DK3063168T3

DK3063168T3 - NEURO PROTECTIVE PEPTIDES

NEURO PROTECTIVE PEPTIDES Download PDF

Info

Publication number: DK3063168T3
Authority: DK; Denmark
Prior art keywords: peptide; peptides; arg arg; protamine; tat
Prior art date: 2013-10-30

Application number

DK14858082.2T

Other languages

Danish (da)

English (en)

Inventor

Bruno Meloni

Original Assignee

Univ Western Australia

Priority date

2013-10-30

Filing date

2014-10-30

Publication date

2019-04-15

2013-10-30 Priority claimed from AU2013904197A external-priority patent/AU2013904197A0/en

2014-10-30 Application filed by Univ Western Australia filed Critical Univ Western Australia

2019-04-15 Application granted granted Critical

2019-04-15 Publication of DK3063168T3 publication Critical patent/DK3063168T3/en

Links

108090000765 processed proteins & peptides Proteins 0.000 title claims description 527
102000004196 processed proteins & peptides Human genes 0.000 title claims description 234
230000000324 neuroprotective effect Effects 0.000 title claims description 108
230000001537 neural effect Effects 0.000 claims description 185
239000004220 glutamic acid Substances 0.000 claims description 135
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 132
235000013922 glutamic acid Nutrition 0.000 claims description 131
238000011282 treatment Methods 0.000 claims description 108
210000004027 cell Anatomy 0.000 claims description 55
239000008194 pharmaceutical composition Substances 0.000 claims description 53
208000028867 ischemia Diseases 0.000 claims description 52
239000000203 mixture Substances 0.000 claims description 34
238000000034 method Methods 0.000 claims description 32
210000002569 neuron Anatomy 0.000 claims description 29
108010011110 polyarginine Proteins 0.000 claims description 28
239000003814 drug Substances 0.000 claims description 27
208000006011 Stroke Diseases 0.000 claims description 26
125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 25
150000007523 nucleic acids Chemical class 0.000 claims description 18
208000024827 Alzheimer disease Diseases 0.000 claims description 17
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 17
239000011575 calcium Substances 0.000 claims description 17
102000040430 polynucleotide Human genes 0.000 claims description 17
108091033319 polynucleotide Proteins 0.000 claims description 17
239000002157 polynucleotide Substances 0.000 claims description 17
208000018737 Parkinson disease Diseases 0.000 claims description 16
VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 claims description 16
VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 claims description 16
229950006874 kainic acid Drugs 0.000 claims description 16
206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 15
229910052791 calcium Inorganic materials 0.000 claims description 15
102000039446 nucleic acids Human genes 0.000 claims description 15
108020004707 nucleic acids Proteins 0.000 claims description 15
230000002265 prevention Effects 0.000 claims description 15
230000002829 reductive effect Effects 0.000 claims description 13
206010015037 epilepsy Diseases 0.000 claims description 12
230000016273 neuron death Effects 0.000 claims description 12
230000030833 cell death Effects 0.000 claims description 11
208000020431 spinal cord injury Diseases 0.000 claims description 11
208000023105 Huntington disease Diseases 0.000 claims description 9
125000000539 amino acid group Chemical group 0.000 claims description 9
230000009460 calcium influx Effects 0.000 claims description 9
230000001419 dependent effect Effects 0.000 claims description 9
229940079593 drug Drugs 0.000 claims description 9
230000001413 cellular effect Effects 0.000 claims description 8
230000004898 mitochondrial function Effects 0.000 claims description 7
201000006417 multiple sclerosis Diseases 0.000 claims description 7
208000033808 peripheral neuropathy Diseases 0.000 claims description 7
230000004083 survival effect Effects 0.000 claims description 7
102000004961 Furin Human genes 0.000 claims description 6
108090001126 Furin Proteins 0.000 claims description 6
208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 claims description 6
208000033300 perinatal asphyxia Diseases 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
108010001857 Cell Surface Receptors Proteins 0.000 claims description 5
102000006437 Proprotein Convertases Human genes 0.000 claims description 5
108010044159 Proprotein Convertases Proteins 0.000 claims description 5
210000001700 mitochondrial membrane Anatomy 0.000 claims description 5
230000006576 neuronal survival Effects 0.000 claims description 5
239000013598 vector Substances 0.000 claims description 5
208000004296 neuralgia Diseases 0.000 claims description 3
208000021722 neuropathic pain Diseases 0.000 claims description 3
230000000295 complement effect Effects 0.000 claims description 2
239000002299 complementary DNA Substances 0.000 claims description 2
230000001159 endocytotic effect Effects 0.000 claims description 2
230000003902 lesion Effects 0.000 claims 3
125000002038 D-arginyl group Chemical group N[C@@H](C(=O)*)CCCNC(=N)N 0.000 claims 2
125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 claims 2
206010008190 Cerebrovascular accident Diseases 0.000 claims 1
102000006240 membrane receptors Human genes 0.000 claims 1
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 164
102000007327 Protamines Human genes 0.000 description 142
108010007568 Protamines Proteins 0.000 description 142
229940048914 protamine Drugs 0.000 description 142
230000035899 viability Effects 0.000 description 130
230000000052 comparative effect Effects 0.000 description 93
208000014674 injury Diseases 0.000 description 65
230000006378 damage Effects 0.000 description 64
208000027418 Wounds and injury Diseases 0.000 description 63
230000003492 excitotoxic effect Effects 0.000 description 53
235000001014 amino acid Nutrition 0.000 description 50
229940024606 amino acid Drugs 0.000 description 48
231100000063 excitotoxicity Toxicity 0.000 description 43
108010051109 Cell-Penetrating Peptides Proteins 0.000 description 41
102000020313 Cell-Penetrating Peptides Human genes 0.000 description 41
150000001413 amino acids Chemical class 0.000 description 40
238000000338 in vitro Methods 0.000 description 40
230000004112 neuroprotection Effects 0.000 description 38
239000004475 Arginine Substances 0.000 description 36
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 36
229930195712 glutamate Natural products 0.000 description 33
125000005647 linker group Chemical group 0.000 description 30
108010068380 arginylarginine Proteins 0.000 description 27
229920001184 polypeptide Polymers 0.000 description 27
235000018102 proteins Nutrition 0.000 description 23
102000004169 proteins and genes Human genes 0.000 description 23
108090000623 proteins and genes Proteins 0.000 description 23
238000002474 experimental method Methods 0.000 description 22
QVVDVENEPNODSI-BTNSXGMBSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylidene Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O QVVDVENEPNODSI-BTNSXGMBSA-N 0.000 description 21
210000004556 brain Anatomy 0.000 description 21
230000001965 increasing effect Effects 0.000 description 21
238000007792 addition Methods 0.000 description 20
230000000302 ischemic effect Effects 0.000 description 18
102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 17
108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 17
239000003431 cross linking reagent Substances 0.000 description 17
230000006870 function Effects 0.000 description 17
238000011534 incubation Methods 0.000 description 17
108010043655 penetratin Proteins 0.000 description 17
-1 TRMP2/7 Proteins 0.000 description 16
XLIJUKVKOIMPKW-BTVCFUMJSA-N [O].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O Chemical compound [O].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O XLIJUKVKOIMPKW-BTVCFUMJSA-N 0.000 description 16
210000001130 astrocyte Anatomy 0.000 description 16
230000003833 cell viability Effects 0.000 description 16
231100000673 dose–response relationship Toxicity 0.000 description 16
MCYTYTUNNNZWOK-LCLOTLQISA-N penetratin Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 MCYTYTUNNNZWOK-LCLOTLQISA-N 0.000 description 16
HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 15
125000003275 alpha amino acid group Chemical group 0.000 description 15
230000000254 damaging effect Effects 0.000 description 15
230000002401 inhibitory effect Effects 0.000 description 15
XPSGESXVBSQZPL-SRVKXCTJSA-N Arg-Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XPSGESXVBSQZPL-SRVKXCTJSA-N 0.000 description 14
102000007590 Calpain Human genes 0.000 description 14
108010032088 Calpain Proteins 0.000 description 14
102000018899 Glutamate Receptors Human genes 0.000 description 14
108010027915 Glutamate Receptors Proteins 0.000 description 14
GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 14
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
201000006474 Brain Ischemia Diseases 0.000 description 13
