ES2263174T3 - Bikunina humana. - Google Patents
Bikunina humana.Info
- Publication number
- ES2263174T3 ES2263174T3 ES97915029T ES97915029T ES2263174T3 ES 2263174 T3 ES2263174 T3 ES 2263174T3 ES 97915029 T ES97915029 T ES 97915029T ES 97915029 T ES97915029 T ES 97915029T ES 2263174 T3 ES2263174 T3 ES 2263174T3
- Authority
- ES
- Spain
- Prior art keywords
- protein
- sequence
- bikunin
- placental bikunin
- amino acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 241000282414 Homo sapiens Species 0.000 title abstract description 89
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 132
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 131
- 238000000034 method Methods 0.000 claims abstract description 48
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 239000013604 expression vector Substances 0.000 claims abstract description 6
- 101000663639 Homo sapiens Kunitz-type protease inhibitor 2 Proteins 0.000 claims description 234
- 150000001413 amino acids Chemical group 0.000 claims description 70
- 230000005764 inhibitory process Effects 0.000 claims description 53
- 230000000694 effects Effects 0.000 claims description 36
- 230000002401 inhibitory effect Effects 0.000 claims description 34
- 239000003814 drug Substances 0.000 claims description 29
- 210000004369 blood Anatomy 0.000 claims description 26
- 239000008280 blood Substances 0.000 claims description 26
- 102000052154 human SPINT2 Human genes 0.000 claims description 25
- 108010022999 Serine Proteases Proteins 0.000 claims description 23
- 102000012479 Serine Proteases Human genes 0.000 claims description 23
- 108010076504 Protein Sorting Signals Proteins 0.000 claims description 19
- 238000005345 coagulation Methods 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 17
- 238000000338 in vitro Methods 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- 210000004556 brain Anatomy 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 13
- 206010027476 Metastases Diseases 0.000 claims description 10
- 230000004054 inflammatory process Effects 0.000 claims description 10
- 206010061218 Inflammation Diseases 0.000 claims description 9
- 230000009401 metastasis Effects 0.000 claims description 9
- 230000002490 cerebral effect Effects 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 7
- 206010048962 Brain oedema Diseases 0.000 claims description 6
- 206010040070 Septic Shock Diseases 0.000 claims description 6
- 230000023555 blood coagulation Effects 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 5
- 208000006752 brain edema Diseases 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 210000000278 spinal cord Anatomy 0.000 claims description 5
- 239000002699 waste material Substances 0.000 claims description 5
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 4
- 206010040047 Sepsis Diseases 0.000 claims description 4
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 claims description 4
- 230000001575 pathological effect Effects 0.000 claims description 4
- 230000036303 septic shock Effects 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010063036 Spinal cord oedema Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 208000013223 septicemia Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000000729 N-terminal amino-acid group Chemical group 0.000 claims 3
- 230000008030 elimination Effects 0.000 claims 3
- 238000003379 elimination reaction Methods 0.000 claims 3
- 206010016654 Fibrosis Diseases 0.000 claims 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 2
- 230000004761 fibrosis Effects 0.000 claims 2
- 206010017758 gastric cancer Diseases 0.000 claims 2
- 208000028867 ischemia Diseases 0.000 claims 2
- 201000011549 stomach cancer Diseases 0.000 claims 2
- 206010008190 Cerebrovascular accident Diseases 0.000 claims 1
- 208000003926 Myelitis Diseases 0.000 claims 1
- 108020004511 Recombinant DNA Proteins 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 30
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 10
- 108020004707 nucleic acids Proteins 0.000 abstract description 9
- 102000039446 nucleic acids Human genes 0.000 abstract description 9
- -1 GUEST CELLS Substances 0.000 abstract description 4
- 229920001184 polypeptide Polymers 0.000 abstract description 3
- 102100039020 Kunitz-type protease inhibitor 2 Human genes 0.000 description 209
- 235000018102 proteins Nutrition 0.000 description 112
- 108010039627 Aprotinin Proteins 0.000 description 104
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 86
- 229960004405 aprotinin Drugs 0.000 description 84
- 102100032859 Protein AMBP Human genes 0.000 description 72
- 101800001691 Inter-alpha-trypsin inhibitor light chain Proteins 0.000 description 70
- 235000001014 amino acid Nutrition 0.000 description 62
- 239000012634 fragment Substances 0.000 description 51
- 239000003112 inhibitor Substances 0.000 description 51
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 47
- 102000004142 Trypsin Human genes 0.000 description 46
- 108090000631 Trypsin Proteins 0.000 description 46
- 239000012588 trypsin Substances 0.000 description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 40
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 40
