CN114127089A - 重组腺相关病毒及其用途 - Google Patents
重组腺相关病毒及其用途 Download PDFInfo
- Publication number
- CN114127089A CN114127089A CN202080031981.XA CN202080031981A CN114127089A CN 114127089 A CN114127089 A CN 114127089A CN 202080031981 A CN202080031981 A CN 202080031981A CN 114127089 A CN114127089 A CN 114127089A
- Authority
- CN
- China
- Prior art keywords
- seq
- amino acid
- capsid
- raav
- capsid protein
- 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.)
- Pending
Links
- 241000702421 Dependoparvovirus Species 0.000 title claims abstract description 37
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 694
- 210000000234 capsid Anatomy 0.000 claims abstract description 414
- 108090000565 Capsid Proteins Proteins 0.000 claims abstract description 347
- 102100023321 Ceruloplasmin Human genes 0.000 claims abstract description 347
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 252
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 173
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 109
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 90
- 230000002207 retinal effect Effects 0.000 claims abstract description 62
- 102000013035 dynein heavy chain Human genes 0.000 claims abstract description 41
- 108060002430 dynein heavy chain Proteins 0.000 claims abstract description 41
- 230000001537 neural effect Effects 0.000 claims abstract description 41
- 239000002245 particle Substances 0.000 claims abstract description 39
- 108090000394 Erythropoietin Proteins 0.000 claims abstract description 36
- 102000003951 Erythropoietin Human genes 0.000 claims abstract description 31
- 229940105423 erythropoietin Drugs 0.000 claims abstract description 26
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000001413 amino acids Chemical class 0.000 claims description 251
- 210000004027 cell Anatomy 0.000 claims description 229
- 239000013598 vector Substances 0.000 claims description 170
- 210000001519 tissue Anatomy 0.000 claims description 133
- 241000282414 Homo sapiens Species 0.000 claims description 109
- 108700019146 Transgenes Proteins 0.000 claims description 99
- 239000013608 rAAV vector Substances 0.000 claims description 90
- 125000000539 amino acid group Chemical group 0.000 claims description 81
- 238000000034 method Methods 0.000 claims description 79
- 241001164825 Adeno-associated virus - 8 Species 0.000 claims description 64
- 210000003734 kidney Anatomy 0.000 claims description 59
- 230000027455 binding Effects 0.000 claims description 53
- 241000702423 Adeno-associated virus - 2 Species 0.000 claims description 52
- 238000003780 insertion Methods 0.000 claims description 49
- 230000037431 insertion Effects 0.000 claims description 49
- 210000004556 brain Anatomy 0.000 claims description 47
- 239000008194 pharmaceutical composition Substances 0.000 claims description 44
- 210000003205 muscle Anatomy 0.000 claims description 38
- 230000008685 targeting Effects 0.000 claims description 38
- 239000013607 AAV vector Substances 0.000 claims description 36
- 238000006467 substitution reaction Methods 0.000 claims description 34
- 241000202702 Adeno-associated virus - 3 Species 0.000 claims description 33
- 241000580270 Adeno-associated virus - 4 Species 0.000 claims description 33
- 241001634120 Adeno-associated virus - 5 Species 0.000 claims description 33
- 241000972680 Adeno-associated virus - 6 Species 0.000 claims description 33
- 241001164823 Adeno-associated virus - 7 Species 0.000 claims description 33
- 210000000988 bone and bone Anatomy 0.000 claims description 33
- 102000005362 Cytoplasmic Dyneins Human genes 0.000 claims description 31
- 108010070977 Cytoplasmic Dyneins Proteins 0.000 claims description 31
- 238000004806 packaging method and process Methods 0.000 claims description 31
- 150000007523 nucleic acids Chemical class 0.000 claims description 29
- 108010033576 Transferrin Receptors Proteins 0.000 claims description 25
- 102000039446 nucleic acids Human genes 0.000 claims description 23
- 108020004707 nucleic acids Proteins 0.000 claims description 23
- 210000002889 endothelial cell Anatomy 0.000 claims description 20
- 238000012384 transportation and delivery Methods 0.000 claims description 19
- 238000006471 dimerization reaction Methods 0.000 claims description 15
- 210000004881 tumor cell Anatomy 0.000 claims description 15
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 14
- 102000006495 integrins Human genes 0.000 claims description 14
- 108010044426 integrins Proteins 0.000 claims description 14
- 125000003729 nucleotide group Chemical group 0.000 claims description 14
- 108010069754 innate repair receptor Proteins 0.000 claims description 13
- 239000002773 nucleotide Substances 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 11
- 230000000913 erythropoietic effect Effects 0.000 claims description 11
- 230000003472 neutralizing effect Effects 0.000 claims description 10
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 9
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 9
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 8
- 108090000901 Transferrin Proteins 0.000 claims description 8
- 102000004338 Transferrin Human genes 0.000 claims description 8
- 239000012581 transferrin Substances 0.000 claims description 8
- 229910052742 iron Inorganic materials 0.000 claims description 7
- 210000003703 cisterna magna Anatomy 0.000 claims description 5
- 238000009593 lumbar puncture Methods 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 4
- XZWYTXMRWQJBGX-VXBMVYAYSA-N FLAG peptide Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=C(O)C=C1 XZWYTXMRWQJBGX-VXBMVYAYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 102000007238 Transferrin Receptors Human genes 0.000 claims 6
- 101710154606 Hemagglutinin Proteins 0.000 claims 4
- 101710093908 Outer capsid protein VP4 Proteins 0.000 claims 4
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 claims 4
- 101710176177 Protein A56 Proteins 0.000 claims 4
- 239000000185 hemagglutinin Substances 0.000 claims 4
- HVLSXIKZNLPZJJ-TXZCQADKSA-N HA peptide Chemical compound C([C@@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HVLSXIKZNLPZJJ-TXZCQADKSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 34
- 210000003169 central nervous system Anatomy 0.000 abstract description 25
- 229940124597 therapeutic agent Drugs 0.000 abstract description 25
- 230000003612 virological effect Effects 0.000 abstract description 13
- 208000012902 Nervous system disease Diseases 0.000 abstract description 6
- 208000025966 Neurological disease Diseases 0.000 abstract description 6
- 208000022873 Ocular disease Diseases 0.000 abstract description 5
- 230000000926 neurological effect Effects 0.000 abstract description 3
- 235000001014 amino acid Nutrition 0.000 description 243
- 229940024606 amino acid Drugs 0.000 description 224
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 89
- 238000010361 transduction Methods 0.000 description 77
- 230000026683 transduction Effects 0.000 description 76
- 235000018102 proteins Nutrition 0.000 description 74
- 230000015572 biosynthetic process Effects 0.000 description 63
- 238000003786 synthesis reaction Methods 0.000 description 62
- 239000003795 chemical substances by application Substances 0.000 description 49
- 201000010099 disease Diseases 0.000 description 46
- 208000035475 disorder Diseases 0.000 description 43
- 241001465754 Metazoa Species 0.000 description 37
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 36
- 241001655883 Adeno-associated virus - 1 Species 0.000 description 34
- 239000000203 mixture Substances 0.000 description 34
- 230000000694 effects Effects 0.000 description 32
- 241000699670 Mus sp. Species 0.000 description 31
- 230000008499 blood brain barrier function Effects 0.000 description 31
- 210000001218 blood-brain barrier Anatomy 0.000 description 31
- 230000000069 prophylactic effect Effects 0.000 description 29
- 238000002347 injection Methods 0.000 description 24
- 239000007924 injection Substances 0.000 description 24
- 108020004414 DNA Proteins 0.000 description 23
- 238000004458 analytical method Methods 0.000 description 22
- 238000011282 treatment Methods 0.000 description 20
- 241000699666 Mus <mouse, genus> Species 0.000 description 19
- 230000014509 gene expression Effects 0.000 description 19
- 239000005090 green fluorescent protein Substances 0.000 description 19
- 210000004185 liver Anatomy 0.000 description 18
- 239000011159 matrix material Substances 0.000 description 18
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 17
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 17
- 230000001965 increasing effect Effects 0.000 description 17
- 238000007481 next generation sequencing Methods 0.000 description 17
- 230000001225 therapeutic effect Effects 0.000 description 17
- 108050003222 Transferrin receptor protein 1 Proteins 0.000 description 16
- 238000001990 intravenous administration Methods 0.000 description 16
- 238000012986 modification Methods 0.000 description 16
- 230000004048 modification Effects 0.000 description 16
- 238000010276 construction Methods 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 15
- 210000001525 retina Anatomy 0.000 description 15
- 210000000056 organ Anatomy 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 241000700605 Viruses Species 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- WZTIQQBMSJTRBR-WYKNNRPVSA-N (4S)-5-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-oxo-4-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCC(=O)N1 WZTIQQBMSJTRBR-WYKNNRPVSA-N 0.000 description 12
- 108010079364 N-glycylalanine Proteins 0.000 description 12
- 238000011529 RT qPCR Methods 0.000 description 12
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 12
- 230000010354 integration Effects 0.000 description 12
- 208000002267 Anti-neutrophil cytoplasmic antibody-associated vasculitis Diseases 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 11
- 108010088797 cibinetide Proteins 0.000 description 11
- 210000001508 eye Anatomy 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 238000003556 assay Methods 0.000 description 10
- 230000008901 benefit Effects 0.000 description 10
- 238000004113 cell culture Methods 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 230000003278 mimic effect Effects 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 230000010415 tropism Effects 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 9
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 8
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 8
- NMCBVGFGWSIGSB-NUTKFTJISA-N Trp-Ala-Leu Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N NMCBVGFGWSIGSB-NUTKFTJISA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000001415 gene therapy Methods 0.000 description 8
- 230000005100 tissue tropism Effects 0.000 description 8
- 238000012546 transfer Methods 0.000 description 8
- 230000032258 transport Effects 0.000 description 8
- 101150044789 Cap gene Proteins 0.000 description 7
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 7
- 238000011887 Necropsy Methods 0.000 description 7
- SZRNDHWMVSFPSP-XKBZYTNZSA-N Ser-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N)O SZRNDHWMVSFPSP-XKBZYTNZSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 235000004279 alanine Nutrition 0.000 description 7
- 238000010171 animal model Methods 0.000 description 7
- 238000013270 controlled release Methods 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 230000002093 peripheral effect Effects 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 238000001890 transfection Methods 0.000 description 7
- 241000701161 unidentified adenovirus Species 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 108091092584 GDNA Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 6
- 108060001084 Luciferase Proteins 0.000 description 6
- 241000282567 Macaca fascicularis Species 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- 241000288906 Primates Species 0.000 description 6
- 108010092854 aspartyllysine Proteins 0.000 description 6
- 230000008827 biological function Effects 0.000 description 6
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 6
- 238000009792 diffusion process Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 210000002216 heart Anatomy 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 210000004379 membrane Anatomy 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 101000834253 Gallus gallus Actin, cytoplasmic 1 Proteins 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 102000029749 Microtubule Human genes 0.000 description 5
- 108091022875 Microtubule Proteins 0.000 description 5
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 235000009582 asparagine Nutrition 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 208000002780 macular degeneration Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 108010016686 methionyl-alanyl-serine Proteins 0.000 description 5
- 210000004688 microtubule Anatomy 0.000 description 5
- 210000002569 neuron Anatomy 0.000 description 5
- 230000002276 neurotropic effect Effects 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 210000003994 retinal ganglion cell Anatomy 0.000 description 5
- 238000012552 review Methods 0.000 description 5
- 210000003497 sciatic nerve Anatomy 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- IBIDRSSEHFLGSD-UHFFFAOYSA-N valinyl-arginine Natural products CC(C)C(N)C(=O)NC(C(O)=O)CCCN=C(N)N IBIDRSSEHFLGSD-UHFFFAOYSA-N 0.000 description 5
- 241000958487 Adeno-associated virus 3B Species 0.000 description 4
- 241000282693 Cercopithecidae Species 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- JSYULGSPLTZDHM-NRPADANISA-N Gln-Ala-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O JSYULGSPLTZDHM-NRPADANISA-N 0.000 description 4
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 4
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 4
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 4
- 241000880493 Leptailurus serval Species 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- VHGIWFGJIHTASW-FXQIFTODSA-N Met-Ala-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O VHGIWFGJIHTASW-FXQIFTODSA-N 0.000 description 4
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 4
- 241000125945 Protoparvovirus Species 0.000 description 4
- 101100150366 Schizosaccharomyces pombe (strain 972 / ATCC 24843) sks2 gene Proteins 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 230000001086 cytosolic effect Effects 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 230000009977 dual effect Effects 0.000 description 4
- 230000002068 genetic effect Effects 0.000 description 4
- 108010092114 histidylphenylalanine Proteins 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 210000000663 muscle cell Anatomy 0.000 description 4
- 210000001672 ovary Anatomy 0.000 description 4
- 108010051242 phenylalanylserine Proteins 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000003753 real-time PCR Methods 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 210000000844 retinal pigment epithelial cell Anatomy 0.000 description 4
- 238000002864 sequence alignment Methods 0.000 description 4
- 210000002027 skeletal muscle Anatomy 0.000 description 4
- 210000000278 spinal cord Anatomy 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- OZRFYUJEXYKQDV-UHFFFAOYSA-N 2-[[2-[[2-[(2-amino-3-carboxypropanoyl)amino]-3-carboxypropanoyl]amino]-3-carboxypropanoyl]amino]butanedioic acid Chemical compound OC(=O)CC(N)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(O)=O OZRFYUJEXYKQDV-UHFFFAOYSA-N 0.000 description 3
- 241000649045 Adeno-associated virus 10 Species 0.000 description 3
- 241000649046 Adeno-associated virus 11 Species 0.000 description 3
- 241000649047 Adeno-associated virus 12 Species 0.000 description 3
- 241000300529 Adeno-associated virus 13 Species 0.000 description 3
- FJVAQLJNTSUQPY-CIUDSAMLSA-N Ala-Ala-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN FJVAQLJNTSUQPY-CIUDSAMLSA-N 0.000 description 3
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 3
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 3
- NHCPCLJZRSIDHS-ZLUOBGJFSA-N Ala-Asp-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O NHCPCLJZRSIDHS-ZLUOBGJFSA-N 0.000 description 3
- GSCLWXDNIMNIJE-ZLUOBGJFSA-N Ala-Asp-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GSCLWXDNIMNIJE-ZLUOBGJFSA-N 0.000 description 3
- KIUYPHAMDKDICO-WHFBIAKZSA-N Ala-Asp-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KIUYPHAMDKDICO-WHFBIAKZSA-N 0.000 description 3
- CZPAHAKGPDUIPJ-CIUDSAMLSA-N Ala-Gln-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O CZPAHAKGPDUIPJ-CIUDSAMLSA-N 0.000 description 3
- LMFXXZPPZDCPTA-ZKWXMUAHSA-N Ala-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N LMFXXZPPZDCPTA-ZKWXMUAHSA-N 0.000 description 3
- CCDFBRZVTDDJNM-GUBZILKMSA-N Ala-Leu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CCDFBRZVTDDJNM-GUBZILKMSA-N 0.000 description 3
- VCSABYLVNWQYQE-SRVKXCTJSA-N Ala-Lys-Lys Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CCCCN)C(O)=O VCSABYLVNWQYQE-SRVKXCTJSA-N 0.000 description 3
- VCSABYLVNWQYQE-UHFFFAOYSA-N Ala-Lys-Lys Natural products NCCCCC(NC(=O)C(N)C)C(=O)NC(CCCCN)C(O)=O VCSABYLVNWQYQE-UHFFFAOYSA-N 0.000 description 3
- FEGOCLZUJUFCHP-CIUDSAMLSA-N Ala-Pro-Gln Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O FEGOCLZUJUFCHP-CIUDSAMLSA-N 0.000 description 3
- YHBDGLZYNIARKJ-GUBZILKMSA-N Ala-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N YHBDGLZYNIARKJ-GUBZILKMSA-N 0.000 description 3
- NCQMBSJGJMYKCK-ZLUOBGJFSA-N Ala-Ser-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O NCQMBSJGJMYKCK-ZLUOBGJFSA-N 0.000 description 3
- YCTIYBUTCKNOTI-UWJYBYFXSA-N Ala-Tyr-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N YCTIYBUTCKNOTI-UWJYBYFXSA-N 0.000 description 3
- JNJHNBXBGNJESC-KKXDTOCCSA-N Ala-Tyr-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JNJHNBXBGNJESC-KKXDTOCCSA-N 0.000 description 3
- JQFJNGVSGOUQDH-XIRDDKMYSA-N Arg-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCN=C(N)N)N)C(O)=O)=CNC2=C1 JQFJNGVSGOUQDH-XIRDDKMYSA-N 0.000 description 3
- UHFUZWSZQKMDSX-DCAQKATOSA-N Arg-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N UHFUZWSZQKMDSX-DCAQKATOSA-N 0.000 description 3
- UZGFHWIJWPUPOH-IHRRRGAJSA-N Arg-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N UZGFHWIJWPUPOH-IHRRRGAJSA-N 0.000 description 3
- FRBAHXABMQXSJQ-FXQIFTODSA-N Arg-Ser-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O FRBAHXABMQXSJQ-FXQIFTODSA-N 0.000 description 3
- YNSUUAOAFCVINY-OSUNSFLBSA-N Arg-Thr-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YNSUUAOAFCVINY-OSUNSFLBSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- AYZAWXAPBAYCHO-CIUDSAMLSA-N Asn-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N AYZAWXAPBAYCHO-CIUDSAMLSA-N 0.000 description 3
- GNKVBRYFXYWXAB-WDSKDSINSA-N Asn-Glu-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O GNKVBRYFXYWXAB-WDSKDSINSA-N 0.000 description 3
- XEDQMTWEYFBOIK-ACZMJKKPSA-N Asp-Ala-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O XEDQMTWEYFBOIK-ACZMJKKPSA-N 0.000 description 3
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 3
- UGKZHCBLMLSANF-CIUDSAMLSA-N Asp-Asn-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O UGKZHCBLMLSANF-CIUDSAMLSA-N 0.000 description 3
- UGIBTKGQVWFTGX-BIIVOSGPSA-N Asp-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)O)N)C(=O)O UGIBTKGQVWFTGX-BIIVOSGPSA-N 0.000 description 3
- PGUYEUCYVNZGGV-QWRGUYRKSA-N Asp-Gly-Tyr Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PGUYEUCYVNZGGV-QWRGUYRKSA-N 0.000 description 3
- ZVGRHIRJLWBWGJ-ACZMJKKPSA-N Asp-Ser-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZVGRHIRJLWBWGJ-ACZMJKKPSA-N 0.000 description 3
- MGSVBZIBCCKGCY-ZLUOBGJFSA-N Asp-Ser-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MGSVBZIBCCKGCY-ZLUOBGJFSA-N 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 206010011906 Death Diseases 0.000 description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- QYTKAVBFRUGYAU-ACZMJKKPSA-N Gln-Asp-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O QYTKAVBFRUGYAU-ACZMJKKPSA-N 0.000 description 3
- GPISLLFQNHELLK-DCAQKATOSA-N Gln-Gln-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N GPISLLFQNHELLK-DCAQKATOSA-N 0.000 description 3
- KVXVVDFOZNYYKZ-DCAQKATOSA-N Gln-Gln-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O KVXVVDFOZNYYKZ-DCAQKATOSA-N 0.000 description 3
- VOLVNCMGXWDDQY-LPEHRKFASA-N Gln-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N)C(=O)O VOLVNCMGXWDDQY-LPEHRKFASA-N 0.000 description 3
- OREPWMPAUWIIAM-ZPFDUUQYSA-N Gln-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(=O)N)N OREPWMPAUWIIAM-ZPFDUUQYSA-N 0.000 description 3
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 3
- SBCYJMOOHUDWDA-NUMRIWBASA-N Glu-Asp-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SBCYJMOOHUDWDA-NUMRIWBASA-N 0.000 description 3
- CUXJIASLBRJOFV-LAEOZQHASA-N Glu-Gly-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O CUXJIASLBRJOFV-LAEOZQHASA-N 0.000 description 3
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-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
- PMNHJLASAAWELO-FOHZUACHSA-N Gly-Asp-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PMNHJLASAAWELO-FOHZUACHSA-N 0.000 description 3
- BEQGFMIBZFNROK-JGVFFNPUSA-N Gly-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)CN)C(=O)O BEQGFMIBZFNROK-JGVFFNPUSA-N 0.000 description 3
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 3
- YTSVAIMKVLZUDU-YUMQZZPRSA-N Gly-Leu-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YTSVAIMKVLZUDU-YUMQZZPRSA-N 0.000 description 3
- VEPBEGNDJYANCF-QWRGUYRKSA-N Gly-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCCN VEPBEGNDJYANCF-QWRGUYRKSA-N 0.000 description 3
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 3
- PNUFMLXHOLFRLD-KBPBESRZSA-N Gly-Tyr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 PNUFMLXHOLFRLD-KBPBESRZSA-N 0.000 description 3
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 3
- BDHUXUFYNUOUIT-SRVKXCTJSA-N His-Asp-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BDHUXUFYNUOUIT-SRVKXCTJSA-N 0.000 description 3
- JODPUDMBQBIWCK-GHCJXIJMSA-N Ile-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O JODPUDMBQBIWCK-GHCJXIJMSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- HYIFFZAQXPUEAU-QWRGUYRKSA-N Leu-Gly-Leu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C HYIFFZAQXPUEAU-QWRGUYRKSA-N 0.000 description 3
- BMVFXOQHDQZAQU-DCAQKATOSA-N Leu-Pro-Asp Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N BMVFXOQHDQZAQU-DCAQKATOSA-N 0.000 description 3
- MPOHDJKRBLVGCT-CIUDSAMLSA-N Lys-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N MPOHDJKRBLVGCT-CIUDSAMLSA-N 0.000 description 3
- XFIHDSBIPWEYJJ-YUMQZZPRSA-N Lys-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN XFIHDSBIPWEYJJ-YUMQZZPRSA-N 0.000 description 3
- LCMWVZLBCUVDAZ-IUCAKERBSA-N Lys-Gly-Glu Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CCC([O-])=O LCMWVZLBCUVDAZ-IUCAKERBSA-N 0.000 description 3
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 3
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 3
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- YRAWWKUTNBILNT-FXQIFTODSA-N Met-Ala-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O YRAWWKUTNBILNT-FXQIFTODSA-N 0.000 description 3
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- UNLYPPYNDXHGDG-IHRRRGAJSA-N Phe-Gln-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 UNLYPPYNDXHGDG-IHRRRGAJSA-N 0.000 description 3
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 3
- YFNOUBWUIIJQHF-LPEHRKFASA-N Pro-Asp-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O YFNOUBWUIIJQHF-LPEHRKFASA-N 0.000 description 3
- UUHXBJHVTVGSKM-BQBZGAKWSA-N Pro-Gly-Asn Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UUHXBJHVTVGSKM-BQBZGAKWSA-N 0.000 description 3
- VVAWNPIOYXAMAL-KJEVXHAQSA-N Pro-Thr-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VVAWNPIOYXAMAL-KJEVXHAQSA-N 0.000 description 3
- IMNVAOPEMFDAQD-NHCYSSNCSA-N Pro-Val-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IMNVAOPEMFDAQD-NHCYSSNCSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- UBRXAVQWXOWRSJ-ZLUOBGJFSA-N Ser-Asn-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)C(=O)N UBRXAVQWXOWRSJ-ZLUOBGJFSA-N 0.000 description 3