208000015474 Central precocious puberty Diseases 0.000 description 13
206010008120 Cerebral ischaemia Diseases 0.000 description 13
208000037064 Papilloma of choroid plexus Diseases 0.000 description 13
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
206010008118 cerebral infarction Diseases 0.000 description 13
239000006144 Dulbecco’s modiﬁed Eagle's medium Substances 0.000 description 12
HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 12
108010088535 Pep-1 peptide Proteins 0.000 description 12
229960002897 heparin Drugs 0.000 description 12
229920000669 heparin Polymers 0.000 description 12
230000003834 intracellular effect Effects 0.000 description 12
102000002274 Matrix Metalloproteinases Human genes 0.000 description 11
108010000684 Matrix Metalloproteinases Proteins 0.000 description 11
241001465754 Metazoa Species 0.000 description 11
102000035195 Peptidases Human genes 0.000 description 11
108091005804 Peptidases Proteins 0.000 description 11
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 11
208000029028 brain injury Diseases 0.000 description 11
210000002889 endothelial cell Anatomy 0.000 description 11
238000009472 formulation Methods 0.000 description 11
229910021653 sulphate ion Inorganic materials 0.000 description 11
IAWXTSMHXFRLQR-UHFFFAOYSA-N 2,3-bis($l^{1}-oxidanyl)-7-nitroquinoxaline-6-carbonitrile Chemical compound O=C1C(=O)N=C2C=C(C#N)C([N+](=O)[O-])=CC2=N1 IAWXTSMHXFRLQR-UHFFFAOYSA-N 0.000 description 10
206010008089 Cerebral artery occlusion Diseases 0.000 description 10
210000003169 central nervous system Anatomy 0.000 description 10
231100000318 excitotoxic Toxicity 0.000 description 10
230000007246 mechanism Effects 0.000 description 10
201000007309 middle cerebral artery infarction Diseases 0.000 description 10
230000004224 protection Effects 0.000 description 10
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 9
241000700159 Rattus Species 0.000 description 9
238000002835 absorbance Methods 0.000 description 9
208000035475 disorder Diseases 0.000 description 9
238000002360 preparation method Methods 0.000 description 9
102000005962 receptors Human genes 0.000 description 9
108020003175 receptors Proteins 0.000 description 9
231100000419 toxicity Toxicity 0.000 description 9
230000001988 toxicity Effects 0.000 description 9
239000003981 vehicle Substances 0.000 description 9
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
108010076667 Caspases Proteins 0.000 description 8
102000011727 Caspases Human genes 0.000 description 8
206010061216 Infarction Diseases 0.000 description 8
108010038807 Oligopeptides Proteins 0.000 description 8
102000015636 Oligopeptides Human genes 0.000 description 8
241000277329 Oncorhynchus keta Species 0.000 description 8
239000004365 Protease Substances 0.000 description 8
210000000170 cell membrane Anatomy 0.000 description 8
150000001875 compounds Chemical class 0.000 description 8
230000001054 cortical effect Effects 0.000 description 8
230000007574 infarction Effects 0.000 description 8
208000037906 ischaemic injury Diseases 0.000 description 8
238000004519 manufacturing process Methods 0.000 description 8
235000002639 sodium chloride Nutrition 0.000 description 8
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 7
231100000070 MTS assay Toxicity 0.000 description 7
238000000719 MTS assay Methods 0.000 description 7
230000001154 acute effect Effects 0.000 description 7
230000008499 blood brain barrier function Effects 0.000 description 7
210000001218 blood-brain barrier Anatomy 0.000 description 7
239000003112 inhibitor Substances 0.000 description 7
239000004090 neuroprotective agent Substances 0.000 description 7
230000037361 pathway Effects 0.000 description 7
230000000149 penetrating effect Effects 0.000 description 7
239000011780 sodium chloride Substances 0.000 description 7
239000000243 solution Substances 0.000 description 7
230000026683 transduction Effects 0.000 description 7
238000010361 transduction Methods 0.000 description 7
102000001671 Acid Sensing Ion Channels Human genes 0.000 description 6
108010068806 Acid Sensing Ion Channels Proteins 0.000 description 6
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
102000004190 Enzymes Human genes 0.000 description 6
108090000790 Enzymes Proteins 0.000 description 6
102000001794 Sodium-Calcium Exchanger Human genes 0.000 description 6
108010040240 Sodium-Calcium Exchanger Proteins 0.000 description 6
230000004913 activation Effects 0.000 description 6
239000002671 adjuvant Substances 0.000 description 6
210000004369 blood Anatomy 0.000 description 6
239000008280 blood Substances 0.000 description 6
230000037396 body weight Effects 0.000 description 6
125000002091 cationic group Chemical group 0.000 description 6
230000002490 cerebral effect Effects 0.000 description 6
239000003937 drug carrier Substances 0.000 description 6
230000000694 effects Effects 0.000 description 6
230000012202 endocytosis Effects 0.000 description 6
229940088598 enzyme Drugs 0.000 description 6
108010062266 glycyl-glycyl-argininal Proteins 0.000 description 6
238000001727 in vivo Methods 0.000 description 6
230000004048 modification Effects 0.000 description 6
238000012986 modification Methods 0.000 description 6
239000001272 nitrous oxide Substances 0.000 description 6
229920000642 polymer Polymers 0.000 description 6
239000013641 positive control Substances 0.000 description 6
210000000278 spinal cord Anatomy 0.000 description 6
JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 description 5
108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 5
101100446513 Mus musculus Fgf4 gene Proteins 0.000 description 5
239000012580 N-2 Supplement Substances 0.000 description 5
210000000269 carotid artery external Anatomy 0.000 description 5
238000003776 cleavage reaction Methods 0.000 description 5
230000003111 delayed effect Effects 0.000 description 5
201000010099 disease Diseases 0.000 description 5
206010016256 fatigue Diseases 0.000 description 5
230000004941 influx Effects 0.000 description 5
VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical class N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 5
239000002858 neurotransmitter agent Substances 0.000 description 5
231100000252 nontoxic Toxicity 0.000 description 5
230000003000 nontoxic effect Effects 0.000 description 5
229920000724 poly(L-arginine) polymer Polymers 0.000 description 5
235000019419 proteases Nutrition 0.000 description 5
230000007017 scission Effects 0.000 description 5
238000001356 surgical procedure Methods 0.000 description 5
239000000725 suspension Substances 0.000 description 5
238000012360 testing method Methods 0.000 description 5
AASYSXRGODIQGY-UHFFFAOYSA-N 1-[1-(2,5-dioxopyrrol-1-yl)hexyl]pyrrole-2,5-dione Chemical group O=C1C=CC(=O)N1C(CCCCC)N1C(=O)C=CC1=O AASYSXRGODIQGY-UHFFFAOYSA-N 0.000 description 4
108010088751 Albumins Proteins 0.000 description 4
102000009027 Albumins Human genes 0.000 description 4
102100039536 Calcium-activated chloride channel regulator 1 Human genes 0.000 description 4
102000000844 Cell Surface Receptors Human genes 0.000 description 4
150000008574 D-amino acids Chemical class 0.000 description 4
108020004414 DNA Proteins 0.000 description 4
UPOJUWHGMDJUQZ-IUCAKERBSA-N Gly-Arg-Arg Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UPOJUWHGMDJUQZ-IUCAKERBSA-N 0.000 description 4
KFMBRBPXHVMDFN-UWVGGRQHSA-N Gly-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCNC(N)=N KFMBRBPXHVMDFN-UWVGGRQHSA-N 0.000 description 4
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
108090000862 Ion Channels Proteins 0.000 description 4
102000004310 Ion Channels Human genes 0.000 description 4
CLBGMWIYPYAZPR-AVGNSLFASA-N Lys-Arg-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O CLBGMWIYPYAZPR-AVGNSLFASA-N 0.000 description 4
239000004472 Lysine Substances 0.000 description 4
102000016193 Metabotropic glutamate receptors Human genes 0.000 description 4
108010010914 Metabotropic glutamate receptors Proteins 0.000 description 4
206010028851 Necrosis Diseases 0.000 description 4
MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
LNLNHXIQPGKRJQ-SRVKXCTJSA-N Pro-Arg-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]1CCCN1 LNLNHXIQPGKRJQ-SRVKXCTJSA-N 0.000 description 4
NLQUOHDCLSFABG-GUBZILKMSA-N Ser-Arg-Arg Chemical compound NC(N)=NCCC[C@H](NC(=O)[C@H](CO)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NLQUOHDCLSFABG-GUBZILKMSA-N 0.000 description 4
DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
108010074436 Sterol Regulatory Element Binding Protein 1 Proteins 0.000 description 4
102100026839 Sterol regulatory element-binding protein 1 Human genes 0.000 description 4
102100023132 Transcription factor Jun Human genes 0.000 description 4
238000010306 acid treatment Methods 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
230000006907 apoptotic process Effects 0.000 description 4
210000001367 artery Anatomy 0.000 description 4
230000004900 autophagic degradation Effects 0.000 description 4
239000000969 carrier Substances 0.000 description 4
