CN100536909C - Methods for preventing mitochondrial permeability transition - Google Patents
Methods for preventing mitochondrial permeability transition Download PDFInfo
- Publication number
- CN100536909C CN100536909C CNB2004800092972A CN200480009297A CN100536909C CN 100536909 C CN100536909 C CN 100536909C CN B2004800092972 A CNB2004800092972 A CN B2004800092972A CN 200480009297 A CN200480009297 A CN 200480009297A CN 100536909 C CN100536909 C CN 100536909C
- Authority
- CN
- China
- Prior art keywords
- dextrorotation
- dmt
- arginine
- application according
- phenylalanine
- 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
- 238000000034 method Methods 0.000 title claims abstract description 50
- 230000002438 mitochondrial effect Effects 0.000 title claims abstract description 25
- 230000037050 permeability transition Effects 0.000 title claims description 17
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 110
- 210000003470 mitochondria Anatomy 0.000 claims description 71
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
- 208000028867 ischemia Diseases 0.000 claims description 30
- 201000010099 disease Diseases 0.000 claims description 28
- 241000124008 Mammalia Species 0.000 claims description 27
- 210000000056 organ Anatomy 0.000 claims description 25
- 210000001519 tissue Anatomy 0.000 claims description 16
- 206010002660 Anoxia Diseases 0.000 claims description 15
- 241000976983 Anoxia Species 0.000 claims description 15
- 206010021143 Hypoxia Diseases 0.000 claims description 15
- 230000007953 anoxia Effects 0.000 claims description 15
- 230000004770 neurodegeneration Effects 0.000 claims description 12
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 9
- 238000012377 drug delivery Methods 0.000 claims description 6
- 238000007913 intrathecal administration Methods 0.000 claims description 6
- 230000003387 muscular Effects 0.000 claims description 6
- 238000007914 intraventricular administration Methods 0.000 claims description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 210000002460 smooth muscle Anatomy 0.000 claims description 4
- 230000000699 topical effect Effects 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 210000002027 skeletal muscle Anatomy 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 230000000747 cardiac effect Effects 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 206010022680 Intestinal ischaemia Diseases 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 abstract description 78
- 125000000539 amino acid group Chemical group 0.000 abstract description 13
- 125000003118 aryl group Chemical group 0.000 abstract description 6
- 230000035699 permeability Effects 0.000 abstract description 6
- 239000004475 Arginine Substances 0.000 description 136
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 134
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 134
- 235000009697 arginine Nutrition 0.000 description 134
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 107
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 100
- 229940024606 amino acid Drugs 0.000 description 96
- UEVAHGMTRWGMTB-JBXUNAHCSA-N (2s)-6-amino-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-phenylpropanoyl]amino]hexanamide Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(N)=O)NC(=O)[C@@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 UEVAHGMTRWGMTB-JBXUNAHCSA-N 0.000 description 93
- 235000001014 amino acid Nutrition 0.000 description 93
- 108010094098 tyrosyl-arginyl-phenylalanyl-lysinamide Proteins 0.000 description 86
- 235000018977 lysine Nutrition 0.000 description 82
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 74
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 74
- 239000004472 Lysine Substances 0.000 description 73
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 59
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 57
- 235000002374 tyrosine Nutrition 0.000 description 57
- 210000004027 cell Anatomy 0.000 description 35
- UXZAXFPFSQRZOZ-UHFFFAOYSA-N ornaline Chemical compound NCCCC(C(O)=O)NC(C(O)=O)CCC(O)=O UXZAXFPFSQRZOZ-UHFFFAOYSA-N 0.000 description 25
- 210000002216 heart Anatomy 0.000 description 24
- 239000011575 calcium Substances 0.000 description 23
- ALBODLTZUXKBGZ-JUUVMNCLSA-N (2s)-2-amino-3-phenylpropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 ALBODLTZUXKBGZ-JUUVMNCLSA-N 0.000 description 22
- SFVLTCAESLKEHH-WKAQUBQDSA-N (2s)-6-amino-2-[[(2s)-2-[[(2r)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-n-[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]hexanamide Chemical compound CC1=CC(O)=CC(C)=C1C[C@H](NC(=O)[C@H](N)CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N)=O)CC1=CC=CC=C1 SFVLTCAESLKEHH-WKAQUBQDSA-N 0.000 description 21
- 239000000872 buffer Substances 0.000 description 20
- 230000008965 mitochondrial swelling Effects 0.000 description 16
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 15
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 15
- 102000051367 mu Opioid Receptors Human genes 0.000 description 15
- 108020001612 μ-opioid receptors Proteins 0.000 description 15
- 102000018832 Cytochromes Human genes 0.000 description 13
- 108010052832 Cytochromes Proteins 0.000 description 13
- 230000001939 inductive effect Effects 0.000 description 13
- 230000010412 perfusion Effects 0.000 description 13
- PFYWPQMAWCYNGW-UHFFFAOYSA-M [6-(dimethylamino)-9-(2-methoxycarbonylphenyl)xanthen-3-ylidene]-dimethylazanium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.COC(=O)C1=CC=CC=C1C1=C2C=CC(=[N+](C)C)C=C2OC2=CC(N(C)C)=CC=C21 PFYWPQMAWCYNGW-UHFFFAOYSA-M 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- WBLZUCOIBUDNBV-UHFFFAOYSA-N 3-nitropropanoic acid Chemical compound OC(=O)CC[N+]([O-])=O WBLZUCOIBUDNBV-UHFFFAOYSA-N 0.000 description 11
- 239000008148 cardioplegic solution Substances 0.000 description 10
- 150000002669 lysines Chemical class 0.000 description 10
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 9
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 9
- 108091005804 Peptidases Proteins 0.000 description 9
- 239000004365 Protease Substances 0.000 description 9
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 9
- 235000004279 alanine Nutrition 0.000 description 9
- 229960002885 histidine Drugs 0.000 description 9
- -1 γ-An Jidingsuan Chemical compound 0.000 description 9
- AHLPHDHHMVZTML-SCSAIBSYSA-N D-Ornithine Chemical compound NCCC[C@@H](N)C(O)=O AHLPHDHHMVZTML-SCSAIBSYSA-N 0.000 description 8
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 210000001700 mitochondrial membrane Anatomy 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 230000001681 protective effect Effects 0.000 description 8
- BMZRVOVNUMQTIN-UHFFFAOYSA-N Carbonyl Cyanide para-Trifluoromethoxyphenylhydrazone Chemical compound FC(F)(F)OC1=CC=C(NN=C(C#N)C#N)C=C1 BMZRVOVNUMQTIN-UHFFFAOYSA-N 0.000 description 7
- 229930105110 Cyclosporin A Natural products 0.000 description 7
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 7
- 108010036949 Cyclosporine Proteins 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- 239000012981 Hank's balanced salt solution Substances 0.000 description 7
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 229960001265 ciclosporin Drugs 0.000 description 7
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 241001597008 Nomeidae Species 0.000 description 6
- 108010062796 arginyllysine Proteins 0.000 description 6
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 6
- 235000014304 histidine Nutrition 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 102000004452 Arginase Human genes 0.000 description 5
- 108700024123 Arginases Proteins 0.000 description 5
- 241000700199 Cavia porcellus Species 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 5
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 125000003275 alpha amino acid group Chemical group 0.000 description 5
- 229960005261 aspartic acid Drugs 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 230000028161 membrane depolarization Effects 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 230000008961 swelling Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 210000004351 coronary vessel Anatomy 0.000 description 4
- 210000000805 cytoplasm Anatomy 0.000 description 4
- 238000001212 derivatisation Methods 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 229960002989 glutamic acid Drugs 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 230000027829 mitochondrial depolarization Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 150000003141 primary amines Chemical class 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 3
- 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 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 230000036770 blood supply Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 229960002719 buserelin Drugs 0.000 description 3
- 230000001964 calcium overload Effects 0.000 description 3
- 125000003636 chemical group Chemical group 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 210000004165 myocardium Anatomy 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 230000010627 oxidative phosphorylation Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 210000000278 spinal cord Anatomy 0.000 description 3
- 230000008733 trauma Effects 0.000 description 3
- 150000003667 tyrosine derivatives Chemical class 0.000 description 3
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- LSNDLIKCFHLFKO-JTQLQIEISA-N (2s)-2-azaniumyl-3-(4-hydroxy-2,6-dimethylphenyl)propanoate Chemical compound CC1=CC(O)=CC(C)=C1C[C@H](N)C(O)=O LSNDLIKCFHLFKO-JTQLQIEISA-N 0.000 description 2
- OQEBBZSWEGYTPG-UHFFFAOYSA-N 3-aminobutanoic acid Chemical compound CC(N)CC(O)=O OQEBBZSWEGYTPG-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- JJMDCOVWQOJGCB-UHFFFAOYSA-N 5-aminopentanoic acid Chemical compound [NH3+]CCCCC([O-])=O JJMDCOVWQOJGCB-UHFFFAOYSA-N 0.000 description 2
- 108010009551 Alamethicin Proteins 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RZZPDXZPRHQOCG-OJAKKHQRSA-O CDP-choline(1+) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-O 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 2
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LHAVJMWIUUIOPK-MENMJLHVSA-N N[C@@H](CCCCN)C(=O)O.C(CC)N[C@@H](CCO)C(=O)O Chemical compound N[C@@H](CCCCN)C(=O)O.C(CC)N[C@@H](CCO)C(=O)O LHAVJMWIUUIOPK-MENMJLHVSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 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
- 239000004473 Threonine Substances 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- LGHSQOCGTJHDIL-UTXLBGCNSA-N alamethicin Chemical compound N([C@@H](C)C(=O)NC(C)(C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)NC(C)(C)C(=O)N[C@H](C(=O)NC(C)(C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NC(C)(C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CO)CC=1C=CC=CC=1)C(C)C)C(=O)C(C)(C)NC(=O)[C@@H]1CCCN1C(=O)C(C)(C)NC(C)=O LGHSQOCGTJHDIL-UTXLBGCNSA-N 0.000 description 2
- 125000002877 alkyl aryl group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- 238000000149 argon plasma sintering Methods 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960001284 citicoline Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008828 contractile function Effects 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 239000012531 culture fluid Substances 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 230000027721 electron transport chain Effects 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 230000004898 mitochondrial function Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000000197 pyrolysis Methods 0.000 description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000007492 two-way ANOVA Methods 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WJJGAKCAAJOICV-JTQLQIEISA-N (2s)-2-(dimethylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound CN(C)[C@H](C(O)=O)CC1=CC=C(O)C=C1 WJJGAKCAAJOICV-JTQLQIEISA-N 0.000 description 1
- OZSNQMIQTHGXPJ-QMMMGPOBSA-N (2s)-2-amino-3-[(2-aminobenzoyl)amino]propanoic acid Chemical compound OC(=O)[C@@H](N)CNC(=O)C1=CC=CC=C1N OZSNQMIQTHGXPJ-QMMMGPOBSA-N 0.000 description 1
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- FSSVRLXFJPQUTM-WCCKRBBISA-N 2-aminoacetic acid;(2s)-2-amino-4-methylsulfanylbutanoic acid Chemical compound NCC(O)=O.CSCC[C@H](N)C(O)=O FSSVRLXFJPQUTM-WCCKRBBISA-N 0.000 description 1
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 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 1
- 229930195573 Amycin Natural products 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- FMGYKKMPNATWHP-UHFFFAOYSA-N Cyperquat Chemical compound C1=C[N+](C)=CC=C1C1=CC=CC=C1 FMGYKKMPNATWHP-UHFFFAOYSA-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
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- OFVBLKINTLPEGH-UHFFFAOYSA-N DL-beta-Homophenylalanine Chemical compound OC(=O)CC(N)CC1=CC=CC=C1 OFVBLKINTLPEGH-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- XMAUFHMAAVTODF-STQMWFEESA-N His-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 XMAUFHMAAVTODF-STQMWFEESA-N 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- 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 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- VQPRNSWQIAHPMS-HNNXBMFYSA-N N(6)-dansyl-L-lysine Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NCCCC[C@H](N)C(O)=O VQPRNSWQIAHPMS-HNNXBMFYSA-N 0.000 description 1
- ZRKWMRDKSOPRRS-UHFFFAOYSA-N N-Methyl-N-nitrosourea Chemical compound O=NN(C)C(N)=O ZRKWMRDKSOPRRS-UHFFFAOYSA-N 0.000 description 1
- HUSDDORJIJKFPS-FMEGDIDESA-N N[C@@H](CC(=O)O)C(=O)O.C(CC)N[C@@H](CCO)C(=O)O Chemical compound N[C@@H](CC(=O)O)C(=O)O.C(CC)N[C@@H](CCO)C(=O)O HUSDDORJIJKFPS-FMEGDIDESA-N 0.000 description 1
- WBTRQCNBBZPYKW-ISAJQFQZSA-N N[C@@H](CC1=CC=CC=C1)C(=O)O.N[C@@H](CCCCN)C(=O)O.C(CC)N[C@@H](CCO)C(=O)O Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)O.N[C@@H](CCCCN)C(=O)O.C(CC)N[C@@H](CCO)C(=O)O WBTRQCNBBZPYKW-ISAJQFQZSA-N 0.000 description 1
- YYQFRPXAXGODIQ-FPAZSGHZSA-N N[C@@H](CCCNC(N)=N)C(=O)O.C(CC)N[C@@H](CCO)C(=O)O Chemical compound N[C@@H](CCCNC(N)=N)C(=O)O.C(CC)N[C@@H](CCO)C(=O)O YYQFRPXAXGODIQ-FPAZSGHZSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000002278 Ribosomal Proteins Human genes 0.000 description 1
- 108010000605 Ribosomal Proteins Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 208000012601 choreatic disease Diseases 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 210000002311 liver mitochondria Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000007257 malfunction 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
- 238000005259 measurement Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical class O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- 239000002756 mu opiate receptor agonist Substances 0.000 description 1
- 229940126487 mu opioid receptor agonist Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000002089 myocardial stunning Diseases 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 210000003360 nephrocyte Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000003399 opiate peptide Substances 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000082 organ preservation Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- JSGHQDAEHDRLOI-UHFFFAOYSA-N oxomalononitrile Chemical compound N#CC(=O)C#N JSGHQDAEHDRLOI-UHFFFAOYSA-N 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000012154 short term therapy Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000001768 subcellular fraction Anatomy 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000004061 uncoupling agent Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Images
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides a method of reducing or preventing mitochondrial permeability transitioning. The method comprises administering an effective amount of an aromatic-cationic peptide having at least one net positive charge; a minimum of four amino acids; a maximum of about twenty amino acids; a relationship between the minimum number of net positive charges (pm) and the total number of amino acid residues (r) wherein 3pm is the largest number that is less than or equal to r+1; and a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (pt) wherein 2a is the largest number that is less than or equal to pt+1, except that when a is 1, pt may also be 1.