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 3
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 3
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 3
- XKFJENWJGHMDLI-QWRGUYRKSA-N Ser-Phe-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O XKFJENWJGHMDLI-QWRGUYRKSA-N 0.000 description 3
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 3
- 108091081024 Start codon Proteins 0.000 description 3
- LVHHEVGYAZGXDE-KDXUFGMBSA-N Thr-Ala-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(=O)O)N)O LVHHEVGYAZGXDE-KDXUFGMBSA-N 0.000 description 3
- WFUAUEQXPVNAEF-ZJDVBMNYSA-N Thr-Arg-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CCCN=C(N)N WFUAUEQXPVNAEF-ZJDVBMNYSA-N 0.000 description 3
- UJQVSMNQMQHVRY-KZVJFYERSA-N Thr-Met-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O UJQVSMNQMQHVRY-KZVJFYERSA-N 0.000 description 3
- IWAVRIPRTCJAQO-HSHDSVGOSA-N Thr-Pro-Trp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O IWAVRIPRTCJAQO-HSHDSVGOSA-N 0.000 description 3
- ZMYCLHFLHRVOEA-HEIBUPTGSA-N Thr-Thr-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ZMYCLHFLHRVOEA-HEIBUPTGSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- YRSOERSDNRSCBC-XIRDDKMYSA-N Trp-His-Cys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CN=CN3)C(=O)N[C@@H](CS)C(=O)O)N YRSOERSDNRSCBC-XIRDDKMYSA-N 0.000 description 3
- VPRHDRKAPYZMHL-SZMVWBNQSA-N Trp-Leu-Glu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 VPRHDRKAPYZMHL-SZMVWBNQSA-N 0.000 description 3
- UJRIVCPPPMYCNA-HOCLYGCPSA-N Trp-Leu-Gly Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N UJRIVCPPPMYCNA-HOCLYGCPSA-N 0.000 description 3
- CYDVHRFXDMDMGX-KKUMJFAQSA-N Tyr-Asn-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O CYDVHRFXDMDMGX-KKUMJFAQSA-N 0.000 description 3
- DWAMXBFJNZIHMC-KBPBESRZSA-N Tyr-Leu-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O DWAMXBFJNZIHMC-KBPBESRZSA-N 0.000 description 3
- PRONOHBTMLNXCZ-BZSNNMDCSA-N Tyr-Leu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 PRONOHBTMLNXCZ-BZSNNMDCSA-N 0.000 description 3
- BYAKMYBZADCNMN-JYJNAYRXSA-N Tyr-Lys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O BYAKMYBZADCNMN-JYJNAYRXSA-N 0.000 description 3
- QPZMOUMNTGTEFR-ZKWXMUAHSA-N Val-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C(C)C)N QPZMOUMNTGTEFR-ZKWXMUAHSA-N 0.000 description 3
- SZTTYWIUCGSURQ-AUTRQRHGSA-N Val-Glu-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SZTTYWIUCGSURQ-AUTRQRHGSA-N 0.000 description 3
- LAYSXAOGWHKNED-XPUUQOCRSA-N Val-Gly-Ser Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LAYSXAOGWHKNED-XPUUQOCRSA-N 0.000 description 3
- ZHQWPWQNVRCXAX-XQQFMLRXSA-N Val-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N ZHQWPWQNVRCXAX-XQQFMLRXSA-N 0.000 description 3
- QIVPZSWBBHRNBA-JYJNAYRXSA-N Val-Pro-Phe Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O QIVPZSWBBHRNBA-JYJNAYRXSA-N 0.000 description 3
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 3
- 210000000411 amacrine cell Anatomy 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 238000011953 bioanalysis Methods 0.000 description 3
- 210000004958 brain cell Anatomy 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000004700 cellular uptake Effects 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000001476 gene delivery Methods 0.000 description 3
- 108010011901 glutaminyl-glutamyl-glutaminyl-leucyl-glutamyl-arginyl-alanyl-leucyl-asparagyl-seryl-serine Proteins 0.000 description 3
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 3
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 3
- 108010059898 glycyl-tyrosyl-lysine Proteins 0.000 description 3
- 108010050848 glycylleucine Proteins 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 108010040030 histidinoalanine Proteins 0.000 description 3
- 108010025306 histidylleucine Proteins 0.000 description 3
- 210000002287 horizontal cell Anatomy 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 108010034529 leucyl-lysine Proteins 0.000 description 3
- 108010090333 leucyl-lysyl-proline Proteins 0.000 description 3
- 108010047926 leucyl-lysyl-tyrosine Proteins 0.000 description 3
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 3
- 108010057821 leucylproline Proteins 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 238000009126 molecular therapy Methods 0.000 description 3
- 238000002703 mutagenesis Methods 0.000 description 3
- 231100000350 mutagenesis Toxicity 0.000 description 3
- 210000001577 neostriatum Anatomy 0.000 description 3
- 210000004498 neuroglial cell Anatomy 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 3
- 108010012581 phenylalanylglutamate Proteins 0.000 description 3
- 210000000608 photoreceptor cell Anatomy 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 108010077112 prolyl-proline Proteins 0.000 description 3
- 101150066583 rep gene Proteins 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 108010061238 threonyl-glycine Proteins 0.000 description 3
- 108010015666 tryptophyl-leucyl-glutamic acid Proteins 0.000 description 3
- 108010038745 tryptophylglycine Proteins 0.000 description 3
- 108010045269 tryptophyltryptophan Proteins 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- BYXHQQCXAJARLQ-ZLUOBGJFSA-N Ala-Ala-Ala Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O BYXHQQCXAJARLQ-ZLUOBGJFSA-N 0.000 description 2
- YSMPVONNIWLJML-FXQIFTODSA-N Ala-Asp-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(O)=O YSMPVONNIWLJML-FXQIFTODSA-N 0.000 description 2
- IKKVASZHTMKJIR-ZKWXMUAHSA-N Ala-Asp-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O IKKVASZHTMKJIR-ZKWXMUAHSA-N 0.000 description 2
- LGFCAXJBAZESCF-ACZMJKKPSA-N Ala-Gln-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O LGFCAXJBAZESCF-ACZMJKKPSA-N 0.000 description 2
- GRPHQEMIFDPKOE-HGNGGELXSA-N Ala-His-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O GRPHQEMIFDPKOE-HGNGGELXSA-N 0.000 description 2
- NHWYNIZWLJYZAG-XVYDVKMFSA-N Ala-Ser-His Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N NHWYNIZWLJYZAG-XVYDVKMFSA-N 0.000 description 2
- LSMDIAAALJJLRO-XQXXSGGOSA-N Ala-Thr-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O LSMDIAAALJJLRO-XQXXSGGOSA-N 0.000 description 2
- XSLGWYYNOSUMRM-ZKWXMUAHSA-N Ala-Val-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O XSLGWYYNOSUMRM-ZKWXMUAHSA-N 0.000 description 2
- VHAQSYHSDKERBS-XPUUQOCRSA-N Ala-Val-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O VHAQSYHSDKERBS-XPUUQOCRSA-N 0.000 description 2
- INOIAEUXVVNJKA-XGEHTFHBSA-N Arg-Thr-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O INOIAEUXVVNJKA-XGEHTFHBSA-N 0.000 description 2
- FSPQNLYOFCXUCE-BPUTZDHNSA-N Arg-Trp-Asn Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N FSPQNLYOFCXUCE-BPUTZDHNSA-N 0.000 description 2
- CGWVCWFQGXOUSJ-ULQDDVLXSA-N Arg-Tyr-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O CGWVCWFQGXOUSJ-ULQDDVLXSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- KXFCBAHYSLJCCY-ZLUOBGJFSA-N Asn-Asn-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O KXFCBAHYSLJCCY-ZLUOBGJFSA-N 0.000 description 2
- VJTWLBMESLDOMK-WDSKDSINSA-N Asn-Gln-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VJTWLBMESLDOMK-WDSKDSINSA-N 0.000 description 2
- FTCGGKNCJZOPNB-WHFBIAKZSA-N Asn-Gly-Ser Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FTCGGKNCJZOPNB-WHFBIAKZSA-N 0.000 description 2
- MOHUTCNYQLMARY-GUBZILKMSA-N Asn-His-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MOHUTCNYQLMARY-GUBZILKMSA-N 0.000 description 2
- 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 2
- RVHGJNGNKGDCPX-KKUMJFAQSA-N Asn-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N RVHGJNGNKGDCPX-KKUMJFAQSA-N 0.000 description 2
- GKKUBLFXKRDMFC-BQBZGAKWSA-N Asn-Pro-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O GKKUBLFXKRDMFC-BQBZGAKWSA-N 0.000 description 2
- VHQSGALUSWIYOD-QXEWZRGKSA-N Asn-Pro-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O VHQSGALUSWIYOD-QXEWZRGKSA-N 0.000 description 2
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 2
- DAYDURRBMDCCFL-AAEUAGOBSA-N Asn-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N DAYDURRBMDCCFL-AAEUAGOBSA-N 0.000 description 2
- BEHQTVDBCLSCBY-CFMVVWHZSA-N Asn-Tyr-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BEHQTVDBCLSCBY-CFMVVWHZSA-N 0.000 description 2
- LRCIOEVFVGXZKB-BZSNNMDCSA-N Asn-Tyr-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LRCIOEVFVGXZKB-BZSNNMDCSA-N 0.000 description 2
- MYRLSKYSMXNLLA-LAEOZQHASA-N Asn-Val-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O MYRLSKYSMXNLLA-LAEOZQHASA-N 0.000 description 2
- WSWYMRLTJVKRCE-ZLUOBGJFSA-N Asp-Ala-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O WSWYMRLTJVKRCE-ZLUOBGJFSA-N 0.000 description 2
- IXIWEFWRKIUMQX-DCAQKATOSA-N Asp-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)CC(O)=O IXIWEFWRKIUMQX-DCAQKATOSA-N 0.000 description 2
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 2
- UQBGYPFHWFZMCD-ZLUOBGJFSA-N Asp-Asn-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O UQBGYPFHWFZMCD-ZLUOBGJFSA-N 0.000 description 2
- RDRMWJBLOSRRAW-BYULHYEWSA-N Asp-Asn-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O RDRMWJBLOSRRAW-BYULHYEWSA-N 0.000 description 2
- IDDMGSKZQDEDGA-SRVKXCTJSA-N Asp-Phe-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=CC=C1 IDDMGSKZQDEDGA-SRVKXCTJSA-N 0.000 description 2
- OYSYWMMZGJSQRB-AVGNSLFASA-N Asp-Tyr-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O OYSYWMMZGJSQRB-AVGNSLFASA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000006992 Color Vision Defects Diseases 0.000 description 2
- PQHYZJPCYRDYNE-QWRGUYRKSA-N Cys-Gly-Phe Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PQHYZJPCYRDYNE-QWRGUYRKSA-N 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 108060002900 Filamin Proteins 0.000 description 2
- 102000013366 Filamin Human genes 0.000 description 2
- 208000003098 Ganglion Cysts Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- LJEPDHWNQXPXMM-NHCYSSNCSA-N Gln-Arg-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O LJEPDHWNQXPXMM-NHCYSSNCSA-N 0.000 description 2
- NPTGGVQJYRSMCM-GLLZPBPUSA-N Gln-Gln-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NPTGGVQJYRSMCM-GLLZPBPUSA-N 0.000 description 2
- IKFZXRLDMYWNBU-YUMQZZPRSA-N Gln-Gly-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N IKFZXRLDMYWNBU-YUMQZZPRSA-N 0.000 description 2
- HPCOBEHVEHWREJ-DCAQKATOSA-N Gln-Lys-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HPCOBEHVEHWREJ-DCAQKATOSA-N 0.000 description 2
- ININBLZFFVOQIO-JHEQGTHGSA-N Gln-Thr-Gly Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CCC(=O)N)N)O ININBLZFFVOQIO-JHEQGTHGSA-N 0.000 description 2
- JKDBRTNMYXYLHO-JYJNAYRXSA-N Gln-Tyr-Leu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 JKDBRTNMYXYLHO-JYJNAYRXSA-N 0.000 description 2
- MKRDNSWGJWTBKZ-GVXVVHGQSA-N Gln-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MKRDNSWGJWTBKZ-GVXVVHGQSA-N 0.000 description 2
- ZMXZGYLINVNTKH-DZKIICNBSA-N Gln-Val-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZMXZGYLINVNTKH-DZKIICNBSA-N 0.000 description 2
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 2
- AUTNXSQEVVHSJK-YVNDNENWSA-N Glu-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O AUTNXSQEVVHSJK-YVNDNENWSA-N 0.000 description 2
- OGNJZUXUTPQVBR-BQBZGAKWSA-N Glu-Gly-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O OGNJZUXUTPQVBR-BQBZGAKWSA-N 0.000 description 2
- WVYJNPCWJYBHJG-YVNDNENWSA-N Glu-Ile-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(O)=O WVYJNPCWJYBHJG-YVNDNENWSA-N 0.000 description 2
- VGUYMZGLJUJRBV-YVNDNENWSA-N Glu-Ile-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O VGUYMZGLJUJRBV-YVNDNENWSA-N 0.000 description 2
- PMSMKNYRZCKVMC-DRZSPHRISA-N Glu-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CCC(=O)O)N PMSMKNYRZCKVMC-DRZSPHRISA-N 0.000 description 2
- TWYFJOHWGCCRIR-DCAQKATOSA-N Glu-Pro-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TWYFJOHWGCCRIR-DCAQKATOSA-N 0.000 description 2
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 2
- XUDLUKYPXQDCRX-BQBZGAKWSA-N Gly-Arg-Asn Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O XUDLUKYPXQDCRX-BQBZGAKWSA-N 0.000 description 2
- CIMULJZTTOBOPN-WHFBIAKZSA-N Gly-Asn-Asn Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CIMULJZTTOBOPN-WHFBIAKZSA-N 0.000 description 2
- JVACNFOPSUPDTK-QWRGUYRKSA-N Gly-Asn-Phe Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JVACNFOPSUPDTK-QWRGUYRKSA-N 0.000 description 2
- IXKRSKPKSLXIHN-YUMQZZPRSA-N Gly-Cys-Leu Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O IXKRSKPKSLXIHN-YUMQZZPRSA-N 0.000 description 2
- BULIVUZUDBHKKZ-WDSKDSINSA-N Gly-Gln-Asn Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O BULIVUZUDBHKKZ-WDSKDSINSA-N 0.000 description 2
- CSMYMGFCEJWALV-WDSKDSINSA-N Gly-Ser-Gln Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O CSMYMGFCEJWALV-WDSKDSINSA-N 0.000 description 2
- RIYIFUFFFBIOEU-KBPBESRZSA-N Gly-Tyr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 RIYIFUFFFBIOEU-KBPBESRZSA-N 0.000 description 2
- OCRQUYDOYKCOQG-IRXDYDNUSA-N Gly-Tyr-Phe Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 OCRQUYDOYKCOQG-IRXDYDNUSA-N 0.000 description 2
- FNXSYBOHALPRHV-ONGXEEELSA-N Gly-Val-Lys Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN FNXSYBOHALPRHV-ONGXEEELSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- XINDHUAGVGCNSF-QSFUFRPTSA-N His-Ala-Ile Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XINDHUAGVGCNSF-QSFUFRPTSA-N 0.000 description 2
- HYWZHNUGAYVEEW-KKUMJFAQSA-N His-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N HYWZHNUGAYVEEW-KKUMJFAQSA-N 0.000 description 2
- YEKYGQZUBCRNGH-DCAQKATOSA-N His-Pro-Ser Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CN=CN2)N)C(=O)N[C@@H](CO)C(=O)O YEKYGQZUBCRNGH-DCAQKATOSA-N 0.000 description 2
- VIJMRAIWYWRXSR-CIUDSAMLSA-N His-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CN=CN1 VIJMRAIWYWRXSR-CIUDSAMLSA-N 0.000 description 2
- XHQYFGPIRUHQIB-PBCZWWQYSA-N His-Thr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CN=CN1 XHQYFGPIRUHQIB-PBCZWWQYSA-N 0.000 description 2
- 101000766306 Homo sapiens Serotransferrin Proteins 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- 108090000144 Human Proteins Proteins 0.000 description 2
- 102000003839 Human Proteins Human genes 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- GAZGFPOZOLEYAJ-YTFOTSKYSA-N Ile-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N GAZGFPOZOLEYAJ-YTFOTSKYSA-N 0.000 description 2
- JTBFQNHKNRZJDS-SYWGBEHUSA-N Ile-Trp-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](C)C(=O)O)N JTBFQNHKNRZJDS-SYWGBEHUSA-N 0.000 description 2
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-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
- 201000003533 Leber congenital amaurosis Diseases 0.000 description 2
- STAVRDQLZOTNKJ-RHYQMDGZSA-N Leu-Arg-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STAVRDQLZOTNKJ-RHYQMDGZSA-N 0.000 description 2
- LLBQJYDYOLIQAI-JYJNAYRXSA-N Leu-Glu-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LLBQJYDYOLIQAI-JYJNAYRXSA-N 0.000 description 2
- VGPCJSXPPOQPBK-YUMQZZPRSA-N Leu-Gly-Ser Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O VGPCJSXPPOQPBK-YUMQZZPRSA-N 0.000 description 2
- USLNHQZCDQJBOV-ZPFDUUQYSA-N Leu-Ile-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O USLNHQZCDQJBOV-ZPFDUUQYSA-N 0.000 description 2
- KOSWSHVQIVTVQF-ZPFDUUQYSA-N Leu-Ile-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O KOSWSHVQIVTVQF-ZPFDUUQYSA-N 0.000 description 2
- QLDHBYRUNQZIJQ-DKIMLUQUSA-N Leu-Ile-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QLDHBYRUNQZIJQ-DKIMLUQUSA-N 0.000 description 2
- QNTJIDXQHWUBKC-BZSNNMDCSA-N Leu-Lys-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QNTJIDXQHWUBKC-BZSNNMDCSA-N 0.000 description 2
- FLNPJLDPGMLWAU-UWVGGRQHSA-N Leu-Met-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(C)C FLNPJLDPGMLWAU-UWVGGRQHSA-N 0.000 description 2
- BIZNDKMFQHDOIE-KKUMJFAQSA-N Leu-Phe-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=CC=C1 BIZNDKMFQHDOIE-KKUMJFAQSA-N 0.000 description 2
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 2
- YNNPKXBBRZVIRX-IHRRRGAJSA-N Lys-Arg-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O YNNPKXBBRZVIRX-IHRRRGAJSA-N 0.000 description 2
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 2
- VSRXPEHZMHSFKU-IUCAKERBSA-N Lys-Gln-Gly Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VSRXPEHZMHSFKU-IUCAKERBSA-N 0.000 description 2
- GNLJXWBNLAIPEP-MELADBBJSA-N Lys-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CCCCN)N)C(=O)O GNLJXWBNLAIPEP-MELADBBJSA-N 0.000 description 2
- IZJGPPIGYTVXLB-FQUUOJAGSA-N Lys-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IZJGPPIGYTVXLB-FQUUOJAGSA-N 0.000 description 2
- NJNRBRKHOWSGMN-SRVKXCTJSA-N Lys-Leu-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O NJNRBRKHOWSGMN-SRVKXCTJSA-N 0.000 description 2
- GHKXHCMRAUYLBS-CIUDSAMLSA-N Lys-Ser-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O GHKXHCMRAUYLBS-CIUDSAMLSA-N 0.000 description 2
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 2
- VWJFOUBDZIUXGA-AVGNSLFASA-N Lys-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCCCN)N VWJFOUBDZIUXGA-AVGNSLFASA-N 0.000 description 2
- 208000001344 Macular Edema Diseases 0.000 description 2
- DTICLBJHRYSJLH-GUBZILKMSA-N Met-Ala-Val Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O DTICLBJHRYSJLH-GUBZILKMSA-N 0.000 description 2
- IHITVQKJXQQGLJ-LPEHRKFASA-N Met-Asn-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N IHITVQKJXQQGLJ-LPEHRKFASA-N 0.000 description 2
- 210000005156 Müller Glia Anatomy 0.000 description 2
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 2
- 108091005461 Nucleic proteins Proteins 0.000 description 2
- BRDYYVQTEJVRQT-HRCADAONSA-N Phe-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O BRDYYVQTEJVRQT-HRCADAONSA-N 0.000 description 2
- KAHUBGWSIQNZQQ-KKUMJFAQSA-N Phe-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 KAHUBGWSIQNZQQ-KKUMJFAQSA-N 0.000 description 2
- GDBOREPXIRKSEQ-FHWLQOOXSA-N Phe-Gln-Phe Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O GDBOREPXIRKSEQ-FHWLQOOXSA-N 0.000 description 2
- FMMIYCMOVGXZIP-AVGNSLFASA-N Phe-Glu-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O FMMIYCMOVGXZIP-AVGNSLFASA-N 0.000 description 2
- VJLLEKDQJSMHRU-STQMWFEESA-N Phe-Gly-Met Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O VJLLEKDQJSMHRU-STQMWFEESA-N 0.000 description 2
- HQCSLJFGZYOXHW-KKUMJFAQSA-N Phe-His-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CS)C(=O)O)N HQCSLJFGZYOXHW-KKUMJFAQSA-N 0.000 description 2
- QRUOLOPKCOEZKU-HJWJTTGWSA-N Phe-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC1=CC=CC=C1)N QRUOLOPKCOEZKU-HJWJTTGWSA-N 0.000 description 2
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 2
- CVAUVSOFHJKCHN-BZSNNMDCSA-N Phe-Tyr-Cys Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(O)=O)C1=CC=CC=C1 CVAUVSOFHJKCHN-BZSNNMDCSA-N 0.000 description 2
- DRVIASBABBMZTF-GUBZILKMSA-N Pro-Ala-Met Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@@H]1CCCN1 DRVIASBABBMZTF-GUBZILKMSA-N 0.000 description 2
- SSSFPISOZOLQNP-GUBZILKMSA-N Pro-Arg-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O SSSFPISOZOLQNP-GUBZILKMSA-N 0.000 description 2
- KTFZQPLSPLWLKN-KKUMJFAQSA-N Pro-Gln-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KTFZQPLSPLWLKN-KKUMJFAQSA-N 0.000 description 2
- XYHMFGGWNOFUOU-QXEWZRGKSA-N Pro-Ile-Gly Chemical compound OC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CCCN1 XYHMFGGWNOFUOU-QXEWZRGKSA-N 0.000 description 2
- FYKUEXMZYFIZKA-DCAQKATOSA-N Pro-Pro-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O FYKUEXMZYFIZKA-DCAQKATOSA-N 0.000 description 2
- NAIPAPCKKRCMBL-JYJNAYRXSA-N Pro-Pro-Phe Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1NCCC1)C1=CC=CC=C1 NAIPAPCKKRCMBL-JYJNAYRXSA-N 0.000 description 2
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 2
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 2
- KIDXAAQVMNLJFQ-KZVJFYERSA-N Pro-Thr-Ala Chemical compound C[C@@H](O)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](C)C(O)=O KIDXAAQVMNLJFQ-KZVJFYERSA-N 0.000 description 2
- FIDNSJUXESUDOV-JYJNAYRXSA-N Pro-Tyr-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O FIDNSJUXESUDOV-JYJNAYRXSA-N 0.000 description 2
- ZMLRZBWCXPQADC-TUAOUCFPSA-N Pro-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 ZMLRZBWCXPQADC-TUAOUCFPSA-N 0.000 description 2
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 2
- 206010038934 Retinopathy proliferative Diseases 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- MMGJPDWSIOAGTH-ACZMJKKPSA-N Ser-Ala-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MMGJPDWSIOAGTH-ACZMJKKPSA-N 0.000 description 2
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 2
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 2
- XXNYYSXNXCJYKX-DCAQKATOSA-N Ser-Leu-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O XXNYYSXNXCJYKX-DCAQKATOSA-N 0.000 description 2
- KZPRPBLHYMZIMH-MXAVVETBSA-N Ser-Phe-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KZPRPBLHYMZIMH-MXAVVETBSA-N 0.000 description 2
- PURRNJBBXDDWLX-ZDLURKLDSA-N Ser-Thr-Gly Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CO)N)O PURRNJBBXDDWLX-ZDLURKLDSA-N 0.000 description 2
- VLMIUSLQONKLDV-HEIBUPTGSA-N Ser-Thr-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VLMIUSLQONKLDV-HEIBUPTGSA-N 0.000 description 2
- BDMWLJLPPUCLNV-XGEHTFHBSA-N Ser-Thr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BDMWLJLPPUCLNV-XGEHTFHBSA-N 0.000 description 2
- QYBRQMLZDDJBSW-AVGNSLFASA-N Ser-Tyr-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O QYBRQMLZDDJBSW-AVGNSLFASA-N 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 208000005400 Synovial Cyst Diseases 0.000 description 2
- JMZKMSTYXHFYAK-VEVYYDQMSA-N Thr-Arg-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O JMZKMSTYXHFYAK-VEVYYDQMSA-N 0.000 description 2
- QGXCWPNQVCYJEL-NUMRIWBASA-N Thr-Asn-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QGXCWPNQVCYJEL-NUMRIWBASA-N 0.000 description 2
- OHAJHDJOCKKJLV-LKXGYXEUSA-N Thr-Asp-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O OHAJHDJOCKKJLV-LKXGYXEUSA-N 0.000 description 2
- RCEHMXVEMNXRIW-IRIUXVKKSA-N Thr-Gln-Tyr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N)O RCEHMXVEMNXRIW-IRIUXVKKSA-N 0.000 description 2
- SHOMROOOQBDGRL-JHEQGTHGSA-N Thr-Glu-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O SHOMROOOQBDGRL-JHEQGTHGSA-N 0.000 description 2
- KCRQEJSKXAIULJ-FJXKBIBVSA-N Thr-Gly-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O KCRQEJSKXAIULJ-FJXKBIBVSA-N 0.000 description 2
- XOWKUMFHEZLKLT-CIQUZCHMSA-N Thr-Ile-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O XOWKUMFHEZLKLT-CIQUZCHMSA-N 0.000 description 2
- IMDMLDSVUSMAEJ-HJGDQZAQSA-N Thr-Leu-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IMDMLDSVUSMAEJ-HJGDQZAQSA-N 0.000 description 2
- 102000002248 Thyroxine-Binding Globulin Human genes 0.000 description 2
- 108010000259 Thyroxine-Binding Globulin Proteins 0.000 description 2
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 2
- XZLHHHYSWIYXHD-XIRDDKMYSA-N Trp-Gln-Arg Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O XZLHHHYSWIYXHD-XIRDDKMYSA-N 0.000 description 2
- YXONONCLMLHWJX-SZMVWBNQSA-N Trp-Glu-Leu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O)=CNC2=C1 YXONONCLMLHWJX-SZMVWBNQSA-N 0.000 description 2
- WMIUTJPFHMMUGY-ZFWWWQNUSA-N Trp-Pro-Gly Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)N)C(=O)NCC(=O)O WMIUTJPFHMMUGY-ZFWWWQNUSA-N 0.000 description 2
- UUZYQOUJTORBQO-ZVZYQTTQSA-N Trp-Val-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 UUZYQOUJTORBQO-ZVZYQTTQSA-N 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
- SDNVRAKIJVKAGS-LKTVYLICSA-N Tyr-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N SDNVRAKIJVKAGS-LKTVYLICSA-N 0.000 description 2
- HKIUVWMZYFBIHG-KKUMJFAQSA-N Tyr-Arg-Gln Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O HKIUVWMZYFBIHG-KKUMJFAQSA-N 0.000 description 2
- JWGXUKHIKXZWNG-RYUDHWBXSA-N Tyr-Gly-Gln Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O JWGXUKHIKXZWNG-RYUDHWBXSA-N 0.000 description 2