230000002860 competitive effect Effects 0.000 description 4
230000001627 detrimental effect Effects 0.000 description 4
239000002270 dispersing agent Substances 0.000 description 4
239000002552 dosage form Substances 0.000 description 4
238000004128 high performance liquid chromatography Methods 0.000 description 4
238000002347 injection Methods 0.000 description 4
239000007924 injection Substances 0.000 description 4
NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
230000003993 interaction Effects 0.000 description 4
238000001990 intravenous administration Methods 0.000 description 4
239000007788 liquid Substances 0.000 description 4
210000004962 mammalian cell Anatomy 0.000 description 4
239000003094 microcapsule Substances 0.000 description 4
230000021597 necroptosis Effects 0.000 description 4
230000017074 necrotic cell death Effects 0.000 description 4
208000015122 neurodegenerative disease Diseases 0.000 description 4
238000010647 peptide synthesis reaction Methods 0.000 description 4
230000003389 potentiating effect Effects 0.000 description 4
BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 4
210000002966 serum Anatomy 0.000 description 4
235000019333 sodium laurylsulphate Nutrition 0.000 description 4
239000002904 solvent Substances 0.000 description 4
125000006850 spacer group Chemical group 0.000 description 4
239000000126 substance Substances 0.000 description 4
LLXVXPPXELIDGQ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)benzoate Chemical compound C=1C=CC(N2C(C=CC2=O)=O)=CC=1C(=O)ON1C(=O)CCC1=O LLXVXPPXELIDGQ-UHFFFAOYSA-N 0.000 description 3
IASNWHAGGYTEKX-IUCAKERBSA-N Arg-Arg-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(O)=O IASNWHAGGYTEKX-IUCAKERBSA-N 0.000 description 3
UISQLSIBJKEJSS-GUBZILKMSA-N Arg-Arg-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(O)=O UISQLSIBJKEJSS-GUBZILKMSA-N 0.000 description 3
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
BUZMZDDKFCSKOT-CIUDSAMLSA-N Glu-Glu-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O BUZMZDDKFCSKOT-CIUDSAMLSA-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
241000725303 Human immunodeficiency virus Species 0.000 description 3
206010021143 Hypoxia Diseases 0.000 description 3
150000008575 L-amino acids Chemical class 0.000 description 3
ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 3
206010029260 Neuroblastoma Diseases 0.000 description 3
108091028043 Nucleic acid sequence Proteins 0.000 description 3
ORPZXBQTEHINPB-SRVKXCTJSA-N Pro-Arg-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1)C(O)=O ORPZXBQTEHINPB-SRVKXCTJSA-N 0.000 description 3
WWXNZNWZNZPDIF-SRVKXCTJSA-N Pro-Val-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 WWXNZNWZNZPDIF-SRVKXCTJSA-N 0.000 description 3
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
101710149951 Protein Tat Proteins 0.000 description 3
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
108010018242 Transcription Factor AP-1 Proteins 0.000 description 3
208000030886 Traumatic Brain injury Diseases 0.000 description 3
206010047163 Vasospasm Diseases 0.000 description 3
150000001412 amines Chemical class 0.000 description 3
238000010171 animal model Methods 0.000 description 3
108010060035 arginylproline Proteins 0.000 description 3
230000006931 brain damage Effects 0.000 description 3
231100000874 brain damage Toxicity 0.000 description 3
210000001168 carotid artery common Anatomy 0.000 description 3
210000004004 carotid artery internal Anatomy 0.000 description 3
230000003727 cerebral blood flow Effects 0.000 description 3
239000003153 chemical reaction reagent Substances 0.000 description 3
229920001577 copolymer Polymers 0.000 description 3
238000004132 cross linking Methods 0.000 description 3
230000034994 death Effects 0.000 description 3
230000003247 decreasing effect Effects 0.000 description 3
235000014113 dietary fatty acids Nutrition 0.000 description 3
239000003085 diluting agent Substances 0.000 description 3
230000002526 effect on cardiovascular system Effects 0.000 description 3
239000000194 fatty acid Substances 0.000 description 3
229930195729 fatty acid Natural products 0.000 description 3
150000004665 fatty acids Chemical class 0.000 description 3
239000007789 gas Substances 0.000 description 3
239000008103 glucose Substances 0.000 description 3
230000007946 glucose deprivation Effects 0.000 description 3
239000001963 growth medium Substances 0.000 description 3
229920001519 homopolymer Polymers 0.000 description 3
238000009396 hybridization Methods 0.000 description 3
230000001976 improved effect Effects 0.000 description 3
230000001939 inductive effect Effects 0.000 description 3
210000004072 lung Anatomy 0.000 description 3
125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 3
238000005259 measurement Methods 0.000 description 3
230000001404 mediated effect Effects 0.000 description 3
239000012528 membrane Substances 0.000 description 3
210000000274 microglia Anatomy 0.000 description 3
210000003061 neural cell Anatomy 0.000 description 3
230000000626 neurodegenerative effect Effects 0.000 description 3
210000000056 organ Anatomy 0.000 description 3
229920001223 polyethylene glycol Polymers 0.000 description 3
238000002203 pretreatment Methods 0.000 description 3
239000000047 product Substances 0.000 description 3
230000001681 protective effect Effects 0.000 description 3
230000009467 reduction Effects 0.000 description 3
230000002441 reversible effect Effects 0.000 description 3
108010007375 seryl-seryl-seryl-arginine Proteins 0.000 description 3
239000007787 solid Substances 0.000 description 3
238000003786 synthesis reaction Methods 0.000 description 3
210000001519 tissue Anatomy 0.000 description 3
231100000331 toxic Toxicity 0.000 description 3
230000002588 toxic effect Effects 0.000 description 3
231100000041 toxicology testing Toxicity 0.000 description 3
230000009529 traumatic brain injury Effects 0.000 description 3
230000000007 visual effect Effects 0.000 description 3
102000038650 voltage-gated calcium channel activity Human genes 0.000 description 3
108091023044 voltage-gated calcium channel activity Proteins 0.000 description 3
238000005406 washing Methods 0.000 description 3
YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
FXYPGCIGRDZWNR-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-[[3-(2,5-dioxopyrrolidin-1-yl)oxy-3-oxopropyl]disulfanyl]propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSCCC(=O)ON1C(=O)CCC1=O FXYPGCIGRDZWNR-UHFFFAOYSA-N 0.000 description 2
102000003678 AMPA Receptors Human genes 0.000 description 2
108090000078 AMPA Receptors Proteins 0.000 description 2
230000002407 ATP formation Effects 0.000 description 2
206010002091 Anaesthesia Diseases 0.000 description 2
206010002388 Angina unstable Diseases 0.000 description 2
102000012002 Aquaporin 4 Human genes 0.000 description 2
108010036280 Aquaporin 4 Proteins 0.000 description 2
OMLWNBVRVJYMBQ-YUMQZZPRSA-N Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O OMLWNBVRVJYMBQ-YUMQZZPRSA-N 0.000 description 2
XEPSCVXTCUUHDT-AVGNSLFASA-N Arg-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CCCN=C(N)N XEPSCVXTCUUHDT-AVGNSLFASA-N 0.000 description 2
HJVGMOYJDDXLMI-AVGNSLFASA-N Arg-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCCNC(N)=N HJVGMOYJDDXLMI-AVGNSLFASA-N 0.000 description 2
AUIJUTGLPVHIRT-FXQIFTODSA-N Arg-Ser-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N)CN=C(N)N AUIJUTGLPVHIRT-FXQIFTODSA-N 0.000 description 2
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
NTQDELBZOMWXRS-IWGUZYHVSA-N Asp-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O NTQDELBZOMWXRS-IWGUZYHVSA-N 0.000 description 2
241000972773 Aulopiformes Species 0.000 description 2
108091003079 Bovine Serum Albumin Proteins 0.000 description 2
OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 2
108010026870 Calcium-Calmodulin-Dependent Protein Kinases Proteins 0.000 description 2
102000019025 Calcium-Calmodulin-Dependent Protein Kinases Human genes 0.000 description 2
101710186245 Calcium-activated chloride channel regulator 1 Proteins 0.000 description 2
206010008111 Cerebral haemorrhage Diseases 0.000 description 2
206010053567 Coagulopathies Diseases 0.000 description 2
229920002261 Corn starch Polymers 0.000 description 2
239000004971 Cross linker Substances 0.000 description 2
UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 2
108010031042 Death-Associated Protein Kinases Proteins 0.000 description 2
102000005721 Death-Associated Protein Kinases Human genes 0.000 description 2
102100038587 Death-associated protein kinase 1 Human genes 0.000 description 2
BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
108700019745 Disks Large Homolog 4 Proteins 0.000 description 2
102000047174 Disks Large Homolog 4 Human genes 0.000 description 2
102000037087 Excitatory amino acid transporters Human genes 0.000 description 2
108091006291 Excitatory amino acid transporters Proteins 0.000 description 2
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
208000010412 Glaucoma Diseases 0.000 description 2
