 유래 세포 투과성 펩타이드와 생리활성 펩타이드 결합체 및 그 용도 |
US20120208755A1 (en) | 2011-02-16 | 2012-08-16 | Intarcia Therapeutics, Inc. | Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers |
KR20120121196A (ko) | 2011-04-26 | 2012-11-05 | 주식회사 글루칸 | 관절염 치료제 |
KR101284772B1 (ko) | 2011-05-24 | 2013-07-17 | 정종문 | 항염증, 진통효과를 가지는 기능성 식품 조성물 |
KR20120133661A (ko) | 2011-05-31 | 2012-12-11 | 주식회사 바이오포트코리아 | 아스타잔틴을 포함하는 항염증제 |
KR101288053B1 (ko) | 2011-07-04 | 2013-07-23 | 동국대학교 산학협력단 | 필발 추출물을 유효성분으로 포함하는 내이손상 예방 및 치료용 조성물 |
KR101361445B1 (ko) | 2011-12-26 | 2014-02-12 | 성균관대학교산학협력단 | 펩타이드, 5-플루오로우라실, 및 성숙수지상세포를 포함하는 암 치료용 약학적 조성물 |
WO2013118899A1 (ja) | 2012-02-10 | 2013-08-15 | 医療法人社団博心厚生会 | 単球増殖剤、単球増殖用培地、単球の製造方法、樹状細胞の製造方法、及び樹状細胞ワクチンの製造方法 |
WO2013135266A1 (en) | 2012-03-12 | 2013-09-19 | Gemvax As | Treatment of non-small cell lung carcinoma by active immunotherapy |
KR20150014483A (ko) | 2012-05-11 | 2015-02-06 | 주식회사 카엘젬백스 | 항염증 활성을 갖는 펩티드 및 이를 포함하는 조성물 |
US9730984B2 (en) | 2012-05-11 | 2017-08-15 | Gemvax & Kael Co., Ltd. | Composition for preventing or treating rheumatoid arthritis |
KR101799904B1 (ko) | 2012-07-11 | 2017-11-22 | 주식회사 젬백스앤카엘 | 세포 투과성 펩티드, 그를 포함한 컨쥬게이트 및 그를 포함한 조성물 |
US20150125438A1 (en) | 2012-07-20 | 2015-05-07 | Sang Jae Kim | Anti-Inflammatory Peptides and Composition Comprising the Same |
ES2758451T3 (es) | 2012-09-19 | 2020-05-05 | Gemvax & Kael Co Ltd | Péptido de penetración celular, conjugado que comprende el mismo y composición que comprende el conjugado |
KR102038487B1 (ko) | 2012-09-19 | 2019-10-30 | 주식회사 젬백스앤카엘 | 텔로머라제 펩티드를 포함하는 항균 또는 항진균용 조성물 |
KR102362341B1 (ko) | 2012-09-19 | 2022-02-14 | 주식회사 젬백스앤카엘 | 세포 투과성 펩티드, 그를 포함한 컨쥬게이트 및 그를 포함한 조성물 |
JP6510410B2 (ja) | 2012-09-19 | 2019-05-08 | ジェムバックス アンド カエル カンパニー,リミティド | 細胞透過性ペプチド、それを含んだコンジュゲート、及びそれを含んだ組成物 |
KR20140104288A (ko) | 2013-02-20 | 2014-08-28 | 주식회사 카엘젬백스 | Tnf-알파 저해제 |
DK2959005T3 (da) | 2013-02-22 | 2022-01-03 | Univ Leland Stanford Junior | Medicinsk anvendelse relateret til telomer forlængelse |
JP6474786B2 (ja) | 2013-04-19 | 2019-02-27 | ジェムバックス アンド カエル カンパニー,リミティド | 虚血性損傷の治療及び予防用の組成物 |
EP3004883B1 (en) | 2013-06-07 | 2022-09-14 | Gemvax & Kael Co., Ltd. | Gv1001, gemcitabine and capecitabine for use in the treatment of pancreatic cancer in high eotaxin baseline level patients |
TWI539960B (zh) | 2013-06-21 | 2016-07-01 | 凱爾傑姆維克斯有限公司 | 激素分泌調節劑、包括其的組成物以及其用途 |
JP6574175B2 (ja) | 2013-07-12 | 2019-09-11 | ジェムバックス アンド カエル カンパニー,リミティド | 細胞透過性ペプチド、及びそれを含むコンジュゲート |
WO2015060673A1 (ko) | 2013-10-23 | 2015-04-30 | 주식회사 카엘젬백스 | 전립선 비대증 치료 및 예방용 조성물 |
KR102494803B1 (ko) | 2013-11-22 | 2023-02-06 | 주식회사 젬백스앤카엘 | 혈관 신생 억제 활성을 가지는 펩티드 및 이를 포함하는 조성물 |
JP6367950B2 (ja) | 2013-12-17 | 2018-08-01 | ジェムバックス アンド カエル カンパニー,リミティド | 前立腺癌治療用組成物 |
EP3130345B9 (en) | 2014-04-11 | 2022-05-04 | Gemvax & Kael Co., Ltd. | Peptide having fibrosis inhibitory activity and composition containing same |
WO2015167067A1 (ko) | 2014-04-30 | 2015-11-05 | 주식회사 카엘젬백스 | 장기, 조직 또는 세포 이식용 조성물, 키트 및 이식 방법 |
KR102413243B1 (ko) | 2014-12-23 | 2022-06-27 | 주식회사 젬백스앤카엘 | 안질환 치료 펩티드 및 이를 포함하는 안질환 치료용 조성물 |
CN107405380B (zh) | 2015-02-27 | 2021-04-20 | 珍白斯凯尔有限公司 | 用于预防听觉损伤的肽及其包含该肽的组合物 |
WO2016190660A1 (ko) | 2015-05-26 | 2016-12-01 | 주식회사 젬백스앤카엘 | 신규 펩티드 및 이를 포함한 조성물 |
TW201718028A (zh) | 2015-10-13 | 2017-06-01 | 賽米克Ip有限責任公司 | Ve-鈣黏蛋白結合性生物結合物 |
EP3372613A4 (en) | 2015-11-03 | 2019-07-10 | Gemvax & Kael Co., Ltd. | PEPTIDE WITH NERVE DAMAGE PREVENTION AND REGENERATION EFFECT AND COMPOSITION THEREOF |
KR20170054310A (ko) | 2015-11-09 | 2017-05-17 | 주식회사 젬백스앤카엘 | 텔로머라제 유래 펩티드를 포함하는 수지상세포 치료제 및 면역 치료제, 및 이를 사용하는 치료방법 |