- AUZADXNWQMBZOO-JYJNAYRXSA-N Tyr-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 AUZADXNWQMBZOO-JYJNAYRXSA-N 0.000 description 2
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 2
- HZDQUVQEVVYDDA-ACRUOGEOSA-N Tyr-Tyr-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HZDQUVQEVVYDDA-ACRUOGEOSA-N 0.000 description 2
- 208000014769 Usher Syndromes Diseases 0.000 description 2
- ASQFIHTXXMFENG-XPUUQOCRSA-N Val-Ala-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O ASQFIHTXXMFENG-XPUUQOCRSA-N 0.000 description 2
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 2
- UQMPYVLTQCGRSK-IFFSRLJSSA-N Val-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N)O UQMPYVLTQCGRSK-IFFSRLJSSA-N 0.000 description 2
- IECQJCJNPJVUSB-IHRRRGAJSA-N Val-Tyr-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CO)C(O)=O IECQJCJNPJVUSB-IHRRRGAJSA-N 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 201000000761 achromatopsia Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 206010064930 age-related macular degeneration Diseases 0.000 description 2
- 108010044940 alanylglutamine Proteins 0.000 description 2
- 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 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 108010060035 arginylproline Proteins 0.000 description 2
- 150000001508 asparagines Chemical class 0.000 description 2
- 108010077245 asparaginyl-proline Proteins 0.000 description 2
- 108010047857 aspartylglycine Proteins 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 108010006025 bovine growth hormone Proteins 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 230000005101 cell tropism Effects 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 201000007254 color blindness Diseases 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000002073 fluorescence micrograph Methods 0.000 description 2
- ZXQYGBMAQZUVMI-GCMPRSNUSA-N gamma-cyhalothrin Chemical compound CC1(C)[C@@H](\C=C(/Cl)C(F)(F)F)[C@H]1C(=O)O[C@H](C#N)C1=CC=CC(OC=2C=CC=CC=2)=C1 ZXQYGBMAQZUVMI-GCMPRSNUSA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000010362 genome editing Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 2
- 108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 108010077515 glycylproline Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 238000002991 immunohistochemical analysis Methods 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 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 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 2
- QANMHLXAZMSUEX-UHFFFAOYSA-N kinetin Chemical compound N=1C=NC=2N=CNC=2C=1NCC1=CC=CO1 QANMHLXAZMSUEX-UHFFFAOYSA-N 0.000 description 2
- 210000005240 left ventricle Anatomy 0.000 description 2
- 108010012058 leucyltyrosine Proteins 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000005244 lower chamber Anatomy 0.000 description 2
- 108010003700 lysyl aspartic acid Proteins 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 108091070501 miRNA Proteins 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 238000010232 migration assay Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 210000003098 myoblast Anatomy 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 2
- 210000003061 neural cell Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 230000001734 parasympathetic effect Effects 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 2
- 239000013646 rAAV2 vector Substances 0.000 description 2
- 230000003439 radiotherapeutic effect Effects 0.000 description 2
- 210000005084 renal tissue Anatomy 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000020874 response to hypoxia Effects 0.000 description 2
- 208000004644 retinal vein occlusion Diseases 0.000 description 2
- 108010026333 seryl-proline Proteins 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 208000002320 spinal muscular atrophy Diseases 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 229960004791 tropicamide Drugs 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- AEGSIYIIMVBZQU-CIUDSAMLSA-N (3s)-3-[[2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1r)-1-carboxy-2-sulfanylethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(O)=O AEGSIYIIMVBZQU-CIUDSAMLSA-N 0.000 description 1
- 101150098072 20 gene Proteins 0.000 description 1
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 description 1
- 108050000246 AAA domains Proteins 0.000 description 1
- 208000036443 AIPL1-related retinopathy Diseases 0.000 description 1
- 241000649044 Adeno-associated virus 9 Species 0.000 description 1
- SFNFGFDRYJKZKN-XQXXSGGOSA-N Ala-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)N)O SFNFGFDRYJKZKN-XQXXSGGOSA-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
- JDIQCVUDDFENPU-ZKWXMUAHSA-N Ala-His-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CNC=N1 JDIQCVUDDFENPU-ZKWXMUAHSA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- GMGWOTQMUKYZIE-UBHSHLNASA-N Ala-Pro-Phe Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 GMGWOTQMUKYZIE-UBHSHLNASA-N 0.000 description 1
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 1
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 1
- 102100022712 Alpha-1-antitrypsin Human genes 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
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 102100030942 Apolipoprotein A-II Human genes 0.000 description 1
- IIABBYGHLYWVOS-FXQIFTODSA-N Arg-Asn-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O IIABBYGHLYWVOS-FXQIFTODSA-N 0.000 description 1
- BGDILZXXDJCKPF-CIUDSAMLSA-N Arg-Gln-Cys Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(O)=O BGDILZXXDJCKPF-CIUDSAMLSA-N 0.000 description 1
- YKZJPIPFKGYHKY-DCAQKATOSA-N Arg-Leu-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YKZJPIPFKGYHKY-DCAQKATOSA-N 0.000 description 1
- BWMMKQPATDUYKB-IHRRRGAJSA-N Arg-Tyr-Asn Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 BWMMKQPATDUYKB-IHRRRGAJSA-N 0.000 description 1
- DDPXDCKYWDGZAL-BQBZGAKWSA-N Asn-Gly-Arg Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N DDPXDCKYWDGZAL-BQBZGAKWSA-N 0.000 description 1
- OSZBYGVKAFZWKC-FXQIFTODSA-N Asn-Pro-Cys Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(O)=O OSZBYGVKAFZWKC-FXQIFTODSA-N 0.000 description 1
- GBAWQWASNGUNQF-ZLUOBGJFSA-N Asp-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N GBAWQWASNGUNQF-ZLUOBGJFSA-N 0.000 description 1
- 201000001321 Bardet-Biedl syndrome Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 108091033409 CRISPR Proteins 0.000 description 1
- 238000010354 CRISPR gene editing Methods 0.000 description 1
- 208000022526 Canavan disease Diseases 0.000 description 1
- 101100348617 Candida albicans (strain SC5314 / ATCC MYA-2876) NIK1 gene Proteins 0.000 description 1
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 1
- 208000033810 Choroidal dystrophy Diseases 0.000 description 1
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 102000005853 Clathrin Human genes 0.000 description 1
- 108010019874 Clathrin Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000036693 Color-vision disease Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 1
- GEEXORWTBTUOHC-FXQIFTODSA-N Cys-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N GEEXORWTBTUOHC-FXQIFTODSA-N 0.000 description 1
- BYALSSDCQYHKMY-XGEHTFHBSA-N Cys-Arg-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CS)N)O BYALSSDCQYHKMY-XGEHTFHBSA-N 0.000 description 1
- OLIYIKRCOZBFCW-ZLUOBGJFSA-N Cys-Asp-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CS)N)C(=O)O OLIYIKRCOZBFCW-ZLUOBGJFSA-N 0.000 description 1
- MRVSLWQRNWEROS-SVSWQMSJSA-N Cys-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CS)N MRVSLWQRNWEROS-SVSWQMSJSA-N 0.000 description 1
- HBHMVBGGHDMPBF-GARJFASQSA-N Cys-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CS)N HBHMVBGGHDMPBF-GARJFASQSA-N 0.000 description 1
- SRIRHERUAMYIOQ-CIUDSAMLSA-N Cys-Leu-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SRIRHERUAMYIOQ-CIUDSAMLSA-N 0.000 description 1
- VDUPGIDTWNQAJD-CIUDSAMLSA-N Cys-Lys-Cys Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CS)C(O)=O VDUPGIDTWNQAJD-CIUDSAMLSA-N 0.000 description 1
- NITLUESFANGEIW-BQBZGAKWSA-N Cys-Pro-Gly Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O NITLUESFANGEIW-BQBZGAKWSA-N 0.000 description 1
- HMWBPUDETPKSSS-DCAQKATOSA-N Cys-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CS)N)C(=O)N[C@@H](CCCCN)C(=O)O HMWBPUDETPKSSS-DCAQKATOSA-N 0.000 description 1
- FCXJJTRGVAZDER-FXQIFTODSA-N Cys-Val-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O FCXJJTRGVAZDER-FXQIFTODSA-N 0.000 description 1
- 206010058202 Cystoid macular oedema Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012645 Diabetic autonomic neuropathy Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 1
- 206010012692 Diabetic uveitis Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 102100035426 DnaJ homolog subfamily B member 7 Human genes 0.000 description 1
- 101100285903 Drosophila melanogaster Hsc70-2 gene Proteins 0.000 description 1
- 101100178718 Drosophila melanogaster Hsc70-4 gene Proteins 0.000 description 1
- 101100178723 Drosophila melanogaster Hsc70-5 gene Proteins 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 102000019205 Dynactin Complex Human genes 0.000 description 1
- 108010012830 Dynactin Complex Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 208000001351 Epiretinal Membrane Diseases 0.000 description 1
- 108010020195 FLAG peptide Proteins 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 208000024412 Friedreich ataxia Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- NNQHEEQNPQYPGL-FXQIFTODSA-N Gln-Ala-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O NNQHEEQNPQYPGL-FXQIFTODSA-N 0.000 description 1
- GMGKDVVBSVVKCT-NUMRIWBASA-N Gln-Asn-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GMGKDVVBSVVKCT-NUMRIWBASA-N 0.000 description 1
- KZEUVLLVULIPNX-GUBZILKMSA-N Gln-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N KZEUVLLVULIPNX-GUBZILKMSA-N 0.000 description 1
- LPYPANUXJGFMGV-FXQIFTODSA-N Gln-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N LPYPANUXJGFMGV-FXQIFTODSA-N 0.000 description 1
- ICDIMQAMJGDHSE-GUBZILKMSA-N Gln-His-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O ICDIMQAMJGDHSE-GUBZILKMSA-N 0.000 description 1
- YRHZWVKUFWCEPW-GLLZPBPUSA-N Gln-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O YRHZWVKUFWCEPW-GLLZPBPUSA-N 0.000 description 1
- STHSGOZLFLFGSS-SUSMZKCASA-N Gln-Thr-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STHSGOZLFLFGSS-SUSMZKCASA-N 0.000 description 1
- UTKICHUQEQBDGC-ACZMJKKPSA-N Glu-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N UTKICHUQEQBDGC-ACZMJKKPSA-N 0.000 description 1
- DYFJZDDQPNIPAB-NHCYSSNCSA-N Glu-Arg-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O DYFJZDDQPNIPAB-NHCYSSNCSA-N 0.000 description 1
- HJIFPJUEOGZWRI-GUBZILKMSA-N Glu-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N HJIFPJUEOGZWRI-GUBZILKMSA-N 0.000 description 1
- NKLRYVLERDYDBI-FXQIFTODSA-N Glu-Glu-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O NKLRYVLERDYDBI-FXQIFTODSA-N 0.000 description 1
- IRXNJYPKBVERCW-DCAQKATOSA-N Glu-Leu-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IRXNJYPKBVERCW-DCAQKATOSA-N 0.000 description 1
- CQAHWYDHKUWYIX-YUMQZZPRSA-N Glu-Pro-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O CQAHWYDHKUWYIX-YUMQZZPRSA-N 0.000 description 1
- QCMVGXDELYMZET-GLLZPBPUSA-N Glu-Thr-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QCMVGXDELYMZET-GLLZPBPUSA-N 0.000 description 1
- CAQXJMUDOLSBPF-SUSMZKCASA-N Glu-Thr-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAQXJMUDOLSBPF-SUSMZKCASA-N 0.000 description 1
- XTQFHTHIAKKCTM-YFKPBYRVSA-N Gly-Glu-Gly Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O XTQFHTHIAKKCTM-YFKPBYRVSA-N 0.000 description 1
- 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 1
- IXHQLZIWBCQBLQ-STQMWFEESA-N Gly-Pro-Phe Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IXHQLZIWBCQBLQ-STQMWFEESA-N 0.000 description 1
- NGRPGJGKJMUGDM-XVKPBYJWSA-N Gly-Val-Gln Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O NGRPGJGKJMUGDM-XVKPBYJWSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010053185 Glycogen storage disease type II Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 101100412102 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) rec2 gene Proteins 0.000 description 1
- 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 1
- 208000032087 Hereditary Leber Optic Atrophy Diseases 0.000 description 1
- 201000002563 Histoplasmosis Diseases 0.000 description 1
- 101000823116 Homo sapiens Alpha-1-antitrypsin Proteins 0.000 description 1
- 101000793406 Homo sapiens Apolipoprotein A-II Proteins 0.000 description 1
- 101000804114 Homo sapiens DnaJ homolog subfamily B member 7 Proteins 0.000 description 1
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 1
- 101000729271 Homo sapiens Retinoid isomerohydrolase Proteins 0.000 description 1
- 101000640899 Homo sapiens Solute carrier family 12 member 2 Proteins 0.000 description 1
- 101150090950 Hsc70-1 gene Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- GQKSJYINYYWPMR-NGZCFLSTSA-N Ile-Gly-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N1CCC[C@@H]1C(=O)O)N GQKSJYINYYWPMR-NGZCFLSTSA-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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 1
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 208000010038 Ischemic Optic Neuropathy Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 101710134365 Kinesin-like protein KIF2A Proteins 0.000 description 1
- 102100023426 Kinesin-like protein KIF2A Human genes 0.000 description 1
- FAIXYKHYOGVFKA-UHFFFAOYSA-N Kinetin Natural products N=1C=NC=2N=CNC=2C=1N(C)C1=CC=CO1 FAIXYKHYOGVFKA-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 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
- 208000032420 Latent Infection Diseases 0.000 description 1
- 206010056715 Laurence-Moon-Bardet-Biedl syndrome Diseases 0.000 description 1
- 201000000639 Leber hereditary optic neuropathy Diseases 0.000 description 1
- OXKYZSRZKBTVEY-ZPFDUUQYSA-N Leu-Asn-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O OXKYZSRZKBTVEY-ZPFDUUQYSA-N 0.000 description 1
- NFHJQETXTSDZSI-DCAQKATOSA-N Leu-Cys-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NFHJQETXTSDZSI-DCAQKATOSA-N 0.000 description 1
- KGCLIYGPQXUNLO-IUCAKERBSA-N Leu-Gly-Glu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O KGCLIYGPQXUNLO-IUCAKERBSA-N 0.000 description 1
- VBZOAGIPCULURB-QWRGUYRKSA-N Leu-Gly-His Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N VBZOAGIPCULURB-QWRGUYRKSA-N 0.000 description 1
- BGZCJDGBBUUBHA-KKUMJFAQSA-N Leu-Lys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O BGZCJDGBBUUBHA-KKUMJFAQSA-N 0.000 description 1
- JLYUZRKPDKHUTC-WDSOQIARSA-N Leu-Pro-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JLYUZRKPDKHUTC-WDSOQIARSA-N 0.000 description 1
- JDBQSGMJBMPNFT-AVGNSLFASA-N Leu-Pro-Val Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O JDBQSGMJBMPNFT-AVGNSLFASA-N 0.000 description 1
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- SQXUUGUCGJSWCK-CIUDSAMLSA-N Lys-Asp-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N SQXUUGUCGJSWCK-CIUDSAMLSA-N 0.000 description 1
- WKUXWMWQTOYTFI-SRVKXCTJSA-N Lys-Met-Gln Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N WKUXWMWQTOYTFI-SRVKXCTJSA-N 0.000 description 1
- QBHGXFQJFPWJIH-XUXIUFHCSA-N Lys-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCN QBHGXFQJFPWJIH-XUXIUFHCSA-N 0.000 description 1
- LECIJRIRMVOFMH-ULQDDVLXSA-N Lys-Pro-Phe Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 LECIJRIRMVOFMH-ULQDDVLXSA-N 0.000 description 1
- DIBZLYZXTSVGLN-CIUDSAMLSA-N Lys-Ser-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O DIBZLYZXTSVGLN-CIUDSAMLSA-N 0.000 description 1
- CFOLERIRBUAYAD-HOCLYGCPSA-N Lys-Trp-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)NCC(O)=O CFOLERIRBUAYAD-HOCLYGCPSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000015439 Lysosomal storage disease Diseases 0.000 description 1
- 208000031471 Macular fibrosis Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- QAHFGYLFLVGBNW-DCAQKATOSA-N Met-Ala-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN QAHFGYLFLVGBNW-DCAQKATOSA-N 0.000 description 1
- 108091007780 MiR-122 Proteins 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 208000010164 Multifocal Choroiditis Diseases 0.000 description 1
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 108010047562 NGR peptide Proteins 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 206010029301 Neurological disorders of the eye Diseases 0.000 description 1
- 208000002537 Neuronal Ceroid-Lipofuscinoses Diseases 0.000 description 1
- 108010065395 Neuropep-1 Proteins 0.000 description 1
- 108091092724 Noncoding DNA Proteins 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030924 Optic ischaemic neuropathy Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102100026459 POU domain, class 3, transcription factor 2 Human genes 0.000 description 1
- 101710133394 POU domain, class 3, transcription factor 2 Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241000701945 Parvoviridae Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- LTAWNJXSRUCFAN-UNQGMJICSA-N Phe-Thr-Arg Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LTAWNJXSRUCFAN-UNQGMJICSA-N 0.000 description 1
- 101000860242 Plasmodium yoelii yoelii Putative chloroquine resistance transporter Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- PULPZRAHVFBVTO-DCAQKATOSA-N Pro-Glu-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PULPZRAHVFBVTO-DCAQKATOSA-N 0.000 description 1
- NMELOOXSGDRBRU-YUMQZZPRSA-N Pro-Glu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H]1CCCN1 NMELOOXSGDRBRU-YUMQZZPRSA-N 0.000 description 1
- WVOXLKUUVCCCSU-ZPFDUUQYSA-N Pro-Glu-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WVOXLKUUVCCCSU-ZPFDUUQYSA-N 0.000 description 1
- WFIVLLFYUZZWOD-RHYQMDGZSA-N Pro-Lys-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WFIVLLFYUZZWOD-RHYQMDGZSA-N 0.000 description 1
- MHBSUKYVBZVQRW-HJWJTTGWSA-N Pro-Phe-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MHBSUKYVBZVQRW-HJWJTTGWSA-N 0.000 description 1
- DWPXHLIBFQLKLK-CYDGBPFRSA-N Pro-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 DWPXHLIBFQLKLK-CYDGBPFRSA-N 0.000 description 1
- QAAYIXYLEMRULP-SRVKXCTJSA-N Pro-Pro-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 QAAYIXYLEMRULP-SRVKXCTJSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 1
- 101150030875 RAB7A gene Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- 206010063897 Renal ischaemia Diseases 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- 102100031176 Retinoid isomerohydrolase Human genes 0.000 description 1
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- 101100007329 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) COS1 gene Proteins 0.000 description 1
- 101100221606 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) COS7 gene Proteins 0.000 description 1
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 1
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 1
- IFPBAGJBHSNYPR-ZKWXMUAHSA-N Ser-Ile-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O IFPBAGJBHSNYPR-ZKWXMUAHSA-N 0.000 description 1
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 1
- JOHPFOKBAAOQDI-UBHSHLNASA-N Ser-Trp-Cys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N JOHPFOKBAAOQDI-UBHSHLNASA-N 0.000 description 1
- SGZVZUCRAVSPKQ-FXQIFTODSA-N Ser-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N SGZVZUCRAVSPKQ-FXQIFTODSA-N 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000027073 Stargardt disease Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 206010042742 Sympathetic ophthalmia Diseases 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- CAGTXGDOIFXLPC-KZVJFYERSA-N Thr-Arg-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CCCN=C(N)N CAGTXGDOIFXLPC-KZVJFYERSA-N 0.000 description 1
- XYEXCEPTALHNEV-RCWTZXSCSA-N Thr-Arg-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O XYEXCEPTALHNEV-RCWTZXSCSA-N 0.000 description 1
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 1
- NQVDGKYAUHTCME-QTKMDUPCSA-N Thr-His-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O NQVDGKYAUHTCME-QTKMDUPCSA-N 0.000 description 1
- ADPHPKGWVDHWML-PPCPHDFISA-N Thr-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N ADPHPKGWVDHWML-PPCPHDFISA-N 0.000 description 1
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 1
- BVOVIGCHYNFJBZ-JXUBOQSCSA-N Thr-Leu-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O BVOVIGCHYNFJBZ-JXUBOQSCSA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- BCYUHPXBHCUYBA-CUJWVEQBSA-N Thr-Ser-His Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O BCYUHPXBHCUYBA-CUJWVEQBSA-N 0.000 description 1
- AHERARIZBPOMNU-KATARQTJSA-N Thr-Ser-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O AHERARIZBPOMNU-KATARQTJSA-N 0.000 description 1
- QYDKSNXSBXZPFK-ZJDVBMNYSA-N Thr-Thr-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYDKSNXSBXZPFK-ZJDVBMNYSA-N 0.000 description 1
- UQCNIMDPYICBTR-KYNKHSRBSA-N Thr-Thr-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O UQCNIMDPYICBTR-KYNKHSRBSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 102100026143 Transferrin receptor protein 2 Human genes 0.000 description 1
- 101710145355 Transferrin receptor protein 2 Proteins 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- MZDJYWGXAIEYEP-BPUTZDHNSA-N Trp-Cys-Arg Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N MZDJYWGXAIEYEP-BPUTZDHNSA-N 0.000 description 1
- GEGYPBOPIGNZIF-CWRNSKLLSA-N Trp-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N)C(=O)O GEGYPBOPIGNZIF-CWRNSKLLSA-N 0.000 description 1
- BIWVVOHTKDLRMP-ULQDDVLXSA-N Tyr-Pro-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O BIWVVOHTKDLRMP-ULQDDVLXSA-N 0.000 description 1
- ZPFLBLFITJCBTP-QWRGUYRKSA-N Tyr-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O ZPFLBLFITJCBTP-QWRGUYRKSA-N 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- AZSHAZJLOZQYAY-FXQIFTODSA-N Val-Ala-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O AZSHAZJLOZQYAY-FXQIFTODSA-N 0.000 description 1
- WFENBJPLZMPVAX-XVKPBYJWSA-N Val-Gly-Glu Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O WFENBJPLZMPVAX-XVKPBYJWSA-N 0.000 description 1
- HPOSMQWRPMRMFO-GUBZILKMSA-N Val-Pro-Cys Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N HPOSMQWRPMRMFO-GUBZILKMSA-N 0.000 description 1
- JAIZPWVHPQRYOU-ZJDVBMNYSA-N Val-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O JAIZPWVHPQRYOU-ZJDVBMNYSA-N 0.000 description 1
- AYHNXCJKBLYVOA-KSZLIROESA-N Val-Trp-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N3CCC[C@@H]3C(=O)O)N AYHNXCJKBLYVOA-KSZLIROESA-N 0.000 description 1
- ODUHAIXFXFACDY-SRVKXCTJSA-N Val-Val-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)C(C)C ODUHAIXFXFACDY-SRVKXCTJSA-N 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001295 alanines Chemical class 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 201000007058 anterior ischemic optic neuropathy Diseases 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 108010054176 apotransferrin Proteins 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 108010013835 arginine glutamate Proteins 0.000 description 1
- 108010006195 arginyl-glycyl-aspartyl-cysteine Proteins 0.000 description 1
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 201000005667 central retinal vein occlusion Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- 208000003571 choroideremia Diseases 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000004081 cilia Anatomy 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229930193282 clathrin Natural products 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 201000006754 cone-rod dystrophy Diseases 0.000 description 1
- 208000006623 congenital stationary night blindness Diseases 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000003792 cranial nerve Anatomy 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 108010068364 cysteinyl-arginyl-prolyl-prolyl-arginine Proteins 0.000 description 1
- 108010004073 cysteinylcysteine Proteins 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 108010060199 cysteinylproline Proteins 0.000 description 1