102100022630 Glutamate receptor ionotropic, NMDA 2B Human genes 0.000 description 2
HQRHFUYMGCHHJS-LURJTMIESA-N Gly-Gly-Arg Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N HQRHFUYMGCHHJS-LURJTMIESA-N 0.000 description 2
101000888572 Homo sapiens Calcium-activated chloride channel regulator 1 Proteins 0.000 description 2
101000956145 Homo sapiens Death-associated protein kinase 1 Proteins 0.000 description 2
241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
208000001953 Hypotension Diseases 0.000 description 2
HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
102000004877 Insulin Human genes 0.000 description 2
108090001061 Insulin Proteins 0.000 description 2
PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
239000012825 JNK inhibitor Substances 0.000 description 2
229940118135 JNK inhibitor Drugs 0.000 description 2
DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
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
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
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 2
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
GAOJCVKPIGHTGO-UWVGGRQHSA-N Lys-Arg-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O GAOJCVKPIGHTGO-UWVGGRQHSA-N 0.000 description 2
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
208000019695 Migraine disease Diseases 0.000 description 2
229940121849 Mitotic inhibitor Drugs 0.000 description 2
102000004108 Neurotransmitter Receptors Human genes 0.000 description 2
108090000590 Neurotransmitter Receptors Proteins 0.000 description 2
102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
101710176384 Peptide 1 Proteins 0.000 description 2
208000018262 Peripheral vascular disease Diseases 0.000 description 2
102000015439 Phospholipases Human genes 0.000 description 2
108010064785 Phospholipases Proteins 0.000 description 2
108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 2
102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 2
239000002202 Polyethylene glycol Substances 0.000 description 2
JLMZKEQFMVORMA-SRVKXCTJSA-N Pro-Pro-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 JLMZKEQFMVORMA-SRVKXCTJSA-N 0.000 description 2
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
101710168705 Protamine-1 Proteins 0.000 description 2
108010029485 Protein Isoforms Proteins 0.000 description 2
102000001708 Protein Isoforms Human genes 0.000 description 2
208000010378 Pulmonary Embolism Diseases 0.000 description 2
206010063837 Reperfusion injury Diseases 0.000 description 2
108010038912 Retinoid X Receptors Proteins 0.000 description 2
206010050496 Reversible ischaemic neurological deficit Diseases 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
102100040435 Sperm protamine P1 Human genes 0.000 description 2
102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
108010037150 Transient Receptor Potential Channels Proteins 0.000 description 2
102000011753 Transient Receptor Potential Channels Human genes 0.000 description 2
208000032109 Transient ischaemic attack Diseases 0.000 description 2
102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 description 2
108050004388 Transient receptor potential cation channel subfamily V member 1 Proteins 0.000 description 2
QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 2
208000007814 Unstable Angina Diseases 0.000 description 2
KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
206010047249 Venous thrombosis Diseases 0.000 description 2
238000009825 accumulation Methods 0.000 description 2
239000002253 acid Substances 0.000 description 2
208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 2
HRMVIAFZYCCHGF-BMCUWHFPSA-N am111 peptide Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC(N)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H]([C@H](C)O)C(=O)N1[C@H](CCC1)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCCCN)C(=O)N1[C@H](CCC1)C(=O)N[C@H](CCCNC(N)=N)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@@H]1N(CCC1)C(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](NC(=O)[C@@H]1N(CCC1)C(=O)[C@@H](CCCNC(N)=N)NC(=O)[C@@H](CO)NC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](N)CC(O)=O)C(C)C)C1=CC=CC=C1 HRMVIAFZYCCHGF-BMCUWHFPSA-N 0.000 description 2
230000037005 anaesthesia Effects 0.000 description 2
238000001949 anaesthesia Methods 0.000 description 2
238000000540 analysis of variance Methods 0.000 description 2
238000002399 angioplasty Methods 0.000 description 2
239000000729 antidote Substances 0.000 description 2
239000007900 aqueous suspension Substances 0.000 description 2
108010062796 arginyllysine Proteins 0.000 description 2
238000003556 assay Methods 0.000 description 2
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
239000003855 balanced salt solution Substances 0.000 description 2
230000008901 benefit Effects 0.000 description 2
235000019445 benzyl alcohol Nutrition 0.000 description 2
UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
230000015572 biosynthetic process Effects 0.000 description 2
230000000903 blocking effect Effects 0.000 description 2
230000036772 blood pressure Effects 0.000 description 2
239000000872 buffer Substances 0.000 description 2
210000004899 c-terminal region Anatomy 0.000 description 2
229910001424 calcium ion Inorganic materials 0.000 description 2
230000001964 calcium overload Effects 0.000 description 2
244000309466 calf Species 0.000 description 2
239000002775 capsule Substances 0.000 description 2
229910052799 carbon Inorganic materials 0.000 description 2
239000001768 carboxy methyl cellulose Substances 0.000 description 2
238000013172 carotid endarterectomy Methods 0.000 description 2
230000008859 change Effects 0.000 description 2
238000006243 chemical reaction Methods 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
230000001684 chronic effect Effects 0.000 description 2
230000035602 clotting Effects 0.000 description 2
230000021615 conjugation Effects 0.000 description 2
239000008120 corn starch Substances 0.000 description 2
229940099112 cornstarch Drugs 0.000 description 2
210000004351 coronary vessel Anatomy 0.000 description 2
210000003618 cortical neuron Anatomy 0.000 description 2
230000008878 coupling Effects 0.000 description 2
238000010168 coupling process Methods 0.000 description 2
238000005859 coupling reaction Methods 0.000 description 2
125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
230000001120 cytoprotective effect Effects 0.000 description 2
230000001086 cytosolic effect Effects 0.000 description 2
239000003405 delayed action preparation Substances 0.000 description 2
238000012377 drug delivery Methods 0.000 description 2
239000003995 emulsifying agent Substances 0.000 description 2
230000002121 endocytic effect Effects 0.000 description 2
239000013604 expression vector Substances 0.000 description 2
125000000524 functional group Chemical group 0.000 description 2
VPSRLGDRGCKUTK-UHFFFAOYSA-N fura-2-acetoxymethyl ester Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=C(C)C=C1OCCOC(C(=C1)N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=CC2=C1OC(C=1OC(=CN=1)C(=O)OCOC(C)=O)=C2 VPSRLGDRGCKUTK-UHFFFAOYSA-N 0.000 description 2
230000004927 fusion Effects 0.000 description 2
230000014509 gene expression Effects 0.000 description 2
239000011521 glass Substances 0.000 description 2
125000005456 glyceride group Chemical group 0.000 description 2
230000036543 hypotension Effects 0.000 description 2
230000007954 hypoxia Effects 0.000 description 2
238000001802 infusion Methods 0.000 description 2
229940125396 insulin Drugs 0.000 description 2
201000004332 intermediate coronary syndrome Diseases 0.000 description 2
238000007917 intracranial administration Methods 0.000 description 2
238000007918 intramuscular administration Methods 0.000 description 2
150000002500 ions Chemical class 0.000 description 2
229960002725 isoflurane Drugs 0.000 description 2
210000004731 jugular vein Anatomy 0.000 description 2
239000008101 lactose Substances 0.000 description 2
230000000670 limiting effect Effects 0.000 description 2
230000007774 longterm Effects 0.000 description 2
239000003055 low molecular weight heparin Substances 0.000 description 2
231100000053 low toxicity Toxicity 0.000 description 2
229940127215 low-molecular weight heparin Drugs 0.000 description 2
108010054155 lysyllysine Proteins 0.000 description 2
230000034701 macropinocytosis Effects 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
238000012423 maintenance Methods 0.000 description 2
239000000463 material Substances 0.000 description 2
239000011159 matrix material Substances 0.000 description 2
206010027599 migraine Diseases 0.000 description 2
230000003278 mimic effect Effects 0.000 description 2
239000002480 mineral oil Substances 0.000 description 2
235000010446 mineral oil Nutrition 0.000 description 2
210000003470 mitochondria Anatomy 0.000 description 2
230000002438 mitochondrial effect Effects 0.000 description 2
238000010369 molecular cloning Methods 0.000 description 2
208000010125 myocardial infarction Diseases 0.000 description 2