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 38
- 238000000746 purification Methods 0.000 description 37
- 239000002299 complementary DNA Substances 0.000 description 36
- 239000000243 solution Substances 0.000 description 33
- 230000003169 placental effect Effects 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 29
- 210000001519 tissue Anatomy 0.000 description 29
- 241000283690 Bos taurus Species 0.000 description 28
- 108091005804 Peptidases Proteins 0.000 description 28
- 102000035195 Peptidases Human genes 0.000 description 28
- 239000004365 Protease Substances 0.000 description 28
- 108010088842 Fibrinolysin Proteins 0.000 description 27
- 210000002826 placenta Anatomy 0.000 description 27
- 229940012957 plasmin Drugs 0.000 description 27
- 238000001356 surgical procedure Methods 0.000 description 26
- 108091034117 Oligonucleotide Proteins 0.000 description 25
- 239000011780 sodium chloride Substances 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 125000003275 alpha amino acid group Chemical group 0.000 description 23
- 229940079593 drug Drugs 0.000 description 23
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 22
- 239000002773 nucleotide Substances 0.000 description 22
- 125000003729 nucleotide group Chemical group 0.000 description 22
- 206010028980 Neoplasm Diseases 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 230000001105 regulatory effect Effects 0.000 description 21
- 229940108519 trasylol Drugs 0.000 description 20
- 238000012163 sequencing technique Methods 0.000 description 19
- 230000014616 translation Effects 0.000 description 19
- 238000013519 translation Methods 0.000 description 18
- 239000007983 Tris buffer Substances 0.000 description 17
- 230000015271 coagulation Effects 0.000 description 17
- 238000010276 construction Methods 0.000 description 17
- 239000000499 gel Substances 0.000 description 17
- 238000004519 manufacturing process Methods 0.000 description 17
- 239000000463 material Substances 0.000 description 17
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 17
- 108020004414 DNA Proteins 0.000 description 16
- 102000003966 Alpha-1-microglobulin Human genes 0.000 description 15
- 108020004705 Codon Proteins 0.000 description 15
- 235000019419 proteases Nutrition 0.000 description 15
- 239000006228 supernatant Substances 0.000 description 15
- 239000000523 sample Substances 0.000 description 14
- 230000004913 activation Effects 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 12
- 102000003839 Human Proteins Human genes 0.000 description 11
- 108090000144 Human Proteins Proteins 0.000 description 11
- 230000008859 change Effects 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 230000009467 reduction Effects 0.000 description 11
- 239000003001 serine protease inhibitor Substances 0.000 description 11
- 238000012384 transportation and delivery Methods 0.000 description 11
- 239000013598 vector Substances 0.000 description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 208000014674 injury Diseases 0.000 description 10
- 230000003389 potentiating effect Effects 0.000 description 10
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 101500025163 Homo sapiens Inter-alpha-trypsin inhibitor light chain Proteins 0.000 description 9
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 9
- 108010067372 Pancreatic elastase Proteins 0.000 description 9
- 102000016387 Pancreatic elastase Human genes 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 235000018417 cysteine Nutrition 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 210000004072 lung Anatomy 0.000 description 9
- 108020004999 messenger RNA Proteins 0.000 description 9
- 239000002243 precursor Substances 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 239000002753 trypsin inhibitor Substances 0.000 description 9
- 101800004538 Bradykinin Proteins 0.000 description 8
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 8
- 102100035792 Kininogen-1 Human genes 0.000 description 8
- 125000000539 amino acid group Chemical group 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000004071 biological effect Effects 0.000 description 8
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 8
- 238000010367 cloning Methods 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 230000005012 migration Effects 0.000 description 8
- 238000013508 migration Methods 0.000 description 8
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 7
- 108010080865 Factor XII Proteins 0.000 description 7
- 102000000429 Factor XII Human genes 0.000 description 7
- 210000004899 c-terminal region Anatomy 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 7
- 150000001945 cysteines Chemical class 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 230000002441 reversible effect Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 230000008733 trauma Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 108700006306 Alpha-1-microglobulin Proteins 0.000 description 6
- 108091035707 Consensus sequence Proteins 0.000 description 6
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229920002684 Sepharose Polymers 0.000 description 6
- 229940122055 Serine protease inhibitor Drugs 0.000 description 6