Description
The application requires No. the 60/444th, 777, U.S. Provisional Application submitting on February 4th, 2003 and the priority of No. the 60/535th, 690, the U.S. Provisional Application submitted on January 8th, 2004.The content of No. the 60/444th, 777, U.S. Provisional Application and the 60/535th, No. 690 is incorporated herein by reference, as a reference.
The present invention finishes under the approval number that is provided by National Institute of Drug Abuse is the government-funded of PO1DA08924-08.U.S. government has certain right in the present invention.
Background technology
Mitochondrion almost is present in all eukaryotic cells, and produces adenosine triphosphate (ATP) by oxidative phosphorylation, thereby is essential for cells survival.Block this important function and can cause cell death.
Mitochondrion is also by gathering calcium (Ca
2+) and playing the part of important role aspect the intracellular calcium adjusting.The uniport body that drives by transmembrane potential produces gathering of calcium in mitochondrial matrix.
The absorption of calcium has activated mitochondrial dehydrogenase, and this keep that energy generates and oxidative phosphorylation aspect may be important.In addition, mitochondrion can be used as excessive endochylema Ca
2+Storage tank, thereby the protection cell avoid Ca
2+Overload and downright bad.
Ischemia or hypoglycemia can cause mitochondrial function not normal, comprise ATP hydrolysis and Ca
2+Overload.This malfunction causes that (the mitochondrion permeability changes mitochondrial permeability transition, MPT).The feature of MPT has: the oxidative phosphorylation uncoupling, and the mitochondrial membrane potential forfeiture, interior membrane permeability increases and swelling.
In addition, the gap is the bank of apoptogene albumen (apoptogenic proteins) between mitochondrial membrane.Therefore, the forfeiture of mitochondrion current potential and MPT can cause apoptogene albumen is discharged in the Cytoplasm.More and more evidences shows MPT relevant with the apoptosis cell death with gangrenosum acne (Crompton, Biochem J.341:233-249,1999), and this is not curious.The slight damage of cell may cause apoptosis rather than necrosis.
Cyclosporin A can suppress MPT.Block the apoptosis that can suppress the various kinds of cell type by the MPT due to the cyclosporin A, comprise the experience ischemia, anoxia, Ca
2+The cell (Kroemer et al., Annu Rev Physiol.60:619-642,1998) of overload and oxidative stress.
Yet cyclosporin A is not best as the medicine of necrosis and apoptotic cell death.For example, cyclosporin A targeting mitochondrion specifically.In addition, it is difficult to be delivered to brain.And, because its immunosuppressive activity has reduced the range of application of cyclosporin A.
Tetrapeptide [Dmt
1] DALDA (2 ', 6 '-dimethyl tyrosine-D-arginine-phenylalanine-lysine-NH
2SS-02) molecular weight is 640, and has 3 clean positive charges under physiological pH.[Dmt
1] DALDA is easy to pass plasma membrane (the Zhao et al. of many mammalian cell types in the mode that non-energy relies on, J Pharmacol Exp.Ther.304:425-432,2003) and pass blood brain barrier (Zhao et al., JPharmacol Exp.Ther.302:188-196,2002).Although [Dmt
1] DALDA has demonstrated is a kind of potential μ-opioid (μ-class Opium, opioid) receptor stimulating agent, but its application does not also expand to and comprises the aspect that suppresses MPT.
Therefore, as ischemia-reperfusion, anoxia, hypoglycemia and owing under the situation of the disease of other of the pathological change that mitochondrial membrane permeability changes (transformations of mitochondrion permeability) is caused and disease, need inhibition MPT.Such disease and disease comprise multiple common neurodegenerative diseases or disease.
Summary of the invention
The invention provides a kind of being used for reduces the mitochondrion quantity of experience mitochondrial permeability transition (MPT) or prevents the method for mitochondrial permeability transition any mammal that needs are arranged, and these purposes and other purpose can realize by the present invention.This method comprises the aromatic series cationic peptide with following feature that gives this mammal effective dose:
(a) at least one clean positive charge;
(b) minimum 3 aminoacid;
(c) maximum about 20 aminoacid;
(d) minimal amount (p of clean positive charge
m) and the sum (r) of amino acid residue between the pass be: 3p wherein
mIt is the maximum number that is less than or equal to r+1; And
(e) sum (p of minimal amount of aromatic radical (a) and clean positive charge
t) between the pass be: wherein 2a is less than or equal to p
t+ 1 maximum number, unless when a is 1, p
tAlso can be 1.
In another specific embodiment, the invention provides a kind of method that in mammiferous isolated organ, reduces the mitochondrion quantity of experience mitochondrial permeability transition (MPT) or prevent mitochondrial permeability transition.This method comprises the aromatic series cationic peptide with following feature that gives this isolated organ effective dose:
(a) at least one clean positive charge;
(b) minimum 3 aminoacid;
(c) maximum about 20 aminoacid;
(d) clean positive charge minimal amount (p
m) and amino acid residue sum (r) between the pass be: 3p wherein
mIt is the maximum number that is less than or equal to r+1; And
(e) sum (p of minimal amount of aromatic radical (a) and clean positive charge
t) between the pass be: wherein, 2a is less than or equal to p
t+ 1 maximum number, unless when a is 1, p
tAlso can be 1.
In another specific embodiment, the invention provides a kind of method that in the mammal that needs is arranged, reduces the mitochondrion quantity of experience mitochondrial permeability transition (MPT) or prevent mitochondrial permeability transition.This method comprises the aromatic series cationic peptide with following feature that gives this mammal effective dose:
(a) at least one clean positive charge;
(b) minimum 3 aminoacid;
(c) maximum about 20 aminoacid;
(d) minimal amount (p of clean positive charge
m) and the sum (r) of amino acid residue between the pass be: 3p wherein
mIt is the maximum number that is less than or equal to r+1; And
(e) sum (p of minimal amount of aromatic radical (a) and clean positive charge
t) between the pass be: wherein 3a is less than or equal to p
t+ 1 maximum number, unless when a is 1, p
tAlso can be 1.
In specific embodiment further, the invention provides a kind of method that in mammiferous isolated organ, reduces the mitochondrion quantity of experience mitochondrial permeability transition (MPT) or prevent mitochondrial permeability transition.This method comprises the aromatic series cationic peptide with following feature that gives this isolated organ effective dose:
(a) at least one clean positive charge;
(b) minimum 3 aminoacid;
(c) maximum about 20 aminoacid;
(d) minimal amount (p of clean positive charge
m) and the sum (r) of amino acid residue between the pass be: 3p wherein
mIt is the maximum number that is less than or equal to r+1; And
(e) sum (p of minimal amount of aromatic radical (a) and clean positive charge
t) between the pass be: wherein, 3a is less than or equal to p
t+ 1 maximum number, unless when a is 1, p
tAlso can be 1.
Description of drawings
Fig. 1: [Dmt in the mitochondrion
1] cell internalizing and the gathering of DALDA (SS-02).(A) take in (ex/em=320/420) with the mitochondrion of fluorescence spectrophotometer measurement SS-19.Add separated mouse liver mitochondrion (0.35mg/ml) and cause the quick cancellation of SS-19 fluorescence intensity (gray line).Reduce cancellation<20% (black line) with the pretreated mitochondrion of FCCP (1.5 μ M).(B) separated mitochondrion with [
3H] SS-02 hatched (incubation) 2 minutes in 37 ℃.In 4 ℃ of centrifugal (termination absorption in 16000 * g) 5 minutes, the radioactivity in the mensuration precipitation.With the pretreated mitochondrion of FCCP suppress [
3H] SS-02 absorption~20%.Data are represented with mean+/-standard error; N=3, *, P<0.05 of adopting Student ' s t-check.(C) TMRM that separated mitochondrion is taken in by the inductive mitochondrial swelling of alamethicin loses, and the SS-19 that takes in then remains on high concentration.Black line is TMRM; Red line is SS-19.(D) as fluorimetric, in separated mitochondrion, add SS-02 (200 μ M) and do not change the mitochondrion current potential by TMRM.Add FCCP (1.5 μ M) and cause rapid depolarization, and Ca
2+(150 μ M) causes depolarization and the progressive beginning of MPT.
Fig. 2 .[Dmt
1] DALDA (SS-02) protective wire plastochondria avoids Ca
2+Overload and the inductive mitochondrial permeability transition of 3-nitropropionic acid (3NP) (MPT).(A) separated mitochondrion has stoped by Ca with the SS-02 pretreatment (representing to add with following arrow) of 10 μ M
2+The generation (upward arrow) of transshipping inductive MPT.Black line is a buffer; Red line is SS-02.(B) separated mitochondrion has increased before MPT takes place with the SS-02 pretreatment and has added Ca at double
2+The mitochondrion toleration.The arrow indication adds buffer or SS-02.Line 1 is a buffer; Line 2 is the SS-02 of 50 μ M; Line 3 is the SS-02 of 100 μ M.(C) SS-02 dose dependent ground delays the generation by the inductive MPT of 1mM3NP.Arrow represents to add buffer or SS-02.Line 1 is a buffer, and line 2 is the SS-02 of 0.5 μ M; Line 3 is the SS-02 of 5 μ M; Line 4 is the SS-02 of 50 μ M.
Fig. 3 .[Dmt
1] DALDA (SS-02) suppresses mitochondrial swelling and cytochrome C discharges.(A) with the SS-02 pretreatment of separated mitochondrion, its dose dependent ground has suppressed the Ca by 200 μ M
2+Rely on the inductive mitochondrial swelling of mode with dosage.By measuring swelling at the absorbance at 540nm place.(B) SS-02 suppresses in the separated mitochondrion by Ca
2+The release of inductive cytochrome C.The burst size of cytochrome C is represented with the percent of total cytochrome C in the mitochondrion.Data are represented with mean+/-standard error, n=3.(C) SS-02 also can suppress by MPP
+(300 μ M) inductive mitochondrial swelling.
Fig. 4 .D-arginine-Dmt-lysine-phenylalanine-NH
2(SS-31) suppressing mitochondrial swelling and cytochrome C discharges.(A) separated mitochondrion has stoped by Ca with SS-31 (10 μ M) pretreatment
2+The generation of inductive MPT.Gray line is a buffer; Red line is SS-31.(B) mitochondrion has suppressed the Ca by 200mM with SS-31 (50 μ M) pretreatment
2+Inductive mitochondrial swelling.Measure swelling by measuring in the light scattering at 570nm place.(C) SS-02 and SS-31 and Cyclosporin A (CsA) are suppressing by Ca
2+The comparison that inductive mitochondrial swelling and cytochrome C discharge.The cytochrome C burst size is represented with the percent of total cytochrome C in the mitochondrion.Data are represented with mean+/-standard error, n=3.
Fig. 5 .[Dmt
1] DALDA (SS-02) and D-arginine-Dmt-lysine-phenylalanine-NH
2(SS-31) in the dirty ischemia-reperfusion process of dabbling guinea-pig heart, protecting myocardial contraction.Heart is with buffer or contain SS-02 (100nM) or the buffer of SS-31 (1nM) perfusion 30 minutes, stands (global) whole-heartedly ischemia of 30 minutes then.Pour into again with same primer solution.There is significant difference (two-way analysis of variance, P<0.001) in discovery in 3 treatment groups.