230000003961 neuronal insult Effects 0.000 description 2
230000007935 neutral effect Effects 0.000 description 2
239000000346 nonvolatile oil Substances 0.000 description 2
239000003921 oil Substances 0.000 description 2
235000019198 oils Nutrition 0.000 description 2
230000036542 oxidative stress Effects 0.000 description 2
239000001301 oxygen Substances 0.000 description 2
229910052760 oxygen Inorganic materials 0.000 description 2
230000007170 pathology Effects 0.000 description 2
230000007903 penetration ability Effects 0.000 description 2
108010011903 peptide receptors Proteins 0.000 description 2
230000007030 peptide scission Effects 0.000 description 2
235000019271 petrolatum Nutrition 0.000 description 2
239000012071 phase Substances 0.000 description 2
229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
239000001267 polyvinylpyrrolidone Substances 0.000 description 2
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
230000001737 promoting effect Effects 0.000 description 2
230000002633 protecting effect Effects 0.000 description 2
230000009145 protein modification Effects 0.000 description 2
229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 2
238000000746 purification Methods 0.000 description 2
239000003642 reactive oxygen metabolite Substances 0.000 description 2
230000004044 response Effects 0.000 description 2
235000019515 salmon Nutrition 0.000 description 2
UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 2
208000007056 sickle cell anemia Diseases 0.000 description 2
230000019491 signal transduction Effects 0.000 description 2
230000011664 signaling Effects 0.000 description 2
229910001415 sodium ion Inorganic materials 0.000 description 2
239000007790 solid phase Substances 0.000 description 2
238000007619 statistical method Methods 0.000 description 2
UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
208000023516 stroke disease Diseases 0.000 description 2
238000006467 substitution reaction Methods 0.000 description 2
JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 2
230000003319 supportive effect Effects 0.000 description 2
239000000829 suppository Substances 0.000 description 2
239000000375 suspending agent Substances 0.000 description 2
230000002194 synthesizing effect Effects 0.000 description 2
239000003826 tablet Substances 0.000 description 2
230000008685 targeting Effects 0.000 description 2
150000003573 thiols Chemical class 0.000 description 2
230000009424 thromboembolic effect Effects 0.000 description 2
230000002537 thrombolytic effect Effects 0.000 description 2
230000000699 topical effect Effects 0.000 description 2
230000008736 traumatic injury Effects 0.000 description 2
102000003298 tumor necrosis factor receptor Human genes 0.000 description 2
210000003556 vascular endothelial cell Anatomy 0.000 description 2
DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 1
VILFTWLXLYIEMV-UHFFFAOYSA-N 1,5-difluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(F)C=C1F VILFTWLXLYIEMV-UHFFFAOYSA-N 0.000 description 1
DIYPCWKHSODVAP-UHFFFAOYSA-N 1-[3-(2,5-dioxopyrrol-1-yl)benzoyl]oxy-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1C(S(=O)(=O)O)CC(=O)N1OC(=O)C1=CC=CC(N2C(C=CC2=O)=O)=C1 DIYPCWKHSODVAP-UHFFFAOYSA-N 0.000 description 1
IPJGAEWUPXWFPL-UHFFFAOYSA-N 1-[3-(2,5-dioxopyrrol-1-yl)phenyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C1=CC=CC(N2C(C=CC2=O)=O)=C1 IPJGAEWUPXWFPL-UHFFFAOYSA-N 0.000 description 1
LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
KHAWDEWNXJIVCJ-UHFFFAOYSA-N 1-fluoro-4-(4-fluoro-3-nitrophenyl)sulfonyl-2-nitrobenzene Chemical compound C1=C(F)C([N+](=O)[O-])=CC(S(=O)(=O)C=2C=C(C(F)=CC=2)[N+]([O-])=O)=C1 KHAWDEWNXJIVCJ-UHFFFAOYSA-N 0.000 description 1
IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 1
CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
FXYZDFSNBBOHTA-UHFFFAOYSA-N 2-[amino(morpholin-4-ium-4-ylidene)methyl]guanidine;chloride Chemical compound Cl.NC(N)=NC(=N)N1CCOCC1 FXYZDFSNBBOHTA-UHFFFAOYSA-N 0.000 description 1
PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
RLFPCLMBTQOMLI-UHFFFAOYSA-N 2-iodo-n-[2-[(2-iodoacetyl)amino]ethyl]acetamide Chemical compound ICC(=O)NCCNC(=O)CI RLFPCLMBTQOMLI-UHFFFAOYSA-N 0.000 description 1
LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
NSFXVRRBGNORBD-UHFFFAOYSA-N 2h-benzo[f]benzotriazole Chemical compound C1=C2C=CC=CC2=CC2=NNN=C21 NSFXVRRBGNORBD-UHFFFAOYSA-N 0.000 description 1
NQXOUNOJWFMRLG-UHFFFAOYSA-N 4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanoic acid;pyrrolidine-2,5-dione Chemical compound O=C1CCC(=O)N1.C1=CC(CCCC(=O)O)=CC=C1N1C(=O)C=CC1=O NQXOUNOJWFMRLG-UHFFFAOYSA-N 0.000 description 1
DNZNQKCREPTWAX-UHFFFAOYSA-N 7-nitroquinoxaline-6-carbonitrile Chemical compound C1=CN=C2C=C(C#N)C([N+](=O)[O-])=CC2=N1 DNZNQKCREPTWAX-UHFFFAOYSA-N 0.000 description 1
QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
NWVVKQZOVSTDBQ-CIUDSAMLSA-N Ala-Glu-Arg Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NWVVKQZOVSTDBQ-CIUDSAMLSA-N 0.000 description 1
LJFNNUBZSZCZFN-WHFBIAKZSA-N Ala-Gly-Cys Chemical compound N[C@@H](C)C(=O)NCC(=O)N[C@@H](CS)C(=O)O LJFNNUBZSZCZFN-WHFBIAKZSA-N 0.000 description 1
VJVQKGYHIZPSNS-FXQIFTODSA-N Ala-Ser-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N VJVQKGYHIZPSNS-FXQIFTODSA-N 0.000 description 1
102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
206010002660 Anoxia Diseases 0.000 description 1
241000976983 Anoxia Species 0.000 description 1
UXJCMQFPDWCHKX-DCAQKATOSA-N Arg-Arg-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UXJCMQFPDWCHKX-DCAQKATOSA-N 0.000 description 1
OVVUNXXROOFSIM-SDDRHHMPSA-N Arg-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O OVVUNXXROOFSIM-SDDRHHMPSA-N 0.000 description 1
XUUXCWCKKCZEAW-YFKPBYRVSA-N Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](N)CCCN=C(N)N XUUXCWCKKCZEAW-YFKPBYRVSA-N 0.000 description 1
CYXCAHZVPFREJD-LURJTMIESA-N Arg-Gly-Gly Chemical compound NC(=N)NCCC[C@H](N)C(=O)NCC(=O)NCC(O)=O CYXCAHZVPFREJD-LURJTMIESA-N 0.000 description 1
GRRXPUAICOGISM-RWMBFGLXSA-N Arg-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O GRRXPUAICOGISM-RWMBFGLXSA-N 0.000 description 1
WKPXXXUSUHAXDE-SRVKXCTJSA-N Arg-Pro-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O WKPXXXUSUHAXDE-SRVKXCTJSA-N 0.000 description 1
UULLJGQFCDXVTQ-CYDGBPFRSA-N Arg-Pro-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UULLJGQFCDXVTQ-CYDGBPFRSA-N 0.000 description 1
YCYXHLZRUSJITQ-SRVKXCTJSA-N Arg-Pro-Pro Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 YCYXHLZRUSJITQ-SRVKXCTJSA-N 0.000 description 1
CPTXATAOUQJQRO-GUBZILKMSA-N Arg-Val-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O CPTXATAOUQJQRO-GUBZILKMSA-N 0.000 description 1
GMRGSBAMMMVDGG-GUBZILKMSA-N Asn-Arg-Arg Chemical compound C(C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N GMRGSBAMMMVDGG-GUBZILKMSA-N 0.000 description 1
FHETWELNCBMRMG-HJGDQZAQSA-N Asn-Leu-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FHETWELNCBMRMG-HJGDQZAQSA-N 0.000 description 1
DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
239000012583 B-27 Supplement Substances 0.000 description 1
102000004506 Blood Proteins Human genes 0.000 description 1
108010017384 Blood Proteins Proteins 0.000 description 1
206010048962 Brain oedema Diseases 0.000 description 1
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 1
101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
235000008733 Citrus aurantifolia Nutrition 0.000 description 1
108020004705 Codon Proteins 0.000 description 1
108010060110 D-JNKI-1 Proteins 0.000 description 1
102000016911 Deoxyribonucleases Human genes 0.000 description 1
108010053770 Deoxyribonucleases Proteins 0.000 description 1
241000255601 Drosophila melanogaster Species 0.000 description 1
239000004150 EU approved colour Substances 0.000 description 1
241000196324 Embryophyta Species 0.000 description 1
208000010228 Erectile Dysfunction Diseases 0.000 description 1
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
206010015548 Euthanasia Diseases 0.000 description 1
208000001640 Fibromyalgia Diseases 0.000 description 1
229920001917 Ficoll Polymers 0.000 description 1
SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
JLXVRFDTDUGQEE-YFKPBYRVSA-N Gly-Arg Chemical compound NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N JLXVRFDTDUGQEE-YFKPBYRVSA-N 0.000 description 1
WKJKBELXHCTHIJ-WPRPVWTQSA-N Gly-Arg-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N WKJKBELXHCTHIJ-WPRPVWTQSA-N 0.000 description 1
XPJBQTCXPJNIFE-ZETCQYMHSA-N Gly-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)CN XPJBQTCXPJNIFE-ZETCQYMHSA-N 0.000 description 1
LBDXVCBAJJNJNN-WHFBIAKZSA-N Gly-Ser-Cys Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O LBDXVCBAJJNJNN-WHFBIAKZSA-N 0.000 description 1
XBGGUPMXALFZOT-VIFPVBQESA-N Gly-Tyr Chemical compound NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-VIFPVBQESA-N 0.000 description 1
239000004471 Glycine Substances 0.000 description 1
102000018932 HSP70 Heat-Shock Proteins Human genes 0.000 description 1