- 201000010206 cystoid macular edema Diseases 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 208000037771 disease arising from reactivation of latent virus Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 210000003495 flagella Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 210000000609 ganglia Anatomy 0.000 description 1
- 238000012224 gene deletion Methods 0.000 description 1
- 238000003197 gene knockdown Methods 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 201000004502 glycogen storage disease II Diseases 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- HPAIKDPJURGQLN-UHFFFAOYSA-N glycyl-L-histidyl-L-phenylalanine Natural products C=1C=CC=CC=1CC(C(O)=O)NC(=O)C(NC(=O)CN)CC1=CN=CN1 HPAIKDPJURGQLN-UHFFFAOYSA-N 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
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229960000027 human factor ix Drugs 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000009540 indirect ophthalmoscopy Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000006749 inflammatory damage Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 229960004184 ketamine hydrochloride Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 229960001669 kinetin Drugs 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002647 laser therapy Methods 0.000 description 1
- 208000025014 late infantile neuronal ceroid lipofuscinosis Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 201000002818 limb ischemia Diseases 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 208000038015 macular disease Diseases 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 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
- 230000007246 mechanism Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 108010034507 methionyltryptophan Proteins 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000005065 mining Methods 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- VYQNWZOUAUKGHI-UHFFFAOYSA-N monobenzone Chemical compound C1=CC(O)=CC=C1OCC1=CC=CC=C1 VYQNWZOUAUKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 201000008051 neuronal ceroid lipofuscinosis Diseases 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000010883 osseointegration Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 108091008695 photoreceptors Proteins 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000012809 post-inoculation Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000001927 retinal artery Anatomy 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 230000004283 retinal dysfunction Effects 0.000 description 1
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 238000011451 sequencing strategy Methods 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000031998 transcytosis Effects 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 230000006107 tyrosine sulfation Effects 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
- C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
- C12N2750/14145—Special targeting system for viral vectors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14151—Methods of production or purification of viral material
- C12N2750/14152—Methods of production or purification of viral material relating to complementing cells and packaging systems for producing virus or viral particles
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本发明涉及重组腺相关病毒(rAAV)，所述重组腺相关病毒具有经工程改造以包含赋予和/或增强所需性质的氨基酸序列的衣壳蛋白。特别地，本发明提供包含来自异源蛋白的肽插入物的经工程改造的衣壳蛋白，所述肽插入物插入所述病毒衣壳的可变区IV(VR‑IV)内或其附近，使得所述插入物表面暴露于AAV颗粒上。本发明还提供将rAAV引导至靶组织的衣壳蛋白，特别地，包含源自促红细胞生成素或动力蛋白的肽的衣壳蛋白，所述肽插入表面暴露的可变区中并且使rAAV靶向视网膜组织和/或包括中枢神经系统在内的神经组织，并递送用于治疗神经和/或眼睛病症的治疗剂。
Description
0.序列表
本申请含有已经以电子方式以ASCII格式提交并且特此以引用的方式整体并入的序列表。2020年3月29日创建的所述ASCII拷贝名为38013_0002P1_SL.txt且大小为637,866字节。
1.技术领域
本发明涉及重组腺相关病毒(rAAV)，其具有经工程改造以包含赋予和/或增强所需性质的氨基酸序列的衣壳蛋白。特别地，本发明提供包括来自异源蛋白的肽插入物的经工程改造的衣壳蛋白，所述肽插入物插入所述病毒衣壳的可变区IV(VR-IV)内或其附近或替代地可变区VIII(VR-VIII)内或其附近，使得所述插入物表面暴露于AAV颗粒上。本发明还提供将rAAV引导至靶组织的衣壳蛋白，特别是包含源自例如促红细胞生成素或动力蛋白的肽的衣壳蛋白，所述肽插入表面暴露的可变区中以使rAAV靶向视网膜和神经组织(包括中枢神经系统)和/或改善视网膜和神经组织的转导，并递送用于治疗神经病症的治疗剂。
2.背景技术
使用腺相关病毒(AAV)作为基因递送载体是用于处理许多未满足的患者需求的有前景途径。已报告数十种天然存在的AAV衣壳，并且在灵长类动物组织中挖掘AAV序列的天然多样性已鉴定出超过100种分布于进化枝中的变体。AAV属细小病毒家族并且是具有相对小的基因组和简单遗传基因组分的单链DNA病毒。在无辅助病毒的情况下，AAV即可确立潜伏性感染。AAV基因组通常具有Rep基因和Cap基因，所述基因侧接有反向末端重复序列(ITR)且充当载体产生的复制和包装信号。衣壳蛋白形成携带基因组DNA且可决定将DNA递送至靶细胞中的组织嗜性的衣壳。
因低病原性和长期靶向基因表达的前景，已使用重组AAV(rAAV)作为基因转移载体，其中将治疗序列包装至各种衣壳中。此类载体已用于临床前基因疗法研究中且目前有超过20种基因疗法产品处于临床研发中。重组AAV(如AAV9)已显示合乎需要的亲神经性性质且使用重组AAV9来治疗CNS疾病的临床试验正在进行中。然而，增强rAAV在人受试者中的亲神经性性质的尝试所取得的成功有限。
仍需要具有增强的亲神经性性质的rAAV载体，所述rAAV载体用于例如穿越血脑屏障以递送疗法，从而治疗与中枢神经系统和眼睛、特别是视网膜相关的病症。还需要具有增强的组织特异性靶向和/或增强的组织特异性转导以递送疗法的rAAV载体。
3.发明内容
提供重组腺相关病毒(rAAV)，所述重组腺相关病毒具有经工程改造以包含赋予和/或增强所需性质(如rAAV基因组的组织靶向、转导和/或整合)的氨基酸序列的衣壳蛋白。特别地，本发明提供包含一个或多个来自异源蛋白的肽插入物的经工程改造的衣壳蛋白，所述肽插入物插入所述病毒衣壳的可变区IV(VR-IV)内或其附近或可变区VIII(VR-VIII)内或其附近，使得所述插入物表面暴露于AAV颗粒上。在特定实施方案中，所述插入物紧接在对应于AAV9衣壳蛋白(SEQ ID NO:118且如图8中所编号)的氨基酸451至461中的一者的氨基酸残基之后，包含在AAV9衣壳的氨基酸454之后(即在氨基酸454与455之间)或在不同AAV类型的衣壳蛋白中在对应于AAV9的氨基酸454的残基之后(例如SEQ ID NO:110-117或119-121)，“对应于”意指使用图8中的序列比对或对于图8中未包含的AAV类型而言使用AAV9衣壳蛋白序列(SEQ ID NO:118)和如本领域中所熟知的AAV衣壳蛋白的类似氨基酸序列比对进行比对)。因此，本发明提供包含来自异源蛋白的肽插入物的经工程改造的衣壳蛋白，所述肽插入物紧接在对应于AAV9的位置454的氨基酸残基的氨基酸之后或其附近插入(如图8中所编号)。在另外特定实施方案中，插入物紧接在对应于AAV9衣壳蛋白(SEQ IDNO:118且如图8中所编号)的氨基酸588的氨基酸残基之后(即介于氨基酸588与589之间)，或在不同AAV类型的衣壳蛋白中在对应于AAV9的氨基酸588的残基之后(例如SEQ ID NO:110-117或119-121)。衣壳蛋白可以是AAV9衣壳蛋白，但还可以是任一AAV衣壳蛋白，如AAV血清型1(SEQ ID NO:110)；AAV血清型2(SEQ ID NO:111)；AAV血清型3(SEQ ID NO:112)AAV血清型4(SEQ ID NO:113)；AAV血清型5(SEQ ID NO:114)；AAV血清型6(SEQ ID NO:115)；AAV7衣壳(SEQ ID NO:116)的451-461；AAV8衣壳(SEQ ID NO:117)的451-461；AAV血清型9(SEQ ID NO:118)；AAV血清型9e(SEQ ID NO:119)；AAV血清型rh10(SEQ ID NO:120)；AAV血清型rh20(SEQ ID NO:121)；和AAV血清型hu.37(SEQ ID NO:122)、AAV血清型rh39(SEQ IDNO:124)和AAV血清型rh74(SEQ ID NO:123或SEQ ID NO:154)(参见图8)。
还提供将rAAV引导至靶组织的衣壳蛋白，特别是包含源自促红细胞生成素或动力蛋白(包含轴丝或细胞质动力蛋白)的肽或促进rAAV基因组的组织靶向和/或细胞摄取和/或整合的肽的衣壳蛋白，所述肽插入表面暴露的可变区中且使rAAV靶向神经组织(包括中枢神经系统)和视网膜组织，并递送用于治疗神经和眼部病症的治疗剂。这些肽有利地插入衣壳蛋白的氨基酸序列中，使得在将衣壳蛋白纳入AAV颗粒中时，所插入肽是表面暴露的。这些肽紧接在AAV9衣壳(SEQ ID NO:118且参见图8的比对)的氨基酸262-273、451-461或585-593中的一者之后或在对应于所述氨基酸的氨基酸中的一者之后，或紧接在对应于编码VP2的第一密码子的氨基酸残基(其是AAV9衣壳的氨基酸138和对应于AAV9衣壳(SEQ IDNO:118且参见图8的比对)的位置138的氨基酸)之后插入。在某些实施方案中，所插入肽是轴丝动力蛋白重链的肽KMQVPFQ(SEQ ID NO:1)、TLAAPFK(SEQ ID NO:2)、QQAAPSF(SEQ IDNO:3)、RYNAPFK(SEQ ID NO:4)、LKLPPIV(SEQ ID NO:5)、PFIKPFE(SEQ ID NO:6)或TLSLPWK(SEQ ID NO:7)中的一者的至少4个邻接氨基酸或5、6、7个邻接氨基酸，或替代地是QEQLERALNSS(SEQ ID NO:8)(其是称为ARA290的促红细胞生成素的非线性表位)的5、6、7、8、9、10或11个邻接氨基酸。
提供包含靶向特定组织的肽(包含促进或增加rAAV基因组的细胞摄取和/或整合者)的经工程改造的衣壳蛋白，其中所述肽插入衣壳蛋白的表面暴露的可变区中。在某些实施方案中，肽靶向以下组织的细胞和/或促进所述细胞中的转导或基因组整合：骨(例如DDDDDDDD(SEQ ID NO:9)的至少4个邻接氨基酸或至少7或8个邻接氨基酸)、脑(LSSRLDA(SEQ ID NO:10)的至少4个氨基酸或至少7个邻接氨基酸或7个邻接氨基酸或是CLSSRLDAC(SEQ ID NO:11)的7、8或9个邻接氨基酸)、肾(肽CLPVASC(SEQ ID NO:12)或LPVAS(SEQ IDNO:13)的至少4或5个邻接氨基酸或是所述肽)、肌肉(肽ASSLNIA(SEQ ID NO:14)的至少4、5、6或7个邻接氨基酸或是所述肽)、视网膜细胞(LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQID NO:16)的至少4个邻接氨基酸或5、6或7个邻接氨基酸)，或源自转铁蛋白受体(HAIYPRH(SEQ ID NO:17)、THRPPMWSPVWP(SEQ ID NO:18)、RTIGPSV(SEQ ID NO:19)或CRTIGPSVC(SEQ ID NO:20)的至少4个邻接氨基酸或至少7个邻接氨基酸或是7个邻接氨基酸)。在某些实施方案中，肽是CLPVASC(SEQ ID NO:12)或是ASSLNIA(SEQ ID NO:14)且含有此肽(例如插入AAV9的位置454之后)的衣壳优先地使具有所述衣壳的rAAV靶向肾(与肝相比)。在其他实施方案中，所插入肽是肽SITLVKSTQTV(SEQ ID NO:21)或TILSRSTQTG(SEQ ID NO:22)或QAVRTSL(SEQ ID NO:23)或QAVRTSH(SEQ ID NO:24)的至少4个邻接氨基酸或至少7或8个邻接氨基酸或是所述肽。在一些实施方案中，所述肽不超过12个邻接氨基酸。在其他实施方案中，提供具有一个或多个氨基酸取代的经工程改造的衣壳，所述取代可改善嗜性、转导或降低免疫中和活性。此类氨基酸修饰包括AAV8的A269S和其他AAV类型衣壳中的相应取代、AAV9的S263F/S269T/A273T和其他AAV类型衣壳中的相应取代、AAV9的W530R或Q474A和其他AAV类型衣壳中的相应取代。具有这些氨基酸取代的衣壳可进一步在AAV8衣壳的498至500使用AAA(丙氨酸)取代NNN(天冬酰胺)或在AAV9衣壳的496至498使用AAA(丙氨酸)取代NNN(天冬酰胺)，或具有其他AAV类型衣壳中的相应取代。
还提供在全身性、静脉内、鞘内、鼻内、腹膜内或玻璃体内施用时促进rAAV在一种或多种组织(包括一种或多种细胞类型)中的转导的经工程改造的衣壳蛋白，其中所述衣壳蛋白包含插入衣壳的表面暴露的可变区(VR)(例如VR-I、VR-IV或VR-VIII)中或插入VP2的第一氨基酸之后(例如紧接在AAV9衣壳(SEQ ID NO:118的氨基酸序列)的残基138之后或紧接在另一AAV衣壳的相应残基之后)的肽，或替代地用本文所述的氨基酸取代中的一者或多者工程改造，并且与具有相应未工程改造的衣壳的AAV的转导相比，在所述施用后具有经工程改造的衣壳的AAV在至少一种组织中的转导有所增加。在某些实施方案中，通过检测转基因(如GFP荧光)来测量转导。
在某些实施方案中，提供纳入本文所述的经工程改造的衣壳的rAAV，包括具有包含目标治疗剂的转基因的基因组的rAAV。提供用于产生本文所述的rAAV的包装细胞。还提供通过递送本文所述的经工程改造的rAAV进行治疗的方法和包括本文所述的经工程改造的rAAV的药物组合物。还提供制造具有本文所述的经工程改造的衣壳的rAAV的方法。
下文通过实例方式来阐释本发明，所述实例描述用肽插入物(基于人轴丝动力蛋白重链尾部、ARA290和其他组织靶向或归巢肽来设计)工程改造的rAAV9衣壳和用氨基酸取代工程改造的衣壳的构建。
3.1.实施方案
1.一种重组腺相关病毒(rAAV)衣壳蛋白，其包含来自非衣壳蛋白的异源蛋白的具有至少4个且至多20个邻接氨基酸的肽插入物，所述肽插入物紧接在对应于图8的AAV9衣壳蛋白(SEQ ID NO:118)的氨基酸451-461中的一者的氨基酸残基之后，其中在所述衣壳蛋白包装为AAV颗粒时所述肽插入物是表面暴露的。
2.如实施方案1的rAAV衣壳蛋白，其中所述衣壳蛋白来自至少一种以下AAV血清型：AAV血清型1(AAV1)、血清型2(AAV2)、血清型3(AAV3)、血清型4(AAV4)、血清型5(AAV5)、血清型6(AAV6)、血清型7(AAV7)、血清型8(AAV8)、血清型rh8(AAVrh8)、血清型9(AAV9)、血清型9e(AAV9e)、血清型rh10(AAVrh10)、血清型rh20(AAVrh20)、血清型rh39(AAVrh39)、血清型hu.37(AAVhu.37)或血清型rh74(AAVrh74)。
3.如实施方案2的rAAV衣壳蛋白，其中所述肽插入物紧接在图8中所描绘序列中的以下位置内的氨基酸残基中的一者之后出现：
AAV1衣壳氨基酸序列(SEQ ID NO 110)的450-459；
AAV2衣壳氨基酸序列(SEQ ID NO:111)的449-458；
AAV3衣壳氨基酸序列(SEQ ID NO:112)的449-459；
AAV4衣壳氨基酸序列(SEQ ID NO:113)的443-453；
AAV5衣壳氨基酸序列(SEQ ID NO:114)的442-445；
AAV6衣壳氨基酸序列(SEQ ID NO:115)的450-459；
AAV7衣壳氨基酸序列(SEQ ID NO:116)的451-461；
AAV8衣壳氨基酸序列(SEQ ID NO:117)的451-461；
AAV9衣壳氨基酸序列(SEQ ID NO:118)的451-461；
AAV9e衣壳氨基酸序列(SEQ ID NO:119)的452-461；
AAVrh10衣壳氨基酸序列(SEQ ID NO:120)的452-461；
AAVrh20衣壳氨基酸序列(SEQ ID NO:121)的452-461；
AAVhu.37衣壳氨基酸序列(SEQ ID NO:122)的452-461；
AAVrh74衣壳氨基酸序列(SEQ ID NO 123或SEQ ID NO:154)的452-461；或
AAVrh39衣壳氨基酸序列(SEQ ID NO:124)的452-461。
4.如实施方案3的rAAV衣壳蛋白，其中所述肽插入物紧接在AAV9衣壳的氨基酸残基I451、N452、G453、S454、G455、Q456、N457、Q458、Q459、T460或L461中的一者之后，或紧接在对应于AAV9衣壳(SEQ ID NO:118)的氨基酸I451、N452、G453、S454、G455、Q456、N457、Q458、Q459、T460或L461的AAV衣壳中的氨基酸残基之后出现，如根据图8的氨基酸编号所比对。
5.如任一前述实施方案的rAAV衣壳蛋白，其中所述异源蛋白是归巢结构域、中和抗体表位或纯化标签。
6.如实施方案5的rAAV衣壳蛋白，其中所述归巢结构域是
神经组织归巢结构域；
轴丝或细胞质动力蛋白归巢结构域；
骨归巢结构域；
肾归巢结构域；
肌肉归巢结构域；
内皮细胞归巢结构域；
整联蛋白受体结合结构域；
转铁蛋白受体结合结构域；
肿瘤细胞靶向结构域；或
视网膜细胞归巢结构域。
7.如实施方案6的rAAV衣壳蛋白，其中所述肽插入物包含具有以下氨基酸序列的至少4个或至少7个邻接氨基酸的动力蛋白肽或动力蛋白归巢肽或由其组成：SITLVKSTQTV(SEQ ID NO:21)、TILSRSTQTG(SEQ ID NO:22)、VVMVGEKPITITQHSVETEG(SEQ ID NO:25)、RSSEEDKSTQTT(SEQ ID NO:26)、KMQVPFQ(SEQ ID NO:1)、LKLPPIV(SEQ ID NO:5)、PFIKPFE(SEQ ID NO:6)、TLSLPWK(SEQ ID NO:7)、QQAAPSF(SEQ ID NO:3)、RYNAPFK(SEQ ID NO:4)、TLAVPFK(SEQ ID NO:27)、TLAAPFK(SEQ ID NO:2)、LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQ ID NO:16)。
8.如实施方案6的rAAV衣壳蛋白，其中来自所述转铁蛋白受体结合结构域的所述肽插入物包含氨基酸序列RTIGPSV(SEQ ID NO:19)或CRTIGPSVC(SEQ ID NO:20)的至少4个或至少7个邻接氨基酸。
9.如实施方案6的rAAV衣壳蛋白，其中来自所述视网膜细胞归巢结构域的所述肽插入物包含氨基酸序列LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQ ID NO:16)。
10.如实施方案9的rAAV衣壳蛋白，其中所述LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQ ID NO:16)肽插入物出现于AAV8衣壳蛋白或AAV9衣壳蛋白中。
11.如前述实施方案中任一项的rAAV衣壳蛋白，其中所述肽插入物在AAV9衣壳蛋白中出现在所述AAV9衣壳蛋白(SEQ ID NO:118)的氨基酸S454之后，或在AAV衣壳蛋白中出现在对应于所述AAV9衣壳蛋白的S454的残基之后，如根据图8中的氨基酸编号所比对。
12.如前述实施方案中任一项的rAAV衣壳蛋白，条件是所述衣壳蛋白并非AAV2衣壳蛋白。
13.一种核酸，所述核酸包含编码如前述实施方案中任一项的rAAV衣壳蛋白或编码与其共有至少80％同一性的氨基酸序列的核苷酸序列。
14.一种包装细胞，所述包装细胞能够表达如实施方案13的核酸以产生包含由所述核苷酸序列编码的所述衣壳蛋白的AAV载体。
15.一种rAAV载体，所述rAAV载体包含如实施方案1-12中任一项的衣壳蛋白。
16.如实施方案15的rAAV载体，所述rAAV载体还包含转基因。
17.一种药物组合物，所述药物组合物包含如实施方案15或16的rAAV载体和药学上可接受的载体。
18.一种将转基因递送至细胞的方法，所述方法包括使所述细胞与如实施方案16的rAAV载体接触，其中将所述转基因递送至所述细胞。
19.一种将转基因递送至有需要的受试者的靶组织或靶细胞或其细胞基质的方法，所述方法包括向所述受试者施用如实施方案16的rAAV载体，其中将所述转基因递送至所述受试者的所述靶组织。
20.一种用于将转基因递送至细胞的药物组合物，所述组合物包含如实施方案16的rAAV载体，其中使所述细胞与所述载体接触。
21.一种用于将转基因递送至有需要的受试者的靶组织的药物组合物，所述药物组合物包含如实施方案16的rAAV载体，其中所述肽插入物是归巢肽并且其中将所述载体施用于所述受试者。
22.根据实施方案18至21的方法或使用的药物组合物，其中所述rAAV载体全身性、静脉内、鞘内、鼻内、腹膜内或玻璃体内施用。
23.根据实施方案18至21的方法或使用的药物组合物，其中所述靶组织或靶细胞或其细胞基质是：
神经组织，并且所述载体包含来自所述神经组织归巢结构域的肽插入物；
骨，并且所述载体包含来自所述骨归巢结构域的肽插入物；
肾，并且所述载体包含来自所述肾归巢结构域的肽插入物；
肌肉，并且所述载体包含来自所述肌肉归巢结构域的肽插入物；
内皮细胞，并且所述载体包含来自所述内皮细胞归巢结构域的肽插入物；
表达整联蛋白受体的细胞，并且所述载体包含来自所述整联蛋白受体结合结构域的肽插入物；
表达转铁蛋白受体的肿瘤细胞，并且所述载体包含来自所述转铁蛋白受体结合结构域的肽插入物；和
肿瘤细胞，并且所述载体包含来自所述肿瘤细胞靶向结构域的肽插入物；或
视网膜细胞，并且所述载体包含来自所述视网膜细胞归巢结构域的肽插入物。
24.一种重组腺相关病毒(rAAV)衣壳蛋白，所述衣壳蛋白包含来自选自由以下组成的组的异源蛋白或结构域的具有至少4个且至多20个邻接氨基酸的肽插入物：
神经组织归巢蛋白或结构域，条件是所述肽插入物不包含序列TLAVPFK(SEQ IDNO:27)；
轴丝或细胞质动力蛋白归巢结构域；
骨归巢结构域；
肾归巢结构域；
肌肉归巢结构域；
内皮细胞归巢结构域；
整联蛋白受体结合结构域；
转铁蛋白受体结合结构域，条件是所述肽插入物不包含序列RTIGPSV(SEQ ID NO:19)和CRTIGPSVC(SEQ ID NO:20)二者；
肿瘤细胞靶向结构域；和
视网膜细胞归巢结构域，条件是所述肽插入物不包含序列LGETTRP(SEQ ID NO:15)和LALGETTRP(SEQ ID NO:16)二者。
其中在所述衣壳蛋白包装为AAV颗粒时，所述肽插入物是表面暴露的。
25.如实施方案24的rAAV衣壳蛋白，其中所述神经组织归巢蛋白或视网膜细胞归巢结构域是人轴丝动力蛋白(HAD)重链尾部。
26.如实施方案25的rAAV衣壳蛋白，其中所述肽插入物包含至少4个且至多12个来自所述HAD重链尾部的二聚化结构域的邻接氨基酸。
27.如实施方案26的rAAV衣壳蛋白，其中所述肽插入物包含至少4个且至多12个来自由以下(描绘于图7A-7M中)组成的组的邻接氨基酸：
(DYH1_人UniProtKB-Q9P2D7的aa 1-1542)(SEQ ID NO.97)；
(DYH2_人UniProtKB-Q9P225的aa 1-1764)(SEQ ID NO.98)；
(DYH3_人UniProtKB-Q8TD57的aa 1-1390)(SEQ ID NO.99)；
(DYH5_人UniProtKB-Q8TE73的aa 1-1941)(SEQ ID NO.100)；
(DYH6_人UniProtKB-Q9C0G6的aa 1-1433)(SEQ ID NO.101)；
(DYH7_人UniProtKB-Q8WXX0的aa 1-1289)(SEQ ID NO.102)；
(DYH8_人UniProtKB-Q96JB1的aa 1-1807)(SEQ ID NO.103)；
(DYH9_人UniProtKB-Q9NYC9的aa 1-1831)(SEQ ID NO.104)；
(DYH10_人UniProtKB-Q8IVF4的aa 1-1793)(SEQ ID NO.105)；
(DYH11_人UniProtKB-Q96DT5的aa 1-1854)(SEQ ID NO.106)；
(DYH12_人UniProtKB-Q6ZR08的aa 1-1214)(SEQ ID NO.107)；
(DYH14_人UniProtKB-Q0VDD8的aa 1-200)(SEQ ID NO.108)；或
(DYH17_人UniProtKB-Q9UFH2的aa 1-1794)(SEQ ID NO.109)。
28.如实施方案27的rAAV衣壳蛋白，其中所述肽插入物包含至少4个且至多12个来自任一轴丝动力蛋白重链序列(图7A-7M)的残基1-200的邻接氨基酸。
29.如实施方案27的rAAV衣壳蛋白，其中所述肽插入物包含7个来自图7A-7M的所述动力蛋白重链序列中的任一者的邻接氨基酸。
30.如实施方案28的rAAV衣壳蛋白，其中所述肽插入物包含7个来自所述动力蛋白重链序列(图7A-7M)中的任一者的残基1-200的邻接氨基酸
31.如实施方案25的rAAV衣壳蛋白，其中所述肽插入物包含以下中的一者的至少4个邻接氨基酸：
KMQVPFQ(SEQ ID NO:1)；
TLAAPFK(SEQ ID NO:2)；
QQAAPSF(SEQ ID NO:3)；
RYNAPFK(SEQ ID NO:4)；
LKLPPIV(SEQ ID NO:5)；
PFIKPFE(SEQ ID NO:6)；或
TLSLPWK(SEQ ID NO:7)。
32.如实施方案25的rAAV衣壳蛋白，其中所述肽插入物由来自以下中的一者的肽组成：
KMQVPFQ(SEQ ID NO:1)；
TLAAPFK(SEQ ID NO:2)；
QQAAPSF(SEQ ID NO:3)；
RYNAPFK(SEQ ID NO:4)；
LKLPPIV(SEQ ID NO:5)；
PFIKPFE(SEQ ID NO:6)；或
TLSLPWK(SEQ ID NO:7)。
33.如实施方案32的rAAV衣壳蛋白，其中所述肽插入物包含氨基酸序列TLAAPFK(SEQ ID NO:2)；
34.如实施方案24的rAAV衣壳蛋白，其中所述神经组织归巢蛋白是小鼠轴丝动力蛋白(MAD)重链尾部。
35.如实施方案24的rAAV衣壳蛋白，其中所述神经组织归巢结构域是结合先天性修复受体且并非红细胞生成性的EPO(促红细胞生成素)结构域或所述结构域的构象类似物。
36.如实施方案35的rAAV衣壳蛋白，其中所述肽插入物包含至少4个且至多11个来自QEQLERALNSS(SEQ ID NO:8)的邻接氨基酸。
37.如实施方案36的rAAV衣壳蛋白，其中所述肽插入物是ARA290序列QEQLERALNSS(SEQ ID NO:8)。
38.如实施方案24的rAAV衣壳蛋白，其中所述神经组织归巢蛋白是具有SRL(丝氨酸-精氨酸-赖氨酸)基序的脑归巢结构域。
39.如实施方案38的rAAV衣壳蛋白，其中来自所述脑归巢结构域的所述肽插入物包含氨基酸序列LSSRLDA(SEQ ID NO:10)或CLSSRLDAC(SEQ ID NO:11)的至少7个邻接氨基酸。
40.如实施方案24的rAAV衣壳蛋白，其中所述轴丝或细胞质动力蛋白归巢结构域是动力蛋白轻链归巢结构域。
41.如实施方案40的rAAV衣壳蛋白，其中来自所述动力蛋白轻链归巢结构域的所述肽插入物是SITLVKSTQTV(SEQ ID NO:21)、TILSRSTQTG(SEQ ID NO:22)、VVMVGEKPITITQHSVETEG(SEQ ID NO:25)或RSSEEDKSTQTT(SEQ ID NO:26)中的一者。
42.如实施方案24的rAAV衣壳蛋白，其中所述骨归巢蛋白是羟磷灰石(HA)结合结构域。
43.如实施方案42的rAAV衣壳蛋白，其中来自所述羟磷灰石(HA)结合结构域的所述肽插入物是序列DDDDDDDD(SEQ ID NO:9)的至少6个氨基酸残基。
44.如实施方案24的rAAV衣壳蛋白，其中所述肾归巢结构域是氨基酸序列CLPVASC(SEQ ID NO:12)。
45.如实施方案44的rAAV衣壳蛋白，其中来自所述肾归巢结构域的所述肽插入物是氨基酸序列LPVAS(SEQ ID NO:13)或CLPVASC(SEQ ID NO:12)。
46.如实施方案24的rAAV衣壳蛋白，其中来自所述肌肉归巢结构域的所述肽插入物是氨基酸序列ASSLNIA(SEQ ID NO:14)。
47.如实施方案24的rAAV衣壳蛋白，其中所述肽插入物是氨基酸序列QAVRTSL(SEQID NO:23)或QAVRTSH(SEQ ID NO:24)。
48.如实施方案24的rAAV衣壳蛋白，其中来自所述内皮细胞归巢结构域的所述肽插入物是氨基酸序列SIGYPLP(SEQ ID NO:28)。
49.如实施方案24的rAAV衣壳蛋白，其中来自所述整联蛋白结合结构域的所述肽插入物具有氨基酸序列CDCRGDCFC(SEQ ID NO:29)。
50.如实施方案24的rAAV衣壳蛋白，其中所述转铁蛋白受体结合结构域是转铁蛋白结构域或其构象类似物或铁模拟物。
51.如实施方案50的rAAV衣壳蛋白，其中来自所述转铁蛋白结构域的所述肽插入物包含来自序列HAIYPRH(SEQ ID NO:17)或THRPPMWSPVWP(SEQ ID NO:18)的至少4个邻接氨基酸且至多12个邻接氨基酸。
52.如实施方案51的rAAV衣壳蛋白，其中所述肽插入物是氨基酸序列HAIYPRH(SEQID NO:17)或THRPPMWSPVWP(SEQ ID NO:18)。
53.如实施方案24的rAAV衣壳蛋白，其中来自所述肿瘤细胞靶向结构域的所述肽插入物是氨基酸序列NGRAHA(SEQ ID NO:30)。
54.如实施方案24-53中任一项的rAAV衣壳蛋白，其中所述肽插入物紧接在以下氨基酸残基中的一者之后出现(如图8中所描绘)：
AAV1衣壳氨基酸序列(SEQ ID NO.110)的138；262-272；450-459；或585-593；
AAV2衣壳氨基酸序列(SEQ ID NO.111)的138；262-272；449-458；或584-592；
AAV3衣壳氨基酸序列(SEQ ID NO.112)的138；262-272；449-459；或585-593；
AAV4衣壳氨基酸序列(SEQ ID NO.113)的137；256-262；443-453；或583-591；
AAV5衣壳氨基酸序列(SEQ ID NO.114)的137；252-262；442-445；或574-582；
AAV6衣壳氨基酸序列(SEQ ID NO.115)的138；262-272；450-459；585-593；
AAV7衣壳氨基酸序列(SEQ ID NO.116)的138；263-273；451-461；586-594；
AAV8衣壳氨基酸序列(SEQ ID NO.117)的138；263-274；452-461；587-595；
AAV9衣壳氨基酸序列(SEQ ID NO.118)的138；262-273；452-461；585-593；
AAV9e衣壳氨基酸序列(SEQ ID NO.119)的138；262-273；452-461；585-593；
AAVrh10衣壳氨基酸序列(SEQ ID NO.120)的138；263-274；452-461；587-595；
AAVrh20衣壳氨基酸序列(SEQ ID NO.121)的138；263-274；452-461；587-595；
AAVhu37衣壳氨基酸序列(SEQ ID NO.122)的138；263-274；452-461；587-595
AAVrh74衣壳氨基酸序列(SEQ ID NO.123或SEQ ID NO.154)的138；263-274；452-461；587-595；或
AAVrh39衣壳氨基酸序列(SEQ ID NO.124)的138；263-274；452-461；587-595。
55.一种重组AAV衣壳蛋白，所述重组AAV衣壳蛋白包含插入AAV9衣壳(SEQ ID NO:118)的氨基酸残基588-589之间或如图8中所比对对应于所述AAV9衣壳的氨基酸残基588-589之间的氨基酸序列TLAAPFK(SEQ ID NO:2)。
56.一种重组AAV衣壳蛋白，所述重组AAV衣壳蛋白包含紧接在AAV9衣壳(SEQ IDNO:118)的氨基酸I451至L461或S268中的一者或如图8中所比对对应于所述AAV9衣壳的氨基酸I451至L461或S268中的一者之后插入的氨基酸序列TLAAPFK(SEQ ID NO:2)。
57.一种重组AAV衣壳蛋白，所述重组AAV衣壳蛋白包含插入AAV9衣壳(SEQ ID NO:118)的氨基酸残基588-589之间或如图8中所比对对应于所述AAV9衣壳的氨基酸残基588-589之间的氨基酸序列QEQLERALNSS(SEQ ID NO:8)。
58.一种重组AAV衣壳蛋白，所述重组AAV衣壳蛋白包含紧接在AAV9衣壳(SEQ IDNO:118)的氨基酸I451至L461或S268中的一者或如图8中所比对对应于所述AAV9衣壳的氨基酸I451-L461或S268中的一者之后插入的氨基酸序列QEQLERALNSS(SEQ ID NO:8)。
59.如实施方案24-54中任一项的rAAV衣壳蛋白，其中所述肽插入物紧接在如图8中所比对对应于AAV9衣壳蛋白(SEQ ID NO:118)的氨基酸451至461、S268或Q588中的一者的氨基酸残基之后出现。
60如实施方案59的rAAV衣壳蛋白，其中所述肽插入物紧接在所述AAV9衣壳蛋白(SEQ ID NO:118)的氨基酸451至461中的一者之后出现。
61.如实施方案24-53中任一项的rAAV衣壳蛋白，其中所述肽插入物出现于第八可变区(VR-VIII)中。
62.如实施方案24-61中任一项的rAAV衣壳蛋白，条件是所述衣壳蛋白并非AAV2衣壳蛋白。
63.一种核酸，所述核酸包含编码实施方案24-62中任一项的rAAV衣壳蛋白或编码与其共有至少80％同一性的氨基酸序列的核苷酸序列。
64.一种包装细胞，所述包装细胞能够表达实施方案63的核酸以产生包含由所述核苷酸序列编码的所述衣壳蛋白的AAV载体。
65.一种rAAV载体，所述rAAV载体包含实施方案24-62中任一项的衣壳蛋白。
66.如实施方案65的rAAV载体，所述rAAV载体还包含转基因。
67.一种药物组合物，所述药物组合物包含实施方案65或66的rAAV载体和药学上可接受的载体。
68.一种将转基因递送至细胞的方法，所述方法包括使所述细胞与实施方案66的rAAV载体接触，其中将所述转基因递送至所述细胞。
69.一种将转基因递送至有需要的受试者的靶组织的方法，所述方法包括向所述受试者施用实施方案66的rAAV载体，其中将所述转基因递送至所述受试者。
70.一种用于将转基因递送至细胞的药物组合物，所述药物组合物包含实施方案66的rAAV载体，其中将所述转基因递送至所述细胞。
71.一种用于将转基因递送至有需要的受试者的靶组织的药物组合物，所述药物组合物包含实施方案66的rAAV载体；其中将转基因递送至所述靶组织。
72.根据实施方案68-71的方法或使用的药物组合物，其中所述rAAV载体全身性、静脉内、鞘内、鼻内、腹膜内或玻璃体内施用。
73.根据实施方案68-71的方法或使用的药物组合物，其中所述载体经由腰部穿刺或经由小脑延髓池来施用。
74.一种重组腺相关病毒(rAAV)衣壳蛋白，所述衣壳蛋白包含具有至少4个来自TLAVPFK(SEQ ID NO:27)、RTIGPSV(SEQ ID NO:19)、CRTIGPSVC(SEQ ID NO:20)、LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQ ID NO:16)中的一者的邻接氨基酸的肽插入物；
其中所述肽插入物紧接在如图8中所比对对应于AAV9衣壳蛋白的氨基酸268、454或588的氨基酸残基之后出现。
75.如实施方案74的rAAV衣壳蛋白，条件是所述衣壳蛋白并非AAV2衣壳蛋白。
76.如实施方案74的rAAV衣壳蛋白，其中所述肽插入物包含位于所述AAV9衣壳蛋白(SEQ ID NO:118)的氨基酸残基454与455之间的氨基酸序列TLAVPFK(SEQ ID NO:27)。
77.如实施方案74的rAAV衣壳蛋白，其中所述肽插入物包含紧接在所述AAV9衣壳蛋白(SEQ ID NO:118)的氨基酸残基262-273中的一者之后的氨基酸序列TLAVPFK(SEQ IDNO:27)。
78.如实施方案74的rAAV衣壳蛋白，其中所述肽插入物包含位于AAV8衣壳蛋白(SEQ ID NO:117)的氨基酸残基454-455之间的氨基酸序列LGETTRP(SEQ ID NO:15)。
79.如实施方案78的rAAV衣壳蛋白，其中所述肽插入物包含氨基酸序列LALGETTRP(SEQ ID NO:16)。
80.如实施方案74的rAAV衣壳蛋白，其中所述肽插入物包含插入AAV8衣壳蛋白(SEQ ID NO:117)的氨基酸残基590-591之间的氨基酸序列LGETTRP(SEQ ID NO:15)。
81.如实施方案80的rAAV衣壳蛋白，其中所述肽插入物包含氨基酸序列LALGETTRP(SEQ ID NO:16)。
82.如实施方案74的rAAV衣壳蛋白，其中所述肽插入物包含紧接在AAV8衣壳蛋白(SEQ ID NO:117)的氨基酸残基263-274中的一者之后的氨基酸序列LGETTRP(SEQ ID NO:15)。
83.如实施方案82的rAAV衣壳蛋白，其中所述肽插入物包含氨基酸序列LALGETTRP(SEQ ID NO:16)。
84.一种核酸，所述核酸包含编码实施方案74-83中任一项的rAAV衣壳蛋白或编码与其共有至少80％同一性的氨基酸序列的核苷酸序列。
85.一种包装细胞，所述包装细胞能够表达实施方案84的核酸以产生包括由所述核苷酸序列编码的所述衣壳蛋白的AAV载体。
86.一种rAAV载体，所述rAAV载体包含实施方案74-83中任一项的衣壳蛋白。
87.如实施方案86的rAAV载体，所述rAAV载体还包含转基因。
88.一种药物组合物，所述药物组合物包含实施方案86或87的rAAV载体和药学上可接受的载体。
89.一种将转基因递送至细胞的方法，所述方法包括使所述细胞与实施方案86或87的rAAV载体接触，其中将所述转基因递送至所述细胞。
90.一种将转基因递送至有需要的受试者的靶组织的方法，所述方法包括向所述受试者施用实施方案86或87的rAAV载体，其中将所述转基因递送至所述靶组织。
91.一种用于将转基因递送至细胞的药物组合物，所述药物组合物包含实施方案86或87的rAAV载体，其中将所述转基因递送至所述细胞。
92.一种用于将转基因递送至有需要的受试者的靶组织的药物组合物，所述药物组合物包含实施方案86或87的rAAV载体，其中将所述转基因递送至所述靶组织。
93.如实施方案89-92的方法或使用的药物组合物，其中所述靶组织是视网膜细胞并且所述肽插入物包含氨基酸序列LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQ ID NO:16)。
94.根据实施方案89-93的方法或使用的药物组合物，其中所述rAAV载体全身性、静脉内、鞘内、鼻内、腹膜内或玻璃体内施用。
95.根据实施方案89-93的方法或使用的药物组合物，其中所述载体经由腰部穿刺或经由小脑延髓池来施用。
96.一种重组AAV衣壳蛋白，所述重组AAV衣壳蛋白相对于野生型或未工程改造的衣壳蛋白包含一个或多个氨基酸取代，其中所述rAAV衣壳蛋白是具有A269S氨基酸取代的AAV8衣壳蛋白(SEQ ID NO:117)或是具有S263G/S269R/A273T取代或W503R或Q474A取代或另一AAV类型衣壳的衣壳蛋白中的相应取代的AAV9衣壳蛋白(SEQ ID NO:118)。
97.如实施方案96的重组AAV衣壳蛋白，所述重组AAV衣壳蛋白还包含498-NNN/AAA-500(对于AAV8衣壳蛋白)或496-NNN/AAA-498(对于AAV9衣壳蛋白(SEQ ID NO:118))或另一AAV类型衣壳的衣壳蛋白中的相应取代。
98.一种核酸，所述核酸包含编码实施方案96或97的rAAV衣壳蛋白或编码与其共有至少80％同一性的氨基酸序列的核苷酸序列。
99.一种包装细胞，所述包装细胞能够表达实施方案98的核酸以产生包含由所述核苷酸序列编码的所述衣壳蛋白的AAV载体。
100.一种rAAV载体，所述rAAV载体包含实施方案96或97中任一项的衣壳蛋白。
101.如实施方案100的rAAV载体，所述rAAV载体还包含转基因。
102.一种药物组合物，所述药物组合物包含实施方案100或101的rAAV载体和药学上可接受的载体。
103.一种将转基因递送至细胞的方法，所述方法包括使所述细胞与实施方案101的rAAV载体接触，其中将所述转基因递送至所述细胞。
104.一种将转基因递送至有需要的受试者的靶组织的方法，所述方法包括向所述受试者施用实施方案101的rAAV载体，其中将所述转基因递送至所述靶组织。
105.一种用于将转基因递送至细胞的药物组合物，所述药物组合物包括实施方案101的rAAV载体，其中将所述转基因递送至所述细胞。
106.一种用于将转基因递送至有需要的受试者的靶组织的药物组合物，所述药物组合物包括实施方案101的rAAV载体，其中将所述转基因递送至所述靶组织。
107.根据实施方案102-106的方法或使用的药物组合物，其中所述rAAV载体全身性、静脉内、鞘内、鼻内、腹膜内或玻璃体内施用。
108.根据实施方案102-106的方法或使用的药物组合物，其中所述载体经由腰部穿刺或经由小脑延髓池来施用。
4.附图说明
图1描绘包含9型腺相关病毒的从残基L447至R476(其中残基451-459加括号)的VR-IV环(AAV9 VR-IV)的衣壳氨基酸序列与其他AAV的相应区域的序列比较。所述图按出现顺序分别公开SEQ ID NO 87-92、88和93-96。
图2描绘AAV衣壳结构的蛋白质模型，其展示衣壳可变区VR-IV、VR-V和VR-VIII。盒突出显示VR-IV的环区，所述环区提供如模型中所代表的表面暴露的氨基酸。
图3描绘野生型AAV9和八(8)种候选经修饰rAAV9载体(1090、1091、1092、1093、1094、1095、1096和1097)的高包装效率(效价)(以基因组拷贝/mL(GC/mL)表示)，其中候选载体各自含有紧接在AAV9VR-IV内的不同位点(分别是残基I451至Q458)之后的FLAG插入物。所有载体都与荧光素酶转基因一起包装于10mL培养物中；误差条代表平均值的标准误差。
图4显示八(8)种候选经修饰rAAV9载体(1090、1091、1092、1093、1094、1095、1096和1097)中的每一者中的l VR-IV环FLAG插入物的表面暴露，如通过经由结合至抗FLAG树脂来免疫沉淀经包装载体所证实。
图5A至5B描绘用携带荧光素酶基因(作为转基因)的衣壳载体转导的Lec2细胞中的转导效率，所述衣壳载体包装成野生型AAV9(9-luc)或八(8)种候选经修饰(插入FLAG肽)rAAV9载体(1090、1091、1092、1093、1094、1095、1096和1097)中的每一者；转导活性表示为荧光素酶活性百分比(将9-luc的活性视为100％)(图5A)或表示为相对光单位(RLU)/微克蛋白质(图5B)。
图6A至6E.图6A描绘图解说明紧接在AAV9的S454之后且具有不同肽长度和组成的插入物可影响AAV颗粒在包装细胞中的产生效率的条形图。10种具有不同组成和长度的肽在S454之后插入AAV9 VR-IV内。在转染后5天对经转染悬浮HEK293细胞的所收获上清液实施qPCR。条形图中所描绘的结果证实，插入物的性质影响了待由HEK293细胞产生和分泌的AAV颗粒的能力，并且由总产率(效价)指示。(误差条代表平均肽长度的标准误差，其在Y轴上以括号注明。)图6B至6E描绘下列细胞系的经转导细胞培养物的荧光图像：(6B)Lec2细胞系、(6C)HT-22细胞系、(6D)hCMEC/D3细胞系和(6E)C2C12细胞系。使用含有GFP转基因的AAV9野生型和S454插入归巢肽衣壳来转导所述细胞系。P1载体因极低转导效率而未包含于图像中，并且P8载体因低效价而未包含。在所测试的每一细胞类型中，AAV9.S454.FLAG展示低转导水平。
图7A至7M描绘人轴丝动力蛋白1-12、14和17的重链尾部结构域的氨基酸序列。
图8描绘具有用于异源肽的插入位点的AAV 1-9e、rh10、rh20、rh39和rh74形式1和形式2的衣壳序列的比对，所述插入位点位于VP2的起始密码子之后且在可变区1(VR-I)、可变区4(VR-IV)和可变区8(VR-VIII)内或其附近，都以灰色突出显示；每一衣壳蛋白的可变区8(VR-VIII)内的特定插入位点由符号“#”展示(在根据AAV9的氨基酸编号的氨基酸残基588之后)。
图9描绘在Q588与A589之间包含肽插入物ARA290的重组AAV9载体的氨基酸序列(SEQ ID NO:153)；ARA290插入物以粗体展示。
图10描绘在施用以下AAV载体后小鼠脑细胞中的GFP(绿色荧光蛋白)转基因的拷贝：AAV9；AAV.PHP.eB，在本文中也称为AAV9e(具有插入位置588与589之间的肽TLAVPFK(SEQ ID NO:27)和修饰A587D/A588G的AAV9)；AAV.hDyn(在588与589之间具有TLAAPFK(SEQID NO:2)的AAV9)；AAV.PHP.S(在位置588与589之间插入肽QAVRTSL(SEQ ID NO:23)的AAV9)；和AAV.PHP.SH(在位置588与589之间插入肽QAVRTSH(SEQ ID NO:24)的AAV9)。
图11A至11C描绘在Q588与A589之间(图11A)、在VR-III的S268与S269之间(图11B)和在VR-IV的S454与G455之间(图11C)包含肽插入物TLAAPFK(SEQ ID NO:2)的重组AAV9载体的氨基酸序列，每一TLAAPFK(SEQ ID NO:2)插入物以粗体展示。
图12A至12C描绘在Q588与A589之间(图12A)、在VR-III的S268与S269之间(图12B)和在VR-IV的S454与G455之间(图12C)包含肽插入物KMQVPFQ(SEQ ID NO:1)的重组AAV9载体的氨基酸序列，每一KMQVPFQ(SEQ ID NO:1)插入物以粗体展示。
图13A至13C描绘在Q588与A589之间(图13A)、在VR-III的S268与S269之间(图13B)和在VR-IV的S454与G455之间(图13C)包含肽插入物QQAAPSF(SEQ ID NO:3)的重组AAV9载体的氨基酸序列，每一QQAAPSF(SEQ ID NO:3)插入物以粗体展示。
图14A至14C描绘在Q588与A589之间(图14A)、在VR-III的S268与S269之间(图14B)和在VR-IV的S454与G455之间(图14C)包含肽插入物RYNAPFK(SEQ ID NO:4)的重组AAV9载体的氨基酸序列，每一RYNAPFK(SEQ ID NO:4)插入物以粗体展示。
图15A至15C描绘在Q588与A589之间(图15A)、在VR-III的S268与S269之间(图15B)和在VR-IV的S454与G455之间(图15C)包含肽插入物LKLPPIV(SEQ ID NO:5)的重组AAV9载体的氨基酸序列，每一LKLPPIV(SEQ ID NO:5)插入物以粗体展示。
图16A至16C描绘在Q588与A589之间(图16A)、在VR-III的S268与S269之间(图16B)和在VR-IV的S454与G455之间(图16C)包含肽插入物PFIKPFE(SEQ ID NO:6)的重组AAV9载体的氨基酸序列，每一PFIKPFE(SEQ ID NO:6)插入物以粗体展示。
图17A至17C描绘在Q588与A589之间(图17A)、在VR-III的S268与S269之间(图17B)和在VR-IV的S454与G455之间(图17C)包含肽插入物TLSLPWK(SEQ ID NO:7)的重组AAV9载体的氨基酸序列，每一TLSLPWK(SEQ ID NO:7)插入物以粗体展示。
图18A至18C描绘在N590与T591之间(图18A)、在VR-III的A269与T270之间(图18B)和在VR-IV的T453与T454之间(图18C)包含肽插入物LGETTRP(SEQ ID NO:15)的重组AAV8载体的氨基酸序列，每一LGETTRP(SEQ ID NO:15)插入物以粗体展示。
图19A至19C描绘在N590与T591之间(图19A)、在VR-III的A269与T270之间(图19B)和在VR-IV的T453与T454之间(图19C)包含肽插入物LALGETTRP(SEQ ID NO:16)的重组AAV8载体的氨基酸序列，每一LALGETTRP(SEQ ID NO:16)插入物以粗体展示。
图20A至20B描绘AAV载体穿越血脑屏障(BBB)细胞层的体外transwell分析(图20A)；并且结果展示，AAV.hDyn(由倒三角形指示)穿越测定的BBB细胞层的速度快于AAV9(正方形)且在更大程度上快于AAV2(圆圈)(图20B)。
图21描绘来自静脉内施用经工程改造和天然衣壳的池的小鼠的脑gDNA的下一代测序(NGS)分析的结果，其公开池中的不同衣壳在小鼠组织中的相对丰度。将三种不同池注射至小鼠中。虚线指示汇集至一起的载体。胃肠外AAV9包含于每一池中作为对照(池1：BC01，池2：BC31，池3：BC01)。池中的每一衣壳的条形码列示于表8a至8c中。
图22A至22H描绘雌性C57Bl/6小鼠中的AAV.hDyn的体内转导特征，其展示初次接受试验的小鼠或在脑(图22A)、肝(图22B)、心脏(图22C)、肺(图22D)、肾(图22E)、骨骼肌(图22F)、坐骨神经(图22G)和卵巢(图22H)中注射AAV9或AAV.hDyn的小鼠中的拷贝数/微克gDNA，其中AAV.hDyn与AAV9相比展示增加的脑生物分布。
图23A至23C描绘整个脑中来自AAV.hDyn的GFP分布，其中来自纹状体(图23A)、海马体(图23B)和皮质(图23C)的脑切片的免疫组织化学染色的图像揭示了通过经修饰载体实现的广泛性脑转导。
图24描绘紧接在氨基酸454之后含有归巢肽插入物的经遗传工程改造的AAV9载体的体内肾/肝转导效率比。此研究中所用归巢肽的细节概述于表8中。
图25描绘在VR-IV的S454与G455之间包含肽插入物TLAVPFK(SEQ ID NO:27)的重组AAV9载体的氨基酸序列，其中TLAVPFK(SEQ ID NO:27)插入物以粗体展示。
5.具体实施方式
提供重组腺相关病毒(rAAV)，所述重组腺相关病毒具有经工程改造以包含赋予和/或增强所需性质(如rAAV基因组的组织靶向、转导和整合)的氨基酸序列的衣壳蛋白。特别地，提供经工程改造的衣壳蛋白，所述衣壳蛋白在病毒衣壳的可变区IV(VR-IV)内或其附近包含来自异源蛋白的具有4至20或7个邻接氨基酸和在实施方案中不超过12个邻接氨基酸的肽插入物，使得在衣壳蛋白包装为AAV颗粒时肽插入物是表面暴露的。还提供重组衣壳蛋白和包含所述重组衣壳蛋白的rAAV，其具有例如来自人轴丝动力蛋白中重链尾部区域的二聚化结构域的靶向特定组织和/或促进rAAV细胞摄取、转导和/或基因组整合的插入肽和如本文所述的其他者(参见表1A和1B)。