Fig. 6. in cardioplegic solution, add [Dmt
1] DALDA significantly strengthened through the dirty contractile function after the ischemia that prolongs of dabbling guinea-pig heart.After stablizing 30 minutes, heart is with St.Thomas cardioplegic solution (CPS) or contain [the Dmt of 100nM
1] the CPS perfusion 3 minutes of DALDA.Caused whole-heartedly in 90 minutes and lose blood by blocking coronary perfusion fully.Krebs-Henseleit solution with oxidation carries out 60 minutes and reperfusion subsequently.Accepting [Dmt
1] ischemia after-contraction power is significantly increased (P<0.001) in the group of DALDA.
The specific embodiment
The present invention is based on inventor's surprising discovery: some aromatic series cationic peptide has reduced the mitochondrion quantity of experience mitochondrial permeability transition (MPT) significantly, even has stoped MPT fully.It is very important reducing the mitochondrion quantity of experience MPT and stoping MPT, because multiple common disease is relevant with disease in MPT and the mammal.In addition, MPT takes place in mammiferous isolated organ easily.These diseases and disease have special clinical meaning, because they influence the crowd of significant proportion in some stage of life.
Peptide
Useful aromatic series cationic peptide is a water solublity and high polar among the present invention.Although these character is arranged, these peptides can be easy to pass cell membrane.
Among the present invention useful aromatic series cationic peptide comprise minimum 3 by the covalently bound aminoacid of peptide bond, and preferably include minimum 4 by the covalently bound aminoacid of peptide bond.
Aminoacid maximum number in the aromatic series cationic peptide of the present invention is for passing through covalently bound about 20 aminoacid of peptide bond.The maximum number of preferred amino acids is about 12, more preferably about 9, and most preferably be about 6.Best situation is that the amino acid number that is present in this peptide is 4.
Aminoacid among the present invention in the useful aromatic series cationic peptide can be any aminoacid.Term " aminoacid " in this article refers to and contains at least one any organic molecule amino and at least one carboxyl.Preferably, at least one amino is positioned at the α position with respect to carboxyl.
These aminoacid can be naturally occurring.Naturally occurring aminoacid comprises, 20 kinds of modal left-handed (L) aminoacid, i.e. alanine (Ala) in mammalian proteins matter, finding naturally for example, arginine (Arg), agedoite (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ileu), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val).
Other naturally occurring aminoacid for example comprise with the irrelevant metabolic process of protein synthesis in synthetic aminoacid.For example, the synthetic ornithine of mammal metabolism and these aminoacid of citrulline in the process that produces urine.
Available peptide can contain the aminoacid that one or more non-naturals exist among the present invention.The aminoacid that these non-naturals exist can be left-handed (L), dextrorotation (D) or their mixture.Best situation is that this peptide does not contain naturally occurring aminoacid.
The aminoacid that non-natural exists is that those are not synthetic in organism homergy process usually, and is not naturally occurring aminoacid in protein.In addition, the aminoacid that preferred available non-natural exists among the present invention is not also by common protease identification.
The aminoacid that non-natural exists can appear at any position of this peptide.For example, the aminoacid that this non-natural exists can be positioned at the N-end, the terminal or any position between N-end and C-end of C-.
For example, the aminoacid of this non-natural existence can comprise these groups of alkyl, aryl or alkaryl.Some examples of alkyl amino acid comprise: butyrine, beta-aminobutyric acid, γ-An Jidingsuan, δ-aminovaleric acid and episilon amino caproic acid.Some examples of aryl amino acid comprise the neighbour, and para-amino benzoic acid.The more amino acid whose examples of alkaryl comprise the neighbour, and equal amido phenenyl acid, and γ-phenyl-beta-aminobutyric acid.
The aminoacid that non-natural exists also comprises naturally occurring amino acid whose derivant.Naturally occurring amino acid whose derivant can comprise as add one or more chemical groups on naturally occurring aminoacid.
For example, one or more chemical groups can be added on one or more positions among 2 ', 3 ', 4 ', 5 ' or 6 ' of aromatic rings of phenylalanine or tyrosine residue, or on the one or more positions among 4 ', 5 ', 6 ' or 7 ' of the benzo ring of trp residue.This group is any chemical group that can add on the aromatic rings.Some examples of these groups comprise the C of side chain or straight chain
1-C
4Alkyl is as methyl, ethyl, n-pro-pyl, isopropyl, butyl, isobutyl group or the tert-butyl group, C
1-C
4Oxyl (being alkoxyl), amino, C
1-C
4Alkylamine and C
1-C
4Dialkylamine (for example methylamine, dimethylamine), nitro, hydroxyl, halogen (promptly fluorine-based, chloro, bromo or iodo).Some specific example of the derivant that naturally occurring amino acid whose non-natural exists comprise norvaline (Nva), nor-leucine (Nle) and hydroxyproline (Hyp).
Another amino acid modified example in the method for the present invention in useful peptide is the aspartic acid of this peptide or the carboxyl derivatization of glutaminic acid residue.An example of derivatization is with ammonia or with as these primary amine of methylamine, ethamine, dimethylamine or diethylamine or secondary amine amidatioon.Another example of derivatization comprises to be used as methanol or ethyl esterification.
Another such modification comprises the amino derivatization of lysine, arginine or histidine residues.For example, these amino can be by acidylate.Some suitable acyl groups comprise, for example comprise any above-mentioned C
1-C
4The benzoyl of alkyl or alkanoyl are as acetyl group or propiono.
Preferably the aminoacid of non-natural existence is stable to common protease, and is more preferably insensitive to it.The amino acid whose example that the stable or insensitive non-natural of protease is existed comprises any amino acid whose dextrorotation of above-mentioned naturally occurring L-(D-) type, and the aminoacid of L-and/or the existence of D-type non-natural.D-aminoacid be not normal presence in protein, although found them in some antibacterial peptide, they are synthetic by the instrument except that the normal ribosomal protein synthesizer of cell.These D-aminoacid used herein can be thought the aminoacid that non-natural exists.
In order to make sensitivity drop to minimum to protease, useful peptide should have and is less than 5 in the method for the present invention, preferably be less than 4, more preferably less than 3, and most preferably be less than 2 the L-aminoacid that can be discerned by common protease that adjoin, no matter whether these aminoacid are naturally occurring or non-natural exists.Best situation is that this peptide only contains D-aminoacid, and does not contain L-aminoacid.
If this peptide contains protease-sensitive aminoacid sequence, then in these aminoacid is preferably the D-aminoacid (dextrorotation arginine) that non-natural exists at least, thereby protease resistant is provided.The example of the responsive sequence of protease comprises easily by two or more basic amino acids that adjoin of common protease such as endopeptidase and trypsin incision.The example of basic amino acid comprises arginine, lysine and histidine.
To have the clean positive charge with respect to the minimal amount of amino acid residue sum in this peptide be very important to this aromatic series cationic peptide under physiological pH.The minimal amount of clean positive charge hereinafter is expressed as (p under the physiological pH
m).The amino acid residue sum hereinafter is expressed as (r) in this peptide.
Hereinafter the minimal amount of the clean positive charge of Tao Luning all is under the physiological pH condition.Term " physiological pH " in this article refers to the tissue of body of mammals and the normal pH among the organ cell.For example people's physiological pH is about 7.4 usually, but normal physiological pH can be any pH from about 7.0 to about 7.8 in the mammal.
" net charge " is meant herein by being present in the entrained positive changes of aminoacid in this peptide and the difference of negative charge number.In this manual, should be understood to net charge measures under physiological pH.The naturally occurring aminoacid that has positive charge under physiological pH comprises L-lysine, L-arginine and L-histidine.The naturally occurring aminoacid that has negative charge under physiological pH comprises L-aspartic acid and L-glutamic acid.
Usually, peptide has the N-terminal amino group of a positive charge and the C-terminal carboxyl group of a negative charge.Electric charge cancels each other out under physiological pH.As an example that calculates net charge, peptide: tyrosine-arginine-phenylalanine-LYS-GLU-histidine-tryptophan-arginine (Tyr-Arg-Phe-Lys-Glu-His-Trp-Arg) has a negative charge aminoacid (promptly, glutamic acid) and four positive charge aminoacid (promptly, two arginine residues, a lysine and a histidine).Therefore above-mentioned peptide contains 3 clean positive charges.
In one embodiment of the invention, this aromatic series cationic peptide clean positive charge minimal amount (p under physiological pH
m) and amino acid residue sum (r) between the pass be: 3P wherein
mIt is the maximum number that is less than or equal to r+1.In this embodiment, clean positive charge minimal amount (p
m) and amino acid residue sum (r) between relation as follows:
(r) | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 |
(p m) | 1 | 1 | 2 | 2 | 2 | 3 | 3 | 3 | 4 | 4 | 4 | 5 | 5 | 5 | 6 | 6 | 6 | 7 |
In another embodiment, this aromatic series cationic peptide is at clean positive charge minimal amount (p
m) and amino acid residue sum (r) between the pass be: 2p wherein
mIt is the maximum number that is less than or equal to r+1.In this embodiment, clean positive charge minimal amount (p
m) and amino acid residue sum (r) between relation as follows:
(r) | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 |
(p m) | 2 | 2 | 3 | 3 | 4 | 4 | 5 | 5 | 6 | 6 | 7 | 7 | 8 | 8 | 9 | 9 | 10 | 10 |
In one embodiment, clean positive charge minimal amount (p
m) equal with amino acid residue sum (r).In another embodiment, this peptide contains 3 or 4 amino acid residues and has a minimum clean positive charge, is preferably minimum 2 clean positive charges and more preferably minimum 3 clean positive charges.
This aromatic series cationic peptide has with respect to clean positive charge sum (p
t) minimum aromatic group is also very important.The minimal amount of aromatic radical is expressed as (a) hereinafter.
Naturally occurring aminoacid with aromatic radical comprises these aminoacid of histidine, tryptophan, tyrosine and phenylalanine.For example, six peptides: lysine-glutamine-tyrosine-arginine-phenylalanine-tryptophan contains 2 clean positive charges (by lysine and arginine residues contribution) and 3 aromatic radicals (by tyrosine, phenylalanine and trp residue contribution).
In one embodiment of the invention, useful aromatic series cationic peptide clean positive charge sum (p under aromatic radical minimal amount (a) and physiological pH in the method for the present invention
t) between the pass be: wherein 3a is less than or equal to p
t+ 1 maximum number is unless work as p
tBe 1, a also can be 1.In this embodiment, minimal amount of aromatic radical (a) and clean positive charge sum (p
t) between relation as follows:
(p t) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 |
(a) | 1 | 1 | 1 | 1 | 2 | 2 | 2 | 3 | 3 | 3 | 4 | 4 | 4 | 5 | 5 | 5 | 6 | 6 | 6 | 7 |
In another embodiment, this aromatic series cationic peptide is at aromatic radical minimal amount (a) and clean positive charge sum (p
t) between the pass be: wherein 2a is less than or equal to p
t+ 1 maximum number.In this embodiment, minimal amount of aromatic amino acid residue (a) and clean positive charge sum (p
t) between relation as follows:
(p t) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 |
(a) | 1 | 1 | 2 | 2 | 3 | 3 | 4 | 4 | 5 | 5 | 6 | 6 | 7 | 7 | 8 | 8 | 9 | 9 | 10 | 10 |
In another embodiment, aromatic radical number (a) and clean positive charge sum (p
t) equate.
Carboxyl, the especially terminal carboxyl group of C-end amino acid preferably carry out amidatioon with for example ammonia and form the C-terminal amide.Another kind of optionally scheme is, the terminal carboxyl group of C-end amino acid can be with any primary amine or secondary amine amidatioon.This primary amine or secondary amine can be, for example alkyl, especially side chain or straight chain C
1-C
4Alkyl or arylamine.Correspondingly, the aminoacid of this peptide C-end can change into amide groups, N-methyl nitrosourea base, N-buserelin base, N, N-dimethylformamide base, N, N-diethylamide base, N-methyl-N-buserelin base, N-phenyl amide base or N-phenyl-N-buserelin base.
Even the free carboxyl group group of asparagine residue, glutamine residue, asparagicacid residue and glutaminic acid residue is not positioned at the C-end of aromatic series cationic peptide of the present invention, and though they be positioned at any position of this peptide can be by amidatioon.The amidatioon of these interior locations can be carried out with ammonia or any above-mentioned primary amine or secondary amine.
In one embodiment, useful aromatic series cationic peptide is a kind of tripeptides with two clean positive charges and at least one aromatic amino acid in the method for the present invention.In a specific embodiment, useful aromatic series cationic peptide is a kind of tripeptides with two clean positive charges and two aromatic amino acids in the method for the present invention.