- 101710102218 Serine protease inhibitor Proteins 0.000 description 6
- 108020005038 Terminator Codon Proteins 0.000 description 6
- 229940122618 Trypsin inhibitor Drugs 0.000 description 6
- 101710162629 Trypsin inhibitor Proteins 0.000 description 6
- 235000010633 broth Nutrition 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000875 corresponding effect Effects 0.000 description 6
- 210000002216 heart Anatomy 0.000 description 6
- 238000009396 hybridization Methods 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 238000002955 isolation Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 5
- 108010071241 Factor XIIa Proteins 0.000 description 5
- 108700026244 Open Reading Frames Proteins 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 5
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 5
- 108010000499 Thromboplastin Proteins 0.000 description 5
- 102000002262 Thromboplastin Human genes 0.000 description 5
- 239000004202 carbamide Substances 0.000 description 5
- 210000000038 chest Anatomy 0.000 description 5
- 238000000855 fermentation Methods 0.000 description 5
- 230000004151 fermentation Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 229910052709 silver Inorganic materials 0.000 description 5
- 239000004332 silver Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 108010080805 Factor XIa Proteins 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 4
- 241000238631 Hexapoda Species 0.000 description 4
- 208000001953 Hypotension Diseases 0.000 description 4
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 229920004890 Triton X-100 Polymers 0.000 description 4
- 239000013504 Triton X-100 Substances 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- 235000011148 calcium chloride Nutrition 0.000 description 4
- 210000001072 colon Anatomy 0.000 description 4
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 239000003999 initiator Substances 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 229920006008 lipopolysaccharide Polymers 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 238000000734 protein sequencing Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000035939 shock Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 208000002109 Argyria Diseases 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 description 3
- 108090000317 Chymotrypsin Proteins 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010029113 Neovascularisation Diseases 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 239000012505 Superdex™ Substances 0.000 description 3
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 3
- 239000007997 Tricine buffer Substances 0.000 description 3
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 3
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 238000001042 affinity chromatography Methods 0.000 description 3
- 208000003455 anaphylaxis Diseases 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 230000000692 anti-sense effect Effects 0.000 description 3
- 239000000074 antisense oligonucleotide Substances 0.000 description 3
- 238000012230 antisense oligonucleotides Methods 0.000 description 3
- 230000008499 blood brain barrier function Effects 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229960002376 chymotrypsin Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 238000001641 gel filtration chromatography Methods 0.000 description 3
- 238000002523 gelfiltration Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 239000002806 plasmin inhibitor Substances 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000002797 proteolythic effect Effects 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 210000000115 thoracic cavity Anatomy 0.000 description 3
- 229960005356 urokinase Drugs 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 2
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 2
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 2
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 241000024188 Andala Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 108090000617 Cathepsin G Proteins 0.000 description 2
- 102100025975 Cathepsin G Human genes 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 108010074860 Factor Xa Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 108010028275 Leukocyte Elastase Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 102100033174 Neutrophil elastase Human genes 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 206010033647 Pancreatitis acute Diseases 0.000 description 2
- 229940122791 Plasmin inhibitor Drugs 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 238000012300 Sequence Analysis Methods 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 210000001132 alveolar macrophage Anatomy 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000002612 cardiopulmonary effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 229960000956 coumarin Drugs 0.000 description 2
- 235000001671 coumarin Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 2
- 150000002019 disulfides Chemical class 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 229940012414 factor viia Drugs 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000000988 hyperfibrinolytic effect Effects 0.000 description 2