还提供具有本文所述的一个或多个促进转导和/或组织嗜性的氨基酸取代的经工程改造的衣壳。还提供包含衣壳蛋白的重组载体以及其药物组合物、编码衣壳蛋白的核酸以及制备衣壳蛋白和具有经工程改造的衣壳的rAAV载体和使用其来靶向递送、改善转导和/或治疗与靶组织有关的病症的方法。特别地，提供包含rAAV的组合物和使用衣壳蛋白的方法，所述衣壳蛋白包含源自促红细胞生成素或动力蛋白的肽或与动力蛋白有关的肽以使rAAV靶向视网膜和/或神经组织(包括中枢神经系统)，并且促进了用于治疗神经病症和/或眼睛、尤其视网膜的病症的治疗剂的递送。还提供包含rAAV的组合物以及其使用方法，所述rAAV包含靶向或归巢于靶组织(如骨、肾、肌肉、肺、视网膜和心脏)的肽插入物。
5.1.定义
术语“AAV”或“腺相关病毒”是指细小病毒科(Parvoviridae)病毒属内的依赖性细小病毒(Dependoparvovirus)。AAV可以是源自天然存在的“野生型”病毒的AAV、源自包装至包含由天然存在的cap基因所编码衣壳蛋白的衣壳中的rAAV基因组和/或包装至包含由非天然存在的衣壳cap基因所编码衣壳蛋白的衣壳中的rAAV基因组的AAV。后者的实例包括具有在天然存在的衣壳的氨基酸序列中包含肽插入物的衣壳蛋白的rAAV。
术语“rAAV”是指“重组AAV”。在一些实施方案中，重组AAV具有其中rep和cap基因中的一部分或全部已被异源序列代替的AAV基因组。
术语“rep-cap辅助质粒”是指提供病毒rep和cap基因功能且有助于从缺乏功能性rep和/或cap基因的rAAV基因组序列产生AAV的质粒。
术语“cap基因”是指编码形成或帮助形成病毒的衣壳外壳的衣壳蛋白的核酸序列。对于AAV而言，衣壳蛋白可以是VP1、VP2或VP3。
术语“rep基因”是指编码病毒复制和产生所需的非结构蛋白的核酸序列。
如本文中所使用，术语“核酸”和“核苷酸序列”包括DNA分子(例如cDNA或基因组DNA)、RNA分子(例如mRNA)、DNA和RNA分子的组合或杂合DNA/RNA分子以及DNA或RNA分子的类似物。可使用例如核苷酸类似物(包含但不限于肌苷或三苯甲基化碱基)来生成此类类似物。此类类似物还可包含含有赋予所述分子有益属性(例如核酸酶抗性或增加穿越细胞膜的能力)的经修饰主链的DNA或RNA分子。核酸或核苷酸序列可以使单链、双链，可含有单链和双链部分二者，并且可含有三链部分，但优选是双链DNA。
如本文中所使用，术语“受试者”、“宿主”和“患者”可互换使用。如本文中所使用，受试者是哺乳动物，如非灵长类动物(例如牛、猪、马、猫、狗、大鼠等)和灵长类动物(例如猴和人)或在某些实施方案中人。
如本文中所使用，术语“治疗剂”是指可用于治疗、控制或改善与疾病或病症有关的症状的任何剂，其中疾病或病症与待由转基因提供的功能有关。如本文中所使用，“治疗有效量”是指在施用于患有靶疾病或病症的受试者时在治疗或控制所述靶疾病或病症中提供至少一种治疗性益处的剂的量(例如由转基因表达的产物的量)。另外，关于本发明的剂的治疗有效量意指在治疗或控制疾病或病症中提供至少一种治疗性益处的剂(单独或与其他疗法组合)的量。
如本文中所使用，术语“防治剂”是指可用于预防疾病或病症、延迟或减缓其进展的任何剂，其中所述疾病或病症与待由转基因提供的功能有关。如本文中所使用，“防治有效量”是指在施用于易患靶疾病或病症的受试者时在预防或延迟所述靶疾病或病症中提供至少一种防治性益处的防治剂的量(例如由转基因表达的产物的量)。防治有效量还可指足以预防或延迟靶疾病或病症的发生或减缓靶疾病或病症的进展的剂的量；足以延迟或最小化靶疾病或病症的发作的量；或足以预防或延迟其复发或扩散的量。防治有效量还可指足以预防或延迟靶疾病或病症的症状恶化的剂的量。另外，关于本发明防治剂的防治有效量意指在预防或延迟疾病或病症中提供至少一种防治性益处的防治剂(单独或与其他剂组合)的量。
可将本发明的防治剂施用于“易患”靶疾病或病症的受试者。“易患”疾病或病症的受试者是展示与疾病或病症发生有关的症状的受试者，或具有这种疾病或病症的基因组成、环境暴露或其他风险因子但其中所述症状尚未处于待诊断为疾病或病症的水平的受试者。例如，具有与缺失基因(待由转基因提供)有关的疾病的家族史的患者可视为易患所述疾病者。另外，在除去原发性肿瘤之后持续存在休眠肿瘤的患者可视为易于复发肿瘤者。
本文所用的“中枢神经系统”(“CNS”)是指循环剂在穿越血脑屏障之后所到达的神经组织，并且包括例如脑、视神经、颅神经和脊髓。CNS还包含脑脊髓液，脑脊髓液填充脊髓的中央管以及脑心室。
5.2.重组AAV衣壳和载体
一个方面涉及重组腺相关病毒(rAAV)的衣壳蛋白，所述衣壳蛋白经工程改造以包含来自并非AAV蛋白的异源蛋白的肽插入物，其中在包装为AAV颗粒时所述肽插入物表面暴露。在一些实施方案中，肽插入物出现于AAV9衣壳的可变区IV(VRIV)内(即在两个氨基酸之间且并不缺失任何衣壳氨基酸)，或出现于另一类型AAV衣壳的相应区域中(参见图8中的比对)。在一些实施方案中，肽插入物出现于AAV9衣壳的可变区VIII(VR-VIII)内(即在两个氨基酸之间且并不缺失任何衣壳氨基酸)，或出现于另一AAV类型的衣壳的相应区域中(参见图8中的比对)。在一些实施方案中，肽插入物来自异源蛋白或结构域(其并非AAV衣壳蛋白或结构域)，其将rAAV颗粒引导至靶组织和/或促进rAAV摄取、转导和/或基因组整合。还提供编码经工程改造的衣壳蛋白及其变体的核酸、用于表达核酸以产生rAAV载体的包装细胞、还包含转基因的rAAV载体和rAAV载体的药物组合物以及使用rAAV载体将转基因递送至有需要的受试者的靶细胞类型或靶组织的方法。
在各个实施方案中，靶组织可以是神经组织、骨、肾、肌肉、眼睛/视网膜或内皮组织或特定受体或肿瘤，并且肽插入物是源自特异性识别和/或结合所述组织或例如一种或多种特定细胞类型(如在靶组织内)或其细胞基质的异源蛋白或结构域。特别地，源自促红细胞生成素或动力蛋白(尤其轴丝动力蛋白或细胞质动力蛋白的重链二聚化结构域)或结合至插入任何表面暴露的可变区中的细胞质动力蛋白或与其缔合的肽可使rAAV靶向神经组织，包含穿越血脑屏障到达CNS且递送用于治疗神经病症的治疗剂。
5.2.1具有肽插入物的rAAV载体
本发明人出人意料地发现适用于AAV9衣壳VR-IV环(参见图2)内和其附近和其他AAV类型衣壳的VR-IV环上的相应区域中的肽插入的位置。尽管先前研究分析了各种AAV中的潜在位置，但无人将AAV9 VR-IV鉴定为适用于此目的(参见例如Wu等人,2000,“Mutational Analysis of the Adeno-Associated Virus Type 2(AAV2)Caps id Gene andConstruction of AAV2 Vectors with Altered Tropism,”J of Virology 74(18):8635-8647；Lochrie等人,2006,“Adeno-associa ted virus(AAV)capsid genes isolated fromrat and mouse liver ge nomic DNA define two new AAV species distantly relatedto AAV-5,”Virology 353:68-82；Shi和Bartlett,2003,“RGD Inclusion in VP3ProvidesAdeno-Associated Virus Type 2(AAV2)-Based Vectors with a Heparan Sulfate-Independent Cell Entry Mechanism,”Molecul ar Therapy 7(4):515525-；Nicklin等人,2001,“Efficient and Selecti ve AAV2-Mediated Gene Transfer Directed toHuman Vascular End othelial Cells”Molecular Therapy 4(2):174-181；Grifman等人,2001,“Incorporation of Tumor-Targeting Peptides into Recombinant Adeno-associated Virus Capsids,”Molecular Therapy 3(6):964-975；Girod等人,1999,“Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2,”Nature Medicine 3(9):1052-1056；Douar等人,2003,“Deleterious effect of peptide insertions in a permi ssive site of the AAV2capsid,”Virology 309:203-208；和Ponnazhag an等人,2001,J.of Virology 75(19):9493-9501)。
因此，提供在新颖插入点处、特别是在衣壳外壳中的表面暴露的可变区内、尤其在衣壳蛋白的可变区IV内或其附近携带肽插入物的rAAV载体。在一些实施方案中，rAAV衣壳蛋白在紧接在对应于AAV9衣壳蛋白(氨基酸序列SEQ ID NO:118且参见图8中其他AAV血清型的衣壳蛋白氨基酸序列与AAV9衣壳的氨基酸序列的比对)的氨基酸451至461中的一者的氨基酸残基之后(即由肽键C-末端连结)包含肽插入物，其中在衣壳蛋白包装为AAV颗粒时所述肽插入物表面暴露。肽插入不应缺失AAV衣壳蛋白的任何残基。通常，肽插入物出现于衣壳蛋白的可变(保守性较差)区(与其他血清型相比)和表面暴露的环中。
描述为插入“在”给定位点处的肽插入是指插入紧接在通常发现于野生型病毒中的所述位点处的残基之后，即具有至其羧基的肽键。例如，AAV9中的Q588处的插入意指，肽插入出现于AAV9野生型衣壳蛋白序列(SEQ ID NO:118)中的Q588与后续氨基酸(A589)之间。在实施方案中，在插入点处或其附近(在5、10、15个残基内或在作为插入位点的结构环内)并不缺失氨基酸残基。
在特定实施方案中，衣壳蛋白是AAV9衣壳蛋白且插入物紧接在氨基酸残基451至461中的至少一者之后出现。在特定实施方案中，肽插入物紧接在AAV9衣壳(氨基酸序列SEQID NO:118)的氨基酸I451、N452、G453、S454、G455、Q456、N457、Q458、Q459、T460或L461之后出现。在某些实施方案中，肽插入AAV9衣壳蛋白的残基S454与G455之间或除AAV9衣壳蛋白(氨基酸序列SEQ ID NO:118)外的AAV衣壳蛋白中对应于S454和G455的残基之间。
在其他实施方案中，提供包含靶向肽的经工程改造的衣壳蛋白，所述靶向肽与衣壳蛋白异源且插入AAV衣壳蛋白中，以使得在纳入AAV载体中时，异源肽表面暴露。所述肽优选地来自人轴丝动力蛋白(HAD)重链尾部或是下文表1A和1B中所列的那些或用于特定组织类型的其他靶向肽。
在其他实施方案中，衣壳蛋白来自至少一种选自以下的AAV类型：AAV血清型1(AAV1)、血清型2(AAV2)、血清型3(AAV3)、血清型4(AAV4)、血清型5(AAV5)、血清型6(AAV6)、血清型7(AAV7)、血清型8(AAV8)、血清型rh8(AAVrh8)、血清型9e(AAV9e)、血清型rh10(AAVrh10)、血清型rh20(AAVrh20)、血清型rh39(AAVrh39)、血清型hu.37(AAVhu.37)和血清型rh74(AAVrh74，型式1和2)(参见图8)，并且插入物紧接在对应于氨基酸残基451至461中的至少一者的氨基酸残基之后出现。所述不同AAV血清型的比对(如图8中所展示)指示不同衣壳氨基酸序列中的“相应”氨基酸残基，是的“相应”氨基酸残基与参考序列中的残基在相同比对位置处对齐。在一些特定实施方案中，在图8中所描绘的序列中，肽插入物紧接在以下各项内的氨基酸残基中的一者之后出现：AAV1衣壳(SEQ ID NO:110)的450-459；AAV2衣壳(SEQ ID NO:111)的449-458；AAV3衣壳(SEQ ID NO:112)的449-459；AAV4衣壳(SEQ IDNO:113)的443-453；AAV5衣壳(SEQ ID NO:114)的442-445；AAV6衣壳(SEQ ID NO:115)的450-459；AAV7衣壳(SEQ ID NO:116)的451-461；AAV8衣壳(SEQ ID NO:117)的451-461；AAV9衣壳(SEQ ID NO:118)的451-461；AAV9e衣壳(SEQ ID NO:119)的452-461；AAVrh10衣壳(SEQ ID NO:120)的452-461；AAVrh20衣壳(SEQ ID NO:121)的452-461；AAVhu.37(SEQID NO:122)的452-461；AAVrh74(SEQ ID NO:123或SEQ ID NO:154)的452-461；或AAVrh39(SEQ ID NO:124)的452-461。在某些实施方案中，rAAV衣壳蛋白包含紧接在AAV9衣壳蛋白(具有SEQ ID NO:118的氨基酸序列且参见图8)的氨基酸588之后(即C-末端)的肽插入物，其中在衣壳蛋白包装为AAV颗粒时所述肽插入物表面暴露。在其他实施方案中，rAAV衣壳蛋白具有并不紧接在AAV9的氨基酸588之后或对应于AAV9的氨基酸588的肽插入物。
在其他实施方案中，在肽是表1A和1B中包含至少4个邻接氨基酸或至少7个邻接氨基酸或恰好7个邻接氨基酸但在实施方案中不超过12个邻接氨基酸的靶向肽或其功能片段时，衣壳蛋白来自至少一种选自以下的AAV类型：AAV血清型1(AAV1)、血清型2(AAV2)、血清型3(AAV3)、血清型4(AAV4)、血清型5(AAV5)、血清型6(AAV6)、血清型7(AAV7)、血清型8(AAV8)、血清型rh8(AAVrh8)、血清型9e(AAV9e)、血清型rh10(AAVrh10)、血清型rh20(AAVrh20)、血清型rh39(AAVrh39)、血清型hu.37(AAVhu.37)和血清型rh74(AAVrh74，型式1和2)(参见图8)，并且肽插入衣壳蛋白中使得在纳入AAV载体中时肽表面暴露的任一点处。在具体实施方案中，肽插入以下位置之后：AAV1衣壳(SEQ ID NO:110)的138、262-272、450-459或585-593；AAV2衣壳(SEQ ID NO:111)的138、262-272、449-458或584-592；AAV3衣壳(SEQ ID NO:112)的138、262-272、449-459或585-593；AAV4衣壳(SEQ ID NO:113)的137、256-262、443-453或583-591；AAV5衣壳(SEQ ID NO:114)的137、252-262、442-445或574-582；AAV6衣壳(SEQ ID NO:115)的138、262-272、450-459、585-593；AAV7衣壳(SEQ ID NO:116)的138、263-273、451-461、586-594；AAV8衣壳(SEQ ID NO:117)的138、263-274、452-461、587-595；AAV9衣壳(SEQ ID NO:118)的138、262-273、452-461、585-593；AAV9e衣壳(SEQ ID NO:119)的138、262-273、452-461、585-593；AAVrh10衣壳(SEQ ID NO:120)的138、263-274、452-461、587-595；AAVrh20衣壳(SEQ ID NO:121)的138、263-274、452-461、587-595；AAVrh74衣壳(SEQ ID NO:123或SEQ ID NO:154)的138、263-274、452-461、587-595；AAVhu37衣壳(SEQ ID NO:122)的138、263-274、452-461、587-595；或AAVrh39衣壳(SEQ IDNO:124)的138、263-274、452-461、587-595(如图8中所编号)。
在一些实施方案中，衣壳蛋白来自除血清型AAV2外的AAV。在一些实施方案中，肽插入物并不紧接在对应于AAV2衣壳蛋白的氨基酸570或611的氨基酸残基之后出现。在一些实施方案中，肽插入物不出现于对应于AAV2衣壳蛋白的氨基酸587-588的氨基酸残基之间(参见Schaffer等人的US 2014/0294771)。在一些实施方案中，具有氨基酸序列DDDDDDDD(SEQ ID NO:9)的骨1肽的插入物并不紧接在AAV2衣壳蛋白的氨基酸138之后出现(参见Alméciga-Díaz等人,2018,Pediatr.Res.84:545)。
还提供包含经工程改造衣壳的AAV载体。在一些实施方案中，AAV载体是非复制性的且不包含编码rep或cap蛋白的核苷酸序列(这些核苷酸序列在rAAV载体的制造中由包装细胞供应)。在一些实施方案中，基于AAV的载体包含来自一种或多种AAV血清型的组分。在一些实施方案中，本文所提供的基于AAV的载体包含来自以下中的一者或多者的衣壳组分：AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、AAV13、AAV14、AAV15、AAV16、AAV.rh8、AAV.rh10、AAV.rh20、AAV.rh39、AAV.Rh74、AAV.RHM4-1、AAV.hu37、AAV.Anc80、AAV.Anc80L65、AAV.7m8、AAV.PHP.B、AAV.PHP.eB、AAV2.5、AAV2tYF、AAV3B、AAV.LK03、AAV.HSC1、AAV.HSC2、AAV.HSC3、AAV.HSC4、AAV.HSC5、AAV.HSC6、AAV.HSC7、AAV.HSC8、AAV.HSC9、AAV.HSC10、AAV.HSC11、AAV.HSC12、AAV.HSC13、AAV.HSC14、AAV.HSC15或AAV.HSC16或其他rAAV颗粒或其两者或更多者的组合。在一些实施方案中，本文所提供的基于AAV的载体包含来自以下中的一者或多者的组分：AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、AAV13、AAV14、AAV15、AAV16、AAV.rh8、AAV.rh10、AAV.rh20、AAV.rh39、AAV.Rh74、AAV.RHM4-1、AAV.hu37、AAV.Anc80、AAV.Anc80L65、AAV.7m8、AAV.PHP.B、AAV.PHP.eB、AAV2.5、AAV2tYF、AAV3B、AAV.LK03、AAV.HSC1、AAV.HSC2、AAV.HSC3、AAV.HSC4、AAV.HSC5、AAV.HSC6、AAV.HSC7、AAV.HSC8、AAV.HSC9、AAV.HSC10、AAV.HSC11、AAV.HSC12、AAV.HSC13、AAV.HSC14、AAV.HSC15或AAV.HSC16或其他rAAV颗粒或其两种或更多种血清型的组合。在一些实施方案中，rAAV颗粒包含与例如选自以下的AAV衣壳血清型的VP1、VP2和/或VP3序列至少80％或更大程度同一(例如85％、85％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、99.5％等，即最高100％同一)的衣壳蛋白：AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、AAV13、AAV14、AAV15、AAV16、AAV.rh8、AAV.rh10、AAV.rh20、AAV.rh39、AAV.Rh74、AAV.RHM4-1、AAV.hu37、AAV.Anc80、rAAV.Anc80L65、AAV.7m8、AAV.PHP.B、AAV.PHP.eB、AAV2.5、AAV2tYF、AAV3B、AAV.LK03、AAV.HSC1、AAV.HSC2、AAV.HSC3、AAV.HSC4、AAV.HSC5、AAV.HSC6、AAV.HSC7、AAV.HSC8、AAV.HSC9、AAV.HSC10、AAV.HSC11、AAV.HSC12、AAV.HSC13、AAV.HSC14、AAV.HSC15或AAV.HSC16或其衍生物、修饰或假型。这些经工程改造的AAV载体可包含含有编码治疗蛋白的转基因的基因组。
在特定实施方案中，用于本文的组合物和方法中的重组AAV是Anc80或Anc80L65(参见例如Zinn等人,2015,Cell Rep.12(6):1056-1068，其以引用的方式整体并入本文中)。在特定实施方案中，用于本文的组合物和方法中的重组AAV是AAV.7m8(包含其变体)(参见例如US 9,193,956；US 9,458,517；US 9,587,282；US 2016/0376323和WO 2018/075798，其中的每一者以引用的方式整体并入本文中)。在特定实施方案中，用于本文的组合物和方法中的AAV是US 9,585,971中所公开的任一AAV(例如AAV-PHP.B)。在特定实施方案中，用于本文的组合物和方法中的AAV是AAV2/Rec2或AAV 2/Rec3载体，其具有源自AAV8和血清型cy5、rh20或rh39的杂合衣壳序列(参见例如Issa等人,2013,PLoS One 8(4):e60361，关于这些载体的内容以引用的方式并入本文中)。在特定实施方案中，用于本文的组合物和方法中的AAV是以下中的任一者中所公开的AAV：US 7,282,199；US 7,906,111；US8,524,446；US 8,999,678；US 8,628,966；US 8,927,514；US 8,734,809；US9,284,357；US9,409,953；US 9,169,299；US 9,193,956；US 9,458,517；US 9,587,282；US 20 15/0374803；US 2015/0126588；US 2017/0067908；US 2013/0224836；US 2016/0215024；US2017/0051257；PCT/US2015/034799；和PCT/EP2015/053335，其中的每一者以引用的方式整体并入本文中。在一些实施方案中，rAAV颗粒具有与下列专利和专利申请中的任一者中所公开的AAV衣壳的VP1、VP2和/或VP3序列至少80％或更大程度同一(例如85％、85％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、99.5％等，即最高100％同一)的衣壳蛋白：美国专利号7,282,199；7,906,111；8,524,446；8,999,678；8,628,966；8,927,514；8,734,809；US 9,284,357；9,409,953；9,169,299；9,193,956；9,458,517；和9,587,282；美国专利申请公布号2015/0374803；2015/0126588；2017/0067908；2013/0224836；2016/0215024；2017/0051257；和国际专利申请号PCT/US2015/034799；PCT/EP2015/053335，其中的每一者以引用的方式整体并入本文中。
在一些实施方案中，rAAV颗粒包含美国专利号9,840,719和WO 2015/013313中所公开的任一AAV衣壳(如AAV.Rh74和RHM4-1)，所述专利中的每一者以引用的方式整体并入本文中。在一些实施方案中，rAAV颗粒包含WO 2014/172669中所公开的任一AAV衣壳(如AAVrh.74)，所述专利以引用的方式整体并入本文中。在一些实施方案中，rAAV颗粒包含AAV2/5衣壳，如Georgiadis等人,2016,Gene Therapy 23:857-862和Georgiadis等人,2018,GeneTherapy 25:450中所描述，所述文献各自以引用的方式整体并入本文中。在一些实施方案中，rAAV颗粒包含WO 2017/070491中所公开的任一AAV衣壳(如AAV2tYF)，所述专利以引用的方式整体并入本文中。在一些实施方案中，rAAV颗粒包含AAVLK03或AAV3B衣壳，如Puzzo等人,2017,Sci.Transl.Med.29(9):418中所描述，所述文献以引用的方式整体并入本文中。在一些实施方案中，rAAV颗粒包含美国专利号8,628,966、US 8,927,514、US 9,923,120和WO 2016/049230中所公开的任一AAV衣壳(如HSC1、HSC2、HSC3、HSC4、HSC5、HSC6、HSC7、HSC8、HSC9、HSC10、HSC11、HSC12、HSC13、HSC14、HSC15或HSC16)，所述专利各自以引用的方式整体并入本文中。
在一些实施方案中，rAAV颗粒具有以下各项中所公开的衣壳蛋白：国际申请公布号WO 2003/052051(参见例如′051公布的SEQ ID NO:2)、WO 2005/033321(参见例如′321公布的SEQ ID NO:123和88)、WO 03/042397(参见例如′397公布的SEQ ID NO:2、81、85和97)、WO 2006/068888(参见例如′888公布的SEQ ID NO:1和3至6)、WO 2006/110689(参见例如′689公布的SEQ ID NO:5-38)、WO2009/104964(参见例如′964公布的SEQ ID NO:1-5、7、9、20、22、24和31)、WO 2010/127097(参见例如′097公布的SEQ ID NO:5-38)和WO 2015/191508(参见例如′508公布的SEQ ID NO:80-294)和美国申请公布号20150023924(参见例如′924公布的SEQ ID NO:1、5-10)，所述专利各自的内容以引用的方式并入本文中。在一些实施方案中，rAAV颗粒具有与以下各项中所公开的AAV衣壳的VP1、VP2和/或VP3序列至少80％或更大程度同一(例如85％、85％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、99.5％等，即最高100％同一)的衣壳蛋白：国际申请公布号WO2003/052051(参见例如′051公布的SEQ ID NO:2)、WO 2005/033321(参见例如′321公布的SEQ ID NO:123和88)、WO 03/042397(参见例如′397公布的SEQ ID NO:2、81、85和97)、WO2006/068888(参见例如′888公布的SEQ ID NO:1和3-6)、WO 2006/110689(参见例如′689公布的SEQ ID NO:5-38)、WO2009/104964(参见例如964公布的SEQ ID NO:1-5、7、9、20、22、24和31)、WO 2010/127097(参见例如′097公布的SEQ ID NO:5-38)和WO 2015/191508(参见例如′508公布的SEQ ID NO:80-294)和美国申请公布号20150023924(参见例如′924公布的SEQ ID NO:1、5-10)。
在其他实施方案中，rAAV颗粒包含假型化AAV衣壳。在一些实施方案中，假型化AAV衣壳是rAAV2/8或rAAV2/9假型化AAV衣壳。本领域中已知用于产生和使用假型化rAAV颗粒的方法(参见例如Duan等人,J.Virol.,75:7662-7671(2001)；Halbert等人,J.Virol.,74:1524-1532(2000)；Zolotukhin等人,Methods 28:158-167(2002)；和Auricchio等人,Hum.Molec.Genet.10:3075-3081,(2001)。
在某些实施方案中，可使用单链AAV(ssAAV)。在某些实施方案中，可使用自我互补性载体(例如scAAV)(参见例如Wu,2007,Human Gene Therapy,18(2):171-82；McCarty等人,2001,Gene Therapy,8(16):1248-1254；US 6,596,535；US 7,125,717；和US 7,456,683，所述文献各自以引用的方式整体并入本文中)。
通常，肽插入物来自异源蛋白或其结构域的邻接氨基酸的序列。待插入肽通常足够长以保留其所来源的蛋白质或结构域的特定生物功能、特性或特征。待插入肽通常足够短以允许衣壳蛋白形成类似或实质上类似于天然无插入衣壳蛋白的外壳。在优选实施方案中，肽插入物具有约4至约30个氨基酸残基的长度、约4至约20、约4至约15、约5至约10或约7个氨基酸的长度。用于插入的肽序列的长度是至少4个氨基酸且长度可以是5、6、7、8、9、10、11、12、13、14或15个氨基酸。在一些实施方案中，肽序列的长度是16、17、18、19或20个氨基酸。在实施方案中，肽长度不超过7个氨基酸、10个氨基酸或12个氨基酸。
AAV衣壳蛋白中的“来自异源蛋白的肽插入物”是指已引入衣壳蛋白中且并非任一AAV血清型衣壳的天然部分的氨基酸序列。非限制性实例包含AAV衣壳蛋白中的人蛋白质的肽。
在一些实施方案中，肽插入物来自归巢蛋白或其归巢结构域或其靶向蛋白或靶向结构域。“归巢结构域”或“归巢蛋白”是相对于其他细胞、组织、器官或肿瘤优先地或选择性地靶向特定细胞类型(包括特定细胞类型的细胞基质)、组织类型、器官、肿瘤类型或诸如此类的结构域或蛋白质。在本发明的上下文中，来自归巢蛋白或结构域的肽给予插入衣壳蛋白中以形成衣壳外壳或AAV载体的一部分的肽，所述肽然后可引导衣壳、外壳或载体靶向特定细胞类型、组织类型、器官、肿瘤类型或诸如此类或以促进AAV基因组的摄取和/或整合。归巢蛋白或结构域的非限制性实例包括神经组织归巢结构域、轴丝或细胞质动力蛋白归巢结构域、骨归巢结构域、肾归巢结构域、肌肉归巢结构域、内皮细胞归巢结构域、视网膜细胞归巢结构域、靶向特定细胞受体的结构域(如整联蛋白受体结合结构域和转铁蛋白受体结合结构域)、肿瘤细胞靶向结构域、来自其他病毒的靶向肽和诸如此类。如本文中所使用，术语“归巢”和“靶向”可互换使用。这些肽还可或可替代地促进rAAV细胞摄取、转导和/或靶组织细胞中的基因组整合。
用作本文所述任一AAV衣壳位点的肽插入物的肽实例呈现于下文表1A至1B中且包含具有肽功能属性的其至少4氨基酸邻接部分或其7氨基酸邻接部分和在一些实施方案中不超过12个邻接氨基酸。还参见例如Laakkonen和Vuorinen,2010,“Homing peptides astargeted delivery vehicles,”Integrative Biology,2:326-337(综述文章)。在某些实施方案中，重组AAV衣壳和AAV载体经工程改造以包含来自下文表1A和1B中的任一者的肽或其至少4、5、6或7氨基酸邻接部分，所述肽或部分以显示肽插入物的方式插入AAV衣壳序列中。在其他实施方案中，肽插入AAV9衣壳(SEQ ID NO:118)的氨基酸序列中位置138、262-273、451-461或585-593或任一其他AAV血清型中对应于所述位置的位置处的氨基酸残基之后(参见图8的衣壳序列比对)。
表1A.归巢肽
表1B
在另一方面中，提供异源肽插入文库。异源肽插入文库是指在病毒衣壳中的不同插入位点处(例如在衣壳的给定可变区内的不同位置处)携带相同肽插入物的rAAV载体的集合体。通常，所用衣壳蛋白包含含有经修饰的rep和cap序列以防止病毒在其通常可复制条件下发生复制(共感染哺乳动物细胞以及诸如腺病毒等辅助病毒)的AAV基因组。然后可测定肽插入文库的成员的rAAV表面上的肽功能展示、组织靶向和/或基因转导。
本发明者还出人意料地发现，可使用特定肽使AAV载体重靶向特定组织、器官或细胞；特别是使得rAAV载体靶向视网膜组织和/或穿越血脑屏障并靶向CNS神经组织的肽。不受限于任一理论，插入AAV衣壳可变区环中的某些肽(如动力蛋白和转铁蛋白源性肽)显示可增强脑或视网膜中的转导效率和/或增强携带转基因的AAV颗粒在内皮细胞基质中、尤其在富层粘蛋白基底膜(例如血脑屏障和视网膜的内限界膜)中的转运。这可增强衣壳化转基因的AAV颗粒在内皮细胞基质中的转运。此类肽和其他肽阐述于下文中。
5.2.2神经组织归巢肽
本发明的另一方面涉及包含经设计以赋予或增强亲神经性性质的肽插入物的衣壳蛋白。神经组织包括但不限于神经元、星形细胞、神经胶质、内皮细胞和保护脑的富层粘蛋白基底细胞基质。本发明涉及工程改造rAAV衣壳以显示促进神经元组织靶向和神经元转导的肽。实例包括(i)来自人轴丝动力蛋白(HAD)重链尾部的区域或小鼠轴丝动力蛋白(MAD)重链尾部的区域的肽；(ii)来自结合先天性修复受体且并非红细胞生成性的促红细胞生成素(EPO)结构域或所述结构域的构象类似物的肽；和(iii)脑靶向肽。
5.2.2.1 rAAV-HAD载体
在某些实施方案中，肽插入物是源自人轴丝动力蛋白(HAD)重链尾部的区域的肽，并且使用所述插入物作为神经组织归巢肽(或神经细胞归巢肽)和/或视网膜细胞归巢肽(其方面更详细地论述于下文中)。在本文中称为“HAD肽”的肽可以是来自HAD重链尾部区域或经设计以模拟其三维结构的构象类似物的至少4个连续氨基酸的序列。包含一个或多个(例如)插入AAV衣壳外壳的表面暴露的环中的HAD肽的重组AAV载体在本文中称为“rAAV-HAD载体”。
动力蛋白是沿微管移动的细胞骨架马达蛋白。存在两种基本类型：(1)细胞质动力蛋白和(2)轴丝动力蛋白。细胞质动力蛋白用于转运细胞内货物且移动有丝分裂纺锤体上的染色体。细胞质动力蛋白通常呈现为两条相同重链和若干条中链和轻链的二聚体。轴丝动力蛋白使得微管滑动于轴丝(包含纤毛和鞭毛中的结构)中。轴丝动力蛋白是以含有一条、两条或三条不同重链的多种形式发现。
人轴丝动力蛋白(HAD)的整体结构涉及“尾部”和“头部”区域。尾部包括募集货物以供沿微管转运的二聚化结构域。头部包含由6个AAA结构域(三重ATP酶)构成的马达结构域，所述AAA结构域“产生力”且驱动动力蛋白马达发生附着和分离，并且由此沿微管表面“行走”。还参见Toda等人,2018,Biophysical Rev 10:677-686；Reck-Pe terson,2018,NatRev Mol Cell Biol；Reck-Peterson等人,2006,“Si ngle-Molecule Analysis of DyneinProcessivity and Stepping Behavi or,”Cell 126:335-348；Urnavicius,2018,Nature554:202；Urnavicius,2015,Science 347:1441；和Zhang等人,2017,Cell 169:1303。另外，参见例如Roberts等人,2013,“Functions and mechanics of dynein motor proteins”Nat Rev Mol Cell Biol.,14(11):713-726；Wadswort h等人,2013,“MicrotubuleMotors:Doin；It without Dynactin,”CurrBiol 23(13):R563-R565；Kelkar等人,2006,“ACommon Mechanis m for Cytoplasmic Dynein-Dependent Microtubule Binding Sharedamong Adeno-Associated Virus and Adenovirus Serotypes,”J.of Virol ogy,7781-7785；和Zhang等人,2017,“Cryo-EM Reveals How Hu man Cytoplasmic Dynein Is Auto-Inhibited and Activated,”Cell,169:1303-1314。
表2鉴定人轴丝动力蛋白的尾部和二聚化结构域以及用作本文所述的经工程改造的衣壳蛋白中的肽插入物的肽。在一些实施方案中，使用来自茎部/尾部区域和/或二聚化结构域(NDD)的轴丝动力蛋白序列的至少4个且至多15个邻接氨基酸或7个邻接氨基酸的插入物(还参见图7A-7M)。
表2.轴丝动力蛋白肽
在一些实施方案中，用于插入AAV衣壳中的肽是从HAD重链尾部区域的二聚化结构域(NDD)设计的。在替代实施方案中，可使用对应于HAD重链尾部的其他部分(即排除动力蛋白马达结构域)的氨基酸序列的肽。在一些实施方案中，肽插入物包含来自HAD重链尾部的二聚化结构域的至少4个(在一实施方案中7个)邻接氨基酸且至多12或15个邻接氨基酸。在特定实施方案中，肽插入物包含来自由以下(描绘于图7A-7M中)组成的组的至少4个邻接氨基酸、7个邻接氨基酸且至多12或15个邻接氨基酸：DYH1_人UniProtKB-Q9P2D7(SEQ ID NO:97)的氨基酸(“aa”)1-1542；DYH2_人UniProtKB-Q9P225(SEQ ID NO:98)的aa 1-1764；DYH3_人UniProtKB-Q8TD57(SEQ ID NO:99)的aa 1-1390；DYH5_人UniProtKB-Q8TE73(SEQID NO:100)的aa 1-1941；DYH6_人UniProtKB-Q9C0G6(SEQ ID NO:101)的aa 1-1433；DYH7_人UniProtKB-Q8WXX0(SEQ ID NO:102)的aa 1-1289；DYH8_人UniProtKB-Q96JB1(SEQ IDNO:3)的aa1-1807；DYH9_人UniProtKB-Q9NYC9(SEQ ID NO:104)的aa1-1831；DYH10_人UniProtKB-Q8IVF4(SEQ ID NO:105)的aa1-1793；DYH11_人UniProtKB-Q96DT5(SEQ ID NO:106)的aa1-1854；DYH12_人UniProtKB-Q6ZR08(SEQ ID NO:107)的aa1-1214；DYH14_人UniProtKB-Q0VDD8(SEQ ID NO:108)的aa1-200；和DYH17
_人UniProtKB-Q9UFH2(SEQ IDNO:109)的aa1-1794)，并且促进了经工程改造以含有所述肽的衣壳的神经组织嗜性和/或转导。在更优选实施方案中，肽插入物包含来自上文所列举的任一动力蛋白重链序列、即来自由以下组成的组的任一者的残基1-200的至少4个邻接氨基酸、7个邻接氨基酸且至多12或15个邻接氨基酸：DYH1_人UniProtKB-Q9P2D7(SEQ ID NO:97)的aa1-1542；DYH2_人UniProtKB-Q9P225(SEQ ID NO:98)的aa 1-1764；DYH3_人UniProtKB-Q8TD57(SEQ ID NO:99)的aa 1-1390；DYH5_人UniProtKB-Q8TE73(SEQ ID NO:100)的aa 1-1941；DYH6_人UniProtKB-Q9C0G6(SEQ ID NO:101)的aa 1-1433；DYH7_人UniProtKB-Q8WXX0(SEQ ID NO:102)的aa 1-1289；DYH8_人UniProtKB-Q96JB1(SEQ ID NO:3)的aa 1-1807；DYH9_人UniProtKB-Q9NYC9(SEQ ID NO:104)的aa 1-1831；DYH10_人UniProtKB-Q8IVF4(SEQ IDNO:105)的aa 1-1793；DYH11_人UniProtKB-Q96DT5(SEQ ID NO:106)的aa 1-1854；DYH12_人UniProtKB-Q6ZR08(SEQ ID NO:107)的aa 1-1214；DYH14_人UniProtKB-Q0VDD8(SEQ IDNO:108)的aa 1-200；和DYH17
_人UniProtKB-Q9UFH2(SEQ ID NO:109)的aa 1-1794))，并且促进经工程改造以含有所述肽的衣壳的神经组织或特异性神经细胞嗜性和/或转导。在更优选的实施方案中，肽插入物来自图7A-7M的任一动力蛋白重链序列的7个邻接氨基酸，或来自任一动力蛋白重链序列(图7A-7M)的残基1-200的7个邻接氨基酸。
在特定实施方案中，肽插入物是来自由以下组成的组的至少4、5、6或7个邻接氨基酸或由其组成：KMQVPFQ(SEQ ID NO:1)、TLAAPFK(SEQ ID NO:2)、QQAAPSF(SEQ ID NO:3)、RYNAPFK(SEQ ID NO:4)、LKLPPIV(SEQ ID NO:5)、PFIKPFE(SEQ ID NO:6)和TLSLPWK(SEQID NO:7)；且可促进经工程改造以含有所述肽的衣壳的神经组织嗜性和/或转导。在更特定实施方案中，肽插入物由来自由以下组成的组的肽组成：KMQVPFQ(SEQ ID NO:1)、TLAAPFK(SEQ ID NO:2)、QQAAPSF(SEQ ID NO:3)、RYNAPFK(SEQ ID NO:4)、LKLPPIV(SEQ ID NO:5)、PFIKPFE(SEQ ID NO:6)和TLSLPWK(SEQ ID NO:7)，并且促进经工程改造以含有所述肽的衣壳的神经组织嗜性和/或转导。在尤其关注的一个实施方案中，肽插入物包含氨基酸序列TLAAPFK(SEQ ID NO:2)或由其组成。
不希望受限于任一理论，本发明的rAAV-HAD载体是基于如下原理：纳入肽的rAAV衣壳将在rAAV表面上展示多个拷贝的人动力蛋白二聚化结构域。当转导靶人细胞时，所述rAAV可直接或经由通过细胞中的动力蛋白衔接子进行募集来负载于靶细胞中的内源性轴丝动力蛋白上。将所述rAAV负载于轴丝动力蛋白上可促进动力蛋白多聚化和/或稳定动力蛋白构象以增强转运活性。
选择来自人轴丝重链动力蛋白的肽结构域来纳入AAV衣壳中以促进rAAV结合至动力蛋白本身尽管违反直觉，但可提供以下若干优点：
(1)轴丝动力蛋白出现于睫状神经元中，并且由此本发明的rAAV-HAD载体可在含有所述结构的感觉神经元、嗅觉神经元、听觉神经元和光感受器中显示增强的亲神经性性质。靶向轴丝动力蛋白(与出现于所有细胞中的细胞质动力蛋白不同)还可赋予神经组织增加的选择性；
(2)出人意料地，重链二聚化肽不干扰轴丝动力蛋白马达结构域的活性(与之相比，先前尝试不能使用合成动力蛋白轻链(LC8)肽来工程改造AAV2衣壳以靶向细胞质动力蛋白，参见例如Bergen等人,2007,“Evaluation of an LC8-Binding Peptide for theAttachment of Artificial Cargo,”Mol Pharm 4(1):119-128；和Xu等人,2005,“Acombination of mutations enhances the neurotropism of AAV2,”Virology,341:203-214)。
(3)本文所用的HAD肽对应于人蛋白且其免疫原性应小于合成肽(例如用于Terwilliger,2005,Virol 341:203中；还参见WO 2016/119150A2)；并且应在人受试者中发挥作用(不同于选择用于小鼠中的含有随机化肽群体的先前技术AAV9衣壳-参见例如Hordeaux等人,2018Mol Ther 26:664,“The Neurotropic Properties of AAV-PHP.B arelimited to C57BL/6J Mice；Matsuzaki等人,2018,Neurosci L ett 665:182-188“Intravenous administration of the AAV-PHP.B ca psid fails to upregulatetransduction efficiency in the marmoset脑”)。
特别地，在将HAD肽工程改造至AAV衣壳如AAV9、AAVrh10和AAVrh20(其对CNS显示强嗜性)中时，递送效率和至CNS的递送得以进一步增强。还参见Castle等人,2014,“Long-distance Axonal Transport of AAV9 is Driven by Dynein and Kinesin-2 and IsTrafficked in a Highly Motile Rab7-positive Compartment”Molecular Therapy,22(3):554-566。
可将HAD肽插入AAV衣壳中(例如)允许表面暴露肽的位点处(例如在可变表面暴露环内)，并且在其他实例中插入本文所述对应于AAV9的VR-I、VR-IV或VR-VIII的位点处。在一些实施方案中，包含HAD肽的rAAV载体穿越血脑屏障且到达CNS。
在一些实施方案中，使用来自小鼠轴丝动力蛋白(MAD)重链尾部的肽。MAD重链尾部还提供神经组织归巢结构域，所述结构域可衍生用于插入AAV衣壳蛋白中且用于再引导rAAV穿越血脑屏障并靶向CNS组织的肽(还参见Deverman等人,2016,“Cre-dependentselection yields AAV variants for widespread gene transfer to the adult脑”NatBiotechnology,34(2):204-209)。
在一些实施方案中，神经组织归巢结构域包含氨基酸序列TLAVPFK(SEQ ID NO:27)；且源自其的肽插入物包含TLAVPFK(SEQ ID NO:27)序列或由其组成。在一些实施方案中，肽插入物包含来自TLAVPFK(SEQ ID NO:27)的4、5或6个连续氨基酸或由其组成。在特定实施方案中，衣壳蛋白是AAV9衣壳蛋白且TLAVPFK(SEQ ID NO:27)插入物紧接在氨基酸残基451至461中的至少一者之后出现。在特定实施方案中，TLAVPFK(SEQ ID NO:27)插入物出现于AAV9衣壳(SEQ ID NO:118)的氨基酸残基I451、N452、G453、S454、G455、Q456、N457、Q458、Q459、T460或L461之后，并且在某些实施方案中在AAV9衣壳的S454之后。在其他实施方案中，衣壳蛋白来自至少一种选自以下的AAV类型：AAV血清型1(AAV1)、血清型2(AAV2)、血清型3(AAV3)、血清型4(AAV4)、血清型5(AAV5)、血清型6(AAV6)、血清型7(AAV7)、血清型8(AAV8)、血清型rh8(AAVrh8、血清型9e(AAV9e)、血清型rh10(AAVrh10)、血清型rh20(AAVrh20)、血清型rh39(AAVrh39)、血清型hu.37(AAVhu.37)和血清型rh74(AAVrh74，型式1和2)(参见图8)，并且TLAVPFK(SEQ ID NO:27)肽插入物紧接在AAV衣壳中对应于AAV9衣壳的氨基酸残基451至461中的一者的氨基酸残基之后出现。这些不同AAV血清型的比对(如图8中所展示)指示不同氨基酸序列中的相应氨基酸残基。在一些特定实施方案中，在图8中所描绘的序列中，TLAVPFK(SEQ ID NO:27)肽插入物紧接在以下各项内的氨基酸残基中的一者之后出现：AAV1衣壳的450-459；AAV2衣壳的449-458；AAV3衣壳的449-459；AAV4衣壳的443-453；AAV5衣壳的442-445；AAV6衣壳的450-459；AAV7衣壳的451-461；AAV8衣壳的451-461；AAV9衣壳的451-461；AAV9e衣壳的452-461；AAVrh10衣壳的452-461；AAVrh20衣壳的452-461；或AAVhu.37的452-461。在一些实施方案中，TLAVPFK(SEQ ID NO:27)肽插入物紧接在对应于AAV9衣壳蛋白的588的氨基酸残基之后出现(参见图8)，其中在衣壳蛋白包装为AAV颗粒时所述肽插入物表面暴露。
在一些实施方案中，TLAVPFK(SEQ ID NO:27)肽插入物不出现于Deverman等人的US 2015/0079038中所阐述的任一位点中，特别地但不限于插入AAV衣壳蛋白的VR-VIII中，更特别地不插入AAV衣壳蛋白中对应于AAV9(SEQ ID NO:118)的氨基酸588至589之间的位置处，或不插入对应于AAV9的氨基酸586至592(包含587、588、589或590)的氨基酸中的一者之后(如图8中所描绘)。在其他实施方案中，衣壳蛋白中的任一位点处的肽插入物不包含肽TLAVPFK(SEQ ID NO:27)或肽QAVRTSL(SEQ ID NO:23)或肽TLAGPFK(SEQ ID NO:53)或由其组成。在其他实施方案中，肽插入物不包含插入AAV衣壳蛋白的VR-VIII环中的肽TLAVPFK(SEQ ID NO:27)或肽QAVRTSL(SEQ ID NO:23)或肽TLAGPFK(SEQ ID NO:53)或由其组成，更特别地不插入AAV衣壳蛋白中对应于AAV9的氨基酸588至589之间的位置处，或不插入对应于AAV9的氨基酸586至592(包含587、588、589或590)的氨基酸中的一者之后(如图8中所描绘)。
5.2.2.2 rAAV-EPO载体
在某些实施方案中，肽插入物是源自促红细胞生成素(EPO)的区域的肽。在本文中称为“EPO肽”的肽可以是来自EPO结构域(其结合IRR但并非红细胞生成性)或经设计以模拟所述结构域的三维结构的构象类似物的连续氨基酸的序列。包含一个或多个(例如)插入AAV衣壳外壳的表面暴露的环中的EPO肽的重组AAV载体在本文中称为“rAAV-EPO载体”。
促红细胞生成素(EPO)主要产生于肾中且帮助增加响应于低氧的红细胞产生。已发现，EPO还例如通过受体介导的细胞摄入来穿越血脑屏障，并且在全身性施用高剂量后可检测于脑脊髓液中。还发现，EPO对CNS施加保护效应，即减少炎症、防止神经元损害且促进修复(参见例如Cerami,2001,“Beyond erythropoiesis:novel application s forrecombinant human erythropoietin,”Semin Hematol.38(3-增刊7):33-39)。然而，为减小红细胞生成的有害副作用和血栓形成风险，研发非红细胞生成形式(包括ARA290)。ARA290是EPO(一种11氨基酸合成肽)的非红细胞生成类似物，其结合先天性修复受体(IRR)(区别于响应于低氧、损伤、炎症或脑损害而表达的红细胞生成性受体的EPO受体)，并且在保护脑组织中施加治疗效应(参见例如Chen等人,2013,“Therapeutic effects ofnonerythropoietic erythropoietin analog ARA290 in experimental autoimmuneencephalomyelitis rat,”J of Neuroimmunology,268:64-70；Collino等人,2015,“Flipping the molecular switch for innate protection and repair of tissues:Long-l asting effects of a non-erythropoietic small peptide engineered fromerythropoietin,”Pharmacology&Therapeutics,151:32-40；和Liu等人,2014,“Erythropoietin-derived non-erythropoietic ameliorates expe rimentalautoimmune neuritis by inflammation suppression and tissue protection,”PLOSOne,9(3):1-10)。
在本发明的一些实施方案中，源自EPO的肽插入物包含至少4个且至多20个邻接氨基酸和在某些实施方案不超过12个邻接氨基酸，所述邻接氨基酸来自并非红细胞生成性且结合先天性修复受体(IRR)的促红细胞生成素氨基酸序列或模型于4至20个非邻接氨基酸上的合成肽，所述非邻接氨基酸形成并非红细胞生成性且结合先天性修复受体(IRR)的促红细胞生成素构象类似物。在具体实施方案中，肽插入物包含来自具有氨基酸序列QEQLERALNSS(SEQ ID NO:8)的合成肽“ARA290”的至少4个且至多11个邻接氨基酸和优选地7个邻接氨基酸。在某些实施方案中，肽插入物包含ARA290序列QEQLERALNSS(SEQ ID NO:8)或由其组成。在一些实施方案中，EPO肽包含低唾液酸化EPO(hsEPO)或具有一个或多个氨基酸修饰以增加其血清半衰期的hsEPO或由其组成。
EPO肽可插入AAV衣壳中例如允许肽的表面暴露的位点处(例如在可变表面暴露环内和在其他实例中AAV衣壳蛋白中的本文所述对应于AAV9的VR-I、VR-IV或VR-VIII的位点)，或可插入VP2的第一氨基酸之后，例如紧接在氨基酸137之后(AAV4、AAV4-4和AAV5)或紧接在氨基酸138之后(AAV1、AAV2、AAV3、AAV3-3、AAV6、AAV7、AAV8、AAV9、AAV9e、rh.10、rh.20、rh.39、rh.74v1、rh.74v2和hu.37)(图8)。在一些实施方案中，包含EPO肽的rAAV载体穿越血脑屏障且到达CNS。在rAAV中使用EPO肽可提供以至少两种方式减少炎症的额外优点。首先，通过结合IRR，rAAV-EPO载体触发受试者的抗炎症性反应，由此抵消可源自向受试者引入外来剂(rAAV载体)的炎症。其次，ARA290已知具有相对较短的半衰期，这有利于快速清除且由此减少触炎症症的时间。
5.2.2.3 rAAV-SRL载体
在某些实施方案中，肽插入物是源自具有SRL(丝氨酸-精氨酸-赖氨酸)基序的脑归巢结构域区域的肽。在本文中称为“SRL肽”的肽可以是来自以下二者的连续氨基酸的序列：具有靶向脑组织的SRL基序的结构域；或经设计以模拟所述结构域的三维结构的构象类似物。包括一个或多个例如插入AAV衣壳外壳的表面暴露的环中的SRL肽的重组AAV载体在本文中称为“rAAV-SRL载体”。
已报告脑归巢肽家族，其中所述家族中的每一肽含有共同氨基酸基序SRL(丝氨酸-精氨酸-亮氨酸)，但含有不同侧接氨基酸序列(参见例如US 5,622,699)。在一些实施方案中，来自所述脑归巢结构域的肽插入物包含来自序列CLSSRLDAC(SEQ ID NO:11)的至少4、5、6、7、8或所有9个氨基酸，尤其包含SRL基序。在一些实施方案中，肽插入物包含序列CLSSRLDAC(SEQ ID NO:11)或由其组成。
已发现，某些归巢肽中的两个半胱氨酸残基可都缺失，这并不显著影响肽的器官归巢活性。例如，具有序列LSSRLDA(SEQ ID NO:10)的肽也可以是脑归巢肽。用于测定半胱氨酸残基或半胱氨酸残基的N-末端或C-末端氨基酸残基对于肽的器官归巢活性的必要性的方法是常规方法且在本领域中众所周知。因此，在一些实施方案中，肽插入物包含来自序列LSSRLDA(SEQ ID NO:10)的至少4、5、6或所有7个氨基酸。在一些实施方案中，肽插入物包含序列LSSRLDA(SEQ ID NO:10)或由其组成。
SRL肽可插入AAV衣壳中例如允许表面暴露肽的位点处(例如在可变表面暴露环内和在其他实例中本文所述对应于AAV9的VR-I、VR-IV或VR-VIII的位点)，或可插入VP2的第一氨基酸之后，例如紧接在氨基酸137之后(AAV4、AAV4-4和AAV5)或紧接在氨基酸138之后(AAV1、AAV2、AAV3、AAV3-3、AAV6、AAV7、AAV8、AAV9、AAV9e、rh.10、rh.20、rh.39、rh.74v1、rh.74v2和hu.37)(图8)。在一些实施方案中，包含SRL肽的rAAV载体穿越血脑屏障且到达CNS。
5.2.3细胞质动力蛋白归巢肽