Useful aromatic series cationic peptide includes but not limited to the example of following peptide in the method for the present invention:
Lysine-dextrorotation arginine-tyrosine-NH
2(Lys-D-Arg-Tyr-NH
2),
Phenylalanine-dextrorotation arginine-histidine (Phe-D-Arg-His),
Dextrorotation tyrosine-tryptophan-lysine-NH
2(D-Tyr-Trp-Lys-NH
2),
Tryptophan-dextrorotation lysine-tyrosine-arginine-NH
2(Trp-D-Lys-Tyr-Arg-NH
2),
Tyrosine-histidine-dextrorotation glycine-methionine (Tyr-His-D-Gly-Met),
Phenylalanine-arginine-right-turn set propylhomoserin-aspartic acid (Phe-Arg-D-His-Asp),
Tyrosine-dextrorotation arginine-phenylalanine-LYS-GLU-NH
2(Tyr-D-Arg-Phe-Lys-Glu-NH
2),
Methionine-tyrosine-dextrorotation lysine-phenylalanine-arginine (Met-Tyr-D-Lys-Phe-Arg),
Right-turn set propylhomoserin-glutamic-lysine-tyrosine-dexamphetamine propylhomoserin-arginine (D-His-Glu-Lys-Tyr-D-Phe-Arg),
Lysine-dextrorotation glutamine-tyrosine-arginine-dexamphetamine propylhomoserin-tryptophan-NH
2(Lys-D-Gln-Tyr-Arg-D-Phe-Trp-NH
2),
Phenylalanine-dextrorotation arginine-lysine-tryptophan-tyrosine-dextrorotation arginine-histidine (Phe-D-Arg-Lys-Trp-Tyr-D-Arg-His),
Glycine-dexamphetamine propylhomoserin-lysine-tyrosine-histidine-dextrorotation arginine-tyrosine-NH
2(Gly-D-Phe-Lys-Tyr-His-D-Arg-Tyr-NH
2),
Valine-dextrorotation lysine-histidine-tyrosine-dexamphetamine propylhomoserin-serine-tyrosine-arginine-NH
2(Val-D-Lys-His-Tyr-D-Phe-Ser-Tyr-Arg-NH
2),
Tryptophan-lysine-phenylalanine-dextrorotation aspartic acid-arginine-tyrosine-right-turn set propylhomoserin-lysine (Trp-Lys-Phe-D-Asp-Arg-Tyr-D-His-Lys),
Lysine-tryptophan-dextrorotation tyrosine-arginine-agedoite-phenylalanine-tyrosine-right-turn set propylhomoserin-NH
2(Lys-Trp-D-Tyr-Arg-Asn-Phe-Tyr-D-His-NH
2),
Threonine-glycine-tyrosine-arginine-dextrorotation HIS-PHE-tryptophan-right-turn set propylhomoserin-lysine (Thr-Gly-Tyr-Arg-D-His-Phe-Trp-D-His-Lys),
Aspartic acid-dextrorotation tryptophan-lysine-tyrosine-dextrorotation HIS-PHE-arginine-dextrorotation glycine-lysine-NH
2(Asp-D-Trp-Lys-Tyr-D-His-Phe-Arg-D-Gly-Lys-NH
2),
Right-turn set propylhomoserin-lysine-tyrosine-dexamphetamine propylhomoserin-glutamic acid-dextrorotation aspartic acid-right-turn set propylhomoserin-dextrorotation lysine-arginine-tryptophan-NH
2(D-His-Lys-Tyr-D-Phe-Glu-D-Asp-D-His-D-Lys-Arg-Trp-NH
2),
Alanine-dexamphetamine propylhomoserin-dextrorotation arginine-tyrosine-lysine-dextrorotation tryptophan-histidine-dextrorotation tyrosine-glycine-phenylalanine (Ala-D-Phe-D-Arg-Tyr-Lys-D-Trp-His-D-Tyr-Gly-Phe),
Tyrosine-dextrorotation HIS-PHE-dextrorotation arginine-aspartic acid-lysine-dextrorotation arginine-histidine-tryptophan-dextrorotation HIS-PHE (Tyr-D-His-Phe-D-Arg-Asp-Lys-D-Arg-His-Trp-D-His-Phe),
Phenylalanine-phenylalanine-dextrorotation tyrosine-arginine-glutamic acid-aspartic acid-dextrorotation lysine-arginine-dextrorotation arginine-HIS-PHE-NH
2(Phe-Phe-D-Tyr-Arg-Glu-Asp-D-Lys-Arg-D-Arg-His-Phe-NH
2),
Phenylalanine-tyrosine-lysine-dextrorotation arginine-tryptophan-histidine-dextrorotation lysine-dextrorotation LYS-GLU-arginine-dextrorotation tyrosine-threonine (Phe-Try-Lys-D-Arg-Trp-His-D-Lys-D-Lys-Glu-Arg-D-Tyr-Thr)
Tyrosine-aspartic acid-dextrorotation lysine-tyrosine-phenylalanine-dextrorotation lysine-dextrorotation arginine-phenylalanine-proline-dextrorotation tyrosine-histidine-lysine (Tyr-Asp-D-Lys-Tyr-Phe-D-Lys-D-Arg-Phe-Pro-D-Tyr-His-Lys)
Glutamic acid-arginine-dextrorotation lysine-tyrosine-D-Val-phenylalanine-right-turn set propylhomoserin-tryptophan-arginine-dextrorotation glycine-tyrosine-arginine-dextrorotation methionine-NH
2(Glu-Arg-D-Lys-Tyr-D-Val-Phe-D-His-Trp-Arg-D-Gly-Tyr-Arg-D-Met-NH
2),
Arginine-dextrorotation leucine-dextrorotation tyrosine-phenylalanine-LYS-GLU-dextrorotation lysine-arginine-dextrorotation tryptophan-lysine-dexamphetamine propylhomoserin-tyrosine-dextrorotation arginine-glycine (Arg-D-Leu-D-Tyr-Phe-Lys-Glu-D-Lys-Arg-D-Trp-Lys-D-Phe-Ty r-D-Arg-Gly)
Dextrorotation glutamic acid-arginine-lysine-dextrorotation arginine-dextrorotation HIS-PHE-phenylalanine-D-Val-tyrosine-arginine-tyrosine-dextrorotation tyrosine-arginine-HIS-PHE-NH
2(D-Glu-Asp-Lys-D-Arg-D-His-Phe-Phe-D-Val-Tyr-Arg-Tyr-D-Ty r-Arg-His-Phe-NH
2),
Aspartic acid-arginine-dexamphetamine propylhomoserin-cysteine-phenylalanine-dextrorotation arginine-dextrorotation lysine-tyrosine-arginine-dextrorotation tyrosine-tryptophan-right-turn set propylhomoserin-tyrosine-dexamphetamine propylhomoserin-lysine-phenylalanine (Asp-Arg-D-Phe-Cys-Phe-D-Arg-D-Lys-Tyr-Arg-D-Tyr-Trp-D-Hi s-Tyr-D-Phe-Lys-Phe)
Histidine-tyrosine-dextrorotation arginine-tryptophan-lysine-phenylalanine-dextrorotation aspartic acid-alanine-arginine-cysteine-dextrorotation tyrosine-HIS-PHE-dextrorotation lysine-tyrosine-histidine-serine-NH
2(His-Tyr-D-Arg-Trp-Lys-Phe-D-Asp-Ala-Arg-Cys-D-Tyr-His-Ph e-D-Lys-Tyr-His-Ser-NH
2),
Glycine-alanine-lysine-phenylalanine-dextrorotation LYS-GLU-arginine-tyrosine-histidine-dextrorotation arginine-dextrorotation arginine-aspartic acid-tyrosine-tryptophan-right-turn set propylhomoserin-tryptophan-histidine-dextrorotation lysine-aspartic acid (Gly-Ala-Lys-Phe-D-Lys-Glu-Arg-Tyr-His-D-Arg-D-Arg-Asp-Ty r-Trp-D-His-Trp-His-D-Lys-Asp)
And
Threonine-tyrosine-arginine-dextrorotation lysine-tryptophan-tyrosine-glutamic acid-aspartic acid-dextrorotation lysine-dextrorotation arginine-HIS-PHE-dextrorotation tyrosine-glycine-valine-isoleucine-right-turn set propylhomoserin-arginine-tyrosine-NH
2(Thr-Tyr-Arg-D-Lys-Trp-Tyr-Glu-Asp-D-Lys-D-Arg-His-Phe-D-Tyr-Gly-Val-Ile-D-His-Arg-Tyr-NH
2).
In one embodiment, useful peptide has μ-opioid receptor agonist activity (that is, activating μ-Opioid Receptors) in the method for the present invention.The activation of μ-Opioid Receptors has analgesic effect usually.
In some cases, the aromatic series cationic peptide that preferably has μ-opioid receptor activity.For example, in the short term therapy process as acute illness and disease, the aromatic series cationic peptide that use can activate μ-Opioid Receptors is useful.These acute illnesss are relevant with moderate or severe pain usually with disease.In these cases, the analgesic effect of this aromatic series cationic peptide is useful in to patient or other mammiferous therapeutic scheme, although it can not activate the aromatic series cationic peptide of μ-Opioid Receptors, also can according to clinical needs with or be not used in combination with analgesic.
In other cases, alternative dispensing means does not preferably have the aromatic series cationic peptide of μ-opioid receptor activity.For example, in the long-term treatment process as chronic disease and disease, the aromatic series cationic peptide that use can activate μ-Opioid Receptors may be incompatible.In these cases, potential side effect of this aromatic series cationic peptide or addiction effect may hinder have μ-the aromatic series cationic peptide of Opioid Receptors activation is to the use in patient or other the mammiferous therapeutic scheme.
Potential side effect can comprise calmness, constipation and respiration inhibition.In these cases, the aromatic series cationic peptide that can not activate μ-Opioid Receptors may be a kind of appropriate medicine.
The example of acute disease comprises: heart attack, apoplexy (apoplexy) and wound.Wound can comprise cerebral trauma and trauma of spinal cord.
Chronic disease and examples of disorders comprise: coronary artery disease as described below and any neurodegenerative diseases.
Useful those peptides that contain tyrosine residue or tyrosine N-end (that is first amino acid position) derivant normally of the peptide with μ-opioid receptor activity in the method for the present invention.Preferred tyrosine derivative comprises: 2 '-methyl-tyrosine (Mmt); 2 ', 6 '-dimethyl tyrosine (2 ' 6 ' Dmt); 3 ', 5 '-dimethyl tyrosine (3 ' 5 ' Dmt); N, 2 ', 6 '-trimethyl tyrosine (Tmt); And 2 '-hydroxyl-6 '-methyl-tyrosine (Hmt).
In a particularly preferred embodiment, the peptide with μ-opioid receptor activity has molecular formula and is: tyrosine-dextrorotation arginine-phenylalanine-lysine-NH
2(Tyr-D-Arg-Phe-Lys-NH
2) (be expressed as with acronym for convenience: DALDA is called SS-01 in this article).3 clean positive charges that provided by these aminoacid of tyrosine, arginine and lysine are provided DALDA, and 2 aromatic groups that provided by phenylalanine and tyrosine.The tyrosine of DALDA can be adorned tyrosine derivative as 2 ', 6 '-dimethyl tyrosine, to have molecular formula be 2 ', 6 '-dimethyl tyrosine-dextrorotation arginine-phenylalanine-lysine-NH thereby generate
2(2 ', 6 '-Dmt-D-Arg-Phe-Lys-NH
2) (that is Dmt,
1-DALDA is called SS-02 in this article) chemical compound.
The peptide that does not have μ-opioid receptor activity does not contain tyrosine residue or tyrosine derivative at N-end (that is amino acid whose position 1) usually.Aminoacid at the N-end can be the aminoacid that any naturally occurring or non-natural except that tyrosine exists.
In one embodiment,-terminal amino acid is the phenylalanine or derivatives thereof.Preferred phenylalanine derivative comprises: 2 '-methylbenzene alanine (Mmp), 2 ', 6 '-dimethyl benzene alanine (Dmp), N, 2 ', 6 '-trimethylbenzene alanine (Tmp) and 2 '-hydroxyl-6 '-methylbenzene alanine (Hmp).
The another kind of molecular formula that does not have the aromatic series cationic peptide of μ-opioid receptor activity is: phenylalanine-dextrorotation arginine-phenylalanine-lysine-NH
2(Phe-D-Arg-Phe-Lys-NH
2) (that is Phe,
1-DALDA is called SS-20 in this article).Alternatively optional, the derivant that the terminal phenylalanine of this N-can be a phenylalanine is as 2 ', 6 '-dimethyl benzene alanine (2 ' 6 ' Dmp).The molecular formula that contains the DALDA of 2 ', 6 '-dimethyl benzene alanine at amino acid position 1 is 2 ', 6 '-Dmp-dextrorotation arginine-phenylalanine-lysine-NH
2(2 ', 6 '-Dmp-D-Arg-Phe-Lys-NH
2) (that is 2 ' 6 ' Dmp,
1-DALDA).