108010027992 HSP70 Heat-Shock Proteins Proteins 0.000 description 1
239000005057 Hexamethylene diisocyanate Substances 0.000 description 1
101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 1
108091006905 Human Serum Albumin Proteins 0.000 description 1
102000008100 Human Serum Albumin Human genes 0.000 description 1
208000013016 Hypoglycemia Diseases 0.000 description 1
FFAUOCITXBMRBT-YTFOTSKYSA-N Ile-Lys-Ile Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FFAUOCITXBMRBT-YTFOTSKYSA-N 0.000 description 1
GLYJPWIRLBAIJH-UHFFFAOYSA-N Ile-Lys-Pro Natural products CCC(C)C(N)C(=O)NC(CCCCN)C(=O)N1CCCC1C(O)=O GLYJPWIRLBAIJH-UHFFFAOYSA-N 0.000 description 1
206010061598 Immunodeficiency Diseases 0.000 description 1
208000029462 Immunodeficiency disease Diseases 0.000 description 1
238000012695 Interfacial polymerization Methods 0.000 description 1
208000032382 Ischaemic stroke Diseases 0.000 description 1
VLSMHEGGTFMBBZ-OOZYFLPDSA-M Kainate Chemical compound CC(=C)[C@H]1C[NH2+][C@H](C([O-])=O)[C@H]1CC([O-])=O VLSMHEGGTFMBBZ-OOZYFLPDSA-M 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
QUOGESRFPZDMMT-UHFFFAOYSA-N L-Homoarginine Natural products OC(=O)C(N)CCCCNC(N)=N QUOGESRFPZDMMT-UHFFFAOYSA-N 0.000 description 1
108010030797 L-JNKI-1 Proteins 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
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
SITWEMZOJNKJCH-UHFFFAOYSA-N L-alanine-L-arginine Natural products CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 1
QUOGESRFPZDMMT-YFKPBYRVSA-N L-homoarginine Chemical compound OC(=O)[C@@H](N)CCCCNC(N)=N QUOGESRFPZDMMT-YFKPBYRVSA-N 0.000 description 1
AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
101100268653 Leptosphaeria maculans (strain JN3 / isolate v23.1.3 / race Av1-4-5-6-7-8) abl5 gene Proteins 0.000 description 1
JKGHDYGZRDWHGA-SRVKXCTJSA-N Leu-Asn-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JKGHDYGZRDWHGA-SRVKXCTJSA-N 0.000 description 1
UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 1
MVVSHHJKJRZVNY-ACRUOGEOSA-N Leu-Phe-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MVVSHHJKJRZVNY-ACRUOGEOSA-N 0.000 description 1
ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
WGLAORUKDGRINI-WDCWCFNPSA-N Lys-Glu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGLAORUKDGRINI-WDCWCFNPSA-N 0.000 description 1
WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 1
ZJWIXBZTAAJERF-IHRRRGAJSA-N Lys-Lys-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N ZJWIXBZTAAJERF-IHRRRGAJSA-N 0.000 description 1
VVURYEVJJTXWNE-ULQDDVLXSA-N Lys-Tyr-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O VVURYEVJJTXWNE-ULQDDVLXSA-N 0.000 description 1
108091054455 MAP kinase family Proteins 0.000 description 1
102000043136 MAP kinase family Human genes 0.000 description 1
239000004907 Macro-emulsion Substances 0.000 description 1
XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
DJJBHQHOZLUBCN-WDSOQIARSA-N Met-Lys-Trp Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DJJBHQHOZLUBCN-WDSOQIARSA-N 0.000 description 1
241000699666 Mus <mouse, genus> Species 0.000 description 1
102000004722 NADPH Oxidases Human genes 0.000 description 1
108010002998 NADPH Oxidases Proteins 0.000 description 1
208000012902 Nervous system disease Diseases 0.000 description 1
208000025966 Neurological disease Diseases 0.000 description 1
101100109292 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) arg-13 gene Proteins 0.000 description 1
101100404023 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) arg-14 gene Proteins 0.000 description 1
101100491597 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) arg-6 gene Proteins 0.000 description 1
101100109397 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) arg-8 gene Proteins 0.000 description 1
239000004677 Nylon Substances 0.000 description 1
239000005642 Oleic acid Substances 0.000 description 1
ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
108010093625 Opioid Peptides Proteins 0.000 description 1
102000001490 Opioid Peptides Human genes 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
229910019142 PO4 Inorganic materials 0.000 description 1
108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
102000014160 PTEN Phosphohydrolase Human genes 0.000 description 1
108090000526 Papain Proteins 0.000 description 1
229930182555 Penicillin Natural products 0.000 description 1
JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
239000004264 Petrolatum Substances 0.000 description 1
108091000080 Phosphotransferase Proteins 0.000 description 1
229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
229920001214 Polysorbate 60 Polymers 0.000 description 1
239000004372 Polyvinyl alcohol Substances 0.000 description 1
CYQQWUPHIZVCNY-GUBZILKMSA-N Pro-Arg-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O CYQQWUPHIZVCNY-GUBZILKMSA-N 0.000 description 1
DRKAXLDECUGLFE-ULQDDVLXSA-N Pro-Leu-Phe Chemical compound CC(C)C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O DRKAXLDECUGLFE-ULQDDVLXSA-N 0.000 description 1
RVQDZELMXZRSSI-IUCAKERBSA-N Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1 RVQDZELMXZRSSI-IUCAKERBSA-N 0.000 description 1
JUJCUYWRJMFJJF-AVGNSLFASA-N Pro-Lys-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1 JUJCUYWRJMFJJF-AVGNSLFASA-N 0.000 description 1
WHNJMTHJGCEKGA-ULQDDVLXSA-N Pro-Phe-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O WHNJMTHJGCEKGA-ULQDDVLXSA-N 0.000 description 1
GZNYIXWOIUFLGO-ZJDVBMNYSA-N Pro-Thr-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZNYIXWOIUFLGO-ZJDVBMNYSA-N 0.000 description 1
102100034750 Protamine-2 Human genes 0.000 description 1
102100025801 Protamine-3 Human genes 0.000 description 1
101710168708 Protamine-3 Proteins 0.000 description 1
102000001253 Protein Kinase Human genes 0.000 description 1
108010058684 R18 peptide Proteins 0.000 description 1
108091030071 RNAI Proteins 0.000 description 1
208000003782 Raynaud disease Diseases 0.000 description 1
208000012322 Raynaud phenomenon Diseases 0.000 description 1
108020004511 Recombinant DNA Proteins 0.000 description 1
GXXTUIUYTWGPMV-FXQIFTODSA-N Ser-Arg-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O GXXTUIUYTWGPMV-FXQIFTODSA-N 0.000 description 1
NRCJWSGXMAPYQX-LPEHRKFASA-N Ser-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CO)N)C(=O)O NRCJWSGXMAPYQX-LPEHRKFASA-N 0.000 description 1
SWSRFJZZMNLMLY-ZKWXMUAHSA-N Ser-Asp-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O SWSRFJZZMNLMLY-ZKWXMUAHSA-N 0.000 description 1
DJACUBDEDBZKLQ-KBIXCLLPSA-N Ser-Ile-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O DJACUBDEDBZKLQ-KBIXCLLPSA-N 0.000 description 1
JIPVNVNKXJLFJF-BJDJZHNGSA-N Ser-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N JIPVNVNKXJLFJF-BJDJZHNGSA-N 0.000 description 1
MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
108020004459 Small interfering RNA Proteins 0.000 description 1
HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
238000000692 Student's t-test Methods 0.000 description 1
210000001744 T-lymphocyte Anatomy 0.000 description 1
108010005515 TAT-mGluR1 peptide Proteins 0.000 description 1
IOWJRKAVLALBQB-IWGUZYHVSA-N Thr-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(O)=O)CC(O)=O IOWJRKAVLALBQB-IWGUZYHVSA-N 0.000 description 1
VULNJDORNLBPNG-SWRJLBSHSA-N Thr-Glu-Trp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N)O VULNJDORNLBPNG-SWRJLBSHSA-N 0.000 description 1
BGHVVGPELPHRCI-HZTRNQAASA-N Thr-Trp-Trp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)O)N)O BGHVVGPELPHRCI-HZTRNQAASA-N 0.000 description 1
AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
239000004473 Threonine Substances 0.000 description 1
235000011941 Tilia x europaea Nutrition 0.000 description 1
108091023040 Transcription factor Proteins 0.000 description 1
102000040945 Transcription factor Human genes 0.000 description 1
IYHRKILQAQWODS-VJBMBRPKSA-N Trp-Trp-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N IYHRKILQAQWODS-VJBMBRPKSA-N 0.000 description 1
HSVPZJLMPLMPOX-BPNCWPANSA-N Tyr-Arg-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O HSVPZJLMPLMPOX-BPNCWPANSA-N 0.000 description 1
WOAQYWUEUYMVGK-ULQDDVLXSA-N Tyr-Lys-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WOAQYWUEUYMVGK-ULQDDVLXSA-N 0.000 description 1
PIFJAFRUVWZRKR-QMMMGPOBSA-N Val-Gly-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O PIFJAFRUVWZRKR-QMMMGPOBSA-N 0.000 description 1
YTNGABPUXFEOGU-SRVKXCTJSA-N Val-Pro-Arg Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O YTNGABPUXFEOGU-SRVKXCTJSA-N 0.000 description 1
AJNUKMZFHXUBMK-GUBZILKMSA-N Val-Ser-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N AJNUKMZFHXUBMK-GUBZILKMSA-N 0.000 description 1
208000003728 Vulvodynia Diseases 0.000 description 1
206010069055 Vulvovaginal pain Diseases 0.000 description 1
229940124532 absorption promoter Drugs 0.000 description 1
125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
230000009471 action Effects 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
235000004279 alanine Nutrition 0.000 description 1