本发明的另一方面涉及包含经设计以赋予或增强细胞质动力蛋白归巢的肽插入物的衣壳蛋白。实例包含源自细胞质动力蛋白归巢结构域(如动力蛋白轻链归巢结构域)的区域的肽(参见例如Midoux等人,2017,“Peptides mediating DNA transport onmicrotubules and their impact on non-viral gene transfer efficiency,”Bioscience Reports(综述文章)，37BSR20170995)。在本文中称为“细胞质动力蛋白归巢肽”的肽可以是来自蛋白质中细胞质动力蛋白归巢区域或经设计以模拟其三维结构的构象类似物的连续氨基酸的序列。这些肽包括SITLVKSTQTV(SEQ ID NO:21)(或者CITLVKSTQTV(SEQ ID NO:54))、TILSRSTQTG(SEQ ID NO:22)、VVMVGEKPITITQHSVETEG(SEQ ID NO:25)、RSSEEDKSTQTT(SEQ ID NO:26)、KSTEDKSTQTP(SEQ ID NO:46)、LGHFTRSTQTS(SEQ ID NO:47)、GVQMAKSTQTF(SEQ ID NO:48)、PKTRNSQTQTD(SEQ ID NO:49)、VTTQNTASQTM(SEQ IDNO:50)和KSSQDKSTQTTGD(SEQ ID NO:51)。蛋白质中与细胞质动力蛋白的轻链缔合的肽或结构域可具有基序TQT(苏氨酸-谷氨酰胺-苏氨酸)或STQT(丝氨酸-苏氨酸-谷氨酰胺-苏氨酸)(SEQ ID NO:55)或甚至KSTQT(赖氨酸-丝氨酸-苏氨酸-谷氨酰胺-苏氨酸)(SEQ ID NO:56)。因此，在某些实施方案中，细胞质动力蛋白归巢肽是含有TQT、STQT(SEQ ID NO:55)或KSTQT(SEQ ID NO:56)基序且具有细胞质动力蛋白归巢活性的肽的一部分。
在一些实施方案中，来自所述动力蛋白轻链归巢结构域的肽插入物包含序列SITLVKSTQTV(SEQ ID NO:21)的至少4、5、6、7、8、9、10或所有11个连续氨基酸，优选地含有TQT、STQT(SEQ ID NO:55)或KSTQT(SEQ ID NO:56)基序和/或具有细胞质动力蛋白归巢活性。在一些实施方案中，肽插入物由序列SITLVKSTQTV(SEQ ID NO:21)的至少4、5、6、7、8、9、10或所有11个连续氨基酸组成，优选地含有TQT、STQT(SEQ ID NO:55)或KSTQT(SEQ ID NO:56)基序和/或具有细胞质动力蛋白归巢活性。
在一些实施方案中，来自所述动力蛋白轻链归巢结构域的肽插入物包含序列TILSRSTQTG(SEQ ID NO:22)的至少4、5、6、7、8、9或所有10个连续氨基酸，优选地含有TQT或STQT(SEQ ID NO:55)基序和/或具有细胞质动力蛋白归巢活性。在一些实施方案中，肽插入物由序列TILSRSTQTG(SEQ ID NO:22)的至少4、5、6、7、8、9或所有10个连续氨基酸组成，优选地含有TQT或STQT(SEQ ID NO:55)基序和/或具有细胞质动力蛋白归巢活性。
在一些实施方案中，来自所述动力蛋白轻链归巢结构域的肽插入物包含序列VVMVGEKPITITQHSVETEG(SEQ ID NO:25)的至少4个且至多所有20个连续氨基酸。在一些实施方案中，肽插入物由序列VVMVGEKPITITQHSVETEG(SEQ ID NO:25)的至少4个且至多所有20个连续氨基酸组成。在一些实施方案中，肽插入物包含序列VVMVGEKPITITQHSVETEG(SEQID NO:25)的7、8、9、10、11、12、13或14或15个连续氨基酸或由其组成。
在一些实施方案中，来自所述动力蛋白轻链归巢结构域的肽插入物包含序列RSSEEDKSTQTT(SEQ ID NO:26)的至少4、5、6、7、8、9、10、11或所有12个连续氨基酸，优选地含有TQT、STQT(SEQ ID NO:55)或KSTQT(SEQ ID NO:56)基序和/或具有细胞质动力蛋白归巢活性。在一些实施方案中，肽插入物由序列RSSEEDKSTQTT(SEQ ID NO:26)的至少4、5、6、7、8、9、10、11或12个连续氨基酸组成，优选地含有TQT、STQT(SEQ ID NO:55)或KSTQT(SEQID NO:56)基序和/或具有细胞质动力蛋白归巢活性。
在一些实施方案中，来自所述动力蛋白轻链归巢结构域的肽插入物包含具有序列KSTEDKSTQTP(SEQ ID NO:46)、LGHFTRSTQTS(SEQ ID NO:47)、GVQMAKSTQTF(SEQ ID NO:48)、PKTRNSQTQTD(SEQ ID NO:49)、VTTQNTASQTM(SEQ ID NO:50)或KSSQDKSTQTTGD(SEQ IDNO:51)的肽中的一者的至少4、5、6、7、8、9、10、11或12个连续氨基酸，优选地含有TQT、STQT(SEQ ID NO:55)或KSTQT(SEQ ID NO:56)基序和/或具有细胞质动力蛋白归巢活性。在一些实施方案中，肽插入物由具有序列KSTEDKSTQTP(SEQ ID NO:46)、LGHFTRSTQTS(SEQ ID NO:47)、GVQMAKSTQTF(SEQ ID NO:48)、PKTRNSQTQTD(SEQ ID NO:49)、VTTQNTASQTM(SEQ IDNO:50)或KSSQDKSTQTTGD(SEQ ID NO:51)的肽中的一者的至少4、5、6、7、8、9、10、11、12或13个连续氨基酸组成，优选地含有TQT、STQT(SEQ ID NO:55)或KSTQT(SEQ ID NO:56)基序和/或具有细胞质动力蛋白归巢活性。
细胞质动力蛋白归巢肽可插入AAV衣壳中例如允许表面暴露肽的位点处(例如在可变表面暴露环内和在其他实例中本文所述对应于AAV9的VR-IV或VIII的位点)，或可插入VP2的第一氨基酸之后，例如紧接在氨基酸137之后(AAV4、AAV4-4和AAV5)或紧接在氨基酸138之后(AAV1、AAV2、AAV3、AAV3-3、AAV6、AAV7、AAV8、AAV9、AAV9e、rh.10、rh.20、rh.39、rh.74v1、rh.74v2和hu.37)(图8)。
5.2.4骨归巢肽
本发明的另一方面涉及包含经设计以赋予或增强骨归巢性质的肽插入物的衣壳蛋白。实例包括来自蛋白质的骨结合结构域或所述结构域的构象类似物的肽。来自骨结合或骨归巢结构域的肽称为骨归巢肽(骨组织归巢或骨细胞或细胞基质归巢)。
在某些实施方案中，肽插入物可以是来自靶向骨组织的HA结合结构域或经设计以模拟所述结构域的三维结构的构象类似物的连续氨基酸的序列。例如，L-Asp的6至8残基片段已展示可增强酶至羟磷灰石的靶向(参见例如Nishioka等人,2006,“Enhancement ofdrug delivery to bone:Characterization of human tissue-nonspecific alkal inephosphatase tagged with an acidic oligopeptide,”Mol Genet Meta b.88(3):244-255；和Kasugai等人,2000,“Selective drug delivery sys tem to bone:small peptide(Asp)6(SEQ ID NO:57)conjugation,”J Bone Miner Res.15(5):936-943)。
在特定实施方案中，来自所述HA结合结构域的肽插入物包含来自序列DDDDDDDD(SEQ ID NO:9)的至少4、5、6、7或所有8个氨基酸。在一些实施方案中，肽插入物由来自序列DDDDDDDD(SEQ ID NO:9)的至少4、5、6、7或所有8个氨基酸组成。在一个特定实施方案中，肽插入物包含DDDDDDDD(SEQ ID NO:9)序列或由其组成。
骨归巢肽可插入AAV衣壳中例如允许表面暴露肽的位点处(例如在可变表面暴露环内和在其他实例中AAV衣壳蛋白中的本文所述对应于AAV9的VR-I、VR-IV或VR-VIII的位点)，或可插入VP2的第一氨基酸之后，即紧接在氨基酸137之后(AAV4、AAV4-4和AAV5)或紧接在氨基酸138之后(AAV1、AAV3、AAV3-3、AAV6、AAV7、AAV8、AAV9、AAV9e、rh.10、rh.20、rh.39、rh.74v1、rh.74v2和hu.37)(图8)。包含一个或多个例如插入AAV衣壳外壳的表面暴露的环中的骨归巢肽的重组AAV载体在本文中称为“rAAV骨归巢载体”。在特定实施方案中，衣壳蛋白是AAV9衣壳蛋白且骨归巢插入物紧接在AAV9衣壳的氨基酸残基451至461中的至少一者之后或紧接在氨基酸138之后出现。在其他实施方案中，衣壳蛋白来自至少一种选自AAV1、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh8、AAV9、AAV9e、AAVrh10、AAVrh20、AAVhu.37、AAVrh39和AAVrh74(型式1和2)(参见图8)的AAV类型，并且骨归巢肽插入物紧接在对应于AAV9的氨基酸残基451至461中的至少一者的氨基酸残基之后出现。这些不同AAV血清型的比对(如图8中所展示)指示不同氨基酸序列中的相应氨基酸残基。
5.2.5肾归巢肽
本发明的另一方面涉及包含经设计以赋予或增强肾归巢性质(包含归巢至肾组织、肾细胞或肾细胞基质)的衣壳蛋白的肽插入物。实例包括来自蛋白质的肾结合结构域或所述结构域的构象类似物的肽。来自肾结合或肾归巢结构域的肽称为肾归巢肽。在某些实施方案中，与肝相比和相对于未经工程改造以含有肾归巢肽的AAV，肾归巢肽优先地靶向肾。
在某些实施方案中，肽插入物可以是来自靶向肾组织的结构域或经设计以模拟所述结构域的三维结构的构象类似物的连续氨基酸的序列。在一些实施方案中，肾归巢结构域包含序列CLPVASC(SEQ ID NO:12)(参见例如US 5,622,699)。在一些实施方案中，来自所述肾归巢结构域的肽插入物包含来自序列CLPVASC(SEQ ID NO:12)的至少4、5、6或所有7个氨基酸。在一些实施方案中，肽插入物包含序列CLPVASC(SEQ ID NO:12)或由其组成。
已发现，某些归巢肽中的两个半胱氨酸残基可都缺失，这并不显著影响肽的器官归巢活性。例如，具有序列LPVAS(SEQ ID NO:13)的肽也可以是肾归巢肽。用于测定半胱氨酸残基或半胱氨酸残基的N-末端或C-末端氨基酸残基对于肽的器官归巢活性的必要性的方法是常规方法且在本领域中众所周知。因此，在一些实施方案中，肽插入物包含来自序列LPVAS(SEQ ID NO:13)的至少4或所有5个氨基酸。在一些实施方案中，肽插入物包含序列LPVAS(SEQ ID NO:13)或由其组成。
肾归巢肽可插入AAV衣壳中例如允许表面暴露肽的位点处(例如在可变表面暴露环内和在其他实例中本文所述对应于AAV9的VR-I、VR-IV或VR-VIII的位点)，或可插入VP2的第一氨基酸之后，例如紧接在氨基酸137之后(AAV4、AAV4-4和AAV5)或紧接在氨基酸138之后(AAV1、AAV2、AAV3、AAV3-3、AAV6、AAV7、AAV8、AAV9、AAV9e、rh.10、rh.20、rh.39、rh.74v1、rh.74v2和hu.37)(图8)。包含一个或多个例如插入AAV衣壳外壳的表面暴露的环中的肾归巢肽的重组AAV载体在本文中称为“rAAV肾归巢载体”。在特定实施方案中，衣壳蛋白是AAV9衣壳蛋白且肾归巢肽插入物紧接在AAV9衣壳的氨基酸残基451至461中的至少一者之后出现。在其他实施方案中，衣壳蛋白来自至少一种选自AAV1、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh8、AAV9、AAV9e、AAVrh10、AAVrh20、AAVrh39、AAVhu.37和AAVrh74(型式1和2)(参见图8)的AAV类型，并且肾归巢肽插入物紧接在对应于AAV9的氨基酸残基451至461中的至少一者的氨基酸残基之后出现。这些不同AAV血清型的比对(如图8中所展示)指示不同氨基酸序列中的相应氨基酸残基。
5.2.6肌肉归巢肽
本发明的另一方面涉及包含经设计以赋予或增强肌肉归巢性质(包含归巢至肌肉组织、肌肉细胞或肌肉细胞基质)的肽插入物的衣壳蛋白。实例包括来自蛋白质的肌肉结合结构域或所述结构域的构象类似物的肽。来自肌肉结合或肌肉归巢结构域的肽称为肌肉归巢肽。
在某些实施方案中，肽插入物可以是来自靶向肌肉的结构域或经设计以模拟所述结构域的三维结构的构象类似物的连续氨基酸的序列。在一些实施方案中，肌肉归巢结构域包含序列ASSLNIA(SEQ ID NO:14)(参见例如Samoylov等人,2002,“Recognition ofcell-specific binding of phage display derived peptides using an acousticwave sensor,”Biomol Eng,18(6):269-272)。在一些实施方案中，来自所述肌肉归巢结构域的肽插入物包含来自序列ASSLNIA(SEQ ID NO:14)的至少4、5、6或所有7个氨基酸。在一些实施方案中，肽插入物包含序列ASSLNIA(SEQ ID NO:14)或由其组成。
肌肉归巢肽可插入AAV衣壳中例如允许表面暴露肽的位点处(例如在可变表面暴露环内和在其他实例中本文所述对应于AAV9的VR-I、VR-IV或VR-VIII的位点)，或可插入VP2的第一氨基酸之后，例如在氨基酸137之后(AAV4、AAV4-4和AAV5)或在氨基酸138处(AAV1、AAV2、AAV3、AAV3-3、AAV6、AAV7、AAV8、AAV9、AAV9e、rh.10、rh.20、rh.39、rh.74v1、rh.74v2和hu.37)(图8)。包含一个或多个例如插入AAV衣壳外壳的表面暴露的环中的肌肉归巢肽的重组AAV载体在本文中称为“rAAV肌肉归巢载体”。在特定实施方案中，衣壳蛋白是AAV9衣壳蛋白且肌肉归巢肽插入物紧接在AAV9衣壳的氨基酸残基451之461中的至少一者之后出现。在其他实施方案中，衣壳蛋白来自至少一种选自AAV1、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh8、AAV9、AAV9e、AAVrh10、AAVrh20、AAVhu.37、AAVrh39和AAVrh74(型式1和2)(参见图8)的AAV类型，并且肌肉归巢肽插入物紧接在对应于AAV9(SEQ ID NO:118)的氨基酸残基451至461中的至少一者的氨基酸残基之后出现。这些不同AAV血清型的比对(如图8中所展示)指示不同氨基酸序列中的相应氨基酸残基。
5.2.7 TfR归巢肽
本发明的另一方面涉及包含经设计以赋予或增强转铁蛋白受体归巢性质的肽插入物的衣壳蛋白。实例包括来自蛋白质的转铁蛋白受体结合结构域或所述结构域的构象类似物的肽。来自转铁蛋白受体结合或转铁蛋白受体归巢结构域的肽称为转铁蛋白受体归巢肽。
人转铁蛋白受体(hTfR)已作为受体介导的胞吞作用的模型且作为细胞增殖的标记物加以研究。hTfR通常高度表达于增殖性细胞(例如肿瘤细胞)中，并且在口腔癌、肝癌、胰腺癌和前列腺癌中过表达至少100倍。这使得hTfR成为有用诊断标记物以及癌症疗法靶标。TfR还表达于血脑屏障上。TfR是由两个相同95kDa亚基构成的二聚体且负责通过细胞的铁摄取。铁在血液中由80kDa转铁蛋白(Tf)携带，所述转铁蛋白结合TfR以形成经由网格蛋白包被小窝内化的复合物。铁从转铁蛋白释放于内体的酸性区域中，从而留下去铁转铁蛋白-受体复合物，所述复合物再循环回细胞表面且去铁转铁蛋白(不结合铁的转铁蛋白)也发生再循环。参见例如Cheng等人,2004,“Structure of the human transferrinreceptor-transferrin complex,”Cell 116(4):565-576。
由于转铁蛋白受体涉及受体介导的穿胞作用，因此其可用作“特洛伊木马(Trojanhorse)”以递送货物跨越血脑屏障，如递送小分子药物、酶或核酸分子。例如，小鼠研究已展示，经工程改造的TfR结合肽由表达TfR的CEF细胞摄取，从而有利于随时间推移经由脑微血管进入脑实质中(参见Lee等人,The FEBS Journal,2001；和Staquicini等人,2011,“Systemic combinatorial peptide selection yields a non-canonical iron-mimicrymechanism for targeting tumors in a mouse model of human glioblastoma,”J.ofClinical Investigation,121(1):161-173)。
在一些实施方案中，TfR肽插入物可增强衣壳化转基因的AAV颗粒在内皮细胞基质中的转运。
在某些实施方案中，肽插入物可以是来自结合TfR的Tf结构域或经设计以模拟所述结构域的三维结构的构象类似物或铁模拟物的连续氨基酸的序列。在一些实施方案中，来自TfR归巢结构域的肽插入物包含来自序列HAIYPRH(SEQ ID NO:17)的4、5、6或所有7个氨基酸，或由序列HAIYPRH(SEQ ID NO:17)组成。在一些实施方案中，来自TfR归巢结构域的肽插入物包含来自序列THRPPMWSPVWP(SEQ ID NO:18)的4、5、6、7、8、9、10、11或所有12个氨基酸或由序列THRPPMWSPVWP(SEQ ID NO:18)(还参见US 2006/0193778)组成。
在一些实施方案中，来自TfR归巢结构域的肽插入物包含来自序列CRTIGPSVC(SEQID NO:20)的4、5、6、7、8或所有9个氨基酸。在一些实施方案中，肽插入物包含序列CRTIGPSVC(SEQ ID NO:20)或由其组成。已发现，某些归巢肽中的两个半胱氨酸残基可都缺失，这并不显著影响肽的器官归巢活性，并且用于测定半胱氨酸残基或半胱氨酸残基的N-末端或C-末端氨基酸残基对于肽的器官归巢活性的必要性的方法是常规方法且在本领域中众所周知。在一些实施方案中，肽插入物包含来自序列RTIGPSV(SEQ ID NO:19)的至少4、5、6或所有7个氨基酸。在一些实施方案中，肽插入物包含序列RTIGPSV(SEQ ID NO:19)或由其组成。
TfR归巢肽可插入AAV衣壳中例如允许表面暴露肽的位点处(例如在可变表面暴露环内和在其他实例中本文所述对应于AAV9的VR-I、VR-IV或VR-VIII的位点)，或可插入VP2的第一氨基酸之后，例如在氨基酸137之后(AAV4、AAV4-4和AAV5)或在氨基酸138处(AAV1、AAV2、AAV3、AAV3-3、AAV6、AAV7、AAV8、AAV9、AAV9e、rh.10、rh.20、rh.39、rh.74v1、rh.74v2和hu.37)(图8)。包含一个或多个例如插入AAV衣壳外壳的表面暴露的环中的TfR归巢肽的重组AAV载体在本文中称为“rAAV TfR归巢载体”。
在一些实施方案中，TfR归巢结构域包含氨基酸序列RTIGPSV(SEQ ID NO:19)；并且其所来源的肽插入物包含RTIGPSV(SEQ ID NO:19)或CRTIGPSVC(SEQ ID NO:20)序列或由其组成。在一些实施方案中，肽插入物包含来自RTIGPSV(SEQ ID NO:19)的4、5、6或所有7个连续氨基酸或由其组成；或包含来自CRTIGPSVC(SEQ ID NO:20)的4、5、6、7、8或所有9个氨基酸或由其组成。在特定实施方案中，衣壳蛋白是AAV9衣壳蛋白且RTIGPSV(SEQ ID NO:19)或CRTIGPSVC(SEQ ID NO:20)插入物紧接在氨基酸残基451至461中的至少一者之后出现。在特定实施方案中，RTIGPSV(SEQ ID NO:19)或CRTIGPSVC(SEQ ID NO:20)插入物出现于AAV9衣壳中选自由以下组成的组的氨基酸残基之后：I451、N452、G453、S454、G455、Q456、N457、Q458、Q459、T460和L461。在其他实施方案中，衣壳蛋白来自至少一种选自AAV血清型1(AAV1)、血清型2(AAV2)、血清型3(AAV3)、血清型4(AAV4)、血清型5(AAV5)、血清型6(AAV6)、血清型7(AAV7)、血清型8(AAV8)、血清型rh8(AAVrh8、血清型9e(AAV9e)、血清型rh10(AAVrh10)、血清型rh20(AAVrh20)、血清型hu37(AAVhu.37)、血清型rh39(AAVrh39)和血清型rh74(AAVrh74，型式1和2)(参见图8)的AAV类型，并且RTIGPSV(SEQ ID NO:19)或CRTIGPSVC(SEQ ID NO:20)肽插入物紧接在对应于氨基酸残基451至461中的至少一者的氨基酸残基之后出现。这些不同AAV血清型的比对(如图8中所展示)指示不同氨基酸序列中的相应氨基酸残基。在一些特定实施方案中，在图8中所描绘的序列中，RTIGPSV(SEQ ID NO:19)或CRTIGPSVC(SEQ ID NO:20)肽插入物紧接在以下各项内的氨基酸残基中的一者之后出现：AAV1衣壳(SEQ ID NO:110)的450-459；AAV2衣壳(SEQ ID NO:111)的449-458；AAV3衣壳(SEQ ID NO:112)的449-459；AAV4衣壳(SEQ ID NO:113)的443-453；AAV5衣壳(SEQ IDNO:114)的442-445；AAV6衣壳(SEQ ID NO:115)的450-459；AAV7衣壳(SEQ ID NO:116)的451-461；AAV8衣壳(SEQ ID NO:117)的451-461；AAV9衣壳(SEQ ID NO:118)的451-461；AAV9e衣壳(SEQ ID NO:119)的452-461；AAVrh10衣壳(SEQ ID NO:120)的452-461；AAVrh20衣壳(SEQ ID NO:121)的452-461；AAVhu.37(SEQ ID NO:122)的452-461；AAVrh74衣壳(SEQID NO:123或SEQ ID NO:154)的452-461；或AAVrh39衣壳(SEQ ID NO:124)的452-461。在一些实施方案中，RTIGPSV(SEQ ID NO:19)或CRTIGPSVC(SEQ ID NO:20)肽插入物紧接在对应于AAV9衣壳蛋白的588的氨基酸残基之后出现(参见图8)，其中在衣壳蛋白包装为AAV颗粒时所述肽插入物表面暴露。
5.2.8视网膜细胞归巢肽
另一方面涉及包含经设计以赋予或增强视网膜细胞归巢性质的肽插入物的衣壳蛋白。实例包括来自蛋白质的视网膜细胞结合结构域或所述结构域的构象类似物的肽。来自视网膜细胞结合或视网膜细胞归巢结构域的肽称为视网膜细胞归巢肽。术语“视网膜细胞”是指发现于视网膜中或其附近的一种或多种细胞类型，包括无长突细胞、双极细胞、水平细胞、米勒神经胶质细胞(Muller glial cell)、光感受器细胞(例如视杆和视锥细胞)、视网膜神经节细胞、视网膜色素上皮细胞和诸如此类，并且特别是人光感受器细胞(例如人视锥细胞和/或人视杆细胞)、人水平细胞、人双极细胞、人无长突细胞以及人视网膜神经节细胞(例如侏儒细胞、阳伞细胞、双层细胞、巨视网膜神经节细胞、光敏性神经节细胞和/或米勒神经胶质细胞)、内限界膜中的内皮细胞和/或外限界膜中的人视网膜色素上皮细胞。
在某些实施方案中，肽插入物可以是来自靶向视网膜组织的视网膜细胞结合结构域或经设计以模拟所述结构域的构象类似物的三维结构的连续氨基酸的序列。
在特定实施方案中，肽插入物是源自人轴丝动力蛋白(HAD)重链尾部的区域的肽。如上所述，在本文中称为“HAD肽”的肽可以是来自HAD重链尾部区域或经设计以模拟其三维结构的构象类似物的连续氨基酸的序列。上文所提供的表2鉴定人轴丝动力蛋白的尾部和二聚化结构域以及用作本文所述经工程改造的衣壳蛋白中的肽插入物(包括用作视网膜细胞归巢肽)的肽。在一些实施方案中，使用具有来自茎部/尾部区域和/或二聚化结构域(NDD)的轴丝动力蛋白序列的至少4个且至多15个邻接氨基酸和优选地7个邻接氨基酸的插入物作为用于靶向视网膜细胞的肽插入物。
在一些实施方案中，用于插入AAV衣壳中的肽是从HAD重链尾部区域的二聚化结构域(NDD)设计的。在替代实施方案中，可使用对应于HAD重链尾部的其他部分(即排除动力蛋白马达结构域)的氨基酸序列的肽。在一些实施方案中，肽插入物包含来自HAD重链尾部的二聚化结构域的至少4个(在一实施方案中7个)邻接氨基酸且至多12或15个邻接氨基酸。在特定实施方案中，肽插入物包含来自由以下(描绘于图7A-7M中)组成的组的至少4个(7个)邻接氨基酸且至多12或15个邻接氨基酸：DYH1_人UniProtKB-Q9P2D7(SEQ ID NO:97)的氨基酸(“aa”)1-1542；DYH2_人UniProtKB-Q9P225(SEQ ID NO:98)的aa 1-1764；DYH3_人UniProtKB-Q8TD57(SEQ ID NO:99)的aa 1-1390；DYH5_人UniProtKB-Q8TE73(SEQ ID NO:100)的aa1-1941；DYH6_人UniProtKB-Q9C0G6(SEQ ID NO:101)的aa1-1433；DYH7_人UniProtKB-Q8WXX0(SEQ ID NO:102)的aa1-1289；DYH8_人UniProtKB-Q96JB1(SEQ ID NO:3)的aa 1-1807；DYH9_人UniProtKB-Q9NYC9(SEQ ID NO:104)的aa 1-1831；DYH10_人UniProtKB-Q8IVF4(SEQ ID NO:105)的aa 1-1793；DYH11_人UniProtKB-Q96DT5(SEQ IDNO:106)的aa 1-1854；DYH12_人UniProtKB-Q6ZR08(SEQ ID NO:107)的aa 1-1214；DYH14_人UniProtKB-Q0VDD8(SEQ ID NO:108)的aa 1-200；和DYH17
_人UniProtKB-Q9UFH2(SEQID NO:109)的aa 1-1794)，并且用于使经工程改造的AAV靶向视网膜细胞。在更优选的实施方案中，肽插入物包含来自上文所列举的任一动力蛋白重链序列、即来自由以下组成的组的任一者的残基1-200的至少4个邻接氨基酸、7个邻接氨基酸且至多12或15个邻接氨基酸：DYH1_人UniProtKB-Q9P2D7(SEQ ID NO:97)的氨基酸(“aa”)1-1542；DYH2_人UniProtKB-Q9P225(SEQ ID NO:98)的aa 1-1764；DYH3_人UniProtKB-Q8TD57(SEQ ID NO:99)的aa 1-1390；DYH5_人UniProtKB-Q8TE73(SEQ ID NO:100)的aa 1-1941；DYH6_人UniProtKB-Q9C0G6(SEQ ID NO:101)的aa 1-1433；DYH7_人UniProtKB-Q8WXX0(SEQ ID NO:102)的aa1-1289；DYH8_人UniProtKB-Q96JB1(SEQ ID NO:3)的aa 1-1807；DYH9_人UniProtKB-Q9NYC9(SEQ ID NO:104)的aa 1-1831；DYH10_人UniProtKB-Q8IVF4(SEQ ID NO:105)的aa1-1793；DYH11_人UniProtKB-Q96DT5(SEQ ID NO:106)的aa 1-1854；DYH12_人UniProtKB-Q6ZR08(SEQ ID NO:107)的aa 1-1214；DYH14_人UniProtKB-Q0VDD8(SEQ ID NO:108)的aa1-200；和DYH17
_人UniProtKB-Q9UFH2(SEQ ID NO:109)的aa 1-1794))，所述肽插入物是用于靶向视网膜细胞。在更优选的实施方案中，肽插入物来自图7A-7M的任一动力蛋白重链序列的7个邻接氨基酸；或来自任一动力蛋白重链序列(图7A至7M)的残基1-200的7个邻接氨基酸且用于使经工程改造的AAV靶向视网膜细胞。
在特定实施方案中，用于靶向视网膜细胞的肽插入物来自由以下组成的组的至少4、5、6或7个邻接氨基酸或由其组成：KMQVPFQ(SEQ ID NO:1)；TLAAPFK(SEQ ID NO:2)；QQAAPSF(SEQ ID NO:3)；RYNAPFK(SEQ ID NO:4)；LKLPPIV(SEQ ID NO:5)；PFIKPFE(SEQ IDNO:6)；和TLSLPWK(SEQ ID NO:7)。在更特定实施方案中，用于靶向视网膜细胞的肽插入物由来自由以下组成的组的肽组成：KMQVPFQ(SEQ ID NO:1)；TLAAPFK(SEQ ID NO:2)；QQAAPSF(SEQ ID NO:3)；RYNAPFK(SEQ ID NO:4)；LKLPPIV(SEQ ID NO:5)；PFIKPFE(SEQ IDNO:6)；和TLSLPWK(SEQ ID NO:7)。在尤其关注的一个实施方案中，肽插入物包含氨基酸序列TLAAPFK(SEQ ID NO:2)或由其组成。
HAD肽可插入AAV衣壳中例如允许表面暴露肽的位点处(例如在可变表面暴露环内和在其他实例中本文所述对应于AAV9的VR-I、VR-IV或VR-VIII的位点)，或可插入VP2的第一氨基酸之后，例如紧接在氨基酸137之后(AAV4、AAV4-4和AAV5)或紧接在氨基酸138之后(AAV1、AAV2、AAV3、AAV3-3、AAV6、AAV7、AAV8、AAV9、AAV9e、rh.10、rh.20、rh.39、rh.74v1、rh.74v2和hu.37)(图8)。在一些实施方案中，使用包含HAD肽的rAAV载体来靶向视网膜细胞。在一个特定实施方案中，使用在氨基酸588-589(SEQ ID NO:118)之间具有TLAAPFK(SEQID NO:2)的AAV9衣壳蛋白来靶向视网膜细胞(参见例如图10、图22A至22H和图23A至23C中所使用的载体)。在一些实施方案中，使用不同AAV的衣壳蛋白来靶向视网膜细胞，其中载体在对应于AAV9(还参见图8)的氨基酸588-589的氨基酸之间包含TLAAPFK(SEQ ID NO:2)。
在优选实施方案中，在局部施用(如玻璃体内注射)后，视网膜细胞归巢肽使得AAV转导视网膜细胞。在更优选的实施方案中，在全身性施用(如静脉内注射)后，视网膜细胞归巢肽使得AAV转导视网膜细胞。在最优选的实施方案中，用于靶向和转导视网膜细胞的经工程改造的AAV包含在SEQ ID NO:118的氨基酸588-589之间具有TLAAPFK(SEQ ID NO:2)的AAV9衣壳蛋白。
在一些实施方案中，来自视网膜细胞结合结构域的肽插入物包含来自序列LALGETTRP(SEQ ID NO:16)的至少4、5、6、7、8或所有9个氨基酸。在一些实施方案中，肽插入物由来自序列LALGETTRP(SEQ ID NO:16)的至少4、5、6、7、8或所有9个氨基酸组成。在一些实施方案中，肽插入物包含来自序列LGETTRP(SEQ ID NO:15)的至少4、5、6或所有7个氨基酸。在特定实施方案中，肽插入物由来自序列LGETTRP(SEQ ID NO:15)的至少4、5、6或所有7个氨基酸组成。在一个特定实施方案中，肽插入物由LGETTRP(SEQ ID NO:15)序列组成。
可将视网膜细胞归巢肽插入AAV衣壳中优选地允许表面暴露肽的位点处(例如在可变表面暴露环内)，并且更优选地插入本文所述对应于AAV9的VR-I、VR-IV或VR-VIII的位点处或AAV8的相应位置中。在特定实施方案中，衣壳蛋白是AAV8衣壳蛋白且LGETTRP(SEQID NO:15)或LALGETTRP(SEQ ID NO:16)插入物紧接在AAV8衣壳(SEQ ID NO:117的氨基酸序列)的氨基酸残基451至461中的至少一者之后出现。在特定实施方案中，衣壳蛋白是AAV9衣壳蛋白且LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQ ID NO:16)插入物紧接在AAV9衣壳的氨基酸残基451至461中的至少一者之后出现，并且在特定实施方案中紧接在AAV9衣壳蛋白的残基454之后。在其他实施方案中，衣壳蛋白来自至少一种选自AAV1、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh8、AAV9、AAV9e、AAVrh10、AAVrh20、AAVhu.37、AAVrh39和AAVrh74(型式1和型式2)(参见图8)的AAV类型，并且LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQ ID NO:16)肽插入物紧接在对应于AAV9衣壳的氨基酸残基451-461中的至少一者的氨基酸残基之后出现，或在某些实施方案中对应于在对应于AAV9衣壳序列的残基454的残基之后。这些不同AAV血清型的比对(如图8中所展示)指示不同AAV衣壳氨基酸序列中的相应氨基酸残基。
在一些实施方案中，视网膜细胞归巢肽并不插入AAV2衣壳蛋白中，而是所用衣壳蛋白来自至少一种选自AAV1、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh8、AAV9、AAV9e、AAVrh10、AAVrh20、AAVhu37、AAVrh39和AAVrh74的AAV类型。在一些实施方案中，视网膜细胞归巢肽并不插入AAV2衣壳蛋白(SEQ ID NO:111)的氨基酸587-588之间。在一些实施方案中，视网膜细胞归巢肽并不插入不同AAV血清型中对应于AAV2衣壳蛋白的氨基酸587-588的氨基酸残基之间。包含一个或多个例如插入AAV衣壳外壳的表面暴露的环中的视网膜细胞归巢肽的重组AAV载体在本文中称为“rAAV视网膜细胞归巢载体”。
5.2.9另外的AAV衣壳插入位点
下文总结本文所述的肽(包含表1A和1B中的肽和表2中的动力蛋白肽)的插入位点，其紧接在如下文所陈述的AAV衣壳的氨基酸残基之后(还参见图8)：
AAV1：138；262-272；450-459；595-593；和在一个特定实施方案中在453-454之间(SEQ ID NO.110)。
AAV2：138；262-272；449-458；584-592；和在特定实施方案中在452-453之间(SEQID NO.111)。
AAV3：138；262-272；449-459；585-593；和在特定实施方案中在452-453之间(SEQID NO.112)。
AAV4：137；256-262；443-453；583-591；和在特定实施方案中在446-447之间(SEQID NO.113)。
AAV5：137；252-262；442-445；574-582；和在特定实施方案中在445-446之间(SEQID NO.114)。
AAV6：138；262-272；450-459；585-593；和在特定实施方案中在452-453之间(SEQID NO.115)。
AAV7：138；263-273；451-461；586-594；和在特定实施方案中在453-454之间(SEQID NO.116)。
AAV8：138；263-274；451-461；587-595；和在特定实施方案中在453-454之间(SEQID NO.117)。
AAV9：138；262-273；452-461；585-593；和在特定实施方案中在454-455之间(SEQID NO.118)。
AAV9e：138；262-273；452-461；585-593；和在特定实施方案中在454-455之间(SEQID NO.119)。
AAVrh10：138；263-274；452-461；587-595；和在特定实施方案中在454-455之间(SEQ ID NO.120)。
AAVrh20：138；263-274；452-461；587-595；和在特定实施方案中在454-455之间(SEQ ID NO.121)。
AAVrh39：138；263-274；452-461；587-595；和在特定实施方案中在454-455之间(SEQ ID NO.124)。
AAVrh74：138；263-274；452-461；587-595；和在特定实施方案中在454-455之间(SEQ ID NO.123或SEQ ID NO.154)。
AAVhu.37：138；263-274；452-461；587-595；和在特定实施方案中在454-455之间(SEQ ID NO.122)
在特定实施方案中，肽插入物出现于AAV9衣壳的氨基酸残基588-589之间或另一AAV类型衣壳的相应残基之间，如通过氨基酸序列比对所测定(例如，如图8中)。在特定实施方案中，肽插入物紧接在AAV9衣壳序列的氨基酸残基I451-L461、S268和Q588之后，或紧接在另一AAV衣壳序列的相应残基之后出现(图8)。
在一些实施方案中，来自一个或多个归巢结构域的一个或多个肽插入物可用于单一系统中。在一些实施方案中，选择和/或进一步修饰衣壳以减小AAV颗粒由受试者的免疫系统的识别，从而例如避免受试者中的预先存在的抗体。在一些实施方案中。在一些实施方案中，选择和/或进一步修饰衣壳以增强所需嗜性/靶向。
5.2.10经修饰的衣壳
在一些实施方案中，通过引入所选单一至多个氨基酸取代来修饰AAV衣壳，所述氨基酸修饰可增加至CNS的有效基因递送、使肝脱靶和/或减小中和抗体的免疫反应。
通过静脉内施用的rAAV载体将基因有效递送至CNS需要穿越血脑屏障。最近已报告AAVrh.10衣壳上使得能够在小鼠的脑血管系统中转运且进行广泛神经元转导的关键残基簇。具体而言，将AAVrh.10源性氨基酸N262、G263、T264、S265、G267、S268、T269和T273鉴定为促进穿越BBB的关键残基(Albright等人,2018,Mapping the StructuralDeterminants Required for AAVrh.10Transport across the Blood-Brain Barrier)。已鉴定衣壳(如AAV8和AAV9衣壳)中促进rAAV血脑屏障穿越、转导、肝脱靶和/或免疫反应减小的氨基酸取代。
在一些实施方案中，提供具有一个或多个氨基酸取代的衣壳，所述氨基酸取代促进了具有经修饰衣壳的rAAV的转导和/或组织嗜性。在特定实施方案中，提供在AAV8衣壳的氨基酸269处具有单一突变(使用丝氨酸代替丙氨酸，A269S)(参见表7，本文中称为AAV8.BBB)和在其他AAV类型中于相应位置处具有氨基酸取代的衣壳。在一些实施方案中，提供在AAV9衣壳的氨基酸263、269和273处具有多个取代(产生下列取代：S263G、S269T和A273T)(在本文中称为AAV9.BBB)或在其他AAV类型中对应于所述位置的取代的衣壳。
暴露于AAV衣壳可产生中和抗体的免疫反应。一种克服此反应的方式系定位AAV特异性中和表位且合理设计能够逃避中和的AAV衣壳。最近已阐述具有高中和效价的完整AAV9衣壳的特异性单株抗体(Giles等人,2018,Mapping an Adeno-associated Virus 9-Specific Neutralizing Epitope To Develop Next-Generation Gene DeliveryVectors)。表位定位至衣壳上的3次对称轴，具体而言定位至残基496-NNN-498和588-QAQAQT-592(SEQ ID NO:58)。衣壳诱变证实，此表位内的单一氨基酸取代显著减小结合和中和。另外，体内研究展示，表位中的突变赋予突变载体“肝脱靶”表型，从而表明相同残基还负责AAV9嗜性。肝脱靶还与在氨基酸503处使用精氨酸代替色氨酸的取代有关。AAV9衣壳中的W503R突变的存在与低聚糖结合亲合力有关(Shen等人,2012,Glycan BindingAvidity Determines the Systemic Fate of Adeno-Associated Virus Type 9)。
在一些实施方案中，提供衣壳，其中通过在氨基酸位置498、499和500(在本文中称为AAV8.BBB.LD)或496、497和498(在本文中称为AAV9.BBB.LD)使用丙氨酸取代天冬酰胺来进一步修饰AAV8.BBB和AAV9.BBB衣壳。在一些实施方案中，通过在氨基酸位置498、499和500处使用丙氨酸取代三个天冬酰胺来修饰AAVrh10衣壳(AAVrh10.LD)(表7)。
在一些实施方案中，提供在AAV9衣壳的氨基酸位置496、497和498处使用丙氨酸代替三个天冬酰胺且还在AAV9衣壳的氨基酸503处使用精氨酸代替色氨酸的衣壳或在其他AAV类型中具有对应于所述位置的取代的衣壳。在一些实施方案中，提供在AAV9衣壳的氨基酸位置474的谷氨酰胺被丙氨酸取代的衣壳或在其他AAV类型中具有对应于此位置的取代的衣壳。
在一些实施方案中，与不包含肽插入物的rAAV相比，本文所述的rAAV增加了受试者(人、非人灵长类动物或小鼠个体)或细胞培养物中的组织特异性(如但不限于CNS)细胞转导。在一些实施方案中，与无肽插入物的情况相比，组织特异性细胞转导增加至少2、10、20、30、40、50、60、70、80、90或100倍。例如，在一些实施方案中，与使用无肽插入物的相同AAV类型的转导相比，组织特异性细胞转导增加50至80倍。可使用本文实例中所阐述和本领域中已知的方法来评估转导的增加。
在一些实施方案中，与不包含肽插入物的rAAV相比，本文所述的rAAV增加了rAAV基因组在受试者(人、非人灵长类动物或小鼠受试者)中的一定细胞或组织类型或细胞培养物中的纳入。在一些实施方案中，与具有无肽插入物衣壳的AAV相比，基因组整合增加至少2、10、20、30、40、50、60、70、80、90或100倍。例如，在一些实施方案中，与使用无肽插入物的相同AAV类型的基因组整合相比，基因组整合增加50-80倍。
5.3.制备rAAV分子的方法
本发明的另一方面涉及制备本文所公开的分子。在一些实施方案中，通过以下方式来制备根据本发明的分子：提供包含编码本文的任一衣壳蛋白分子的核酸序列的核苷酸；和使用包装细胞系统来制备具有由衣壳蛋白构成的衣壳外壳的相应rAAV颗粒。在一些实施方案中，核酸序列编码与本文所述的衣壳蛋白分子的序列具有至少60％、70％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或99.9％同一性的序列，并且保留(或实质上保留)衣壳蛋白和来自异源蛋白或其结构域的所插入肽的生物功能。在一些实施方案中，核酸编码与AAV9衣壳蛋白(SEQ ID NO:118且参见图8)的序列具有至少60％、70％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或99.9％同一性的序列，同时保留(或实质上保留)AAV9衣壳蛋白和所插入肽的生物功能。
衣壳蛋白、外壳和rAAV颗粒可通过本领域中已知技术产生。在一些实施方案中，病毒基因组包含至少一个反向末端重复序列以允许包装至载体中。在一些实施方案中，病毒基因组还包含cap基因和/或用于表达和剪接cap基因的rep基因。在其他实施方案中，cap和rep基因由包装细胞提供且不存在于病毒基因组中。
在一些实施方案中，将编码经工程改造的衣壳蛋白的核酸克隆至AAV Rep-Cap辅助质粒中以代替现有衣壳基因。在一起引入宿主细胞中时，此质粒帮助将rAAV基因组包装至呈衣壳外壳形式的经工程改造的衣壳蛋白中。包装细胞可以是拥有促进AAV基因组复制、衣壳组装和包装所需的基因的任何细胞类型。非限制性实例包括293细胞或其衍生物、HELA细胞或昆虫细胞。
对于重组DNA、寡核苷酸合成以及组织培养和转化，可使用标准技术(例如电穿孔、脂质转染)。酶促反应和纯化技术可根据制造商的说明书来实施，或以本领域内常用方法来实施，或如本文所述来实施。通常可根据本领域内熟知的常规方法且如各种一般且更具体参考文献中所阐述实施下列技术和程序，遍及本说明书引用且论述所述参考文献。参见例如Sambrook等人,Molecular Cloning:A Laboratory Manual(第2版，Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.(1989))，其出于任何目的以引用的方式并入本文中。除非提供具体定义，否则结合本文所述的分析化学、合成有机化学以及医学和药物化学所利用的术语和其中的实验室程序以及技术是本领域内熟知且常用的那些。化学合成、化学分析、药物制备、配制和递送以及患者的治疗可使用标准技术。基于AAV的病毒载体的核酸序列以及制备重组AAV和AAV衣壳的方法教示于例如US 7,282,199、US 7,790,449、US 8,318,480、US 8,962,332和PCT/EP2014/076466中，其各自以引用的方式整体并入本文中。
在一些实施方案中，rAAV提供可用于治疗和防治应用中的转基因递送载体，如下文更详细地论述。在一些实施方案中，rAAV载体还包含本领域技术人员已知的调控控制元件，所述调控控制元件影响由核酸(转基因)编码的RNA和/或蛋白质产物在受试者的靶细胞内的表达。调控控制元件可以是组织特异性，即仅在靶细胞/组织中具有活性(或实质上更大活性或显著更大活性)。在具体实施方案中，AAV载体包含可操作地连接至允许表达于靶组织中的转基因的调控序列(如启动子)。启动子可以是组成型启动子，例如CB7启动子。另外启动子包含：巨细胞病毒(CMV)启动子、劳斯肉瘤病毒(Rous sarcoma virus，RSV)启动子、MMT启动子、EF-1α启动子、UB6启动子、鸡β-肌动蛋白启动子、CAG启动子、RPE65启动子、视蛋白启动子、TBG(甲状腺素结合球蛋白)启动子、APOA2启动子、SERPINA1(hAAT)启动子或MIR122启动子。在一些实施方案中，尤其在可期望关闭转基因表达的情况下，使用诱导型启动子(例如低氧诱导型或雷帕霉素诱导型启动子)。
在特定实施方案中提供包含病毒基因组(所述病毒基因组包含用于在调控元件的控制下表达转基因的表达盒且侧接有ITR)和经工程改造的病毒衣壳的AAV9载体，所述经工程改造的病毒衣壳是如本文所述或与AAV9衣壳蛋白(参见图8)的氨基酸序列至少95％、96％、97％、98％、99％或99.9％同一，同时保留经工程改造的AAV9衣壳的生物功能。在某些实施方案中，所编码AAV9衣壳具有野生型AAV9的序列以及如本文所述的肽插入物，并且另外相对于野生型AAV序列具有1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个氨基酸取代并保留AAV9衣壳的生物功能。还提供除AAV9载体以外的经工程改造的AAV载体(如经工程改造的AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV9e、AAVrh10、AAVrh20、AAVhu.37、AAVrh39或AAVrh74载体)，相对于野生型或所述AAV类型的未工程改造的序列，所述经工程改造的AAV载体具有如本文所述的肽插入物和1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个氨基酸取代且保留其生物功能。
重组腺病毒可以是第一代载体，其具有E1缺失、具有或不具有E3缺失且具有插入任一缺失区域中的表达盒。重组腺病毒可以是第二代载体，其含有E2和E4区域的全部或部分缺失。辅助依赖性腺病毒仅保留腺病毒反向末端重复序列和包装信号(phi)。通常将转基因插入包装信号与3’ITR之间，其中含有或不含用以使基因组保持于接近大约36kb的野生型大小的填充序列。用于产生腺病毒载体的示例性方案可参见Alba等人,2005,“Gutlessadenovirus:last generation adenovirus for gene therapy,”Gene Therapy 12:S18-S27，其以引用的方式整体并入本文中。
用于将转基因递送至靶组织的rAAV载体、细胞或器官具有针对所述特定靶组织、细胞或器官的嗜性。还可使用组织特异性启动子。构建体还可增强由载体驱动的转基因表达的表达控制元件(例如内含子，例如鸡β-肌动蛋白内含子、小鼠微小病毒(MVM)内含子、人因子IX内含子(例如FIX截短内含子1)、β-球蛋白剪接供体/免疫球蛋白重链剪接受体内含子、腺病毒剪接供体/免疫球蛋白剪接受体内含子、SV40晚期剪接供体/剪接受体(19S/16S)内含子和杂合腺病毒剪接供体/IgG剪接受体内含子；和聚A信号，例如兔β-球蛋白聚A信号、人生长激素(hGH)聚A信号、SV40晚期聚A信号、合成聚A(SPA)信号和牛生长激素(bGH)聚A信号。参见例如Powell和Rivera-Soto,2015,Discov.Med.,19(102):49-57。
在某些实施方案中，可例如经由本领域技术人员已知的任何密码子优化技术对本文所公开的核酸序列进行密码子优化(参见例如Quax等人,2015,Mol Cell 59:149-161的综述)。
在一个具体实施方案中，本文所述的构建体包含下列组分：(1)AAV9反向末端重复序列，其侧接于表达盒；(2)控制元件，其包含a)CB7启动子(包括CMV增强子/鸡β-肌动蛋白启动子)、b)鸡β-肌动蛋白内含子和c)兔β-球蛋白聚A信号；和(3)转基因，其提供(例如编码)目标核酸或蛋白质产物。在一个具体实施方案中，本文所述的构建体包含下列组分：(1)AAV9反向末端重复序列，其侧接于表达盒；(2)控制元件，其包含a)低氧诱导型启动子、b)鸡β-肌动蛋白内含子和c)兔β-球蛋白聚A信号；和(3)转基因，其提供(例如编码)目标核酸或蛋白质产物。
本文所提供的病毒载体可使用宿主细胞(例如哺乳动物宿主细胞，包括来自人、猴、小鼠、大鼠、兔或仓鼠的宿主细胞)制得。非限制性实例包括：A549、WEHI、10T1/2、BHK、MDCK、COS1、COS7、BSC 1、BSC 40、BMT 10、VERO、W138、HeLa、293、Saos、C2C12、L、HT1080、HepG2、原代成纤维细胞、肝细胞和成肌细胞。通常，使用编码转基因和相关元件的序列(即载体基因组)和用于在宿主细胞中产生病毒的遗传组分(例如复制和衣壳基因，例如AAV的rep和cap基因)来稳定转化宿主细胞。关于产生具有AAV8衣壳的重组AAV载体的方法，参见美国专利号7,282,199B2的具体实施方式的部分IV，所述专利以引用的方式整体并入本文中。可例如通过
分析来测定所述载体的基因组拷贝效价。可例如通过CsCl2沉降来回收病毒体。或者，可使用昆虫细胞中的杆状病毒表达系统来产生AAV载体。综述可参见Aponte-Ubillus等人,2018,Appl.Microbiol.Biotechnol.102:1045-1054，其关于制造技术以引用的方式整体并入本文中。
可使用体外测定(例如细胞培养测定)来测量来自本文所述的载体的转基因表达，由此指示例如载体功效。例如，可使用
细胞系(Lonza)(源自人胚胎视网膜细胞的细胞系)或视网膜色素上皮细胞(例如视网膜色素上皮细胞系hTERT RPE-1(可从
获得))来评估转基因表达。或者，可使用源自肝或其他细胞类型的细胞系，例如但不限于HuH-7、HEK293、纤维肉瘤HT-1080、HKB-11和CAP细胞。一旦表达，就可使用本领域中已知的测定来测定所表达产物(即转基因产物)的特性，包括测定糖基化和酪氨酸硫酸化模式。
5.4.治疗和防治用途
另一方面涉及涉及经由根据本发明的rAAV载体向有需要的受试者施用转基因的疗法，所述疗法用于延迟、预防、治疗和/或控制疾病或病症和/或改善一种或多种其相关症状。有需要的受试者包括患有疾病或病症的受试者或易患所述疾病或病症的受试者(例如处于发展或复发所述疾病或病症的风险的受试者)。通常，携带特定转基因的rAAV可用于受试者的给定疾病或病症，其中受试者的对应于转基因的天然基因在提供正确基因产物或正确量的基因产物方面具有缺陷。转基因然后可提供受试者中的缺陷性基因的拷贝。
通常，转基因包含恢复在相应天然基因中具有基因突变的受试者中的蛋白质功能的cDNA。在一些实施方案中，cDNA包含用于实施基因组工程改造(如经由同源重组的基因组编辑)的相关RNA。在一些实施方案中，转基因编码治疗性RNA(如shRNA)、人工miRNA或影响剪接的元件。
下文的表3A-3B提供可用于本文所述的任何rAAV载体中、尤其用于本文所述的新颖插入位点中以治疗或预防与转基因有关的疾病(也列于表3A-3B中)的转基因的列表。如本文所述，可如本文所述工程改造AAV载体以靶向适当组织，从而递送转基因以实现治疗或防治用途。可选择工程改造适当AAV血清型以优化载体的组织嗜性和转导。
表3A
表3B
例如，包含编码神经胶质源性生长因子(GDGF)的转基因的rAAV载体可用于治疗/预防/控制帕金森氏病。通常，全身性施用rAAV载体。例如，可通过静脉内、鞘内、鼻内和/或腹膜内施用来提供rAAV载体。
在特定方面中，本发明rAAV可用于递送至与待治疗/预防的病症或疾病有关的靶组织或靶细胞类型(包含与靶细胞类型有关的细胞基质)。与特定组织或细胞类型有关的疾病或病症是与身体的其他组织或细胞类型相比在很大程度上影响特定组织或细胞类型的那些，或是其中病症的效应或症状出现于特定组织或细胞类型中的那些。将转基因递送至有需要的受试者的靶组织的方法涉及向受试者施用rAAV，其中肽插入物是归巢肽。在帕金森氏病的情况下，例如，可使用包括将rAAV引导至神经组织的肽插入物的rAAV载体，特别地，其中肽插入物可促进rAAV穿越血脑屏障并到达CNS。所述肽插入物包含源自神经组织归巢结构域的那些，如本文所述的“EPO肽”或“HAD肽”。
例如，包含EPO肽的衣壳蛋白可用于使AAV再靶向CNS并穿越血脑屏障。包含EPO肽的衣壳蛋白可进一步对CNS组织具有保护效应，例如，其中EPO插入物结合先天性修复受体，从而活化IRR生物开关并抑制炎症和/或引发CNS修复。在一些实施方案中，本发明的包含EPO肽的rAAV可用于下列病症中的一者或多者：器官缺血性损伤、中风、心肌梗塞、肾损伤、肾病、脑损伤、肾缺血、肢体缺血、自身免疫性脑脊髓炎、自身免疫性神经炎、多发性硬化、格林-巴利综合征(Guillain-Barre Syndrome)、神经病变性疼痛、糖尿病并发症(如糖尿病性视网膜病变和糖尿病性自主神经病变)和类肉瘤病。
对于与神经组织有关的疾病或病症，可使用包含来自神经组织归巢结构域的肽插入物(例如本文所述的任一者)的rAAV载体。与神经组织有关的疾病/病症包括阿尔茨海默氏病、肌肉萎缩性侧索硬化(ALS)、肌肉萎缩性侧索硬化(ALS)、贝敦氏症、贝敦氏幼年型NCL形式、卡纳万氏病(Canavan disease)、慢性疼痛、弗里德赖希氏共济失调、多形性成胶质细胞瘤、亨廷顿氏病(Huntington's disease)、婴儿晚期神经元蜡样脂褐质沉积症(LINCL)、溶酶体贮积症、莱伯氏先天性黑蒙、多发性硬化、帕金森氏病、庞贝氏病、雷特氏综合征、脊髓损伤、脊髓性肌萎缩(SMA)、中风和创伤性脑损伤。载体还可含有对患有疾病或病症或处于发展疾病或病症的风险的受试者具有治疗/防治益处的转基因(参见表3A-3B)。
对于与骨有关的疾病或病症而言，可使用包含来自骨归巢结构域的肽插入物(例如本文所述的)的rAAV载体。
对于与肾有关的疾病或病症而言，可使用包含来自肾归巢结构域的肽插入物(例如本文所述的)的rAAV载体。
对于与肌肉有关的疾病或病症而言，可使用包含来自肌肉归巢结构域的肽插入物(例如本文所述的)的rAAV载体。
对于与内皮细胞有关的疾病或病症而言，可使用包含来自内皮细胞归巢结构域的肽插入物(例如本文所述的)的rAAV载体。
对于与整联蛋白受体或表达特定整联蛋白受体的细胞有关的疾病或病症而言，可使用包含来自整联蛋白受体结合结构域的肽插入物(例如本文所述的)的rAAV载体。
对于与转铁蛋白受体或表达转铁蛋白受体的细胞有关的疾病或病症(例如高度表达转铁蛋白受体的肿瘤)而言，可使用包含来自转铁蛋白受体结合结构域的肽插入物(例如本文所述的)的rAAV载体。
对于与肿瘤有关的疾病或病症而言，可使用包含来自所述肿瘤细胞靶向结构域的肽插入物的rAAV载体。
对于与视网膜或眼睛有关的疾病或病症而言，可使用包含来自所述视网膜细胞归巢结构域(包含HAD肽)的肽插入物的rAAV载体。肽插入物增加了视网膜嗜性，从而引导rAAV靶向受试者的眼睛或视网膜并穿越血眼屏障。术语“视网膜细胞”是指发现于视网膜中或其附近的细胞类型中的一者或多者，包含无长突细胞、双极细胞、水平细胞、米勒神经胶质细胞、光感受器细胞(例如视杆和视锥)、视网膜神经节细胞(例如侏儒细胞、阳伞细胞、双层细胞、巨视网膜神经节细胞和光敏性神经节细胞)、视网膜色素上皮、内限界膜的内皮细胞和诸如此类。
通常，在rAAV载体包含用于视网膜细胞归巢的肽插入物的情况下，通过体内注射(例如直接注射至眼睛中)来施用载体。例如，包括用于增加视网膜嗜性的肽插入物的rAAV可玻璃体内注射。在一些实施方案中，通过眼内注射(例如穿过平坦部进入眼睛的玻璃体或房水中)来施用用于增加视网膜嗜性的rAAV。在一些实施方案中，用于增加视网膜嗜性的rAAV是通过眼球周注射或结膜下注射来施用。具有用于视网膜细胞归巢的肽插入物的rAAV载体的一个优点在于，受试者可避免手术(例如避免用以植入代之以通过注射递送的治疗剂的手术)。在某些实施方案中，通过本文所述的rAAV载体经由玻璃体内注射来递送治疗剂，从而提供治疗有效量以治疗与眼睛有关的疾病或病症、特别是与受试者的视网膜有关的疾病或病症。在更多实施方案中，在以下情况后实现治疗：单一玻璃体内注射、不超过两个玻璃体内注射、不超过三个玻璃体内注射、不超过四个玻璃体内注射、不超过五个玻璃体内注射或不超过六个玻璃体内注射。