In a preferred embodiment, Dmt
1The aminoacid sequence of-DALDA (SS-02) rearranges, and makes Dmt not be positioned at the N-end.Not having the molecular formula that the example of the aromatic series cationic peptide of μ-opioid receptor activity has like this is: dextrorotation arginine-2 ' 6 ' Dmt-lysine-phenylalanine-NH
2(D-Arg-2 ' 6 ' Dmt-Lys-Phe-NH
2) (being called SS-31 in this manual).
DALDA, Phe
1-DALDA, SS-31 and their derivant may further include functional analogue.If this analog has and DALDA, Phe
1The similar function of-DALDA or SS-31, then this peptide b referred to as DALDA, Phe
1The functional analogue of-DALDA or SS-31.For example, this analog can be DALDA, Phe
1The replacement variant of-DALDA or SS-31, one or more aminoacid are by other aminoacid replacement in this replacement variant.
DALDA, Phe
1The suitable replacement variant of-DALDA or SS-31 comprises conservative aminoacid replacement.Aminoacid can be grouped as follows according to their physicochemical properties:
(a) nonpolar amino acid: alanine (A) serine (S) threonine (T) proline (P) glycine (G) (Ala (A) Ser (S) Thr (T) Pro (P) Gly (G));
(b) acidic amino acid: agedoite (N) aspartic acid (D) glutamic acid (E) glutamine (Q) (Asn (N) Asp (D) Glu (E) Gln (Q));
(c) basic amino acid: histidine (H) arginine (R) lysine (K) (His (H) Arg (R) Lys (K));
(d) hydrophobic amino acid: methionine (M) leucine (L) isoleucine (I) valine (V) (Met (M) Leu (L) Ile (I) Val (V)); And
(e) aromatic amino acid: phenylalanine (F) tyrosine (T) tryptophan (W) histidine (H) (Phe (F) Tyr (Y) Trp (W) His (H)).
An aminoacid in the peptide is called conservative the replacement by another aminoacid replacement on the same group, and this physicochemical properties that can keep original peptide.On the contrary, aminoacid in the peptide is generally more likely changed the character of original peptide by on the same group another aminoacid replacement not.
In practice of the present invention, the example that can activate the useful analog of μ-Opioid Receptors includes but not limited to the aromatic series cationic peptide shown in the table 1.
Table 1
Amino acid amino acid amino acid amino acid amino acid position 5 C-ends
3 positions 4 (if present), 2 positions, 1 position, position are modified
Tyrosine dextrorotation arginine phenylalanine lysine NH
2
Tyrosine dextrorotation arginine phenylalanine ornaline (Orn) NH
2
Tyrosine dextrorotation arginine phenylalanine Dab NH
2
Tyrosine dextrorotation arginine phenylalanine Dap NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine lysine NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine lysine cysteine NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine lysine-NH (CH
2)
2-NH-dns NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine lysine-NH (CH
2)
2-NH-atn NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine dns lysine NH
2
2 ' 6 ' Dmt dextrorotation citicoline phenylalanine lysine NH
2
(D-Cit)
2 ' 6 ' Dmt dextrorotation citicoline phenylalanine Ahp NH
2
(D-Cit)
2 ' 6 ' Dmt dextrorotation arginine phenylalanine ornaline (Orn) NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine Dab NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine Dap NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine Ahp (2-aminoheptylic acid) NH
2
Bio-2 ' 6 ' Dmt dextrorotation arginine phenylalanine lysine NH
2
3 ' 5 ' Dmt dextrorotation arginine phenylalanine lysine NH
2
3 ' 5 ' Dmt dextrorotation arginine phenylalanine ornaline (Orn) NH
2
3 ' 5 ' Dmt dextrorotation arginine phenylalanine Dab NH
2
3 ' 5 ' Dmt dextrorotation arginine phenylalanine Dap NH
2
Tyrosine dextrorotation arginine tyrosine lysine NH
2
Tyrosine dextrorotation arginine tyrosine ornaline (Orn) NH
2
Tyrosine dextrorotation arginine tyrosine Dab NH
2
Tyrosine dextrorotation arginine tyrosine Dap NH
2
2 ' 6 ' Dmt dextrorotation arginine tyrosine lysine NH
2
2 ' 6 ' Dmt dextrorotation arginine tyrosine ornaline (Orn) NH
2
2 ' 6 ' Dmt dextrorotation arginine tyrosine Dab NH
2
2 ' 6 ' Dmt dextrorotation arginine tyrosine Dap NH
2
2 ' 6 ' Dmt dextrorotation arginase 12 ' 6 ' Dmt lysine NH
2
2 ' 6 ' Dmt dextrorotation arginase 12 ' 6 ' Dmt ornalines (Orn) NH
2
2 ' 6 ' Dmt dextrorotation arginase 12 ' 6 ' Dmt Dab NH
2
2 ' 6 ' Dmt dextrorotation arginase 12 ' 6 ' Dmt Dap NH
2
3 ' 5 ' Dmt dextrorotation arginine, 3 ' 5 ' Dmt arginine NH
2
3 ' 5 ' Dmt dextrorotation arginine, 3 ' 5 ' Dmt lysine NH
2
3 ' 5 ' Dmt dextrorotation arginine, 3 ' 5 ' Dmt ornaline (Orn) NH
2
3 ' 5 ' Dmt dextrorotation arginine, 3 ' 5 ' Dmt Dab NH
2
Tyrosine dextrorotation lysine phenylalanine Dap NH
2
Tyrosine dextrorotation lysine phenylalanine arginine NH
2
Tyrosine dextrorotation lysine phenylalanine lysine NH
2
Tyrosine dextrorotation lysine phenylalanine ornaline (Orn) NH
2
2 ' 6 ' Dmt dextrorotation lysine phenylalanine Dab NH
2
2 ' 6 ' Dmt dextrorotation lysine phenylalanine Dap NH
2
2 ' 6 ' Dmt dextrorotation lysine phenylalanine arginine NH
2
2 ' 6 ' Dmt dextrorotation lysine phenylalanine lysine NH
2
3 ' 5 ' Dmt dextrorotation lysine phenylalanine ornaline (Orn) NH
2
3 ' 5 ' Dmt dextrorotation lysine phenylalanine Dab NH
2
3 ' 5 ' Dmt dextrorotation lysine phenylalanine Dap NH
2
3 ' 5 ' Dmt dextrorotation lysine phenylalanine arginine NH
2
Tyrosine dextrorotation lysine tyrosine lysine NH
2
Tyrosine dextrorotation lysine tyrosine ornaline (Orn) NH
2
Tyrosine dextrorotation lysine tyrosine Dab NH
2
Tyrosine dextrorotation lysine tyrosine Dap NH
2
2 ' 6 ' Dmt dextrorotation lysine tyrosine lysine NH
2
2 ' 6 ' Dmt dextrorotation lysine tyrosine ornaline (Orn) NH
2
2 ' 6 ' Dmt dextrorotation lysine tyrosine Dab NH
2
2 ' 6 ' Dmt dextrorotation lysine tyrosine Dap NH
2
2 ' 6 ' Dmt dextrorotation lysines, 2 ' 6 ' Dmt lysine NH
2
2 ' 6 ' Dmt dextrorotation lysines, 2 ' 6 ' Dmt ornaline (Orn) NH
2
2 ' 6 ' Dmt dextrorotation lysines, 2 ' 6 ' Dmt Dab NH
2
2 ' 6 ' Dmt dextrorotation lysines, 2 ' 6 ' Dmt Dap NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine dnsDap NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine atnDap NH
2
3 ' 5 ' Dmt dextrorotation lysines, 3 ' 5 ' Dmt lysine NH
2
3 ' 5 ' Dmt dextrorotation lysines, 3 ' 5 ' Dmt ornaline (Orn) NH
2
3 ' 5 ' Dmt dextrorotation lysines, 3 ' 5 ' Dmt Dab NH
2
3 ' 5 ' Dmt dextrorotation lysines, 3 ' 5 ' Dmt Dap NH
2
Tyrosine dextrorotation lysine phenylalanine arginine NH
2
Tyrosine dextrorotation ornaline phenylalanine arginine NH
2
(Orn)
Tyrosine dextrorotation Dab phenylalanine arginine NH
2
Tyrosine dextrorotation Dap phenylalanine arginine NH
2
2 ' 6 ' Dmt dextrorotation arginine phenylalanine arginine NH
2
2 ' 6 ' Dmt dextrorotation lysine phenylalanine arginine NH
2
2 ' 6 ' Dmt dextrorotation ornaline phenylalanine arginine NH
2
(D-Orn)
2 ' 6 ' Dmt dextrorotation Dab phenylalanine arginine NH
2
3 ' 5 ' Dmt dextrorotation Dap phenylalanine arginine NH
2
3 ' 5 ' Dmt dextrorotation arginine phenylalanine arginine NH
2
3 ' 5 ' Dmt dextrorotation lysine phenylalanine arginine NH
2
3 ' 5 ' Dmt dextrorotation ornaline phenylalanine arginine NH
2
(D-Orn)
Tyrosine dextrorotation lysine tyrosine arginine NH
2
Tyrosine dextrorotation ornaline tyrosine arginine NH
2
(D-Orn)
Tyrosine dextrorotation Dab tyrosine arginine NH
2
Tyrosine dextrorotation Dap tyrosine arginine NH
2
2 ' 6 ' Dmt dextrorotation arginase 12 ' 6 ' Dmt arginine NH
2
2 ' 6 ' Dmt dextrorotation lysines, 2 ' 6 ' Dmt arginine NH
2
2 ' 6 ' Dmt dextrorotation ornalines, 2 ' 6 ' Dmt arginine NH
2
(D-Orn)
2 ' 6 ' Dmt dextrorotation Dab, 2 ' 6 ' Dmt arginine NH
2
3 ' 5 ' Dmt dextrorotation Dap, 3 ' 5 ' Dmt arginine NH
2
3 ' 5 ' Dmt dextrorotation arginine, 3 ' 5 ' Dmt arginine NH
2
3 ' 5 ' Dmt dextrorotation lysines, 3 ' 5 ' Dmt arginine NH
2
3 ' 5 ' Dmt dextrorotation ornalines, 3 ' 5 ' Dmt arginine NH
2
(D-Orn)
Mmt dextrorotation arginine phenylalanine lysine NH
2
Mmt dextrorotation arginine phenylalanine ornaline (Orn) NH
2
Mmt dextrorotation arginine phenylalanine Dab NH
2
Mmt dextrorotation arginine phenylalanine Dap NH
2
Tmt dextrorotation arginine phenylalanine lysine NH
2
Tmt dextrorotation arginine phenylalanine ornaline (Orn) NH
2
Tmt dextrorotation arginine phenylalanine Dab NH
2
Tmt dextrorotation arginine phenylalanine Dap NH
2
Hmt dextrorotation arginine phenylalanine lysine NH
2
Hmt dextrorotation arginine phenylalanine ornaline (Orn) NH
2
Hmt dextrorotation arginine phenylalanine Dab NH
2
Hmt dextrorotation arginine phenylalanine Dap NH
2
Mmt dextrorotation lysine phenylalanine lysine NH
2
Mmt dextrorotation lysine phenylalanine ornaline (Orn) NH
2
Mmt dextrorotation lysine phenylalanine Dab NH
2
Mmt dextrorotation lysine phenylalanine Dap NH
2
Mmt dextrorotation lysine phenylalanine arginine NH
2
Tmt dextrorotation lysine phenylalanine lysine NH
2
Tmt dextrorotation lysine phenylalanine ornaline (Orn) NH
2
Tmt dextrorotation lysine phenylalanine Dab NH
2
Tmt dextrorotation lysine phenylalanine Dap NH
2
Tmt dextrorotation lysine phenylalanine arginine NH
2
Hmt dextrorotation lysine phenylalanine lysine NH
2
Hmt dextrorotation lysine phenylalanine ornaline (Orn) NH
2
Hmt dextrorotation lysine phenylalanine Dab NH
2
Hmt dextrorotation lysine phenylalanine Dap NH
2
Hmt dextrorotation lysine phenylalanine arginine NH
2
Mmt dextrorotation lysine phenylalanine arginine NH
2
Mmt dextrorotation ornaline phenylalanine arginine NH
2
(D-Orn)
Mmt dextrorotation Dab phenylalanine arginine NH
2
Mmt dextrorotation Dap phenylalanine arginine NH
2
Mmt dextrorotation arginine phenylalanine arginine NH
2
Tmt dextrorotation lysine phenylalanine arginine NH
2
Tmt dextrorotation ornaline phenylalanine arginine NH
2
(D-Orn)
Tmt dextrorotation Dab phenylalanine arginine NH
2
Tmt dextrorotation Dap phenylalanine arginine NH
2
Tmt dextrorotation arginine phenylalanine arginine NH
2
Hmt dextrorotation lysine phenylalanine arginine NH
2
Hmt dextrorotation ornaline phenylalanine arginine NH
2
(D-Orn)
Hmt dextrorotation Dab phenylalanine arginine NH
2
Hmt dextrorotation Dap phenylalanine arginine NH
2
Hmt dextrorotation arginine phenylalanine arginine NH
2
The Dab=DAB
The Dap=diaminopropionic acid
Dmt=dimethyl tyrosine
Mmt=2 '-methyl-tyrosine
Tmt=N, 2 ', 6 '-trimethyl tyrosine
Hmt=2 '-hydroxyl-6 '-methyl-tyrosine
DnsDap=β-dansyl-L-α, β-diaminopropionic acid
AtnDap=β-o-amino benzoyl acyl group-L-α, β-diaminopropionic acid
The Bio=biotin.