- 230000036543 hypotension Effects 0.000 description 2
- 230000008105 immune reaction Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 238000001823 molecular biology technique Methods 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 230000003589 nefrotoxic effect Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 2
- 210000005059 placental tissue Anatomy 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 238000012809 post-inoculation Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000004952 protein activity Effects 0.000 description 2
- 210000000512 proximal kidney tubule Anatomy 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 239000013014 purified material Substances 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 102000035160 transmembrane proteins Human genes 0.000 description 2
- 108091005703 transmembrane proteins Proteins 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- CFOQGBUQTOGYKI-UHFFFAOYSA-N (4-nitrophenyl) 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=C([N+]([O-])=O)C=C1 CFOQGBUQTOGYKI-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- KJHXUWKRYKGYPV-UHFFFAOYSA-N 2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]azaniumyl]acetate;prop-2-enamide Chemical compound NC(=O)C=C.OCC(CO)(CO)NCC(O)=O KJHXUWKRYKGYPV-UHFFFAOYSA-N 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
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 102000000119 Beta-lactoglobulin Human genes 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 201000004813 Bronchopneumonia Diseases 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 101001007681 Candida albicans (strain WO-1) Kexin Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102000003846 Carbonic anhydrases Human genes 0.000 description 1
- 108090000209 Carbonic anhydrases Proteins 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 108010017826 DNA Polymerase I Proteins 0.000 description 1
- 102000004594 DNA Polymerase I Human genes 0.000 description 1
- 238000001712 DNA sequencing Methods 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
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010014824 Endotoxic shock Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108050001049 Extracellular proteins Proteins 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010048049 Factor IXa Proteins 0.000 description 1
- 108010054265 Factor VIIa Proteins 0.000 description 1
- 108010074864 Factor XI Proteins 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000004196 Heart Aneurysm Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 101000605522 Homo sapiens Kallikrein-1 Proteins 0.000 description 1
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 1
- 101000964392 Homo sapiens Zinc finger protein 354A Proteins 0.000 description 1
- 101000964396 Homo sapiens Zinc finger protein 354B Proteins 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 108010077861 Kininogens Proteins 0.000 description 1
- 102000010631 Kininogens Human genes 0.000 description 1
- 108010093008 Kinins Proteins 0.000 description 1
- 102000002397 Kinins Human genes 0.000 description 1
- 108010060630 Lactoglobulins Proteins 0.000 description 1
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
- 102100032352 Leukemia inhibitory factor Human genes 0.000 description 1
- 208000006552 Lewis Lung Carcinoma Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229940124761 MMP inhibitor Drugs 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027457 Metastases to liver Diseases 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 208000034486 Multi-organ failure Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 208000004221 Multiple Trauma Diseases 0.000 description 1
- 208000023637 Multiple injury Diseases 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- 101800000135 N-terminal protein Proteins 0.000 description 1
- 102100022365 NAD(P)H dehydrogenase [quinone] 1 Human genes 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 101800001452 P1 proteinase Proteins 0.000 description 1
- 102100038124 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 229920000148 Polycarbophil calcium Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000035965 Postoperative Complications Diseases 0.000 description 1
- 206010036595 Premature delivery Diseases 0.000 description 1
- 108091008109 Pseudogenes Proteins 0.000 description 1
- 102000057361 Pseudogenes Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102100030951 Tissue factor pathway inhibitor Human genes 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 1
- 206010046996 Varicose vein Diseases 0.000 description 1
- 102100040317 Zinc finger protein 354A Human genes 0.000 description 1
- 102100040334 Zinc finger protein 354B Human genes 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000012084 abdominal surgery Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 108010003510 anhydrotrypsin Proteins 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 208000007474 aortic aneurysm Diseases 0.000 description 1