与眼睛或视网膜有关的疾病/病症称为“眼部疾病”。眼部疾病的非限制性实例包括前部缺血性视神经病变；急性黄斑性视神经视网膜病变；巴德-别德尔综合征(Bardet-Biedl syndrome)；白塞氏病(Behcet'sdisease)；视网膜分支静脉阻塞；视网膜中央静脉阻塞；无脉络膜症；脉络膜新生血管形成；脉络膜视网膜退化；视锥视杆营养不良；色觉病症(例如色盲、红色盲、绿色盲和蓝色盲)；先天性静止性夜盲；糖尿病性葡萄膜炎；视网膜前膜病症；遗传性黄斑变性；组织胞浆菌病；黄斑变性(例如急性黄斑变性、非渗出性年龄相关性黄斑变性、渗出性年龄相关性黄斑变性)；糖尿病性视网膜病变；水肿(例如黄斑水肿、囊样黄斑水肿、糖尿病性黄斑水肿)；青光眼；莱伯氏先天性黑蒙；莱伯氏遗传性视神经病变；黄斑毛细血管扩张；多灶性脉络膜炎；非视网膜病变性糖尿病性视网膜功能障碍；眼部创伤；眼部肿瘤；增殖性玻璃体视网膜病变(PVR)；早产儿视网膜病变；视网膜劈裂症；色素性视网膜炎；视网膜动脉阻塞性疾病、视网膜脱离、斯塔加特氏疾病(Stargardt disease)(眼底黄色斑点症)；交感性眼炎；葡萄膜扩散；葡萄膜炎性视网膜疾病；厄舍综合征(Ushersyndrome)；伏格特-小柳-原田(Vogt Koyanagi-Harada，VKH)综合征；或与眼部激光或光动力学疗法有关的后眼疾患。
本发明的rAAV载体还可促进寡核苷酸、药物、成像剂、无机纳米颗粒、脂质体、抗体至靶细胞或组织的递送、特别是靶向递送。rAAV载体还可促进非编码性DNA、RNA或寡核苷酸至靶组织的递送、特别是靶向递送。
所述剂可提供为如本领域中已知和/或如本文所述的药学上可接受的组合物。同样，本发明的rAAV分子可单独施用或与其他防治剂和/或治疗剂组合施用。
本文所提供施用的剂量含量和频率被术语治疗有效和防治有效涵盖。剂量和频率通常根据每一患者的特定因素取决于所施用的特定治疗剂或防治剂、疾病的严重程度和类型、施用途径以及患者的年龄、体重、反应和既往病史而有所变化，并且应根据从业人员的判断和每一患者的情况来决定。合适方案可由本领域技术人员通过考虑此类因素且通过遵循(例如)文献中所报告和Physician's Desk Reference(第56版，2002)中所推荐的剂量来选择。防治剂和/或治疗剂可重复施用。若干程序方面可有所变化，例如施用防治剂或治疗剂的暂时方案和此类剂是单独施用还是以混合物形式施用。
可通过标准临床技术来确定本发明的剂的有效量。可根据从体外或动物模型测试系统获得的剂量反应曲线来推断有效剂量。对于本发明方法中所使用的任一剂而言，可首先从细胞培养测定估计治疗有效剂量。可在动物模型中配制剂量以实现循环血浆浓度范围(包括IC50，即实现症状的半最大抑制的测试化合物的浓度)，如在细胞培养物中所测定。所述信息可用于更准确地确定人中可用的剂量。可通过例如高效液相色谱来测量血浆中的水平。
在用于人中之前，可在合适动物模型系统中测试防治剂和/或治疗剂以及其组合。所述动物模型系统包括但不限于大鼠、小鼠、鸡、牛、猴、猪、狗、兔等。可使用本领域中熟知的任一动物系统。此类模型系统广泛使用且为本领域技术人员所熟知。在一些实施方案中，使用基于大鼠、小鼠或除灵长类动物外的其他小型哺乳动物的CNS疾患的动物模型系统。
一旦本发明的防治剂和/或治疗剂已在动物模型中进行了测试，其就可在临床试验中测试以确立其功效。根据本领域技术人员已知的常用方法来进行确立性临床试验，并且可确立本发明的剂的最佳剂量和施用途径以及毒性特征。例如，可设计临床试验以测试本发明的rAAV分子在人患者中的功效和毒性。
本发明的防治剂和/或治疗剂的毒性和功效可在细胞培养物或实验动物中通过标准药物程序来测定，例如用于测定LD50(对群体的50％致死的剂量)和ED50(在群体的50％中治疗有效的剂量)的程序。毒性效应与治疗效应之间的剂量比是治疗指数且可表示为比率LD50/ED50。展现较大治疗指数的防治剂和/或治疗剂是优选的。尽管可使用展现毒性副作用的防治剂和/或治疗剂，但应小心设计使此类剂靶向受影响组织的位点的递送系统以最小化对未感染细胞的潜在损害且由此减少副作用。
本发明的rAAV分子的施用时间和施用量通常可有效获得所需的治疗和/或防治益处。可使用从细胞培养测定和动物研究获得的数据来确定用于人中的防治剂和/或治疗剂的剂量范围和/或时间表。所述剂的剂量在具有较少毒性或没有毒性的循环浓度(包括ED50)范围内。所述剂量可取决于所用剂型和所用施用途径在此范围内有所变化。
用于患者的rAAV载体的治疗有效剂量通常是约0.1ml至约100ml含有约1×109至约1×1016基因组rAAV载体或约1×1010至约1×1015、约1×1012至约1×1016或约1×1014至约1×1016AAV基因组的浓度的溶液。可监测转基因的表达水平以测定/调整剂量含量、频率、时间安排和诸如此类。
使用治疗或防治有效量的本发明的剂治疗受试者可包括单一治疗或者可包括一系列治疗。例如，包含本发明的剂的药物组合物可每天一次、每天两次或每天三次施用。在一些实施方案中，可按以下频率施用剂：每天一次、每隔一天、每周一次、每周两次、每两周一次、每月一次、每6周一次、每两个月一次、每年两次或每年一次。还应了解，某些剂的有效剂量(例如包含本发明的双重抗原结合分子的剂的有效剂量)可在治疗过程中增加或降低。
在一些实施方案中，指示持续治疗(例如长期)，例如持续治疗和/或控制慢性疾病或病症。例如，在特定实施方案中，在一定时间段内施用本发明的剂，例如持续至少6个月、至少一年、至少两年、至少5年、至少10年、至少15年、至少20年或持续于有需要的受试者的余生中。
本发明的rAAV分子可单独施用或与其他防治剂和/或治疗剂组合施用。每一防治剂或治疗剂可在相同时间或以任何顺序在不同时间点依序施用；然而，如果不在相同时间施用，则其应在时间上充分靠近施用以提供所需的治疗或防治效应。每一治疗剂可以任何适当形式且通过任何合适途径单独施用。
在各个实施方案中，不同防治剂和/或治疗剂按以下间隔施用：小于1小时间隔、约1小时间隔、约1小时至约2小时间隔、约2小时至约3小时间隔、约3小时至约4小时间隔、约4小时至约5小时间隔、约5小时至约6小时间隔、约6小时至约7小时间隔、约7小时至约8小时间隔、约8小时至约9小时间隔、约9小时至约10小时间隔、约10小时至约11小时间隔、约11小时至约12小时间隔、不超过24小时间隔或不超过48小时间隔。在某些实施方案中，两种或更多种剂在同一患者访视内施用。
施用本发明的剂的方法包括但不限于胃肠外施用(例如真皮内、肌内、腹膜内、静脉内和皮下，包含输注或快速浓注)、硬膜外和通过吸收穿过上皮或皮肤粘膜或粘膜衬里(例如鼻内、口腔粘膜、直肠和肠粘膜等)。在特定实施方案中，例如在转基因意图表达于CNS中的情况下，经由腰部穿刺或经由小脑延髓池施用载体。
在某些实施方案中，本发明的剂静脉内施用且可与其他生物活性剂一起施用。
在另一具体实施方案中，本发明的剂可以持续释放制剂形式来递送，例如，制剂提供延迟释放且由此延长所施用剂的半衰期。适合使用的受控释放系统包括但不限于扩散控制系统、溶剂控制系统和化学控制系统。扩散控制系统包括例如储槽装置，其中将本发明的分子包封于装置内，从而通过穿过扩散屏障的渗透来控制分子释放。常用储槽装置包括例如膜、胶囊、微胶囊、脂质体和空心纤维。单体式(基质)装置是第二类扩散控制系统，其中双重抗原结合分子分散或溶于速率控制基质(例如聚合物基质)中。本发明的剂可均匀分散于整个速率控制基质中且释放速率由穿过基质的扩散来控制。适用于单体式基质装置中的聚合物包括天然聚合物、合成聚合物和以合成方式改性的天然聚合物以及聚合物衍生物。
可使用本领域技术人员已知的任何技术来产生包含本文所述的一种或多种剂的持续释放制剂。参见例如美国专利号4,526,938；PC T公布WO 91/05548；PCT公布WO 96/20698；Ning等人,“Intratu moral Radioimmunotheraphy of a Human Colon CancerXenograft Using a Sustained-Release Gel,”Radiotherapy&Oncology,39:179189,1996；Song等人,“Antibody Mediated Lung Targeting of Long-CirculatingEmulsions,”PDA Journal of Pharmaceutical Science&Technology,50:372 397,1995；Cleek等人,“Biodegradable Polyme ric Carriers for a bFGF Antibody forCardiovascular Application,”Pro.Intl.Symp.Control.Rel.Bioact.Mater.,24:853854,1997；和Lam等人,“Microencapsulation of Recombinant Humanized Monoclo nalAntibody for Local Delivery,”Proc.Int'l.Symp.Control Rel.Bi oact.Mater.,24:759 760,1997，其各自以引用的方式整体并入本文中。在一个实施方案中，可在受控释放系统中使用泵(参见Langer，同上；Sefton,CRC Crit.Ref.Biomed.Eng.,14:20,1987；Buchwald等人,Surgery,88:507,1980；和Saudek等人,N.Engl.J.Med.,321:574,1989)。在另一个实施方案中，可使用聚合材料来实现包含双重抗原结合分子或其抗原结合片段的剂的受控释放(参见例如MedicalApplications of Controlled Release,Langer和Wise(编辑),CRC Pre s.,Boca Raton,Fla.(1974)；Controlled Drug Bioavailability,DrugProduct Design and Performance,Smolen和Ball(编辑),Wiley,N.Y.(1984)；Ranger和Peppas,J.,Macromol.Sci.Rev.Macromol.Che m.,23:61,1983；还参见Levy等人,Science,228:190,1985；During等人,Ann.Neurol.,25:351,1989；Howard等人,J.Neurosurg.,7 1:105,1989)；美国专利号5,679,377；美国专利号5,916,597；美国专利号5,912,015；美国专利号5,989,463；美国专利号5,128,326；PCT公布号WO 99/15154；和PCT公布号WO 99/20253)。在又一实施方案中，受控释放系统可置于治疗靶标(例如受影响关节)附近，由此仅需要全身性剂量的一部分(参见例如Goodson,Medical Applications of ControlledRelease(同上)，第2卷，第115 138页(1984))。其他受控释放系统论述于Langer,Science,249:1527 1533,1990的综述中。
另外，可使用rAAV来体内递送用于诸如以下的科学研究的转基因：光遗传学、使用miRNA的基因敲低、用于条件性基因缺失的重组酶递送、使用CRISPR的基因编辑和诸如此类。
5.5.药物组合物和药盒
本发明进一步提供包含药学上可接受的载体和本发明的剂的药物组合物，所述剂包含本发明rAAV分子。在一些实施方案中，药物组合物包含用于施用于受试者的与药学上可接受的载体组合的rAAV。在一个实施方案中，术语“药学上可接受”意指已获得联邦或州政府管理机构批准或已列于美国药典(U.S.Pharmacopeia)或其他公认药典中可用于动物(且更特别地用于人)中。术语“载体”是指与剂一起施用的稀释剂、佐剂(例如弗氏完全和不完全佐剂(Freund's complete and incomplete adjuvant))、赋形剂或媒介物。此类药物载体可以是无菌液体，如水和油，包括石油、动物、植物或合成来源的那些，包括例如花生油、大豆油、矿物油、芝麻油和诸如此类。在静脉内施用药物组合物时，水是常用载体。还可采用盐水溶液和水性右旋糖和甘油溶液作为液体载体、尤其用于可注射溶液。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、水稻、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇和诸如此类。药学上可接受的载体、赋形剂和稳定剂的其他实例包括但不限于本领域中已知的缓冲剂，例如磷酸盐、柠檬酸盐和其他有机酸；抗氧化剂，包括抗坏血酸；低分子量多肽；蛋白质，如血清白蛋白和明胶；亲水性聚合物，如聚乙烯基吡咯烷酮；氨基酸，如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸；单糖、二糖和其他碳水化合物，包含葡萄糖、甘露糖或糊精；螯合剂，如EDTA；糖醇，如甘露醇或山梨醇；成盐抗衡离子，如钠；和/或非离子型表面活性剂，如TWEENTM、聚乙二醇(PEG)和PLURONICSTM。除上述成分外，本发明的药物组合物还可包含润滑剂、湿润剂、甜味剂、调味剂、乳化剂、悬浮剂和防腐剂。这些组合物可采用溶液、悬浮液、乳液、片剂、丸剂、胶囊、粉末、持续释放制剂和诸如此类的形式。
在本发明的某些实施方案中，提供用于根据本发明的方法使用的药物组合物，所述药物组合物包含治疗和/或防治有效量的本发明的剂以及药学上可接受的载体。
在某些实施方案中，本发明的剂是实质上纯化的(即实质上不含限制其效应或产生不期望的副作用的物质)。在一个具体实施方案中，宿主或受试者是动物，例如哺乳动物，如非灵长类动物(例如牛、猪、马、猫、狗、大鼠等)和灵长类动物(例如猴(如食蟹猴)和人)。在某一实施方案中，宿主是人。
本发明进一步提供可用于上述方法中的药盒。在一个实施方案中，药盒在例如一个或多个容器中包括本发明的一种或多种剂。在另一个实施方案中，药盒在一个或多个容器中还包括可用于治疗疾患的一种或多种其他防治剂或治疗剂。
本发明还提供包装于指示剂或活性剂的量的气密性密封容器(如安瓿或药袋)中的本发明的剂。在一个实施方案中，剂以干燥灭菌冻干粉末或无水浓缩物形式供应于气密性密封容器中且可例如使用水或盐水重构至用于施用至受试者的适当浓度。通常，剂是作为干燥无菌冻干粉剂以至少5mg、更通常至少10mg、至少15mg、至少25mg、至少35mg、至少45mg、至少50mg或至少75mg的单位剂量供应于气密性密封容器中。冻干剂应在其原始容器中储存于2℃与8℃之间且剂应在重构之后12小时内、通常6小时内、5小时内、3小时内或1小时内施用。在一个替代实施方案中，本发明的剂以液体形式供应于指示剂或活性剂的量和浓度的气密性密封容器中。通常，液体形式的剂以至少1mg/ml、至少2.5mg/ml、至少5mg/ml、至少8mg/ml、至少10mg/ml、至少15mg/kg或至少25mg/ml供应于气密性密封容器中。
本发明的组合物包含可用于制造药物组合物的原料药物组合物(例如不纯或非无菌组合物)以及药物组合物(即适于施用至受试者或患者的组合物)。原料药物组合物可用于制备单位剂型，所述单位剂型例如包含防治或治疗有效量的本文所公开的剂或那些剂和药学上可接受的载体的组合。
本发明进一步提供药物包装或药盒，其包括填充有本发明的一种或多种剂的一个或多个容器。另外，可用于治疗靶疾病或病症的一种或多种其他防治剂或治疗剂也可包含于药物包装或药盒中。本发明还提供药物包装或药盒，其包括填充有本发明药物组合物的一种或多种成分的一个或多个容器。任选地，此类容器可附带有监管药物或生物产品的制造、使用或销售的政府机构所规定形式的公告，所述公告反映政府机构已批准用于人施用的制造、使用或销售。
通常，本发明组合物的成分可单独供应或以单位剂型混合在一起，例如作为于指示剂或活性剂的量的气密性密封容器(如安瓿或药袋)中的干燥冻干粉末或无水浓缩物。如果组合物待通过输注来施用，则可使用含有无菌药物级水或盐水的输注瓶来分配所述组合物。如果组合物通过注射来施用，则可提供含有注射用无菌水或盐水的安瓿，从而可在施用之前混合所述成分。
6.实施例
下列实施例报告AAV9衣壳上的表面暴露的环的分析以鉴定用于经由插入诱变进行衣壳工程改造的候选者。通过实施例方式来阐释本发明，所述实施例阐述经工程改造以含有基于人轴丝动力蛋白重链尾部所设计的7聚体肽的rAAV9衣壳的构建。简言之，使用三个标准来选择可适用于短肽插入物的表面环：1)与相邻环具有最小侧链相互作用；2)各血清型之间具有可变序列和结构(缺乏保守序列)；和3)可能中断通常靶向的中和抗体表位。构建一组肽插入突变体且针对可行衣壳组装、肽表面暴露和效力来筛选单独突变体。然后使用主要候选者作为用于插入归巢肽的模板以测试这些肽插入点是否可用于使rAAV载体重靶向目标组织。其他实施例证明本文所述的某些经修饰的AAV衣壳的增加的转导和组织嗜性。
6.1.实施例1-AAV9衣壳的分析
图1和2描绘9型腺相关病毒的可变区4(AAV9 VR-IV)的分析(通过与其他AAV VR-IV进行氨基酸序列对比)(图1)和蛋白质模型(图2)。如所观察到，AAV9 VR-IV暴露于3重棘蛋白的尖端或外表面上。进一步的分析指示，在VR-IV与VR-V之间存在较少侧链相互作用且VR-IV的序列和结构在各AAV血清型中可变，并且另外可能中断通常靶向的中和抗体表位且由此减小经修饰衣壳的免疫原性。
6.2.实施例2-AAV9突变体的构建
构建8种AAV9突变体，其各自包含位于VR-IV环中的不同插入点处的异源肽。异源肽是FLAG标签，其紧接在鉴定为pRGNX1090-1097的载体中的下列残基之后插入，如表4中所示。
表4
6.3.实施例3-包装效率的分析
图3描绘野生型AAV9和八(8)种候选rAAV9载体(1090、1091、1092、1093、1094、1095、1096和1097)的高包装效率(以基因组拷贝/mL(GC/mL)表示)，其中候选载体各自在AAV9 VR-IV内的不同位点处含有FLAG插入物。所有载体都与荧光素酶转基因一起包装于10mL培养物中以有助于测定哪些插入点不中断衣壳包装；误差条代表平均值的标准误差。
如所观察到，所有候选者都高效包装。
6.4.实施例4-表面FLAG暴露的分析
图4描绘八(8)种候选rAAV9载体(1090、1091、1092、1093、1094、1095、1096和1097)中的每一者中的FLAG插入物的表面暴露，如通过经由结合至抗FLAG树脂来免疫沉淀经转导载体所证实。与抗FLAG的结合指示允许形成在表面上展示肽插入物的衣壳的插入点。
将经转导细胞裂解且离心。将500μL细胞培养上清液负载于20μL琼脂糖-FLAG珠粒上且使用还直接负载于凝胶上的SDS-PAGE负载缓冲液进行洗脱。对于阴性对照而言，使用不含FLAG插入物的293-ssc上清液。
如所观察到，1090具有候选载体中的最低效价，从而指示最少蛋白质发生下拉。极低效价还可见于阳性对照中。可能并未负载足够量的阳性对照以用于在SDS-PAGE上进行可视化。
6.5.实施例5-转导效率的分析
图5A-5B描绘用携带荧光素酶基因(作为转基因)的衣壳载体转导的Lec2细胞中的转导效率，所述衣壳载体包装成野生型AAV9(9-luc)或八(8)种候选rAAV9载体(1090、1091、1092、1093、1094、1095、1096和1097)中的每一者；活性表示为荧光素酶活性百分比(将9-luc的活性视为100％)(图5A)或表示为相对光单位(RLU)/微克蛋白质(图5B)。
在αMEM和10％FBS中生长CHO源Lec2细胞。以约2×108GC载体的MOI(MOI为约10,000)来转导Lec2细胞且使用ViraDuctin试剂进行处理(在以约10,000GC/细胞的MOI转导Lec2细胞但使用40μg/mL氯化锌(ZnCl2)处理时观察到类似结果；结果未展示)。Lec2细胞来自CHO的脯氨酸营养缺陷物。
如所观察到，体外转导效率低于使用野生型AAV9(9-luc)所获得的转导效率。然而，先前研究已展示，引入归巢肽可降低非靶细胞(如293、Lec2或HeLa)中的体外基因转移，而显著增加靶细胞中的体外基因转移(参见例如Nicklin等人2001；和Grifman等人2001)。
6.6.实施例6-包装效率作为插入肽组成和长度的因子的分析
图6A描绘图解说明紧接在AAV9衣壳(SEQ ID NO:118)的S454之后且具有不同肽长度和组成的插入物可影响AAV颗粒在包装细胞系中的产生效率的条形图。10种具有不同组成和长度的肽在S454之后(在残基454与455之间)插入AAV9 VR-IV内。在转染后5天对经转染悬浮HEK293细胞的所收获上清液实施qPCR。条形图中所描绘的结果证实，插入物的性质和长度可影响以高效价产生AAV颗粒且包装于293细胞中的能力。(误差条代表平均肽长度的标准误差，其在Y轴上以括号注明。)
研究具有衣壳蛋白的AAV9载体，所述衣壳蛋白在S454插入位点处含有具有下列肽序列的归巢肽(表5)。在转导于10mL培养基中之前一天，以1×106个细胞/mL接种悬浮适应性HEK293细胞。使用
(Polypus transfection)以1:1.75的DNA:PEI比率进行三重质粒DNA转染。将细胞离心且在转染后5天收获上清液，并储存于-80℃下。
表5.
| 肽编号 | 组织或靶名称 | 肽序列 | SEQ ID NO: |
| P1 | 骨1(D8) | DDDDDDDD | 9 |
| P2 | 脑1 | LSSRLDA | 10 |
| P3 | 脑2 | CLSSRLDAC | 11 |
| P4 | 肾1 | LPVAS | 13 |
| P5 | 肾2 | CLPVASC | 12 |
| P6 | 肌肉1 | ASSLNIA | 14 |
| P7 | TfR1 | HAIYPRH | 17 |
| P8 | TfR2 | THRPPMWSPVWP | 18 |
| P9 | TfR3 | RTIGPSV | 19 |
| P10 | TfR4 | CRTIGPSVC | 20 |
在转染后5天，对经转染悬浮HEK293细胞的所收获上清液实施qPCR。对样品实施DNA酶I处理以去除残余质粒或细胞DNA且然后热处理以使DNA酶I失活并使衣壳变性。经由qPCR使用TaqMan Universal PCR Master Mix,No AmpEraseUNG(ThermoFisherScientific)和针对包装于转基因构建体中的聚A序列的引物/探针来滴定样品。使用RGX-501载体BDS来建立标准曲线。
紧接在S454之后且长度介于5至10个氨基酸之间的肽插入物产生具有适当效价的AAV颗粒，而可能具有大小上限，其中针对具有12个氨基酸长度的肽插入物观察到显著包装缺陷。
6.7.实施例7-归巢肽在插入S454之后时改变AAV9的体外转导性质。
图6B-E描绘(图6B)Lec2细胞系(唾液酸缺陷性上皮细胞系)、(图6C)HT-22细胞系(神经元细胞系)、(图6D)hCMEC/D3细胞系(脑内皮细胞系)和(图6E)C2C12细胞系(肌肉细胞系)的细胞培养物的荧光图像。使用含有GFP转基因的AAV9野生型和表5中S454插入归巢肽衣壳来转导所述细胞系。
在转导之前24小时，以5-20×103个细胞/孔(取决于细胞系)将细胞系平铺于96孔中。使用AAV9-GFP载体(含有或不含插入物)以1×1010个颗粒/孔转导细胞且在转导之后48-96小时(取决于每一细胞系中的表达速率差异)经由Cytation5(BioTek)进行分析。如实施例5中一般来培养Lec2细胞，根据制造商方案来培养血脑屏障hCMEC/D3(EMD Millipore)细胞，在DMEM和10％FBS中培养HT-22和HUH7细胞，并且将C2C12成肌细胞平铺于DMEM和10％FBS中并分化三天，然后在补充有2％马血清和0.1％胰岛素的DMEM中进行转染。在所测试的每一细胞类型中，AAV9.S454.FLAG展示低转导水平。
图像展示，在插入AAV9衣壳蛋白中的S454之后时，与未修饰AAV9衣壳相比，归巢肽可改变AAV9的体外转导性质。用于所有细胞系的P7(TfR1肽，HAIYPRH(SEQ ID NO:17))展示最高转导速率，随后是P9(TfR3肽，RTIGPSV(SEQ ID NO:19))。在所有细胞类型中，P4(肾1肽，LPVAS(SEQ ID NO:13))所展示的转导速率略高于AAV9野生型。与Lec2和HT-22细胞系培养物相比，在脑内皮hCMEC/D3细胞系和C2C12肌肉细胞系培养物中针对P6(肌肉1肽，ASSLNIA(SEQ ID NO:14))观察到较高转导速率。P1载体因极低转导效率而未包含于图像中，并且P8载体因低效价而未包含。
6.8.实施例8-人轴丝动力蛋白(HAD)的分析
图7A-7M分别描绘人轴丝动力蛋白1-12、14和17的重链尾部结构域的氨基酸序列。
6.9.实施例9-AAV衣壳的肽插入点分析
图8描绘具有用于人轴丝动力蛋白肽的插入位点的AAV 1-9e、rh10、rh20、rh39、rh74和hu.37的衣壳序列的比对，所述插入位点位于VP2的起始密码子、可变区1(VR-I)、可变区4(VR-IV)和可变区8(VR-VIII)内或其附近且以灰色突出显示；每一衣壳蛋白的可变区8(VR-VIII)内的特定插入位点由符号“#”展示(在根据AAV9的氨基酸编号的氨基酸残基588之后)。
6.10.实施例10-含有ARA290的rAAV衣壳的构建
图9描绘在AAV9衣壳氨基酸序列的Q588与A589之间包含肽插入物ARA290的重组AAV9载体衣壳的氨基酸序列(SEQ ID NO:153)。
6.11.实施例11-各种载体的AAV基因组拷贝/μg基因组DNA的比较
图10描绘在施用下列AAV载体后表达于小鼠脑细胞中的GFP(绿色荧光蛋白)转基因拷贝：AAV9；AAV.PHP.eB；AAV.hDyn(在588-589之间具有TLAAPFK(SEQ ID NO:2)且衣壳序列并无其他氨基酸修饰的AAV9)；AAV.PHP.S；和AAV.PHP.SH(参见表10)。
AAV.PHP.B是在AAV9衣壳中具有TLAVPFK(SEQ ID NO:27)插入物的衣壳，其中衣壳序列并无其他氨基酸修饰。AAV.PHP.eB是在AAV9衣壳中具有TLAVPFK(SEQ ID NO:27)插入物的衣壳，其中衣壳序列在PHP.B插入物上游具有两个氨基酸修饰(还参见表10)。表6A总结研究中所用的衣壳。
表6A
材料和方法
制备编码GFP转基因的AAV9、AAV.PHPeB、AAV.hDyn、AAV.PHP.S和AAV.PHP.SH的构建体且配制于1xPBS+0.001％普罗尼克(Pluronic)中。基于第1天体重将雌性C57BL/6小鼠随机化至治疗组中。根据下文表6B，向5组雌性C57BL/6小鼠各自静脉内施用AAV9.GFP、AAV.PHPeB.GFP、AAV.hDyn.GFP、AAV.PHP.S.GFP或AAV.PHP.SH.GFP。给药体积为10mL/kg(0.200mL/20g小鼠)。小鼠在开始日期时为8-12周龄。在施用后第15天，对动物实施安乐死，并且收集周边组织(包含脑组织、肝、前肢二头肌、心脏、肾、肺、卵巢和坐骨神经)。
表6B
| 组 | N | 剂 | 制剂剂量 | 途径 | 时间表 |
| 1 | 9 | AAV9 | 2.5E12 GC/kg | 静脉内 | 第1天 |
| 2 | 5 | PHPeB | 2.5E12 GC/kg | 静脉内 | 第1天 |
| 3 | 5 | hDyn | 2.5E12 GC/kg | 静脉内 | 第1天 |
| 4 | 5 | PHP.S | 2.5E12 GC/kg | 静脉内 | 第1天 |
| 5 | 5 | PHP.SH | 2.5E12 GC/kg | 静脉内 | 第1天 |
使用定量PCR(qPCR)来测定每μg脑基因组DNA中的载体基因组数量。加工来自经注射小鼠的脑样品且使用来自Qiagen的血液和组织基因组DNA试剂盒来分离基因组DNA。在QuantStudio 5仪器(Life Technologies Inc)上使用对eGFP具有特异性的引物-探针组合遵循标准曲线方法来运行qPCR测定。
施用AAV.hDyn的小鼠中的AAV载体基因组拷贝/μg脑基因组DNA至少高于所有其他AAV血清型：AAV9、AAV.PHPeB、PHP.S和PHP.SH一个对数(参见图10)。如可在此研究中观察到，AAV.hDyn的GC/μg基因组DNA最高，AAV.hDyn是在AAV9衣壳的残基588-589之间含有“TLAAPFK”(SEQ ID NO:2)肽插入物(来自人轴丝动力蛋白的肽)的AAV9衣壳。研究证实，在全身性施用携带eGFP的AAV.hDyn的5只小鼠中，小鼠脑中的平均转导大于1E04 GC/μg转基因。然而，其他经修饰AAV9衣壳(包含载体AAV.PHPeB，其含有“TLAVPFK”(SEQ ID NO:27)序列(来自小鼠动力蛋白的肽))在全身性治疗后显示，小鼠脑中的转导小于1E03 GC/μg转基因。
6.12.实施例12-组织归巢rAAV载体在治疗方法中的应用
鉴定可通过提供核酸(转基因)来治疗/预防的病症(参见表3A-3B)。鉴定患有与靶组织有关的病症的受试者。向受试者施用第一量的本发明rAAV载体，其中所述载体包含具有归巢至靶组织的肽插入物且携带待递送的转基因的衣壳蛋白。如果需要，则向受试者施用第二或第三剂量的载体，直至将治疗有效量的转基因递送至靶组织以向受试者提供治疗或防治益处为止。
在一些实施方案中，提供向视网膜施用转基因的方法，其中静脉内、全身性或玻璃体内施用衣壳化转基因的AAV.hDyn衣壳。
6.13.实施例13-含有TLAAPFK(SEQ ID NO:2)的rAAV衣壳的构建
图11A描绘在VR-IIIV的Q588与A589之间包含具有氨基酸序列TLAAPFK(SEQ IDNO:2)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图11B描绘在VR-III的S268与S269之间包含具有氨基酸序列TLAAPFK(SEQ ID NO:2)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图11C描绘在VR-IV的S454与G455之间包含具有氨基酸序列TLAAPFK(SEQ ID NO:2)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
6.14.实施例14-含有KMQVPFQ(SEQ ID NO:1)的rAAV衣壳的构建
图12A描绘在VR-VIII的Q588与A589之间包含具有氨基酸序列KMQVPFQ(SEQ IDNO:1)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图12B描绘在VR-III的S268与S269之间包含具有氨基酸序列KMQVPFQ(SEQ ID NO:1)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图12C描绘在VR-IV的S454与G455之间包含具有氨基酸序列KMQVPFQ(SEQ ID NO:1)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
6.15.实施例15-含有QQAAPSF(SEQ ID NO:3)的rAAV衣壳的构建
图13A描绘在VR-VIII的Q588与A589之间包含具有氨基酸序列QQAAPSF(SEQ IDNO:3)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图13B描绘在VR-III的S268与S269之间包含具有氨基酸序列QQAAPSF(SEQ ID NO:3)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图13C描绘在VR-IV的S454与G455之间包含具有氨基酸序列QQAAPSF(SEQ ID NO:3)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
6.16.实施例16-含有RYNAPFK(SEQ ID NO:4)的rAAV衣壳的构建
图14A描绘在VR-VIII的Q588与A589之间包含具有氨基酸序列RYNAPFK(SEQ IDNO:4)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图14B描绘在VR-III的S268与S269之间包含具有氨基酸序列RYNAPFK(SEQ ID NO:4)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图14C描绘在VR-IV的S454与G455之间包含具有氨基酸序列RYNAPFK(SEQ ID NO:4)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
6.17.实施例17-含有LKLPPIV(SEQ ID NO:5)的rAAV衣壳的构建
图15A描绘在VR-VIII的Q588与A589之间包含具有氨基酸序列LKLPPIV(SEQ IDNO:5)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图15B描绘在VR-III的S268与S269之间包含具有氨基酸序列LKLPPIV(SEQ ID NO:5)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图15C描绘在VR-IV的S454与G455之间包含具有氨基酸序列LKLPPIV(SEQ ID NO:5)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
6.18.实施例18-含有PFIKPFE(SEQ ID NO:6)的rAAV衣壳的构建
图16A描绘在VR-VIII的Q588与A589之间包含具有氨基酸序列PFIKPFE(SEQ IDNO:6)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图16B描绘在VR-III的S268与S269之间包含具有氨基酸序列PFIKPFE(SEQ ID NO:6)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图16C描绘在VR-IV的S454与G455之间包含具有氨基酸序列PFIKPFE(SEQ ID NO:6)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
6.19.实施例19-含有TLSLPWK(SEQ ID NO:7)的rAAV衣壳的构建
图17A描绘在VR-VIII的Q588与A589之间包含具有氨基酸序列TLSLPWK(SEQ IDNO:7)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图17B描绘在VR-III的S268与S269之间包含具有氨基酸序列TLSLPWK(SEQ ID NO:7)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
图17C描绘在VR-IV的S454与G455之间包含具有氨基酸序列TLSLPWK(SEQ ID NO:7)的肽插入物的重组AAV9载体衣壳的氨基酸序列。所插入肽以粗体表示。
6.20.实施例20-含有LGETTRP(SEQ ID NO:15)的rAAV衣壳的构建
图18A描绘在VR-VIII的N590与T591之间包含具有氨基酸序列LGETTRP(SEQ IDNO:15)的肽插入物的重组AAV8载体衣壳的氨基酸序列。所插入肽以粗体表示。
图18B描绘在VR-III的A269与T270之间包含具有氨基酸序列LGETTRP(SEQ ID NO:15)的肽插入物的重组AAV8载体衣壳的氨基酸序列。所插入肽以粗体表示。
图18C描绘在VR-IV的T453与T454之间包含具有氨基酸序列LGETTRP(SEQ ID NO:15)的肽插入物的重组AAV8载体衣壳的氨基酸序列。所插入肽以粗体表示。
6.21.实施例21-含有LALGETTRP(SEQ ID NO:16)的rAAV衣壳的构建
图19A描绘在VR-VIII的N590与T591之间包含具有氨基酸序列LALGETTRP(SEQ IDNO:16)的肽插入物的重组AAV8载体衣壳的氨基酸序列。所插入肽以粗体表示。
图19B描绘在VR-III的A269与T270之间包含具有氨基酸序列LALGETTRP(SEQ IDNO:16)的肽插入物的重组AAV8载体衣壳的氨基酸序列。所插入肽以粗体表示。
图19C描绘在VR-IV的T453与T454之间包含具有氨基酸序列LALGETTRP(SEQ IDNO:16)的肽插入物的重组AAV8载体衣壳的氨基酸序列。所插入肽以粗体表示。
6.22.实施例22:经修饰衣壳的体外和体内评估
通过肽插入或引导诱变来修饰AAV衣壳序列且加以汇集以得到与GFP表达盒包装至一起的条形码化库。然后在体外测定中评估经修饰载体，并且在小鼠中使用下一代测序(NGS)和定量PCR来评价体内生物分布。将AAV.hDyn鉴定为此池中的高脑转导载体且在小鼠中于个别递送研究中进一步评估以表征其转导特征。另外，对脑切片实施免疫组织化学分析以理解此载体的细胞嗜性。
6.22.1实施例22A-穿越血脑屏障的转导的体外测试
在体外transwell测定中使用hCMEC/D3 BBB细胞(SCC066,Mi llipore-Sigma)来测试经修饰衣壳穿越血脑屏障的能力(参见图20A-20B)。更具体而言，所述测定基本上改编自Sade,H.等人(2014PLoS ONE 9(4):e96340)A human Blood-Brain Barriertranscytosis assayreveals Antibody Transcytosis influenced by pH-dependentReceptorBinding，2014年4月，第9卷，第4期；和Zhang,X.,Blood-brai n barrier shuttlepeptides enhance AAV transduction in the brain aft er systemicadministration,2018Biomaterials 176:71-83。简言之，将5×104个hCMEC/D3细胞/cm2接种于12孔板中的胶原包被的trans well插件中。每一插件含有500μL培养基且下室含有1mL培养基。每隔一天更换培养基。在接种后10天(零(0)时间点)去除上清液。在此0时间点下，通过将1×109GC载体添加至上插入室培养基中来转导细胞。在转导后以间隔0.5、3、6和23小时取出10μL下室上清液样品以供测试。一式两份测试每一条件(载体)，并且经由qPCR针对聚A一式三份测量效价。
图20A-20B描绘AAV.hDyn(在氨基酸残基588-589之间具有TLAAPFK(SEQ ID NO:2)的AAV9)穿越血脑屏障(BBB)细胞层的体外transwell测定(图20A)；且结果展示，AAV.hDyn(由图中的倒三角形指示)穿越测定的BBB细胞层的速度快于AAV9(正方形)且在更大程度上快于AAV2(圆圈)(图20B)。所研发体外测定预测了增强的BBB穿越输送且还可使用类似测定来预测至其他器官的靶向。
6.22.2实施例22B-经修饰衣壳的转导和生物分布
6.22.2.1材料和方法
通过在以下位置插入各种肽序列来对广泛使用的AAV衣壳(包含AAV8、AAV9和AAVrh.10)实施衣壳修饰：在VR-IV的位置S454之后(表7)，或在AAV衣壳的VR-VIII表面暴露环的位置Q588之后，以及插入VP2的起始密码子(其始于氨基酸137(AAV4、AAV4-4和AAV5)或氨基酸138(AAV1、AAV2、AAV3、AAV3-3、AAV6、AAV7、AAV8、AAV9、AAV9e、rh.10、rh.20、rh.39、rh.74和hu.37))之后(图8)(某些衣壳序列还参见表10)。还使用所选单一至多个氨基酸突变来修饰衣壳。还参见Yost等人,Structure-guided engineering of surface exposedloops on AAV Capsids.2019ASGCT Annual Meeting；和Wu等人,2000J.Virology(同上)。据证实，在小规模进行这些衣壳修饰中的任一者后，包装效率并无负面影响。
在体外于Lec2细胞中测试具有某些经修饰衣壳的rAAV的转导，如上文在实施例5中所阐述。在Lec2细胞中测试转导的经修饰AAV如下：eB 588Ad、eB 588Hep、eB 588p79、eB588Rab、AAV9 588Ad、AAV9 588Hep、AAV9 588p79、AAV9 588Rab、eB VP2 Ad、eB VP2 Hep、eBVP2 p79、eB VP2 Rab、AAV9 VP2 Ad、AAV9 VP2Hep、AAV9 VP2 p79、AAV9 VP2 Rab(与AAV9相比)。关于AAV衣壳的同一性，参见下文表7B。
为测试生物分布，将经修饰AAV与含有对应于每一个别衣壳的特定条形码的eGFP转基因盒包装至一起。汇集新颖条形码化载体且注射至小鼠中以增加筛选效率。
为分析基因改变的AAV载体的生物分布，制备各种编码GFP的载体且配制于1×PBS+0.0001％普罗尼克酸中。使用含有十(10)个bp条形码的顺式质粒制备所有载体以使得能够获得下一代测序(NGS)库(池)制剂。根据表7A-C，将三(3)个载体池(研究1、研究2和研究3载体)静脉内注射至5只雌性C57Bl/6小鼠的小组中。每一研究的给药体积为10mL/kg(0.2mL/20g小鼠)。
基于第1天体重将小鼠随机化至治疗组中且其在开始日期的年龄为8至12周。在施用后第15天，对动物实施安乐死且收集周边组织(包含脑、肾、肝、坐骨神经、肺、心脏和肌肉组织)。在单独注射来自池的所选衣壳的研究中，遵循相同方案。
使用来自Qiagen的Dneasy血液和组织试剂盒(69506)从组织样品分离基因组DNA(gDNA)。使用如由制造商(Illumina)所推荐含有用于NGS以及独特双重索引(UDI)和多重测序策略的重叠的引物来扩增每一载体的条形码区域。使用利用试剂nano和micro试剂盒v2(MS-103-1001/1002)的Illumina MiSeq来测定从小鼠收集的每一样品中每一条形码化AAV载体的相对丰度。因此，如上所述将下文表7A-C中的每一载体样品条形码化以允许鉴别每一读数且在最终数据分析之前加以分选。基于原始注射池中的AAV组成将数据归一化，并且使用从qPCR分析获得的总基因组拷贝数利用对条形码化样品具有特异性的引物-探针组合进行量化。
表7A
表7B
表7C
在单独注射来自池的所选衣壳的研究中，使用qPCR测定每μg组织基因组DNA中的载体基因组数量。在QuantStudio 5(Life Technologies,Inc.)使用对eGFP具有特异性的引物-探针组合遵循标准曲线方法来进行qPCR(图22)。
在将单独载体注射至小鼠中以供表征的研究中，将福尔马林(formalin)固定的小鼠脑在振动刀片切片机(VT1000S,Leica)上以40μm厚度切片且使用针对GFP的抗体探测浮动切片以查看所递送载体的细胞分布。
更具体而言，使用Vibratome(Leica,VT-1000)将来自注射AAV.hDyn的小鼠的固定脑切片，并且使用抗GFP抗体(AB3080,Millipore Sigma)、Vectastain ABC试剂盒(PK-6100,Vector Labs)和DAB过氧化物酶试剂盒(SK-4100,Vector Labs)评估GFP表达。GFP表达细胞广泛分布于注射AAV.hDyn的小鼠的整个脑中，包含分布于脑的皮质、纹状体和海马体中。图23A-23C展示来自这些区域的图像且比例尺为400um(论述于下文中)。
6.22.2.2结果
结果展示于图21、图22A-22H和图23A-23C中。
未展示Lec2细胞转导测定的数据。AAV9 588Hep(在位置588之后插入肽TILSRSTQTG(SEQ ID NO:22)(表1b中的DLC-AS2)的AAV9)所展现的转导显著大于(4倍)野生型AAV9，并且AAV9 VP2 Ad(在位置138之后插入肽SITLVKSTQTV(SEQ ID NO:21)(表1b中的DLC-AS1)的AAV9)、AAV9 VP2 Hep(在位置138之后插入肽TILSRSTQTG(SEQ ID NO:22)(表1b中的DLC-AS2)的AAV9)和AAV9 VP2 Rab(在位置138之后插入肽RSSEEDKSTQTT(SEQ ID NO:26)(表1b中的DLC-AS4)的AAV9)所展现的Lec2细胞转导略大于AAV9。所测定的其他AAV展现低于AAV9的转导水平。
图21描绘脑gDNA的下一代测序(NGS)分析的结果，其公开在静脉内注射后递送至小鼠脑的衣壳池的相对丰度(组成百分比)。基于原始注射池中的AAV组成将数据归一化，并且使用从qPCR分析获得的总基因组拷贝数利用对eGFP序列具有特异性的引物-探针组合进行量化。所展示数据来自三个不同实验。虚线指示汇集至一起的载体。使用亲代AAV9作为标准品且包含于每一池中。“BC”标识符如上文表7A、7B和7C中所指示。
图22A-22H描绘雌性C57Bl/6小鼠中的AAV.hDyn的体内转导特征，其展示初次接受试验的小鼠或在脑(图22A)、肝(图22B)、心脏(图22C)、肺(图22D)、肾(图22E)、骨骼肌(图22F)、坐骨神经(图22G)和卵巢(图22H)中注射AAV9或AAV.hDyn的小鼠中的拷贝数/微克gDNA，其中AAV.hDyn与AAV9相比展示增加的脑生物分布。在施用AAV.hDyn的小鼠中，每μg脑基因组DNA中的AAV载体基因组拷贝至少高于亲代AAV9载体一个对数。
图23A-23C展示上述免疫组织化学分析中所分析的区域的图像；比例尺为400μm。图23A-23C描绘整个脑中来自AAV.hDyn的GFP分布，其中来自纹状体(图23A)、海马体(图23B)和皮质(图23C)的脑切片的免疫组织化学染色的图像公开了通过经修饰载体实现的整体性脑转导。
6.22.2.3结论
通过VR-IV和VR-VIII的表面暴露环中的插入物或通过特定氨基酸突变所实施的AAV衣壳修饰并不影响其包装效率且能够在本文所述的产生系统中产生类似效价。
与所测试的其他经修饰AAV载体和AAV9相比，向小鼠静脉内施用AAV.hDyn产生较高的病毒基因组相对丰度和较大脑细胞转导。
6.23.实施例23-归巢肽肾1C在全身性递送后显示增强的转导
通过肽插入来修饰AAV衣壳序列且加以汇集以得到与GFP表达盒包装至一起的条形码化库。然后在小鼠中使用下一代测序(NGS)和定量PCR体内评估经修饰AAV9载体的生物分布特征。在VR-IV的S454与G455之间包含具有氨基酸序列CLPVASC(SEQ ID NO:12)(肾1C)或ASSLNIA(SEQ ID NO:14)(肌肉1)的肽插入物的重组AAV9载体展示增加的肾转导效率(与肝相比)(图24)。
6.23.1材料和方法
通过将各种归巢肽序列插入AAV衣壳的VR-IV表面暴露环的位置S454之后来对AAV9实施衣壳修饰。据证实，在小规模进行所述衣壳修饰中的任一者后，包装效率并无负面影响。肽序列展示于下文的表8中。将所有经修饰AAV与含有对应于每一个别衣壳的特定条形码的eGFP转基因盒包装至一起。汇集所述新颖条形码化载体以增加筛选效率(如上文在实施例22B中所阐释；参见研究3，表7C)。
将经遗传改变的AAV载体静脉内注射至小鼠中，如上文在实施例22B中针对研究3的经改变载体所阐释。基于原始注射池中的AAV组成将数据归一化并使用从qPCR分析获得的总基因组拷贝数利用对eGFP序列具有特异性的引物-探针组合进行量化，并且更仔细地检验肾至肝组织靶向。
6.23.2结果和结论
图24描绘具有不同归巢肽插入物(表8)的AAV9 S454载体在雌性C57Bl/6小鼠中的肾/肝体内转导比。使用肾/肝转导与经修饰衣壳池的总肾转导进行计算。AAV9 S454肾1和AAV9 S454肾2(肾1C)所展示的肾生物分布大于亲代AAV9。尽管亲代AAV9载体所展示的肝转导大于肾(比率为约0.25)，但插入肾归巢肽1C(以及还有肌肉1)使得此比率增至约1.0。在施用AAV9 S454肾1或AAV9 S454肌肉1的小鼠中，每μg肾gDNA中的AAV载体基因组拷贝高于所有其他AAV9 S454载体至少5倍(参见图24)。
表8.生物分布研究中所使用的归巢肽
通过在VR-IV表面暴露环中插入不同归巢肽来实施的AAV衣壳修饰并不影响其包装效率且能够在本文所述的产生系统中产生类似效价。
较其他经修饰AAV9载体和所测试亲代AAV9载体，向小鼠静脉内施用AAV9 S454肾1和AAV9 S454肾1C产生较高的病毒基因组相对丰度和较大肾细胞转导。向小鼠静脉内施用AAV9 S454肾1或AAV9 S454肌肉1载体还产生较低肝细胞转导。
6.24.实施例24-含有TLAVPFK(SEQ ID NO:27)的rAAV衣壳的构建
图25描绘在VR-IV的S454与G455之间包含具有氨基酸序列TLAVPFK(SEQ ID NO:27)的肽插入物的重组AAV9载体衣壳的氨基酸序列。
6.25.实施例25-rAAV载体池在食蟹猴中的生物分布
在食蟹猴中进行单一静脉内、大脑心室内或玻璃体内注射后，评估具有经工程改造衣壳和GFP转基因的重组AAV的池的施用、体内和死亡后观察以及生物分布(表9)。所述池含有多个衣壳，每一衣壳含有允许在施用食蟹猴后使用下一代测序(NGS)分析进行鉴别的独特条形码标识符。选择食蟹猴作为测试系统，这是因为已确立其可用于且可接受作为用于大型动物物种中的AAV生物分布研究并进一步转用于人的模型。此研究中的所有动物都未使用先前治疗进行治疗。所述池可至少包括表9中所列示的具有经工程改造衣壳的下列重组AAV。
表9.用于食蟹猴研究的重组AAV
6.25.1.研究设计
使用9只雌性食蟹猴动物。根据体重使用计算机生成的随机数将基于临床体征数据和预筛选抗体效价判断为适用于实验的动物置于研究组中。使用三个不同施用途径且收集相关组织以评估与不同途径有关的生物分布(通过NGS和PCR测量)。向三只动物的左侧心室中植入导管以供大脑心室内(ICV)剂量施用(组1)，三只动物接受单一静脉内输注(组2)且三只动物接受单一玻璃体内注射(组3)。两只动物用作代替动物且根据需要实施植入。组1中的动物将进行MRI扫描以确定适当放置ICV导管的坐标。
以3mL/min的速率施用静脉内输注，随后施用0.2mL媒介物以从静脉内导管冲洗剂量。三只静脉内动物将以4mL/kg的体积接受单一剂量的经汇集重组AAV。总剂量(vg)和剂量体积(mL/kg)记录于原始数据中。基于文献综述和在非人灵长类动物中的先前研究，经确定需要1×1013GC/kg体重的IV剂量以从全身性递送在CNS以及周边组织(包含骨骼肌)中获得所需分布。
ICV植入动物将以1mL的体积接受单一浓注剂量的AAV-NAV-GFPbc(通过缓慢输注，大约0.1mL/min)，随后施用0.1mL媒介物以从导管系统冲洗剂量。ICV剂量是基于来自先前非人灵长类动物研究的分布数据以支持当前临床程序。
在50μL的剂量体积下以浓注形式双侧性施用玻璃体内(IVT)注射。
6.25.2.观察结果和检验
从开始给药之前大约两周开始每天记录临床体征至少一次且持续于整个研究期中。观察动物的临床效应、疾病和/或死亡的体征。可基于动物状况在研究主管和/或技师的判断下来记录其他观察结果。
在剂量施用之前和在第2、8、15和22天对第3组动物实施眼科检验。使用肌内氯胺酮(ketamine)盐酸盐使所有动物镇静以在第1天后实施眼科检验。为在第1天进行检验，使用可注射麻醉剂使动物镇静(参照部分15.3.3)。在检验之前，使用1％托吡卡胺(tropicamide)使眼睛放大。所述检验将包含裂隙灯活组织检视法和间接检眼镜检查。另外，在给药之前、在剂量施用后即刻(约10至15分钟)和在第2和22天对第3组动物实施压平眼压测量法。
在剂量施用之前大约2至3周，从周边静脉收集血液样品(约3mL)以供中和抗体分析。
6.25.3.生物分析样品收集
在剂量施用之前、在剂量施用后3(±10分钟)、6(±10分钟)和24(±0.5小时)小时来，从仅第2组动物(IV)的周边静脉收集全血液样品品(约0.5mL)以供生物分析(AAV衣壳清除)。使用注射器和针收集样品，转移至两个K2 EDTA管中并记录时间。
在剂量施用之前(第1天)、在第8和15天和在尸体剖检之前(第22天)，从禁食动物的周边静脉收集血液样品(约5mL)以供PBMC分析。使用锂肝素管获得样品且记录时间。
在剂量施用(第1天，2mL)和尸体剖检(第22天，5mL)之前，从周边静脉收集血液样品以供生物分析。将样品收集于凝结管中且记录时间。将管维持于室温下直至完全凝结，然后在室温下以大约2400rpm离心15分钟。收获血清，置于经标记小瓶(将尸体剖检样品分成1mL等分样品)中，冷冻于液氮中，并且储存于-60℃或更低温度下。
在剂量施用之前从仅第1组动物的小脑延髓池脊髓穿刺物收集CSF(约1.5mL)。在尸体剖检之前即刻从所有动物(组1-3)的小脑延髓池脊髓穿刺物收集CSF(约2mL)。尝试收集CSF，但因脊髓穿刺不成功，因此可能无法在所有间隔下从动物收集样品。在收集后，将样品储存于冰上直至处理。
6.25.4.尸体剖检
在治疗至少21天后(第22天)，对发现死亡或垂死处死和计划尸体剖检的任一动物实施肉眼尸体剖检。使用8mg/kg氯胺酮HCl(肌内)使所有动物(发现死亡者除外)镇静，维持于异氟醚/氧混合物上且提供200IU/kg肝素钠的静脉内浓注。经由左心室向动物灌注于盐水中的0.001％亚硝酸钠。对发现死亡的动物进行尸体剖检，但并不实施灌注。
从所有动物(包括发现死亡者)保存下列组织：骨髓、脑、盲肠、结肠、背侧神经根和神经节、十二指肠、食管、具有视神经的眼睛、肉眼病灶、心脏、回肠、空肠、肾、膝关节、肝、具有支气管的肺、淋巴结、卵巢、胰腺、坐骨神经、骨骼肌、脊髓、脾、甲状腺、气管和迷走神经。
6.25.5.生物分析
通过qPCR和下一代测序(NGS)评估从第2组(IV)动物收集的全血。
如果需要，则通过流式细胞术和酶联免疫吸附斑点(ELISpot)评估从所有动物收集的PBMC样品。
根据需要，通过ELISA和基于细胞的测定来评估血清和/或CSF中循环中和抗体以及游离载体的存在。
通过定量PCR和NGS方法检验组织中的载体拷贝数和转录物数量。
6.26.衣壳氨基酸序列
表10提供本文所述研究中所阐述和/或使用的某些经工程改造衣壳蛋白的氨基酸序列。以灰色阴影指示异源肽和氨基酸取代。
表10.衣壳氨基酸序列
7.等效物
尽管参考具体实施方案详细阐述了本发明，但应理解，功能等效的变化在本发明范围内。实际上，除本文中所展示和阐述的修改外，本领域技术人员依据前述说明和附图还将明了本发明的各种修改。此类修改意图属于随附权利要求的范围内。本领域技术人员仅使用常规实验将认识到或能够确定本文所述本发明的具体实施方案的许多等效物。此类等效物意图涵盖于下文权利要求内。
本说明书中所提及的所有公布、专利和专利申请都以引用的方式并入本文的说明书中，其并入程度如同明确地且单独地指出将每一个别公布、专利或专利申请的全部内容以引用的方式并入一般。
本文的论述提供所述技术所面临问题的本质的更佳理解且不应以任何方式解释为对现有技术的承认，还不应将本文任何参考文献的引用解释为承认所述参考文献构成本发明的“现有技术”。
本文所引用的所有参考文献(包含专利申请和公布)的全部内容都以引用的方式并入本文中且出于所有目的，其并入程度如同出于所有目的特定地且个别地指示将每一个别公布或专利或专利申请的全部内容以引用的方式并入一般。本领域技术人员应明了，可在不背离本发明的精神和范围的情况下对本发明作出多种修改和变化。本文所述的具体实施方案仅以实例方式提供，并且本发明仅受限于各项随附权利要求以及所述权利要求所授权的等效物的全部范围。
序列表
<110> 再生生物股份有限公司(REGENXBIO INC.)