108010047495 alanylglycine Proteins 0.000 description 1
KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
230000004075 alteration Effects 0.000 description 1
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
229940063655 aluminum stearate Drugs 0.000 description 1
150000001408 amides Chemical class 0.000 description 1
125000003277 amino group Chemical group 0.000 description 1
230000036592 analgesia Effects 0.000 description 1
230000007953 anoxia Effects 0.000 description 1
239000005557 antagonist Substances 0.000 description 1
230000000890 antigenic effect Effects 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
108010080488 arginyl-arginyl-leucine Proteins 0.000 description 1
108010029539 arginyl-prolyl-proline Proteins 0.000 description 1
229910052786 argon Inorganic materials 0.000 description 1
229960001230 asparagine Drugs 0.000 description 1
235000009582 asparagine Nutrition 0.000 description 1
108010036999 aspartyl-alanyl-histidyl-lysine Proteins 0.000 description 1
208000006673 asthma Diseases 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
230000001580 bacterial effect Effects 0.000 description 1
235000013871 bee wax Nutrition 0.000 description 1
239000012166 beeswax Substances 0.000 description 1
230000009286 beneficial effect Effects 0.000 description 1
229940049706 benzodiazepine Drugs 0.000 description 1
WQZGKKKJIJFFOK-FPRJBGLDSA-N beta-D-galactose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-FPRJBGLDSA-N 0.000 description 1
108010005774 beta-Galactosidase Proteins 0.000 description 1
229940000635 beta-alanine Drugs 0.000 description 1
230000000975 bioactive effect Effects 0.000 description 1
238000006065 biodegradation reaction Methods 0.000 description 1
230000004071 biological effect Effects 0.000 description 1
229960002685 biotin Drugs 0.000 description 1
235000020958 biotin Nutrition 0.000 description 1
239000011616 biotin Substances 0.000 description 1
230000017531 blood circulation Effects 0.000 description 1
229940098773 bovine serum albumin Drugs 0.000 description 1
229960003150 bupivacaine Drugs 0.000 description 1
DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
239000008112 carboxymethyl-cellulose Substances 0.000 description 1
210000001011 carotid body Anatomy 0.000 description 1
239000012876 carrier material Substances 0.000 description 1
239000004359 castor oil Substances 0.000 description 1
235000019438 castor oil Nutrition 0.000 description 1
238000004113 cell culture Methods 0.000 description 1
230000005889 cellular cytotoxicity Effects 0.000 description 1
230000004640 cellular pathway Effects 0.000 description 1
230000033077 cellular process Effects 0.000 description 1
230000007541 cellular toxicity Effects 0.000 description 1
230000004700 cellular uptake Effects 0.000 description 1
239000001913 cellulose Substances 0.000 description 1
229920002678 cellulose Polymers 0.000 description 1
235000010980 cellulose Nutrition 0.000 description 1
210000001638 cerebellum Anatomy 0.000 description 1
210000004720 cerebrum Anatomy 0.000 description 1
229940081733 cetearyl alcohol Drugs 0.000 description 1
238000012512 characterization method Methods 0.000 description 1
238000010382 chemical cross-linking Methods 0.000 description 1
238000007385 chemical modification Methods 0.000 description 1
229940110456 cocoa butter Drugs 0.000 description 1
235000019868 cocoa butter Nutrition 0.000 description 1
239000008119 colloidal silica Substances 0.000 description 1
230000001268 conjugating effect Effects 0.000 description 1
238000010276 construction Methods 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
238000001816 cooling Methods 0.000 description 1
230000036757 core body temperature Effects 0.000 description 1
210000005257 cortical tissue Anatomy 0.000 description 1
239000006071 cream Substances 0.000 description 1
210000004748 cultured cell Anatomy 0.000 description 1
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
235000018417 cysteine Nutrition 0.000 description 1
238000012217 deletion Methods 0.000 description 1
230000037430 deletion Effects 0.000 description 1
230000006866 deterioration Effects 0.000 description 1
238000011161 development Methods 0.000 description 1
230000018109 developmental process Effects 0.000 description 1
206010012601 diabetes mellitus Diseases 0.000 description 1
235000005911 diet Nutrition 0.000 description 1
230000037213 diet Effects 0.000 description 1
GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
ZLFRJHOBQVVTOJ-UHFFFAOYSA-N dimethyl hexanediimidate Chemical compound COC(=N)CCCCC(=N)OC ZLFRJHOBQVVTOJ-UHFFFAOYSA-N 0.000 description 1
ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
235000019797 dipotassium phosphate Nutrition 0.000 description 1
230000006806 disease prevention Effects 0.000 description 1
BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 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
210000005064 dopaminergic neuron Anatomy 0.000 description 1
230000002222 downregulating effect Effects 0.000 description 1
230000003828 downregulation Effects 0.000 description 1
239000000890 drug combination Substances 0.000 description 1
206010013663 drug dependence Diseases 0.000 description 1
229960001484 edetic acid Drugs 0.000 description 1
239000003792 electrolyte Substances 0.000 description 1
230000001804 emulsifying effect Effects 0.000 description 1
239000008387 emulsifying waxe Substances 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
210000001163 endosome Anatomy 0.000 description 1
238000005516 engineering process Methods 0.000 description 1
239000003623 enhancer Substances 0.000 description 1
230000002708 enhancing effect Effects 0.000 description 1
BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
239000005038 ethylene vinyl acetate Substances 0.000 description 1
230000007717 exclusion Effects 0.000 description 1
230000029142 excretion Effects 0.000 description 1
230000008317 extracellular mechanism Effects 0.000 description 1
239000000284 extract Substances 0.000 description 1
235000019197 fats Nutrition 0.000 description 1
210000001105 femoral artery Anatomy 0.000 description 1
239000012091 fetal bovine serum Substances 0.000 description 1
210000002950 fibroblast Anatomy 0.000 description 1
239000000796 flavoring agent Substances 0.000 description 1
235000013305 food Nutrition 0.000 description 1
239000012634 fragment Substances 0.000 description 1
230000002538 fungal effect Effects 0.000 description 1
108020001507 fusion proteins Proteins 0.000 description 1
102000037865 fusion proteins Human genes 0.000 description 1
230000009368 gene silencing by RNA Effects 0.000 description 1
238000001415 gene therapy Methods 0.000 description 1
238000007429 general method Methods 0.000 description 1
230000002068 genetic effect Effects 0.000 description 1
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
229960002449 glycine Drugs 0.000 description 1
125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
108010026364 glycyl-glycyl-leucine Proteins 0.000 description 1
108010087823 glycyltyrosine Proteins 0.000 description 1
210000003128 head Anatomy 0.000 description 1
230000036541 health Effects 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 description 1
210000001320 hippocampus Anatomy 0.000 description 1
HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
125000001183 hydrocarbyl group Chemical group 0.000 description 1
239000000017 hydrogel Substances 0.000 description 1
229920001600 hydrophobic polymer Polymers 0.000 description 1
229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
229960002591 hydroxyproline Drugs 0.000 description 1
230000002218 hypoglycaemic effect Effects 0.000 description 1
230000007813 immunodeficiency Effects 0.000 description 1
230000008676 import Effects 0.000 description 1
201000001881 impotence Diseases 0.000 description 1
238000010874 in vitro model Methods 0.000 description 1
230000006698 induction Effects 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
229940102223 injectable solution Drugs 0.000 description 1
229940102213 injectable suspension Drugs 0.000 description 1
239000007928 intraperitoneal injection Substances 0.000 description 1
238000007919 intrasynovial administration Methods 0.000 description 1
238000007913 intrathecal administration Methods 0.000 description 1
238000010253 intravenous injection Methods 0.000 description 1
238000007914 intraventricular administration Methods 0.000 description 1
230000002427 irreversible effect Effects 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
QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
239000000787 lecithin Substances 0.000 description 1
235000010445 lecithin Nutrition 0.000 description 1
229940067606 lecithin Drugs 0.000 description 1
239000004571 lime Substances 0.000 description 1
239000002502 liposome Substances 0.000 description 1
238000011068 loading method Methods 0.000 description 1
239000006210 lotion Substances 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
108010043322 lysyl-tryptophyl-alpha-lysine Proteins 0.000 description 1