- ZPNFWUPYTFPOJU-MPSLMFKFSA-N aprotinin Chemical compound CC[C@H](C)[C@@H]1NC(=O)[C@@H](CCCNC(N)=N)NC(=O)[C@@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]2CSSC[C@H]3NC(=O)CNC(=O)CNC(=O)[C@H](Cc4ccc(O)cc4)NC(=O)[C@H](NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CSSC[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc4ccccc4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC3=O)C(=O)N[C@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](CSSC[C@@H](NC(=O)[C@H](Cc3ccccc3)NC(=O)[C@@H](CC(O)=O)NC(=O)[C@H]3CCCN3C(=O)[C@H](N)CCCNC(N)=N)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N3CCC[C@@H]3C(=O)N3CCC[C@H]3C(=O)N[C@H](Cc3ccc(O)cc3)C(=O)N[C@H]([C@H](C)O)C(=O)NCC(=O)N3CCC[C@H]3C(=O)N2)C(=O)NCC(=O)NCC(=O)N[C@H](C)C(O)=O)NC(=O)[C@@H](CC(C)C)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](Cc2ccc(O)cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc(O)cc2)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](NC1=O)[C@H](C)CC)[C@@H](C)O)C(C)C ZPNFWUPYTFPOJU-MPSLMFKFSA-N 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 108010066657 azoreductase Proteins 0.000 description 1
- 108010058966 bacteriophage T7 induced DNA polymerase Proteins 0.000 description 1
- 239000013602 bacteriophage vector Substances 0.000 description 1
- 238000002869 basic local alignment search tool Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 229940125691 blood product Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000004900 c-terminal fragment Anatomy 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000007675 cardiac surgery Methods 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 210000004004 carotid artery internal Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 230000005796 circulatory shock Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000005546 dideoxynucleotide Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 108091007735 digestive proteases Proteins 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 231100000284 endotoxic Toxicity 0.000 description 1
- 230000002346 endotoxic effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000009841 epithelial lesion Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000011990 functional testing Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000002682 general surgery Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 201000003911 head and neck carcinoma Diseases 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 102000052502 human ELANE Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 108700016226 indium-bleomycin Proteins 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 description 1
- 229960003666 liquefied phenol Drugs 0.000 description 1
- 208000012866 low blood pressure Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000025036 lymphosarcoma Diseases 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000005541 medical transmission Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 210000004898 n-terminal fragment Anatomy 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 231100000381 nephrotoxic Toxicity 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 230000001067 neuroprotector Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 210000001706 olfactory mucosa Anatomy 0.000 description 1
- 239000000082 organ preservation Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 210000000680 phagosome Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 201000011461 pre-eclampsia Diseases 0.000 description 1
- 108010005768 preproaprotinin Proteins 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 230000012743 protein tagging Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 230000005944 tissue migration Effects 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 238000011541 total hip replacement Methods 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 230000003144 traumatizing effect Effects 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 108010036927 trypsin-like serine protease Proteins 0.000 description 1
- 230000001810 trypsinlike Effects 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 108010088854 urinastatin Proteins 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 230000003462 zymogenic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8114—Kunitz type inhibitors
- C07K14/8117—Bovine/basic pancreatic trypsin inhibitor (BPTI, aprotinin)
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
-
- 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
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
-
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8114—Kunitz type inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Zoology (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Wood Science & Technology (AREA)
- Cardiology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Communicable Diseases (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Plant Pathology (AREA)
- Microbiology (AREA)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1310696P | 1996-03-11 | 1996-03-11 | |
| US13106P | 1996-03-11 | ||
| US1979396P | 1996-06-14 | 1996-06-14 | |
| US19793P | 1996-06-14 | ||
| US72525196A | 1996-10-04 | 1996-10-04 | |
| US725251 | 1996-10-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2263174T3 true ES2263174T3 (es) | 2006-12-01 |
Family
ID=27359773