The example that can not activate the useful analog of μ-Opioid Receptors in practice of the present invention includes but not limited to the aromatic series cationic peptide shown in the table 2.
Table 2
Amino acid amino acid amino acid amino acid C-end
3 positions 4,2 positions, 1 position, position are modified
Dextrorotation arginine Dmt lysine phenylalanine NH
2
Dextrorotation arginine Dmt phenylalanine lysine NH
2
Dextrorotation arginine phenylalanine lysine Dmt NH
2
Dextrorotation arginine phenylalanine Dmt lysine NH
2
Dextrorotation arginine lysine Dmt phenylalanine NH
2
Dextrorotation arginine lysine phenylalanine Dmt NH
2
Phenylalanine lysine Dmt dextrorotation arginine NH
2
Phenylalanine lysine dextrorotation arginine Dmt NH
2
Phenylalanine dextrorotation arginine Dmt lysine NH
2
Phenylalanine dextrorotation arginine lysine Dmt NH
2
Phenylalanine Dmt dextrorotation arginine lysine NH
2
Phenylalanine Dmt lysine dextrorotation arginine NH
2
Lysine phenylalanine dextrorotation arginine Dmt NH
2
Lysine phenylalanine Dmt dextrorotation arginine NH
2
Lysine Dmt dextrorotation arginine phenylalanine NH
2
Lysine Dmt phenylalanine dextrorotation arginine NH
2
Lysine dextrorotation arginine phenylalanine Dmt NH
2
Lysine dextrorotation arginine Dmt phenylalanine NH
2
Dextrorotation arginine Dmt dextrorotation arginine phenylalanine NH
2
Dextrorotation arginine Dmt dextrorotation arginine Dmt NH
2
Dextrorotation arginine Dmt dextrorotation arginine tyrosine NH
2
Dextrorotation arginine Dmt dextrorotation arginine tryptophan NH
2
Tryptophan dextrorotation arginine phenylalanine lysine NH
2
Tryptophan dextrorotation arginine tyrosine lysine NH
2
Tryptophan dextrorotation arginine tryptophan lysine NH
2
Tryptophan dextrorotation arginine Dmt lysine NH
2
Dextrorotation arginine tryptophan lysine phenylalanine NH
2
Dextrorotation arginine tryptophan phenylalanine lysine NH
2
Dextrorotation arginine tryptophan lysine Dmt NH
2
Dextrorotation arginine tryptophan Dmt lysine NH
2
Dextrorotation arginine lysine tryptophan phenylalanine NH
2
Dextrorotation arginine lysine tryptophan Dmt NH
2
Cha dextrorotation arginine phenylalanine lysine NH
2
Alanine dextrorotation arginine phenylalanine lysine NH
2
The Cha=cyclohexyl
Aminoacid in the peptide shown in table 1 and the table 2 both can be that the L-conformation also can be the D-conformation.
Therapeutic Method
Peptide mentioned above can be used for treating any disease or the disease relevant with MPT.These diseases and disease include but not limited to: the tissue or the ischemia of organ and/or perfusion again, any one in anoxia and the numerous neurodegenerative diseases.Need treatment or prevent that the mammal of MPT from being those mammals that suffer from these diseases or disease.
Ischemia in mammalian tissues or the organ is a kind of by oxygen lack (anoxia) and/or the caused many-sided pathological symptom of glucose (that is substrate) shortage.Oxygen among tissue or the organ cell and/or glucose lack and to cause the reduction of energy generative capacity or completely lose and the active ion that takes place is subsequently striden the forfeiture of the function of film transportation.Oxygen and/or glucose lack the pathological change that also can cause in other cell membrane, comprise the permeability changes in the mitochondrial membrane.The other molecule can be leaked in the Cytoplasm and causes apoptosis cell apoptosis (apoptotic cell death) as being closed in apoptotic proteins in the mitochondrion usually.Serious ischemia can cause necrocytosis.
Ischemia in particular organization or the organ or anoxia can be by to the forfeitures of the blood supply of this tissue or organ or seriously reduce and cause.The forfeiture of blood supply or serious minimizing can be caused by for example thromboembolia type apoplexy, coronary atherosclerosis or peripheral blood vessel.Be subjected to the normally muscle of organizing that ischemia or anoxia influence, as cardiac muscle, skeletal muscle or smooth muscle.
The organ that influenced by ischemia or anoxia can be to suffer ischemia or anoxybiotic any organ.Be subjected to the example of the organ that ischemia or anoxia influence to comprise brain, heart, kidney and prostate.For example, myocardial ischemia or anoxia are caused by arteriosclerosis or thrombus obstruction that normally the oxygen that they cause being transported to cardiac muscular tissue by heart arter and capillary blood supply reduces or forfeiture.Such myocardial ischemia or anoxia can cause affected myocardium pain and necrosis, and finally can cause heart failure.
Ischemia in skeletal muscle or the smooth muscle or anoxia can be caused by similar reason.For example, ischemia in intestinal smooth muscle or appendicular skeleton flesh or anoxia also can be caused by arteriosclerosis or thrombus obstruction.
Again perfusion be to reduce or any tissue of blocking blood flow or organ in recover blood flow.For example, can recover blood flow to any tissue or organ that influenced by ischemia or anoxia.The recovery of blood flow (perfusion again) can realize by any means well known by persons skilled in the art.For example, the perfusion again of ischemic heart tissue can or use thrombolytic drug to realize by angioplasty (reconstructive vascular operation), coronary bypass grafting.
The neurodegenerative diseases that method of the present invention can also be used for the treatment of or prevention is relevant with MPT.The neurodegenerative diseases relevant with MPT comprises: for example parkinson, Alzheimer, hungtington's chorea and amyotrophic lateral sclerosis disease (ALS is also referred to as Luo Gaihe league (unit of length) disease).Method of the present invention can be used to delay these relevant with MPT or the generation of other neurodegenerative diseases or its process that slows down.Method of the present invention is useful especially when early stage patient for the treatment of the neurodegenerative diseases relevant with MPT and susceptible personnel.
Useful peptide also can be used for preserving mammiferous organ among the present invention before transplanting.For example, isolated organ may be vulnerable to MPT owing to lack blood flow.Therefore, this Toplink is used for preventing MPT at isolated organ.
Isolated organ can be placed as those standard buffer solutions commonly used in the art.For example, isolated heart can place the cardioplegic solution that contains above-mentioned peptide.The concentration of peptide in standard buffer solution can be easy to be measured by those skilled in the art.For example, this concentration can be that about 0.1nM arrives between about 10 μ M, is preferably about 1 μ M to about 10 μ M.
This peptide can also give to carry out the mammal of Drug therapy disease and disease.If these side effects of pharmaceutical drugs comprise MPT, then using the mammal of this medicine will from peptide of the present invention, obtain great benefit.
By influencing the example that MPT comes the medicine of inducing cytotoxic is the chemotherapeutics amycin.
Synthesizing of skin
Peptide useful in the method for the present invention can come chemosynthesis by any method well known in the art.The suitable method of synthetic this albumen comprises: for example by Stuart and Young at " Solid Phase Peptide Systhesis; " second edition, Pierce Chemical Company (1984), and at " Solid Phase Peptide Systhesis, " Methods Enzymol.
289, the method described in the Academic Press, Inc, New York (1997).
Medication
In the method for the invention, useful peptide is suffered the quantity of mitochondrion MPT or stops the effective dose of MPT to give mammal with minimizing.This effective dose is examined the method that the doctor is familiar with and is measured with facing with the doctor in preclinical phase test and clinical trial.
In the method for the invention, the useful peptide of effective dose preferably in pharmaceutical composition, can have the mammal that needs by in the numerous known methods that give medical compounds any one.
This peptide can whole body administration or topical.In one embodiment, this peptide is an intravenous administration.For example, useful aromatic series cationic peptide can come administration by quick intravenous injection in the method for the present invention.Yet preferably this peptide comes administration in the mode of constant speed intravenous infusion.
This peptide can be injected directly in the coronary artery in for example angioplasty or coronary bypass, or is applied on the coronary stent.
This peptide also can be taken orally, topical, intranasal administration, intramuscular administration, subcutaneous administration or transdermal administration.In a preferred embodiment, the transdermal administration of the aromatic series cationic peptide in the inventive method realizes that by ionotherapy wherein charged peptide sees through skin by electric current and carries.
Other route of administration comprises Intraventricular or intrathecal drug delivery.The Intraventricular administration is meant in the chamber system that is administered to brain.Intrathecal drug delivery is meant in the subarachnoid gap that is administered to spinal cord.Therefore, Intraventricular or intrathecal drug delivery can be preferred for influencing the disease and the disease of central nervous system organ or tissue.In a preferred embodiment, intrathecal drug delivery is used for trauma of spinal cord.
Peptide useful in the method for the present invention can also give mammal by the mode that continues to discharge, and this is being known in the art.Sustained release administration is the medicament delivery method that reaches certain levels of drugs at special time period.This level is normally by serum or determination of plasma concentration.
Known any dosage form all is applicable to the administration of aromatic series cationic peptide useful in the method for the present invention in the pharmaceutical field.For oral administration, can use the liquid or solid dosage form.Some examples of dosage form comprise: tablet, gel capsule, pill, lozenge, elixir, suspensoid, syrup, wafer, chewing agent (chewing gum) or the like.This peptide can with well known to a person skilled in the art appropriate drug carrier (vehicle) or mixed with excipients.The example of carrier or excipient comprises: the clay of starch, milk, sucrose, some type, gel, lactic acid, stearic acid or its salt (comprising magnesium stearate or calcium stearate), Talcum, Vegetable oil lipoprotein or vegetable oil, natural gum and ethylene glycol.
For whole body administration, Intraventricular administration, intrathecal drug delivery, topical, intranasal administration, subcutaneous administration or transdermal administration, the dosage form of useful aromatic series cationic peptide can utilize traditional known diluent, carrier or excipient etc. as being used for this area to carry this peptide in the inventive method.For example, this dosage form can contain one or more following substances: stabilizing agent, surfactant is preferably non-ionic surface active agent, and optional salt and/or buffer.This peptide can be carried with the form of aqueous solution or dried frozen aquatic products.
Stabilizing agent can be, for example the such aminoacid of glycine; Or the oligosaccharide as sucrose, quaternary sugar, lactose or glucosan.Another kind of optionally scheme is, this stabilizing agent can be, for example the such sugar alcohol of mannitol; Or their compositions.Preferably, stabilizing agent or stabiliser compositions constituted peptide weight about 0.1% to about 10%.
Surfactant is preferably non-ionic surface active agent, as polysorbate.The example of suitable surfactant comprises: polysorbas20, Tween 80; Polyethylene Glycol or polyoxyethylene polyoxypropylene glycol (ether), 0.001% (w/v) is to the PluronicF-68 of about 10% (w/v) according to appointment.
Salt or buffer can be respectively any salt or buffer as sodium chloride or sodium phosphate/potassium.Preferably, buffer makes the pH of pharmaceutical composition maintain about 5.5 in about 7.5 scope.Salt and/or buffer also are used for Morie osmolarity is maintained the level that is suitable for to human or animal's administration.Preferably salt or buffer present the rough isotonic concentration of about 150 μ M to about 300 μ M.
In the method for the invention, the dosage form of useful peptide can contain one or more additives commonly used in addition.Some examples of these additives comprise: the solubilizing agent as glycerol; As benzalkonium chloride (mixture of quaternary ammonium compound is called " quaternary ammonium compound "), benzyl alcohol, chloretone or the such antioxidant of methaform; Anesthetis as morphine derivatives; Or above-mentioned isotonic agent etc.For further anti-oxidation or other corruption, this pharmaceutical composition can be encapsulated in the bottle with impervious stopper and preserve under nitrogen.
This mammal can be any mammal, comprises as farm-animals, as sheep, pig, cattle and horse; House pet is as Canis familiaris L. and cat; Laboratory animal is as rat, mice and rabbit.In a preferred embodiment, this mammal is the people.