-
2013
- 2013-03-15 KR KR1020147034320A patent/KR20150014483A/ko not_active IP Right Cessation
- 2013-03-15 CN CN202211006340.6A patent/CN115927242A/zh active Pending
- 2013-03-15 ES ES13713371T patent/ES2691070T3/es active Active
- 2013-03-15 KR KR1020217005717A patent/KR20210025132A/ko not_active IP Right Cessation
- 2013-03-15 WO PCT/EP2013/055327 patent/WO2013167298A1/en active Application Filing
- 2013-03-15 KR KR1020227014717A patent/KR102578891B1/ko active IP Right Grant
- 2013-03-15 CN CN201810794313.7A patent/CN108949717B/zh active Active
- 2013-03-15 JP JP2015510686A patent/JP6466833B2/ja active Active
- 2013-03-15 EP EP13713371.6A patent/EP2850097B1/en active Active
- 2013-03-15 CN CN201380036618.7A patent/CN104507961B/zh active Active
- 2013-03-15 US US14/400,321 patent/US9527888B2/en active Active
- 2013-03-15 CN CN201810797270.8A patent/CN108841802B/zh active Active
- 2013-03-15 CN CN202310636408.7A patent/CN116694597A/zh active Pending
- 2013-03-15 EP EP18184847.4A patent/EP3428181A3/en active Pending
- 2013-03-15 WO PCT/EP2013/055329 patent/WO2013167299A1/en active Application Filing
- 2013-05-01 TW TW102115617A patent/TWI640632B/zh active
- 2013-05-01 TW TW106131711A patent/TWI649423B/zh active
- 2013-05-01 TW TW111127474A patent/TW202246301A/zh unknown
- 2013-05-01 TW TW110101563A patent/TWI784394B/zh active
- 2013-05-01 TW TW102115616A patent/TWI665304B/zh active
- 2013-05-01 TW TW107131413A patent/TWI719344B/zh active
- 2013-05-01 TW TW106131665A patent/TWI640320B/zh active
- 2013-05-07 ES ES17208839T patent/ES2750003T3/es active Active
- 2013-05-07 US US14/400,291 patent/US9540419B2/en active Active
- 2013-05-07 KR KR1020147006695A patent/KR102043426B1/ko active IP Right Grant
- 2013-05-07 CN CN201810436830.7A patent/CN108478786B/zh active Active
- 2013-05-07 WO PCT/EP2013/059460 patent/WO2013167574A1/en active Application Filing
- 2013-05-07 JP JP2015510786A patent/JP6294306B2/ja active Active
- 2013-05-07 KR KR1020157011995A patent/KR101685551B1/ko active IP Right Grant
- 2013-05-07 CN CN201380036639.9A patent/CN104507962B/zh active Active
-
2016
- 2016-11-04 US US15/343,502 patent/US10039811B2/en active Active
- 2016-11-17 US US15/354,139 patent/US10206981B2/en active Active
-
2017
- 2017-09-11 JP JP2017174211A patent/JP6546232B2/ja active Active
-
2018
- 2018-06-06 JP JP2018108788A patent/JP6923485B2/ja active Active
- 2018-07-02 US US16/025,352 patent/US10960056B2/en active Active
- 2018-12-21 US US16/230,732 patent/US10888606B2/en active Active
-
2019
- 2019-06-20 JP JP2019114719A patent/JP7007333B2/ja active Active
-
2020
- 2020-10-26 US US17/080,653 patent/US11369665B2/en active Active
- 2020-12-04 US US17/112,935 patent/US11622998B2/en active Active
-
2021
- 2021-10-07 JP JP2021165541A patent/JP7449909B2/ja active Active
-
2022
- 2022-06-08 US US17/835,278 patent/US11857607B2/en active Active
-
2023
- 2023-02-22 US US18/172,787 patent/US20230293644A1/en active Pending
- 2023-08-09 US US18/446,712 patent/US20240091320A1/en active Pending
- 2023-08-09 US US18/447,049 patent/US20240000902A1/en active Pending
-
2024
- 2024-03-04 JP JP2024032114A patent/JP2024052952A/ja active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010003520A2 (en) * | 2008-06-16 | 2010-01-14 | Genovax S.R.L. | Anti-tumor immunotherapy |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI640632B (zh) | 抗發炎胜肽及包含其之成分(三) | |
TWI647311B (zh) | 抗發炎胜肽及包含其之成分(一) | |
EP3333180B1 (en) | Anti-inflammatory peptides and composition comprising the same | |
TWI836435B (zh) | 抗發炎胜肽及包含其之成分 |