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES97915029T Expired - Lifetime ES2263174T3 (es) | 1996-03-11 | 1997-03-10 | Bikunina humana. |
Country Status (27)
| Country | Link |
|---|---|
| US (3) | US6583108B1 (ref) |
| EP (1) | EP0891426B1 (ref) |
| JP (2) | JP3469584B2 (ref) |
| KR (1) | KR100356956B1 (ref) |
| AR (3) | AR006188A1 (ref) |
| AT (1) | ATE328083T1 (ref) |
| AU (1) | AU716923B2 (ref) |
| BR (1) | BR9708021A (ref) |
| CA (1) | CA2247888A1 (ref) |
| CO (1) | CO4600683A1 (ref) |
| DE (1) | DE69735996T2 (ref) |
| DK (1) | DK0891426T3 (ref) |
| ES (1) | ES2263174T3 (ref) |
| HR (1) | HRP970144B1 (ref) |
| HU (1) | HU226419B1 (ref) |
| ID (1) | ID16224A (ref) |
| IL (1) | IL126115A (ref) |
| IN (1) | IN192874B (ref) |
| MY (1) | MY120693A (ref) |
| NZ (1) | NZ331540A (ref) |
| PA (1) | PA8426301A1 (ref) |
| PL (1) | PL188387B1 (ref) |
| PT (1) | PT891426E (ref) |
| SV (1) | SV1997000018A (ref) |
| TR (1) | TR199801794T2 (ref) |
| WO (1) | WO1997033996A2 (ref) |
| YU (1) | YU8997A (ref) |
Families Citing this family (58)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6057287A (en) | 1994-01-11 | 2000-05-02 | Dyax Corp. | Kallikrein-binding "Kunitz domain" proteins and analogues thereof |
| DE69632435T2 (de) * | 1995-07-24 | 2005-05-12 | Mitsubishi Chemical Corp. | Inhibitor des Hepatozytwachstumsfaktoraktivators |
| WO1997033996A2 (en) | 1996-03-11 | 1997-09-18 | Bayer Corporation | Human bikunin |
| WO1998033920A2 (en) * | 1997-01-31 | 1998-08-06 | Human Genome Sciences, Inc. | Tissue factor pathway inhibitor-3 |
| WO2000037099A2 (en) * | 1998-12-22 | 2000-06-29 | Bayer Aktiengesellschaft | Method for accelerating the rate of mucociliary clearance by using a kunitz-type serine protease inhibitor |
| AU3731400A (en) | 1999-03-05 | 2000-09-21 | Trustees Of University Technology Corporation, The | Methods and compositions useful in inhibiting apoptosis |
| US6489308B1 (en) | 1999-03-05 | 2002-12-03 | Trustees Of University Of Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of nitric-oxide-induced clinical conditions |
| US20040235715A1 (en) * | 1999-11-12 | 2004-11-25 | Bayer Corporation | Method of producing glycosylated bikunin |
| IL140993A0 (en) | 2000-05-15 | 2002-02-10 | Bayer Ag | Trypsin substrate and diagnostic device, and method of using same |
| IL140994A (en) * | 2000-05-15 | 2005-12-18 | Bayer Ag | Urinary trypsin inhibitor assay containing a chelating agent |
| US6955921B2 (en) * | 2001-04-30 | 2005-10-18 | Bayer Corporation | Trypsin substrate and diagnostic device, and method of using same |
| WO2003040330A2 (en) * | 2001-11-05 | 2003-05-15 | Curagen Corporation | Therapeutic polypeptides, nucleic acids encoding same, and methods of use |
| US7153829B2 (en) | 2002-06-07 | 2006-12-26 | Dyax Corp. | Kallikrein-inhibitor therapies |
| DK2311432T3 (en) | 2002-06-07 | 2015-02-02 | Dyax Corp | Modified Kunitz domain polypeptides and their use in reducing ischemia or the onset of a systemic inflammatory response associated with a surgical procedure |
| CN1747747B (zh) | 2003-01-06 | 2012-09-05 | 安吉奥开米公司 | 作为穿过血脑屏障的载体的抑酶肽及类似物 |
| US8460243B2 (en) | 2003-06-10 | 2013-06-11 | Abbott Diabetes Care Inc. | Glucose measuring module and insulin pump combination |
| US7244616B2 (en) | 2003-06-27 | 2007-07-17 | Bayer Pharmaceuticals Corporation | Use of molecular chaperones for the enhanced production of secreted, recombinant proteins in mammalian cells |
| US7722536B2 (en) | 2003-07-15 | 2010-05-25 | Abbott Diabetes Care Inc. | Glucose measuring device integrated into a holster for a personal area network device |
| PL2520654T3 (pl) | 2003-08-26 | 2017-08-31 | The Regents Of The University Of Colorado, A Body Corporate | Inhibitory aktywności proteazy serynowej i ich zastosowanie w sposobach i kompozycjach do leczenia zakażeń bakteryjnych |
| JP2007508019A (ja) * | 2003-10-10 | 2007-04-05 | マルチセル テクノロジーズ、インコーポレイテッド | 活性のある治療用タンパク質を生成するための細胞系の使用 |
| JP2007536206A (ja) * | 2003-10-16 | 2007-12-13 | バイエル・ヘルスケア・エルエルシー | 尿中トリプシンインヒビターを検出するためのモノクローナル抗体 |
| EP1586587A1 (en) * | 2004-04-16 | 2005-10-19 | Exonhit Therapeutics SA | Compositions and methods for detecting angiogenesis |
| CA3110101A1 (en) | 2004-06-04 | 2005-12-15 | Abbott Diabetes Care Inc. | Systems and methods for managing diabetes care data |
| US7235530B2 (en) | 2004-09-27 | 2007-06-26 | Dyax Corporation | Kallikrein inhibitors and anti-thrombolytic agents and uses thereof |
| US20090016959A1 (en) * | 2005-02-18 | 2009-01-15 | Richard Beliveau | Delivery of antibodies to the central nervous system |
| CN101160403B (zh) | 2005-02-18 | 2014-08-13 | 安吉奥开米公司 | 转运化合物穿过血脑屏障的分子 |
| WO2007011693A2 (en) * | 2005-07-14 | 2007-01-25 | Medistem Laboratories, Inc. | Compositions of placentally-derived stem cells for the treatment of cancer |
| JP5436856B2 (ja) | 2005-07-15 | 2014-03-05 | アンジオケム インコーポレーティッド | 薬学的複合体における担体としてのアプロチニンポリペプチドの使用 |
| US8093017B2 (en) | 2005-12-07 | 2012-01-10 | Siemens Heathcare Diagnostics Inc. | Detection of soluble adiponectin receptor peptides and use in diagnostics and therapeutics |
| US8828703B2 (en) * | 2005-12-29 | 2014-09-09 | Dyax Corp. | Protease inhibition |
| US8063012B2 (en) * | 2006-09-19 | 2011-11-22 | Phylogica Limited | Neuroprotective peptide inhibitors of AP-1 signaling and uses therefor |