Embodiment
Embodiment 1:[Dmt
1] the DALDA permeates cell membranes
Utilize human gut epithelial cell system (Caco-2) research [
3H] [Dmt
1] cell of DALDA takes in, and confirm with SH-SY5Y cell (human nerve's blastoma cell), HEK293 cell (human embryos nephrocyte) and CRFK cell (renal epithelial cell).Be coated with on 12 orifice plates of collagen (5 * 10
5Cells/well) cell monolayer was cultivated three days.At the 4th day, the HBSS washed twice cell with preheating contained 250nM[with 0.2ml then
3H] [Dmt
1] HBSS of DALDA hatches the different time until 1 hour in 37 ℃ or 4 ℃.
In the time of 5 minutes, in cell pyrolysis liquid, promptly can observe [
3H] [Dmt
1] DALDA, and in the time of 30 minutes, reach steady-state level.Hatch in cell pyrolysis liquid, reclaim after 1 hour [
3H] [Dmt
1] total amount of DALDA accounts for about 1% of total dose.Though [
3H] [Dmt
1] absorption of DALDA is slack-off during than 37 ℃ in the time of 4 ℃, but in the time of 45 minutes, can reach 76.5% and in the time of 1 hour, reach 86.3%.[
3H] [Dmt
1] internalization of DALDA is not limited to the Caco-2 cell, in SH-SY5Y cell, HEK293 cell and CRFK cell, also can observe.[
3H] [Dmt
1] IC of DALDA estimates about higher 50 times than EC.
In one independently tests, with [the Dmt of finite concentration scope (1 μ M-3mM)
1] DALDA is in 37 ℃ of following incubated cells 1 hour.After incubation period, finish, use HBSS washed cell 4 times, in each hole, add the 0.1N NaOH that 0.2ml contains 1%SDS.Then cellular content is transferred in the scintillation vial, and carried out radiocounting.For the radioactivity of internalization and the active area of surface combination are separated, introduced acid pickling step.Before lysis, with cell with 0.2M acetic acid/0.05M NaCl of 0.2ml in hatching 5 minutes on ice.
[Dmt
1] DALDA takes in the Caco-2 cell is to use a kind of [Dmt by confocal laser scanning microscope, CLSM (CLSM)
1] fluorescence analog (Dmt-dextrorotation arginine-phenylalanine-dnsDap-NH of DALDA
2) confirm; Wherein dnsDap is β-dansyl-1-α, β-diaminopropionic acid).Cell culture as previously mentioned, and on culture dish at the bottom of (35mm) glass (MatTek Corp., Ashland, MA) tiling two days.Discard culture fluid (base), cell was hatched 1 hour in 37 ℃ with the HBSS that 1ml contains 0.1 this fluorescence peptide analogues of μ M to 1.0 μ M.Use ice-cold HBSS washed cell 3 times then, and cover with the PBS of 200 μ l, then under the room temperature with have C-apochromatism 63 */Nikon confocal laser scanning microscope, CLSM that 1.2W proofreaies and correct object lens finished micro-imaging in 10 minutes.Excite by UV laser at 340nm, and measure emission light in the 520nm place.In order to carry out the optical fault micro-imaging on the Z-direction, per 2.0 μ m are cut the 5-10 frame.
CLSM has confirmed the [Dmt with 0.1 μ M
1, DnsDap
4] DALDA in 37 ℃ hatch 1 hour after, fluorescence Dmt-dextrorotation arginine-phenylalanine-dnsDap-NH
2Take in the Caco-2 cell.The absorption of fluorescence peptide is similar in the time of 37 ℃ and 4 ℃ the time.Though fluorescence diffusion occurred in whole kytoplasm, but be excluded in outside the nucleus fully.
Embodiment 2:[Dmt
1] the DALDA targeting navigates to mitochondrion
In order to detect [Dmt
1] subcellular fraction of DALDA distributes preparation fluorescence analog [Dmt
1, AtnDap
4] DALDA (Dmt-dextrorotation arginine-phenylalanine-atnDap-NH
2Wherein atn is β-o-amino benzoyl acyl group-1-α, β-diaminopropionic acid).This analog contains β-anthraniloyl-1-α, and β-diaminopropionic acid is with the lysine residue on the alternative site 4.Cell culture is as described in the embodiment 1, and at the bottom of (35mm) glass culture dish (MatTek Corp., Ashland MA) go up tiling 2 days.Discard culture fluid, and contain 0.1 μ M[Dmt with 1ml
1, AtnDap
4] HBSS of DALDA is in 37 ℃ of incubated cells 15 minutes to 1 hour.
Cell also can be used the tetramethylrhodamin methyl ester, and (TMRM 25nM), a kind of dyes mitochondrial dyestuff, hatches 15 minutes under 37 ℃.Use ice-cold HBSS washed cell 3 times then, and cover with the PBS of 200 μ l, and under the room temperature with have C-apochromatism 63 */Nikon confocal laser scanning microscope, CLSM that 1.2W proofreaies and correct object lens finished micro-imaging in 10 minutes.
For [Dmt
1, AtnDap
4] DALDA, excite in the 350nm place by the UV laser instrument, measure emission light at the 520nm place.For TMRM, excite at the 536nm place, and measure emission light in the 560nm place.
37 ℃ hatch at least 15 minutes after, CLSM shows fluorescence [Dmt
1, AtnDap
4] DALDA takes in the Caco-2 cell.Though the absorption of dyestuff is got rid of outside nucleus fully,, this blue dyes distributes yet demonstrating striated in Cytoplasm.With TMRM mitochondrion is marked as redness.By stack [Dmt
1, AtnDap
4] distribution of DALDA and the distribution of TMRM show [Dmt
1, AtnDap
4] mitochondrion of DALDA distributes.
Embodiment 3:[Dmt
1] DALDA takes in the mitochondrion
For separate mitochondria from Hepar Mus, put to death mice by decapitation.Liver is taken out and places fast refrigerative liver homogenate liquid.With shears mouse liver is cut into tiny fragment, then with the manual homogenate of glass homogenizer.
With homogenate under 4 ℃, 1000 * g centrifugal 10 minutes.The sucking-off supernatant is also transferred in the Merlon pipe, and recentrifuge is 10 minutes under 4 ℃, 3000 * g.Abandoning supernatant, and carefully remove the oils and fats of managing on the sidewall.
To precipitate resuspending in liver homogenate liquid, and twice of homogenate repeatedly.The mitochondrion of final purification is precipitated resuspending in homogenate.Protein concentration in the mitochondrion preparation process detects with the Bradford method.
To use at the mitochondrion of the about 1.5mg in the 400 μ l buffer [
3H] [Dmt
1] DALDA hatched 5-30 minute in 37 ℃.Get off mitochondrion is centrifugal then, measure radioactive amount of mitochondrion part and buffer section.Suppose that the mitochondrial matrix volume is 0.7 μ l/mg albumen (Lim et al., J.Physiol 545:961-974,2002), then find [
3H] [Dmt
1] high 200 times in the concentration ratio buffer of DALDA in mitochondrion.Therefore, [Dmt
1] DALDA obtained concentrating in mitochondrion.
Based on these data, when using [Dmt
1] when DALDA pours into the guinea pig heart that exsomatizes, [Dmt
1] concentration of DALDA in mitochondrion can be estimated as:
[Dmt
1] the concentration 0.1 μ M of DALDA in coronary perfusion liquid
[Dmt
1] the concentration 5 μ Ms of DALDA in the myocyte
[Dmt
1] the concentration 1.0mM of DALDA in mitochondrion
Embodiment 4:Separated mitochondrion is to [Dmt
1] the gathering of DALDA (Fig. 1)
In order further to prove [Dmt
1] DALDA is that selectivity is distributed in the mitochondrion, we have detected [Dmt
1, AtnDap
4] DALDA and [
3H] [Dmt
1] DALDA picked-up enters the dirty mitochondrial situation of separated Hepar Mus.Can observe the rapid cancellation of fluorescence after adding mitochondrion, show [Dmt
1, AtnDap
4] the quick picked-up (Figure 1A) of DALDA.Can cause the rapid unpolarized uncoupling agents FCCP of mitochondrion (right-(trifluoromethoxy)-phenylhydrazone carbonyl cyanide) pretreatment mitochondrion, [Dmt with a kind of
1, AtnDap
4] picked-up of DALDA only reduces<20%.Therefore, [Dmt
1, AtnDap
4] picked-up of DALDA is not potential dependent.
In order to confirm that Mitochondrially targeted location is not the artefact (artifact) of fluorogen, we also detected [
3H] [Dmt
1] mitochondrion of DALDA takes in.Separated mitochondrion usefulness [
3H] [Dmt
1] DALDA hatches, and in mitochondrion precipitation and supernatant detection of radioactive.From 2 minutes to 8 minutes, the radioactive amount in the precipitation did not change.The mitochondrion of handling with FCCP only reduced be connected with the mitochondrion precipitation [
3H] [Dmt
1] the DALDA amount~20% (Figure 1B).
FCCP is to [Dmt
1] the faint influence of DALDA picked-up shows: [Dmt
1] DALDA may be connected with mitochondrial membrane or be arranged in intermembranous gap rather than be positioned at substrate.We are subsequently by using alamethicin to detect mitochondrial swelling to [Dmt to induce swelling and outer membrane rupture
1, AtnDap
4] influence in mitochondrion, gathered of DALDA.Different with TMRM, [Dmt
1] DALDA absorption only part reversed (Fig. 1 C) by mitochondrial swelling.Therefore, [Dmt
1] DALDA is connected with mitochondrial membrane.
Embodiment 5:[Dmt
1] DALDA do not change mitochondrial respiratory or current potential (Fig. 1 D)
[Dmt
1] DALDA gathering in mitochondrion do not change mitochondrial function.[Dmt with 100 μ M
1] DALDA hatches the dirty mitochondrion of separated Hepar Mus and do not change the oxygen consumption in stage 3 and stages 4 process or change breathing rate (3/ stage 4 of stage) (6.2/6.0).Mitochondrial membrane potential is measured (Fig. 1 D) with TMRM.Add mitochondrion and cause the rapid cancellation of TMRM signal, this signal shows mitochondrial depolarization by adding FCCP quick-recovery soon.Add Ca
2+(150 μ M) causes rapid depolarization, simultaneous progressively to lose the cancellation indication of MPT.Add [Dmt separately
1] DALDA, even when 200 μ M, do not cause mitochondrial depolarization or MPT yet.
Embodiment 6:[Dmt
1] DALDA protective wire plastochondria avoids by Ca
2+With the inductive MPT of 3-nitropropionic acid (Fig. 2)
Except mitochondrial membrane potential not being had the direct influence [Dmt
1] DALDA can also the protective wire plastochondria avoids because Ca
2+The MPT that overload causes.Adding Ca
2+Before, with [Dmt
1] the separated mitochondrion of DALDA (10 μ M) pretreatment 2 minutes, only cause of short duration depolarization to stop the beginning (Fig. 2 A) of MPT simultaneously.[Dmt
1] the DALDA dose dependent increased the Ca of mitochondrion to accumulation
2+The tolerance that stimulates.Fig. 2 B shows [Dmt
1] DALDA increased the Ca of the adding that separated mitochondrion can tolerate before MPT
2+Amount.
3-nitropropionic acid (3NP) is a kind of irreversible inhibitor of the succinate dehydrogenase among the electron transport chain complex II.In separated mitochondrion, add 3NP (1mM) and caused the decline of mitochondrion current potential, and caused the beginning (Fig. 2 C) of MPT.With [Dmt
1] DALDA pretreatment mitochondrion dose dependent ground delayed the beginning (Fig. 3 C) by the inductive MPT of 3NP.
In order to prove [Dmt
1] DALDA can pass cell membrane and protective wire plastochondria and avoid the mitochondrial depolarization that caused by 3NP, do not have or exist [Dmt
1] handled the Caco-2 cell 4 hours with 3NP (10mM) under the situation of DALDA (0.1 μ M), hatch with TMRM then and under LSCM, detect.In control cells, can be clear that mitochondrion presents the stria shape in whole Cytoplasm.In the cell of handling with 3NP, TMRM fluorescence significantly reduces, and shows general depolarization.In contrast, use [Dmt simultaneously
1] DALDA handles, the protective wire plastochondria is avoided the mitochondrial depolarization that caused by 3NP.
Embodiment 7:[Dmt
1] DALDA protective wire plastochondria avoids mitochondrial swelling and cytochrome C discharges
The opening of MPT hole causes mitochondrial swelling.We are by measuring the 540nm absorbance (A of place
540) reduction detect [Dmt
1] DALDA is to the influence of mitochondrial swelling.Then that mitochondrial suspension is centrifugal, and with the cytochrome C in the ELISA test kit detection line plastochondria that is purchased precipitation and the supernatant.Suppressed by Ca with the separated mitochondrion of SS-02 pretreatment
2+Transship caused swelling (Fig. 3 A) and and the release (Fig. 3 B) of cytochrome C.Except suppressing by Ca
2+Transship caused MPT, SS-02 can also suppress by MPP
+The mitochondrial swelling that (1-methyl-4-phenylpyridinium (phenylpyridium) ion) causes, MPP
+It is a kind of inhibitor (Fig. 3 C) of the complex I of mitochondrion electron transport chain.