239000000391 magnesium silicate Substances 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
229940099273 magnesium trisilicate Drugs 0.000 description 1
229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
235000019793 magnesium trisilicate Nutrition 0.000 description 1
230000010534 mechanism of action Effects 0.000 description 1
239000002609 medium Substances 0.000 description 1
230000028161 membrane depolarization Effects 0.000 description 1
210000001259 mesencephalon Anatomy 0.000 description 1
108020004999 messenger RNA Proteins 0.000 description 1
229930182817 methionine Natural products 0.000 description 1
239000004530 micro-emulsion Substances 0.000 description 1
238000000386 microscopy Methods 0.000 description 1
239000004005 microsphere Substances 0.000 description 1
229940042472 mineral oil Drugs 0.000 description 1
238000002156 mixing Methods 0.000 description 1
235000019799 monosodium phosphate Nutrition 0.000 description 1
230000035772 mutation Effects 0.000 description 1
210000003098 myoblast Anatomy 0.000 description 1
239000002088 nanocapsule Substances 0.000 description 1
239000002105 nanoparticle Substances 0.000 description 1
239000007922 nasal spray Substances 0.000 description 1
230000004770 neurodegeneration Effects 0.000 description 1
230000003088 neuroexcitatory effect Effects 0.000 description 1
230000000508 neurotrophic effect Effects 0.000 description 1
230000008599 nitrosative stress Effects 0.000 description 1
231100000344 non-irritating Toxicity 0.000 description 1
230000005937 nuclear translocation Effects 0.000 description 1
238000010899 nucleation Methods 0.000 description 1
238000007899 nucleic acid hybridization Methods 0.000 description 1
239000002773 nucleotide Substances 0.000 description 1
125000003729 nucleotide group Chemical group 0.000 description 1
229920001778 nylon Polymers 0.000 description 1
GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
239000002674 ointment Substances 0.000 description 1
ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
239000004006 olive oil Substances 0.000 description 1
235000008390 olive oil Nutrition 0.000 description 1
239000003399 opiate peptide Substances 0.000 description 1
229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
229960003104 ornithine Drugs 0.000 description 1
229940055729 papain Drugs 0.000 description 1
235000019834 papain Nutrition 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
230000036961 partial effect Effects 0.000 description 1
230000035515 penetration Effects 0.000 description 1
229940049954 penicillin Drugs 0.000 description 1
230000009984 peri-natal effect Effects 0.000 description 1
210000003668 pericyte Anatomy 0.000 description 1
230000003094 perturbing effect Effects 0.000 description 1
229960000482 pethidine Drugs 0.000 description 1
229940066842 petrolatum Drugs 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
235000021317 phosphate Nutrition 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
102000020233 phosphotransferase Human genes 0.000 description 1
229920003023 plastic Polymers 0.000 description 1
239000004033 plastic Substances 0.000 description 1
229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
229920000747 poly(lactic acid) Polymers 0.000 description 1
229920000058 polyacrylate Polymers 0.000 description 1
229920000728 polyester Polymers 0.000 description 1
239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
229920001451 polypropylene glycol Polymers 0.000 description 1
229920001296 polysiloxane Polymers 0.000 description 1
229920000136 polysorbate Polymers 0.000 description 1
229940113124 polysorbate 60 Drugs 0.000 description 1
229920002451 polyvinyl alcohol Polymers 0.000 description 1
235000019422 polyvinyl alcohol Nutrition 0.000 description 1
230000008092 positive effect Effects 0.000 description 1
230000002980 postoperative effect Effects 0.000 description 1
230000001242 postsynaptic effect Effects 0.000 description 1
235000010241 potassium sorbate Nutrition 0.000 description 1
239000004302 potassium sorbate Substances 0.000 description 1
229940069338 potassium sorbate Drugs 0.000 description 1
239000002243 precursor Substances 0.000 description 1
239000003761 preservation solution Substances 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
150000003141 primary amines Chemical class 0.000 description 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
238000012545 processing Methods 0.000 description 1
230000000750 progressive effect Effects 0.000 description 1
108010004914 prolylarginine Proteins 0.000 description 1
235000013772 propylene glycol Nutrition 0.000 description 1
108010076339 protamine 2 Proteins 0.000 description 1
108060006633 protein kinase Proteins 0.000 description 1
208000002815 pulmonary hypertension Diseases 0.000 description 1
210000000664 rectum Anatomy 0.000 description 1
238000009877 rendering Methods 0.000 description 1
230000010410 reperfusion Effects 0.000 description 1
210000003994 retinal ganglion cell Anatomy 0.000 description 1
150000003839 salts Chemical class 0.000 description 1
239000000523 sample Substances 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
231100000004 severe toxicity Toxicity 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
229910000162 sodium phosphate Inorganic materials 0.000 description 1
VUFNRPJNRFOTGK-UHFFFAOYSA-M sodium;1-[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]oxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)C1CCC(CN2C(C=CC2=O)=O)CC1 VUFNRPJNRFOTGK-UHFFFAOYSA-M 0.000 description 1
230000003381 solubilizing effect Effects 0.000 description 1
235000010199 sorbic acid Nutrition 0.000 description 1
229940075582 sorbic acid Drugs 0.000 description 1
239000004334 sorbic acid Substances 0.000 description 1
239000001587 sorbitan monostearate Substances 0.000 description 1
235000011076 sorbitan monostearate Nutrition 0.000 description 1
229940035048 sorbitan monostearate Drugs 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
238000013222 sprague-dawley male rat Methods 0.000 description 1
238000012453 sprague-dawley rat model Methods 0.000 description 1
239000007921 spray Substances 0.000 description 1
230000003019 stabilising effect Effects 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
208000005809 status epilepticus Diseases 0.000 description 1
229960005322 streptomycin Drugs 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
208000011117 substance-related disease Diseases 0.000 description 1
210000003523 substantia nigra Anatomy 0.000 description 1
125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
239000004094 surface-active agent Substances 0.000 description 1
238000013268 sustained release Methods 0.000 description 1
239000012730 sustained-release form Substances 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
230000000946 synaptic effect Effects 0.000 description 1
MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
125000003831 tetrazolyl group Chemical group 0.000 description 1
229940126585 therapeutic drug Drugs 0.000 description 1
125000003396 thiol group Chemical group [H]S* 0.000 description 1
ATGUDZODTABURZ-UHFFFAOYSA-N thiolan-2-ylideneazanium;chloride Chemical compound Cl.N=C1CCCS1 ATGUDZODTABURZ-UHFFFAOYSA-N 0.000 description 1
210000001685 thyroid gland Anatomy 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
231100000048 toxicity data Toxicity 0.000 description 1
238000013417 toxicology model Methods 0.000 description 1
FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
108091006106 transcriptional activators Proteins 0.000 description 1
201000010875 transient cerebral ischemia Diseases 0.000 description 1
230000005945 translocation Effects 0.000 description 1
230000032258 transport Effects 0.000 description 1
238000011269 treatment regimen Methods 0.000 description 1
125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
108010051110 tyrosyl-lysine Proteins 0.000 description 1
239000004474 valine Substances 0.000 description 1
230000002792 vascular Effects 0.000 description 1
235000013311 vegetables Nutrition 0.000 description 1
239000013603 viral vector Substances 0.000 description 1
238000010792 warming Methods 0.000 description 1
239000001993 wax Substances 0.000 description 1
238000005303 weighing Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
239000003871 white petrolatum Substances 0.000 description 1
210000002268 wool Anatomy 0.000 description 1
230000029663 wound healing Effects 0.000 description 1
150000003751 zinc Chemical class 0.000 description 1
KNJNGVKTAFTUFL-OCMUWRIYSA-N ω-conotoxin Chemical compound N([C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H]1C(N[C@@H](CSSC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H]1C(N[C@@H](CCCN=C(N)N)C(=O)N[C@H](CO)C(=O)NCC(=O)N[C@H](CCCCN)C(=O)N[C@H](CSSC1)C(N)=O)=O)=O)C(=O)[C@@H]1CSSC[C@@H](N)C(=O)N[C@H](CCCCN)C(=O)NCC(=O)N[C@H](CCCCN)C(=O)NCC(=O)N[C@H](C)C(=O)N[C@@H](CCCCN)C(=O)N1 KNJNGVKTAFTUFL-OCMUWRIYSA-N 0.000 description 1
108091058550 ω-conotoxin Proteins 0.000 description 1