| WO2008058167A2 (en) * | 2006-11-07 | 2008-05-15 | Case Western Reserve University | Method for treating disorders associated with complement activation |
| WO2008077478A1 (en) * | 2006-12-22 | 2008-07-03 | Bayer Schering Pharma Aktiengesellschaft | Preparation and use of variants of the kunitz domain 2 of the human placental bikunin gene |
| US9365634B2 (en) | 2007-05-29 | 2016-06-14 | Angiochem Inc. | Aprotinin-like polypeptides for delivering agents conjugated thereto to tissues |
| US8822409B2 (en) * | 2007-06-20 | 2014-09-02 | Phylogica Limited | Compositions and uses thereof for the treatment of acute respiratory distress syndrome (ARDS) and clinical disorders associated with therewith |
| WO2009026334A2 (en) * | 2007-08-21 | 2009-02-26 | Genzyme Corporation | Treatment with kallikrein inhibitors |
| DE102007056231A1 (de) | 2007-09-08 | 2009-03-12 | Bayer Healthcare Ag | Herstellung und Verwendung von Varianten humander Kunitz-Typ Protease-Inhibitoren (hKTPI) |
| RU2518240C2 (ru) * | 2008-04-18 | 2014-06-10 | Ангиочем Инк. | Композиция, на основе гидрофобных агентов и способ ее получения(варианты) |
| RU2531591C2 (ru) | 2008-10-15 | 2014-10-20 | Ангиокем Инк. | Конъюгаты этопозида и доксорубицина для доставки лекарственных средств |
| US8921314B2 (en) | 2008-10-15 | 2014-12-30 | Angiochem, Inc. | Conjugates of GLP-1 agonists and uses thereof |
| MX2011005963A (es) | 2008-12-05 | 2011-09-01 | Angiochem Inc | Conjugados de neurotensina o analogos de neurotensina y sus usos. |
| CN102300987A (zh) | 2008-12-17 | 2011-12-28 | 安吉奥开米公司 | 膜型-1基质金属蛋白抑制剂及其用途 |
| US8637454B2 (en) | 2009-01-06 | 2014-01-28 | Dyax Corp. | Treatment of mucositis with kallikrein inhibitors |
| AU2010239069B2 (en) | 2009-04-20 | 2015-05-14 | Angiochem Inc | Treatment of ovarian cancer using an anticancer agent conjugated to an Angiopep-2 analog |
| MX2012000016A (es) | 2009-07-02 | 2012-03-26 | Angiochem Inc | Conjugados de peptidos multimericos y sus usos. |
| ES2688093T3 (es) | 2010-01-06 | 2018-10-30 | Dyax Corp. | Proteínas de unión a calicreína plasmática |
| EP2371857A1 (en) * | 2010-04-01 | 2011-10-05 | CSL Behring GmbH | Factor XII inhibitors for treating interstitial lung disease |
| IL269565B2 (en) | 2011-01-06 | 2024-06-01 | Dyax Corp | Plasma kallikrein binding proteins |
| US10136845B2 (en) | 2011-02-28 | 2018-11-27 | Abbott Diabetes Care Inc. | Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same |
| KR20200044138A (ko) | 2011-06-24 | 2020-04-28 | 더 리젠츠 오브 더 유니버시티 오브 콜로라도, 어 바디 코포레이트 | 알파-1 안티트립신 융합 분자용 조성물, 방법 및 용도 |
| JP2015504675A (ja) | 2012-01-10 | 2015-02-16 | ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド，ア ボディー コーポレイトＴＨＥ ＲＥＧＥＮＴＳ ＯＦ ＴＨＥ ＵＮＩＶＥＲＳＩＴＹ ＯＦ ＣＯＬＯＲＡＤＯ，ａ ｂｏｄｙ ｃｏｒｐｏｒａｔｅ | アルファ−１アンチトリプシン融合分子の組成物、方法、及び使用 |
| WO2014026283A1 (en) | 2012-08-14 | 2014-02-20 | Angiochem Inc. | Peptide-dendrimer conjugates and uses thereof |
| MA39347B2 (fr) | 2014-02-24 | 2020-05-29 | Takeda Pharmaceuticals Co | Protéines de fusion d'uti |
| EP3122782A4 (en) | 2014-03-27 | 2017-09-13 | Dyax Corp. | Compositions and methods for treatment of diabetic macular edema |
| US10980892B2 (en) | 2015-06-15 | 2021-04-20 | Angiochem Inc. | Methods for the treatment of leptomeningeal carcinomatosis |
| BR112018011622A2 (pt) | 2015-12-11 | 2018-11-27 | Dyax Corp | método para tratar ataque de angioedema hereditário (hae) ou reduzir a taxa de ataque de hae |
| CA3167336A1 (en) | 2020-01-13 | 2021-07-22 | Takeda Pharmaceutical Company Limited | Plasma kallikrein inhibitors and uses thereof for treating pediatric hereditary angioedema attack |
| BR112022017718A2 (pt) | 2020-03-05 | 2022-11-16 | Diamedica Usa Inc | Polipeptídeos de ulinastatina |
Family Cites Families (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223482A (en) | 1986-11-17 | 1993-06-29 | Scios Nova Inc. | Recombinant Alzheimer's protease inhibitory amyloid protein and method of use |
| US5106833A (en) | 1987-07-23 | 1992-04-21 | Washington University | Coagulation inhibitors |
| US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
| WO1992015605A2 (en) | 1991-03-01 | 1992-09-17 | Protein Engineering Corporation | Inhibitors of human neutrophil elastase and human cathepsin g |
| US5663143A (en) | 1988-09-02 | 1997-09-02 | Dyax Corp. | Engineered human-derived kunitz domains that inhibit human neutrophil elastase |
| ES2066033T3 (es) * | 1989-05-13 | 1995-03-01 | Bayer Ag | Inhibidores de las proteinasas, procedimiento para su preparacion y composiciones farmaceuticas que los contienen. |
| DK408089D0 (da) | 1989-08-18 | 1989-08-18 | Novo Nordisk As | Proteiner |
| EP0439442B1 (en) | 1990-01-25 | 1996-03-06 | Washington University | Factor x-laci hybrid protein |
| RU2054180C1 (ru) | 1991-08-21 | 1996-02-10 | Жирнов Олег Петрович (н/п) | Способ лечения вирусных респираторных инфекций |
| IL104325A (en) | 1992-01-07 | 2000-10-31 | Novo Nordisk As | Variants of human kunitz-type protease inhibitor domain II of tissue factor pathway inhibitor (TFPI) pharmaceutical compositions containing them a DNA construct encoding them their expression vectors a cell containing said DNA constructs and methods for the production of all the above |