Embodiment 8:Dextrorotation arginine-Dmt-lysine-phenylalanine-NH
2(D-Arg-Dmt-Lys-Phe-NH
2) (SS-31) can avoid MPT, mitochondrial swelling and cytochrome C release by the protective wire plastochondria.
Non-opioid peptide SS-21 has same protective wire plastochondria and avoids by Ca
2+The MPT that causes (Fig. 4 A), mitochondrial swelling (Fig. 4 B) and cytochrome C discharge the ability of (Fig. 4 C).Research method such as preceding research method to SS-02.In the present embodiment, mitochondrial swelling detects by the light scattering at monitoring 570nm place.
Embodiment 9:[Dmt
1] DALDA (SS-02) and dextrorotation arginine-Dmt-lysine-phenylalanine-NH
2(D-Arg-Dmt-Lys-Phe-NH
2) (SS-31) protect cardiac muscle to avoid by the caused myocardial stunning of ischemia-reperfusion.
The sharp separation guinea pig heart, intubate is also poured in the mode of driving in the wrong direction in 34 ℃ with the Krebs-Henseleit solution (pH7.4) of oxidation to aorta in position subsequently.With the heart excision, place on improved Langendorff perfusion equipment then, and perfusion (40cm water column) under constant voltage.Be inserted into the hooklet of the left ventricle apex of the heart and the silk ribbon that firmly is connected on power-displacement transducer (pick off) is measured contractility with one.Coronary flow detects by regularly collecting Pulmonic effluent.
With heart buffer, [Dmt
1] DALDA (SS-02) (100nM) or dextrorotation arginine-Dmt-lysine-phenylalanine-NH
2(D-Arg-Dmt-Lys-Phe-NH
2) (SS-31) (1nM) perfusion 30 minutes, carry out 30 minutes whole body ischemia then.Pour into again with employed same solution before the ischemia.
Two-way analysis of variance demonstrates three processed group and (has significant difference aspect P<0.001=), heart rate (P=0.003) and the coronary artery flow velocity (P<0.001) at contractility.In the buffer group, contractility reduces (Fig. 5) before than ischemia greatly between flush phase again.The heart of handling with SS-02 and SS-31 has much better ischemia tolerance (Fig. 5) than the heart of handling with buffer.Especially SS-31 can suppress heart fully and pauses and press down.In addition, the coronary artery flow velocity has kept stable well in dabbling whole process again, does not have heart rate to reduce.
Embodiment 10:[Dmt
1] DALDA (SS-02) improved the organ preservation
For heart transplantation, in transportation, donor's heart is kept in the cardioplegic solution.This preservation liquid contains high potassium, can stop heartbeat effectively and preserve energy.Yet the time-to-live of isolated heart remains very limited.
We are to [Dmt
1] the DALDA survival that whether prolongs organ tests.In these researchs, with [Dmt
1] DALDA joins (St.Thomas) in the cardioplegic solution commonly used and detect after the ischemia that prolongs, [Dmt
1] whether DALDA can improve the survival (model of the external survival of intracorporeal organ) of heart.
Separated guinea pig heart pours in the mode of driving in the wrong direction in 34 ℃ with the Krebs-Henseleit solution of oxidation.After stablizing 30 minutes, heart is with containing or do not contain 100nM[Dmt
1] cardioplegic solution CPS (St.Tohomas) perfusion 3 minutes of DALDA.Then by blocking coronary perfusion 90 minutes fully to cause the whole body ischemia.Krebs-Henseleit solution with oxidation carries out 60 minutes and reperfusion subsequently.Continuous monitoring contractility, heart rate and coronary artery flow velocity in the whole test.
Add [Dmt in the cardioplegic solution
1] DALDA significantly improved the contractile function (Fig. 6) after the ischemia that prolongs.
Claims (30)
1. the aromatic series cationic peptide is used for having the mammal of needs to reduce the mitochondrion quantity of experience mitochondrial permeability transition (MPT) or prevents application in the medicine of mitochondrial permeability transition in preparation, wherein, give the described aromatic series cationic peptide of described mammal effective dose, described peptide is represented by following any molecular formula: D-arginine-2 ', 6 '-dimethyl tyrosine-lysine-phenylalanine-NH
2, 2 ', 6 '-dimethyl tyrosine-D-arginine-phenylalanine-lysine-NH
2(Dmt
1-DALDA).
2. application according to claim 1, the administration of wherein said peptide oral administration.
3. application according to claim 1, wherein said peptide is through topical.
4. application according to claim 1, wherein said peptide intranasal administration.
5. application according to claim 1, wherein said peptide is through the whole body administration.
6. application according to claim 3, wherein said peptide is through intravenous administration.
7. application according to claim 1, wherein said peptide is through subcutaneous administration.
8. application according to claim 1, wherein said peptide is through the intramuscular administration.
9. application according to claim 1, wherein said peptide is through the Intraventricular administration.
10. application according to claim 1, wherein said peptide is through intrathecal drug delivery.
11. application according to claim 1, wherein said peptide is through transdermal administration.
12. application according to claim 11, wherein said transdermal administration adopts ionotherapy.
13. application according to claim 1, wherein said mammal is being stood ischemia.
14. application according to claim 1, wherein said mammal are standing to pour into again.
15. application according to claim 1, wherein said mammal is being stood anoxia.
16. application according to claim 13, wherein said ischemia is caused by apoplexy.
17. application according to claim 13, wherein said ischemia are the intestinal ischemia.
18. application according to claim 13, wherein said ischemia is present in the muscular tissue.
19. application according to claim 18, wherein said muscular tissue is cardiac muscular tissue.
20. application according to claim 18, wherein said muscular tissue is skeletal muscle tissue.
21. application according to claim 18, wherein said muscular tissue is smooth muscle tissue.
22. application according to claim 1, wherein said mammal is being stood anoxia.
23. application according to claim 1, wherein said mammal is suffering from neurodegenerative diseases or disease.
24. application according to claim 23, wherein said neurodegenerative diseases or disease are Parkinson's diseases.
25. application according to claim 23, wherein said neurodegenerative diseases or disease are Alzheimer's disease.
26. application according to claim 23, wherein said neurodegenerative diseases or disease are Heng Tingdunshi diseases.
27. application according to claim 23, wherein said neurodegenerative diseases or disease are amyotrophic lateral sclerosis (ALS).
28. application according to claim 1, wherein said mammal is being stood drug-induced MPT.
29. according to the described application of claim 1, wherein said mammal is human.
30. method that in mammiferous isolated organ, reduces the mitochondrion quantity of experience mitochondrial permeability transition (MPT) or stop mitochondrial permeability transition, described method comprises the aromatic series cationic peptide that gives described isolated organ effective dose, described peptide is represented by following any molecular formula: D-arginine-2 ', 6 '-dimethyl tyrosine-lysine-phenylalanine-NH
2, 2 ', 6 '-dimethyl tyrosine-D-arginine-phenylalanine-lysine-NH
2(Dmt
1-DALDA).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410412683.1A CN104225574B (en) | 2003-02-04 | 2004-02-03 | Methods for preventing mitochondrial permeability transition |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US44477703P | 2003-02-04 | 2003-02-04 | |
US60/444,777 | 2003-02-04 | ||
US60/535,690 | 2004-01-08 |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410412683.1A Division CN104225574B (en) | 2003-02-04 | 2004-02-03 | Methods for preventing mitochondrial permeability transition |
CN201210177633.0A Division CN102784383B (en) | 2003-02-04 | 2004-02-03 | Methods for preventing mitochondrial permeability transition |
CN2012100218642A Division CN102617706A (en) | 2003-02-04 | 2004-02-03 | Methods for preventing mitochondrial permeability transition |
CN2008101770569A Division CN101440124B (en) | 2003-02-04 | 2004-02-03 | Methods for preventing mitochondrial permeability transition |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1787831A CN1787831A (en) | 2006-06-14 |
CN100536909C true CN100536909C (en) | 2009-09-09 |
Family
ID=36784999
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008101770569A Expired - Lifetime CN101440124B (en) | 2003-02-04 | 2004-02-03 | Methods for preventing mitochondrial permeability transition |
CNB2004800092972A Expired - Lifetime CN100536909C (en) | 2003-02-04 | 2004-02-03 | Methods for preventing mitochondrial permeability transition |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008101770569A Expired - Lifetime CN101440124B (en) | 2003-02-04 | 2004-02-03 | Methods for preventing mitochondrial permeability transition |
Country Status (2)
Country | Link |
---|---|
CN (2) | CN101440124B (en) |
SI (1) | SI1599216T1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103764159A (en) * | 2011-06-14 | 2014-04-30 | 康肽德生物医药技术有限公司 | Aromatic-cationic peptides and uses of same |
CN102784383B (en) * | 2003-02-04 | 2014-09-17 | 科内尔研究基金会 | Methods for preventing mitochondrial permeability transition |
CN104105499A (en) * | 2011-12-09 | 2014-10-15 | 康肽德生物医药技术有限公司 | Aromatic-cationic peptides and uses of same |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014520246A (en) * | 2011-03-24 | 2014-08-21 | コーネル ユニヴァーシティー | Aromatic cationic peptides and uses thereof |
US9988422B2 (en) | 2011-09-29 | 2018-06-05 | Stealth Biotherapeutics Corp | Aromatic-cationic peptides and methods for using same |
JP6346092B2 (en) * | 2011-10-17 | 2018-06-20 | コーネル ユニヴァーシティー | Aromatic cationic peptides and uses thereof |
EP3170506B1 (en) * | 2012-03-30 | 2018-05-16 | Stealth Peptides International, Inc. | Methods and compositions for the prevention and treatment neuropathy |
CA2916884C (en) * | 2013-03-01 | 2021-02-09 | Stealth Biotherapeutics Corp | Methods for the treatment of mitochondrial disease |
CN115990242A (en) | 2013-03-01 | 2023-04-21 | 康德生物医疗有限公司 | Methods and compositions for preventing or treating Bass syndrome |
AU2014324580B2 (en) * | 2013-09-30 | 2020-02-27 | Cornell University | Cardiolipin-targeted peptides inhibit beta-amyloid oligomer toxicity |
MX2023002772A (en) * | 2020-09-09 | 2024-04-05 | Social Profit Network | Methods and compositions for delivery of biotin to mitochondria. |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2329709A1 (en) * | 1998-04-24 | 1999-11-04 | Mitokor | Compounds and methods for treating mitochondria-associated diseases |
US6472378B2 (en) * | 1998-08-31 | 2002-10-29 | Pro-Neuron, Inc. | Compositions and methods for treatment of mitochondrial diseases |
-
2004
- 2004-02-03 CN CN2008101770569A patent/CN101440124B/en not_active Expired - Lifetime
- 2004-02-03 SI SI200432120T patent/SI1599216T1/en unknown
- 2004-02-03 CN CNB2004800092972A patent/CN100536909C/en not_active Expired - Lifetime
Non-Patent Citations (3)
Title |
---|
A highly potent peptide analgesic that protectsagainstischemia-reperfusion-induced myocardial stunning. WU ET AL.AM. J. PHYSIOL. HEART CIRC. PHYSIOL.,Vol.283 . 2002 |
A highly potent peptide analgesic that protectsagainstischemia-reperfusion-induced myocardial stunning. WU ET AL.AM. J. PHYSIOL. HEART CIRC. PHYSIOL.,Vol.283. 2002 * |
nhibition of the mitochondrial permeability transitionbycyclosporin A during long time frame eperiments:Relationshipbetween pore opening and the activity ofmictochondrialphospholipases. BROEKEMEIER ET AL.BIOCHEMISTRY,Vol.34 . 1995 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102784383B (en) * | 2003-02-04 | 2014-09-17 | 科内尔研究基金会 | Methods for preventing mitochondrial permeability transition |
CN103764159A (en) * | 2011-06-14 | 2014-04-30 | 康肽德生物医药技术有限公司 | Aromatic-cationic peptides and uses of same |
CN104105499A (en) * | 2011-12-09 | 2014-10-15 | 康肽德生物医药技术有限公司 | Aromatic-cationic peptides and uses of same |
Also Published As
Publication number | Publication date |
---|---|
SI1599216T1 (en) | 2014-02-28 |
CN1787831A (en) | 2006-06-14 |
CN101440124B (en) | 2012-07-18 |
CN101440124A (en) | 2009-05-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102784383B (en) | Methods for preventing mitochondrial permeability transition | |
US20230149501A1 (en) | Methods for reducing oxidative damage | |
CN100536909C (en) | Methods for preventing mitochondrial permeability transition | |
AU2012202035B2 (en) | Methods for reducing CD36 expression | |
AU2018200395A1 (en) | Methods for reducing cd36 expression |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1090571 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1090571 Country of ref document: HK |
|
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20090909 |