| IL104326A0 (en) | 1992-01-07 | 1993-05-13 | Novo Nordisk As | Variant of human kunitz-type protease inhibitor |
| JPH07509229A (ja) | 1992-07-13 | 1995-10-12 | コルバス・インターナショナル、インコーポレイテッド | ウシ膵トリプシン阻害因子から誘導される因子Ｘａの阻害因子 |
| US5436153A (en) | 1992-12-02 | 1995-07-25 | Sprecher; Cindy A. | Human amyloid protein precursor homolog and Kunitz-type inhibitor |
| AU5684594A (en) | 1992-12-02 | 1994-06-22 | Novo Nordisk A/S | Novel human amyloid protein precursor homologue and kunitz-type inhibitors |
| JP2769083B2 (ja) | 1993-02-22 | 1998-06-25 | 日清食品株式会社 | エラスターゼ阻害活性を有する新規ペプチドおよびその製造方法 |
| US5455338A (en) | 1993-11-05 | 1995-10-03 | Zymogenetics, Inc. | DNA encoding novel human kunitz-type inhibitors and methods relating thereto |
| DE69533472T2 (de) | 1994-01-11 | 2006-01-12 | Dyax Corp., Cambridge | Kallikreinhemmende "kunitz-domäne"-proteine und derivaten davon |
| ATE529444T1 (de) | 1994-01-11 | 2011-11-15 | Dyax Corp | Inhibitoren des humanplasmins, die sich von den kunitz domänen ableiten |
| US5795954A (en) | 1994-03-04 | 1998-08-18 | Genentech, Inc. | Factor VIIa inhibitors from Kunitz domain proteins |
| WO1996003503A1 (en) | 1994-07-21 | 1996-02-08 | The Green Cross Corporation | Process for producing urinary trypsin inhibitor and domains thereof, novel polypeptide related to the both, and process for producing the polypeptide |
| US5541228A (en) * | 1994-10-14 | 1996-07-30 | Bristol-Myers Squibb Co. | Melatonergic agents |
| JPH11504938A (ja) | 1995-05-08 | 1999-05-11 | サイオス インク． | クニッツ型プロテアーゼ阻害因子 |
| US5786328A (en) | 1995-06-05 | 1998-07-28 | Genentech, Inc. | Use of kunitz type plasma kallikrein inhibitors |
| DE69632435T2 (de) | 1995-07-24 | 2005-05-12 | Mitsubishi Chemical Corp. | Inhibitor des Hepatozytwachstumsfaktoraktivators |
| US5736364A (en) | 1995-12-04 | 1998-04-07 | Genentech, Inc. | Factor viia inhibitors |
| WO1997033996A2 (en) | 1996-03-11 | 1997-09-18 | Bayer Corporation | Human bikunin |
| WO1998033920A2 (en) | 1997-01-31 | 1998-08-06 | Human Genome Sciences, Inc. | Tissue factor pathway inhibitor-3 |
| US6294648B1 (en) * | 1999-07-20 | 2001-09-25 | Bayer Corporation | Protein having proteinase inhibitor activity |
-
1997
- 1997-03-10 WO PCT/US1997/003894 patent/WO1997033996A2/en not_active Ceased
- 1997-03-10 IL IL126115A patent/IL126115A/en not_active IP Right Cessation
- 1997-03-10 YU YU8997A patent/YU8997A/sh unknown
- 1997-03-10 EP EP97915029A patent/EP0891426B1/en not_active Expired - Lifetime
- 1997-03-10 DE DE69735996T patent/DE69735996T2/de not_active Expired - Fee Related
- 1997-03-10 JP JP53280497A patent/JP3469584B2/ja not_active Expired - Fee Related
- 1997-03-10 BR BR9708021A patent/BR9708021A/pt not_active Application Discontinuation
- 1997-03-10 KR KR10-1998-0707163A patent/KR100356956B1/ko not_active Expired - Fee Related
- 1997-03-10 DK DK97915029T patent/DK0891426T3/da active
- 1997-03-10 AU AU22077/97A patent/AU716923B2/en not_active Ceased
- 1997-03-10 PL PL97328822A patent/PL188387B1/pl not_active IP Right Cessation
- 1997-03-10 NZ NZ331540A patent/NZ331540A/en unknown
- 1997-03-10 HU HU9902698A patent/HU226419B1/hu not_active IP Right Cessation
- 1997-03-10 PT PT97915029T patent/PT891426E/pt unknown
- 1997-03-10 AT AT97915029T patent/ATE328083T1/de not_active IP Right Cessation
- 1997-03-10 CA CA002247888A patent/CA2247888A1/en not_active Abandoned
- 1997-03-10 TR TR1998/01794T patent/TR199801794T2/xx unknown
- 1997-03-10 ES ES97915029T patent/ES2263174T3/es not_active Expired - Lifetime
- 1997-03-11 SV SV1997000018A patent/SV1997000018A/es not_active Application Discontinuation
- 1997-03-11 PA PA19978426301A patent/PA8426301A1/es unknown
- 1997-03-11 AR ARP970100967A patent/AR006188A1/es active IP Right Grant
- 1997-03-11 IN IN601DE1997 patent/IN192874B/en unknown
- 1997-03-11 HR HR970144A patent/HRP970144B1/xx not_active IP Right Cessation
- 1997-03-11 CO CO97013175A patent/CO4600683A1/es unknown
- 1997-03-11 MY MYPI97001015A patent/MY120693A/en unknown
- 1997-03-11 ID IDP970779A patent/ID16224A/id unknown
-
1998
- 1998-08-31 US US09/144,428 patent/US6583108B1/en not_active Expired - Fee Related
-
2001
- 2001-10-10 US US09/974,026 patent/US7019123B2/en not_active Expired - Fee Related
-
2003
- 2003-04-23 JP JP2003119118A patent/JP2004000208A/ja active Pending
-
2006
- 2006-03-27 US US11/390,775 patent/US7452859B2/en not_active Expired - Fee Related
- 2006-04-20 AR ARP060101562A patent/AR053063A2/es unknown
-
2007
- 2007-01-11 AR ARP070100116A patent/AR058982A1/es unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0891426B1 (en) | Human bikunin | |
| WO1997033996A9 (en) | Human bikunin | |
| US6613890B2 (en) | Protease inhibitor peptides | |
| ES2318075T3 (es) | Metodo para acelerar la velocidad de eliminacion mucociliar. | |
| US20090170766A1 (en) | Chimeric Kunitz Domains and their Use | |
| EP1752538A1 (en) | Human bikunin | |
| TW555764B (en) | Human bikunin | |
| CA2407668A1 (en) | Human bikunin | |
| MXPA98007060A (en) | Bikunina hum | |
| JP2006512308A (ja) | 糖尿病関連及び／又は動脈低治癒性創傷の治療及び／又は予防のための、α−１−アンチキモトリプシン（ａｎｔｉｃｈｙｍｏｔｒｙｐｓｉｎ）ポリペプチドまたはそれをコードしている核酸の、α−１−アンチトリプシン（ａｎｔｉｔｒｙｐｓｉｎ）ポリペプチドまたはそれをコードしている核酸と組み合わせた使用 | |
| US20070140979A1 (en) | Method for accelerating the rate of mucociliary clearance |