<120> 重组腺相关病毒及其用途
<130> 38013.0002P1
<140>
<141>
<150> 62/963,512
<151> 2020-01-20
<150> 62/924,107
<151> 2019-10-21
<150> 62/839,368
<151> 2019-04-26
<150> 62/833,516
<151> 2019-04-12
<150> 62/829,608
<151> 2019-04-04
<160> 152
<170> PatentIn version 3.5
<210> 1
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 1
Lys Met Gln Val Pro Phe Gln
1 5
<210> 2
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 2
Thr Leu Ala Ala Pro Phe Lys
1 5
<210> 3
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 3
Gln Gln Ala Ala Pro Ser Phe
1 5
<210> 4
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 4
Arg Tyr Asn Ala Pro Phe Lys
1 5
<210> 5
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 5
Leu Lys Leu Pro Pro Ile Val
1 5
<210> 6
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 6
Pro Phe Ile Lys Pro Phe Glu
1 5
<210> 7
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 7
Thr Leu Ser Leu Pro Trp Lys
1 5
<210> 8
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 8
Gln Glu Gln Leu Glu Arg Ala Leu Asn Ser Ser
1 5 10
<210> 9
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 9
Asp Asp Asp Asp Asp Asp Asp Asp
1 5
<210> 10
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 10
Leu Ser Ser Arg Leu Asp Ala
1 5
<210> 11
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 11
Cys Leu Ser Ser Arg Leu Asp Ala Cys
1 5
<210> 12
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 12
Cys Leu Pro Val Ala Ser Cys
1 5
<210> 13
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 13
Leu Pro Val Ala Ser
1 5
<210> 14
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 14
Ala Ser Ser Leu Asn Ile Ala
1 5
<210> 15
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 15
Leu Gly Glu Thr Thr Arg Pro
1 5
<210> 16
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 16
Leu Ala Leu Gly Glu Thr Thr Arg Pro
1 5
<210> 17
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 17
His Ala Ile Tyr Pro Arg His
1 5
<210> 18
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 18
Thr His Arg Pro Pro Met Trp Ser Pro Val Trp Pro
1 5 10
<210> 19
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 19
Arg Thr Ile Gly Pro Ser Val
1 5
<210> 20
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 20
Cys Arg Thr Ile Gly Pro Ser Val Cys
1 5
<210> 21
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 21
Ser Ile Thr Leu Val Lys Ser Thr Gln Thr Val
1 5 10
<210> 22
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 22
Thr Ile Leu Ser Arg Ser Thr Gln Thr Gly
1 5 10
<210> 23
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 23
Gln Ala Val Arg Thr Ser Leu
1 5
<210> 24
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 24
Gln Ala Val Arg Thr Ser His
1 5
<210> 25
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 25
Val Val Met Val Gly Glu Lys Pro Ile Thr Ile Thr Gln His Ser Val
1 5 10 15
Glu Thr Glu Gly
20
<210> 26
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 26
Arg Ser Ser Glu Glu Asp Lys Ser Thr Gln Thr Thr
1 5 10
<210> 27
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 27
Thr Leu Ala Val Pro Phe Lys
1 5
<210> 28
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 28
Ser Ile Gly Tyr Pro Leu Pro
1 5
<210> 29
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 29
Cys Asp Cys Arg Gly Asp Cys Phe Cys
1 5
<210> 30
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 30
Asn Gly Arg Ala His Ala
1 5
<210> 31
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 31
Cys Gly Phe Glu Arg Val Arg Gln Cys Pro Glu Arg Cys
1 5 10
<210> 32
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 32
Cys Gly Phe Glu Leu Glu Thr Cys
1 5
<210> 33
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 33
Cys Val Ala Leu Cys Arg Glu Ala Cys Gly Glu Gly Cys
1 5 10
<210> 34
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 34
Ser Trp Cys Glu Pro Gly Trp Cys Arg
1 5
<210> 35
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 35
Tyr Ser Gly Lys Trp Gly Trp
1 5
<210> 36
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 36
Gly Ser Leu Gly Gly Arg Ser
1 5
<210> 37
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 37
Leu Met Leu Pro Arg Ala Asp
1 5
<210> 38
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 38
Cys Lys Cys Cys Arg Ala Lys Asp Cys
1 5
<210> 39
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 39
Ser Met Ser Ile Ala Arg Leu
1 5
<210> 40
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 40
Cys Arg Pro Pro Arg
1 5
<210> 41
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 41
Cys Lys Arg Ala Val Arg
1 5
<210> 42
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 42
Cys Pro Lys Thr Arg Arg Val Pro Cys
1 5
<210> 43
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 43
Cys Arg Ser Thr Arg Ala Asn Pro Cys
1 5
<210> 44
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 44
Cys Ala Arg Pro Ala Arg
1 5
<210> 45
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 45
Cys Pro Gly Pro Glu Gly Ala Gly Cys
1 5
<210> 46
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 46
Lys Ser Thr Glu Asp Lys Ser Thr Gln Thr Pro
1 5 10
<210> 47
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 47
Leu Gly His Phe Thr Arg Ser Thr Gln Thr Ser
1 5 10
<210> 48
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 48
Gly Val Gln Met Ala Lys Ser Thr Gln Thr Phe
1 5 10
<210> 49
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 49
Pro Lys Thr Arg Asn Ser Gln Thr Gln Thr Asp
1 5 10
<210> 50
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 50
Val Thr Thr Gln Asn Thr Ala Ser Gln Thr Met
1 5 10
<210> 51
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 51
Lys Ser Ser Gln Asp Lys Ser Thr Gln Thr Thr Gly Asp
1 5 10
<210> 52
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 52
Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
<210> 53
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 53
Thr Leu Ala Gly Pro Phe Lys
1 5
<210> 54
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 54
Cys Ile Thr Leu Val Lys Ser Thr Gln Thr Val
1 5 10
<210> 55
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 55
Ser Thr Gln Thr
1
<210> 56
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 56
Lys Ser Thr Gln Thr
1 5
<210> 57
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 57
Asp Asp Asp Asp Asp Asp
1 5
<210> 58
<211> 6
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 58
Gln Ala Gln Ala Gln Thr
1 5
<210> 59
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
肽
<400> 59
His Ala Ile Tyr Pro Arg
1 5
<210> 60
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 60
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Gln Ala Val Arg
580 585 590
Thr Ser Leu Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 61
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 61
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Gln Ala Val Arg
580 585 590
Thr Ser His Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 62
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 62
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Thr Leu Ala Val
580 585 590
Pro Phe Lys Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 63
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 63
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Asp Gly Thr Leu Ala Val
580 585 590
Pro Phe Lys Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 64
<211> 738
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 64
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 65
<211> 738
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 65
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
Gln Ala Ala Ala Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 66
<211> 736
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 66
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp Asn
260 265 270
Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 67
<211> 736
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 67
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp Asn
260 265 270
Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Ala
485 490 495
Ala Ala Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 68
<211> 738
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 68
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Gln Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Ala Ala Ala Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala
580 585 590
Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Asp
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 69
<211> 736
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 69
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Ala
485 490 495
Ala Ala Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 70
<211> 736
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 70
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Ala
485 490 495
Ala Ala Ser Glu Phe Ala Arg Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 71
<211> 736
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 71
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Arg Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 72
<211> 736
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 72
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Ala Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 73
<211> 744
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 73
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Asp Asp Asp Asp Asp Asp Asp Asp Gly Gln
450 455 460
Asn Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala
465 470 475 480
Val Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg
485 490 495
Val Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro
500 505 510
Gly Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro
515 520 525
Gly Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro
530 535 540
Leu Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn
545 550 555 560
Val Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr
565 570 575
Thr Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His
580 585 590
Gln Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly
595 600 605
Ile Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly
610 615 620
Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser
625 630 635 640
Pro Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu
645 650 655
Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys
660 665 670
Asp Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser
675 680 685
Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn
690 695 700
Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu
705 710 715 720
Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly
725 730 735
Thr Arg Tyr Leu Thr Arg Asn Leu
740
<210> 74
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 74
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Leu Ser Ser Arg Leu Asp Ala Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 75
<211> 745
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 75
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Cys Leu Ser Ser Arg Leu Asp Ala Cys Gly
450 455 460
Gln Asn Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met
465 470 475 480
Ala Val Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln
485 490 495
Arg Val Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp
500 505 510
Pro Gly Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn
515 520 525
Pro Gly Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe
530 535 540
Pro Leu Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp
545 550 555 560
Asn Val Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys
565 570 575
Thr Thr Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn
580 585 590
His Gln Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln
595 600 605
Gly Ile Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn
660 665 670
Lys Asp Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val
705 710 715 720
Glu Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 76
<211> 741
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 76
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Leu Pro Val Ala Ser Gly Gln Asn Gln Gln
450 455 460
Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly
465 470 475 480
Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr
485 490 495
Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser
500 505 510
Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala
515 520 525
Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly
530 535 540
Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala
545 550 555 560
Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro
565 570 575
Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala
580 585 590
Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro
595 600 605
Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp
610 615 620
Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met
625 630 635 640
Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn
645 650 655
Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu
660 665 670
Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile
675 680 685
Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile
690 695 700
Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val
705 710 715 720
Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr
725 730 735
Leu Thr Arg Asn Leu
740
<210> 77
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 77
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Cys Leu Pro Val Ala Ser Cys Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 78
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 78
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Ala Ser Ser Leu Asn Ile Ala Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 79
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 79
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser His Ala Ile Tyr Pro Arg His Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 80
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 80
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Arg Thr Ile Gly Pro Ser Val Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 81
<211> 745
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 81
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Cys Arg Thr Ile Gly Pro Ser Val Cys Gly
450 455 460
Gln Asn Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met
465 470 475 480
Ala Val Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln
485 490 495
Arg Val Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp
500 505 510
Pro Gly Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn
515 520 525
Pro Gly Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe
530 535 540
Pro Leu Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp
545 550 555 560
Asn Val Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys
565 570 575
Thr Thr Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn
580 585 590
His Gln Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln
595 600 605
Gly Ile Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn
660 665 670
Lys Asp Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val
705 710 715 720
Glu Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 82
<211> 747
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 82
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Ile Thr Leu Val Lys Ser Thr Gln Thr Val Ser Glu Phe
500 505 510
Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu
515 520 525
Met Asn Pro Gly Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg
530 535 540
Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly
545 550 555 560
Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu
565 570 575
Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala
580 585 590
Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln
595 600 605
Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr
610 615 620
Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe
625 630 635 640
His Pro Ser Pro Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro
645 650 655
Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala
660 665 670
Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly
675 680 685
Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys
690 695 700
Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn
705 710 715 720
Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg
725 730 735
Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 83
<211> 746
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 83
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Thr Ile Leu Ser Arg Ser Thr Gln Thr Gly Ser Glu Phe Ala
500 505 510
Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met
515 520 525
Asn Pro Gly Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe
530 535 540
Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg
545 550 555 560
Asp Asn Val Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile
565 570 575
Lys Thr Thr Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr
580 585 590
Asn His Gln Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn
595 600 605
Gln Gly Ile Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu
610 615 620
Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His
625 630 635 640
Pro Ser Pro Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln
645 650 655
Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe
660 665 670
Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln
675 680 685
Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg
690 695 700
Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn
705 710 715 720
Val Glu Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro
725 730 735
Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 84
<211> 753
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 84
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Thr Ile Leu Ser Arg Ser
130 135 140
Thr Gln Thr Gly Ala Pro Gly Lys Lys Arg Pro Val Glu Gln Ser Pro
145 150 155 160
Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly Lys Ser Gly Ala Gln Pro
165 170 175
Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr Gly Asp Thr Glu Ser Val
180 185 190
Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro Ala Ala Pro Ser Gly Val
195 200 205
Gly Ser Leu Thr Met Ala Ser Gly Gly Gly Ala Pro Val Ala Asp Asn
210 215 220
Asn Glu Gly Ala Asp Gly Val Gly Ser Ser Ser Gly Asn Trp His Cys
225 230 235 240
Asp Ser Gln Trp Leu Gly Asp Arg Val Ile Thr Thr Ser Thr Arg Thr
245 250 255
Trp Ala Leu Pro Thr Tyr Asn Asn His Leu Tyr Lys Gln Ile Ser Asn
260 265 270
Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser
275 280 285
Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser
290 295 300
Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro
305 310 315 320
Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr
325 330 335
Asp Asn Asn Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val
340 345 350
Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser
355 360 365
Ala His Glu Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile
370 375 380
Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly
385 390 395 400
Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg
405 410 415
Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe
420 425 430
His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro
435 440 445
Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Ile Asn Gly Ser
450 455 460
Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn
465 470 475 480
Met Ala Val Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln
485 490 495
Gln Arg Val Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala
500 505 510
Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met
515 520 525
Asn Pro Gly Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe
530 535 540
Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg
545 550 555 560
Asp Asn Val Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile
565 570 575
Lys Thr Thr Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr
580 585 590
Asn His Gln Ser Asp Gly Thr Leu Ala Val Pro Phe Lys Ala Gln Ala
595 600 605
Gln Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp
610 615 620
Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro
625 630 635 640
His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly
645 650 655
Met Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro
660 665 670
Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile
675 680 685
Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu
690 695 700
Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser
705 710 715 720
Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly
725 730 735
Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn
740 745 750
Leu
<210> 85
<211> 754
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 85
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ser Ile Thr Leu Val Lys
130 135 140
Ser Thr Gln Thr Val Ala Pro Gly Lys Lys Arg Pro Val Glu Gln Ser
145 150 155 160
Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly Lys Ser Gly Ala Gln
165 170 175
Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr Gly Asp Thr Glu Ser
180 185 190
Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro Ala Ala Pro Ser Gly
195 200 205
Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly Ala Pro Val Ala Asp
210 215 220
Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser Ser Gly Asn Trp His
225 230 235 240
Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile Thr Thr Ser Thr Arg
245 250 255
Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu Tyr Lys Gln Ile Ser
260 265 270
Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn Ala Tyr Phe Gly Tyr
275 280 285
Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe
290 295 300
Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg
305 310 315 320
Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val
325 330 335
Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr
340 345 350
Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly
355 360 365
Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met
370 375 380
Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val
385 390 395 400
Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu
405 410 415
Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro
420 425 430
Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn
435 440 445
Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Ile Asn Gly
450 455 460
Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser
465 470 475 480
Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg
485 490 495
Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe
500 505 510
Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu
515 520 525
Met Asn Pro Gly Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg
530 535 540
Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly
545 550 555 560
Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu
565 570 575
Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala
580 585 590
Thr Asn His Gln Ser Asp Gly Thr Leu Ala Val Pro Phe Lys Ala Gln
595 600 605
Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val
610 615 620
Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
625 630 635 640
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
645 650 655
Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
660 665 670
Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe
675 680 685
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
690 695 700
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
705 710 715 720
Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu
725 730 735
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
740 745 750
Asn Leu
<210> 86
<211> 9
<212> PRT
<213> 未知(Unknown)
<220>
<223> 未知的描述：
血凝素序列
<400> 86
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
1 5
<210> 87
<211> 35
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<220>
<221> MOD_RES
<222> (14)..(14)
<223> Gln、Thr、Asn或Gly
<220>
<221> MOD_RES
<222> (15)..(15)
<223> Asn、Gln或Thr
<220>
<221> MOD_RES
<222> (23)..(23)
<223> Gly、Ala、Leu或Asn
<220>
<221> MOD_RES
<222> (30)..(30)
<223> Val、Asp、Leu、Asn、Glu或Ala
<400> 87
Tyr Tyr Leu Ser Arg Thr Gln Asn Thr Gly Gly Thr Ala Xaa Xaa Gln
1 5 10 15
Thr Leu Leu Phe Ser Gln Xaa Gly Pro Ser Asn Met Ser Xaa Gln Ala
20 25 30
Lys Asn Trp
35
<210> 88
<211> 35
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 88
Tyr Tyr Leu Asn Arg Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn Lys
1 5 10 15
Asp Leu Leu Phe Ser Arg Gly Ser Pro Ala Gly Met Ser Val Gln Pro
20 25 30
Lys Asn Trp
35
<210> 89
<211> 35
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 89
Tyr Tyr Leu Ser Arg Thr Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser
1 5 10 15
Arg Leu Gln Phe Ser Gln Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser
20 25 30
Arg Asn Trp
35
<210> 90
<211> 36
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 90
Tyr Tyr Leu Asn Arg Thr Gln Gly Thr Thr Ser Gly Thr Thr Asn Gln
1 5 10 15
Ser Arg Leu Leu Phe Ser Gln Ala Gly Pro Gln Ser Met Ser Leu Gln
20 25 30
Ala Arg Asn Trp
35
<210> 91
<211> 36
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 91
Trp Gly Leu Gln Ser Thr Thr Thr Gly Thr Thr Leu Asn Ala Gly Thr
1 5 10 15
Ala Thr Thr Asn Phe Thr Lys Leu Arg Pro Thr Asn Phe Ser Asn Phe
20 25 30
Lys Lys Asn Trp
35
<210> 92
<211> 29
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 92
Tyr Arg Phe Val Ser Thr Asn Asn Thr Gly Gly Val Gln Phe Asn Lys
1 5 10 15
Asn Leu Ala Gly Arg Tyr Ala Asn Thr Tyr Lys Asn Trp
20 25
<210> 93
<211> 36
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 93
Tyr Tyr Leu Ala Arg Thr Gln Ser Asn Pro Gly Gly Thr Ala Gly Asn
1 5 10 15
Arg Glu Leu Gln Phe Tyr Gln Gly Gly Pro Ser Thr Met Ala Glu Gln
20 25 30
Ala Lys Asn Trp
35
<210> 94
<211> 35
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 94
Tyr Tyr Leu Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln
1 5 10 15
Thr Leu Gly Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala
20 25 30
Lys Asn Trp
35
<210> 95
<211> 34
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 95
Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr
1 5 10 15
Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg
20 25 30
Asn Tyr
<210> 96
<211> 35
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 96
Tyr Tyr Leu Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln
1 5 10 15
Gln Leu Leu Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala
20 25 30
Lys Asn Trp
35
<210> 97
<211> 1542
<212> PRT
<213> 智人(homo sapiens)
<400> 97
Met Glu Gln Pro Asn Ser Lys Gly Tyr Ser Leu Gly Arg Thr Pro Gln
1 5 10 15
Gly Pro Glu Cys Ser Ser Ala Pro Ala Val Gln Val Gly Thr His Arg
20 25 30
Gly Leu Glu Tyr Asn Pro Gly Lys Ile Leu Pro Gly Ser Asp Tyr Gly
35 40 45
Leu Gly Asn Pro Pro Ala Leu Asp Pro Lys Leu Pro His Leu Pro Leu
50 55 60
Pro Pro Ala Pro Pro Thr Leu Ser Asp Leu Gly Gln Pro Arg Lys Ser
65 70 75 80
Pro Leu Thr Gly Thr Asp Lys Lys Tyr Pro Leu Met Lys Gln Arg Gly
85 90 95
Phe Tyr Ser Asp Ile Leu Ser Pro Gly Thr Leu Asp Gln Leu Gly Glu
100 105 110
Val Cys Arg Gly Pro Arg Met Ser Gln Asn Leu Leu Arg Gln Ala Asp
115 120 125
Leu Asp Lys Phe Thr Pro Arg Val Gly Ser Phe Glu Val Pro Glu Asp
130 135 140
Phe Gln Glu Arg Met Glu Gln Gln Cys Ile Gly Ser Thr Thr Arg Leu
145 150 155 160
Leu Ala Gln Thr Asp Phe Pro Leu Gln Ala Tyr Glu Pro Lys Met Gln
165 170 175
Val Pro Phe Gln Val Leu Pro Gly Gln His Pro Arg Lys Ile Glu Ile
180 185 190
Glu Arg Arg Lys Gln Gln Tyr Leu Ser Leu Asp Ile Glu Gln Leu Leu
195 200 205
Phe Ser Gln Gly Ile Asp Ser Asn Lys Leu Met Pro Arg His Leu Asp
210 215 220
His Gln His Pro Gln Thr Ile Glu Gln Gly His Asp Pro Ile Phe Pro
225 230 235 240
Ile Tyr Leu Pro Leu Lys Val Phe Asp Asn Glu Asp Phe Asp Cys Arg
245 250 255
Thr Pro Arg Glu Trp Ile Asn Met Gly Leu Glu Pro Gly Ser Leu Asp
260 265 270
Arg Lys Pro Val Pro Gly Lys Ala Leu Leu Pro Thr Asp Asp Phe Leu
275 280 285
Gly His Glu Asp Pro Lys Ser Gln Lys Leu Lys Tyr Lys Trp Cys Glu
290 295 300
Val Gly Val Leu Asp Tyr Asp Glu Glu Lys Lys Leu Tyr Leu Val His
305 310 315 320
Lys Thr Asp Glu Lys Gly Leu Val Arg Asp Glu Met Gly Arg Pro Ile
325 330 335
Leu Asn Ala Gly Val Thr Thr Glu Gly Arg Pro Pro Leu Gln Val Cys
340 345 350
Gln Tyr Trp Val Pro Arg Ile Gln Leu Leu Phe Cys Ala Glu Asp Pro
355 360 365
Cys Met Phe Ala Gln Arg Val Val Gln Ala Asn Ala Leu Arg Lys Asn
370 375 380
Thr Glu Ala Leu Leu Leu Tyr Asn Leu Tyr Val Asp Cys Met Pro Ser
385 390 395 400
Asp Gly Gln His Val Ile Ser Glu Gln Ser Leu Ser Lys Ile Lys Gln
405 410 415
Trp Ala Leu Ser Thr Pro Arg Met Arg Lys Gly Pro Ser Val Leu Glu
420 425 430
His Leu Ser Ser Leu Ala Arg Glu Val Ser Leu Asp Tyr Glu Arg Ser
435 440 445
Met Asn Lys Ile Asn Phe Asp His Val Val Ser Ser Lys Pro Glu Thr
450 455 460
Phe Ser Tyr Val Thr Leu Pro Lys Lys Glu Glu Glu Gln Val Pro Glu
465 470 475 480
Arg Gly Leu Val Ser Val Pro Lys Tyr His Phe Trp Glu Gln Lys Glu
485 490 495
Asp Phe Thr Phe Val Ser Leu Leu Thr Arg Pro Glu Val Ile Thr Ala
500 505 510
Leu Ser Lys Val Arg Ala Glu Cys Asn Lys Val Thr Ala Met Ser Leu
515 520 525
Phe His Ser Ser Leu Ser Lys Tyr Ser His Leu Glu Glu Phe Glu Gln
530 535 540
Ile Gln Ser Gln Thr Phe Ser Gln Val Gln Met Phe Leu Lys Asp Ser
545 550 555 560
Trp Ile Ser Ser Leu Lys Val Ala Met Arg Ser Ser Leu Arg Asp Met
565 570 575
Ser Lys Gly Trp Tyr Asn Leu Tyr Glu Thr Asn Trp Glu Val Tyr Leu
580 585 590
Met Ser Lys Leu Arg Lys Leu Met Glu Leu Val Lys Tyr Met Leu Gln
595 600 605
Asp Thr Leu Arg Phe Leu Val Gln Asp Ser Leu Ala Ser Phe Ser Gln
610 615 620
Phe Ile Ser Asp Thr Cys Cys Ser Val Leu Asn Cys Thr Asp Asp Met
625 630 635 640
Val Trp Gly Asp Asp Leu Ile Asn Ser Pro Tyr Arg Pro Arg Lys Asn
645 650 655
Pro Leu Phe Ile Met Asp Leu Val Leu Asp Ser Ser Gly Val His Tyr
660 665 670
Ser Thr Pro Leu Glu Gln Phe Glu Ala Ser Leu Leu Asn Leu Phe Asp
675 680 685
Lys Gly Ile Leu Ala Thr His Ala Val Pro Gln Leu Glu Lys Leu Val
690 695 700
Met Glu Asp Ile Phe Ile Ser Gly Asp Pro Leu Leu Glu Ser Val Gly
705 710 715 720
Leu His Glu Pro Leu Val Glu Glu Leu Arg Ala Thr Ile Ala Ser Ala
725 730 735
Val Ser Lys Ala Met Ile Pro Leu Gln Ala Tyr Ala Lys Glu Tyr Arg
740 745 750
Lys Tyr Leu Glu Leu Asn Asn Asn Asp Ile Ala Ser Phe Leu Lys Thr
755 760 765
Tyr Gln Thr Gln Gly Leu Leu Ala Gln Glu Val Arg Glu Val Val Leu
770 775 780
Thr His Leu Arg Glu Lys Glu Ile Leu Asp Ser Ser Leu Pro Ser Ser
785 790 795 800
Ile Ile Ile Gly Pro Phe Tyr Ile Asn Thr Asp Asn Val Lys Gln Ser
805 810 815
Leu Ser Lys Lys Arg Lys Ala Leu Ala Thr Ser Val Leu Asp Ile Leu
820 825 830
Ala Lys Asn Leu His Lys Glu Val Asp Ser Ile Cys Glu Glu Phe Arg
835 840 845
Ser Ile Ser Arg Lys Ile Tyr Glu Lys Pro Asn Ser Ile Glu Glu Leu
850 855 860
Ala Glu Leu Arg Glu Trp Met Lys Gly Ile Pro Glu Arg Leu Val Gly
865 870 875 880
Leu Glu Glu Arg Ile Val Lys Val Met Asp Asp Tyr Gln Val Met Asp
885 890 895
Glu Phe Leu Tyr Asn Leu Ser Ser Asp Asp Phe Asn Asp Lys Trp Ile
900 905 910
Ala Ser Asn Trp Pro Ser Lys Ile Leu Gly Gln Ile Glu Leu Val Gln
915 920 925
Gln Gln His Val Glu Asp Glu Glu Lys Phe Arg Lys Ile Gln Ile Met
930 935 940
Asp Gln Asn Asn Phe Gln Glu Lys Leu Glu Gly Leu Gln Leu Val Val
945 950 955 960
Ala Gly Phe Ser Ile His Val Glu Ile Ser Arg Ala His Glu Ile Ala
965 970 975
Asn Glu Val Arg Arg Val Lys Lys Gln Leu Lys Asp Cys Gln Gln Leu
980 985 990
Ala Met Leu Tyr Asn Asn Arg Glu Arg Ile Phe Ser Leu Pro Ile Thr
995 1000 1005
Asn Tyr Asp Lys Leu Ser Arg Met Val Lys Glu Phe Gln Pro Tyr
1010 1015 1020
Leu Asp Leu Trp Thr Thr Ala Ser Asp Trp Leu Arg Trp Ser Glu
1025 1030 1035
Ser Trp Met Asn Asp Pro Leu Ser Ala Ile Asp Ala Glu Gln Leu
1040 1045 1050
Glu Lys Asn Val Val Glu Ala Phe Lys Thr Met His Lys Cys Val
1055 1060 1065
Lys Gln Phe Lys Asp Met Pro Ala Cys Gln Glu Val Ala Leu Asp
1070 1075 1080
Ile Arg Ala Arg Ile Glu Glu Phe Lys Pro Tyr Ile Pro Leu Ile
1085 1090 1095
Gln Gly Leu Arg Asn Pro Gly Met Arg Ile Arg His Trp Glu Thr
1100 1105 1110
Leu Ser Asn Gln Ile Asn Ile Asn Val Arg Pro Lys Ala Asn Leu
1115 1120 1125
Thr Phe Ala Arg Cys Leu Glu Met Asn Leu Gln Asp His Ile Glu
1130 1135 1140
Ser Ile Ser Lys Val Ala Glu Val Ala Gly Lys Glu Tyr Ala Ile
1145 1150 1155
Glu Gln Ala Leu Asp Lys Met Glu Lys Glu Trp Ser Thr Ile Leu
1160 1165 1170
Phe Asn Val Leu Pro Tyr Lys Ala Thr Asp Thr Tyr Ile Leu Lys
1175 1180 1185
Ser Pro Asp Glu Ala Ser Gln Leu Leu Asp Asp His Ile Val Met
1190 1195 1200
Thr Gln Asn Met Ser Phe Ser Pro Tyr Lys Lys Pro Phe Glu Gln
1205 1210 1215
Arg Ile Asn Ser Trp Glu Asn Lys Leu Lys Leu Thr Gln Glu Val
1220 1225 1230
Leu Glu Glu Trp Leu Asn Cys Gln Arg Ser Trp Leu Tyr Leu Glu
1235 1240 1245
Pro Ile Phe Ser Ser Glu Asp Ile Asn Gln Gln Leu Pro Val Glu
1250 1255 1260
Ser Lys Arg Tyr Gln Thr Met Glu Arg Ile Trp Lys Lys Ile Met
1265 1270 1275
Lys Asn Ala Tyr Glu Asn Arg Glu Val Ile Asn Val Cys Ser Asp
1280 1285 1290
Leu Arg Met Leu Asp Ser Leu Arg Asp Cys Asn Lys Ile Leu Asp
1295 1300 1305
Leu Val Gln Lys Gly Leu Ser Glu Tyr Leu Glu Thr Lys Arg Ser
1310 1315 1320
Ala Phe Pro Arg Phe Tyr Phe Leu Ser Asp Asp Glu Leu Leu Glu
1325 1330 1335
Ile Leu Ser Gln Thr Lys Asp Pro Thr Ala Val Gln Pro His Leu
1340 1345 1350
Arg Lys Cys Phe Glu Asn Ile Ala Arg Leu Leu Phe Gln Glu Asp
1355 1360 1365
Leu Glu Ile Thr His Met Tyr Ser Ala Glu Gly Glu Glu Val Gln
1370 1375 1380
Leu Cys Phe Ser Ile Tyr Pro Ser Ser Asn Val Glu Asp Trp Leu
1385 1390 1395
Arg Glu Val Glu Arg Ser Met Lys Ala Ser Val His Asp Ile Ile
1400 1405 1410
Glu Lys Ala Ile Arg Ala Tyr Pro Thr Met Pro Arg Thr Gln Trp
1415 1420 1425
Val Leu Asn Trp Pro Gly Gln Val Thr Ile Ala Gly Cys Gln Thr
1430 1435 1440
Tyr Trp Thr Met Glu Val Ala Glu Ala Leu Glu Ala Gly Asn Leu
1445 1450 1455
Arg Ser Gln Leu Phe Pro Gln Leu Cys Gln Gln Leu Ser Asp Leu
1460 1465 1470
Val Ala Leu Val Arg Gly Lys Leu Ser Arg Met Gln Arg Ala Val
1475 1480 1485
Leu Ser Ala Leu Ile Val Ile Glu Val His Ala Lys Asp Val Val
1490 1495 1500
Ser Lys Leu Ile Gln Glu Asn Val Val Ser Val Asn Asp Phe Gln
1505 1510 1515
Trp Ile Ser Gln Leu Arg Tyr Tyr Trp Thr Asn Asn Asp Leu Tyr
1520 1525 1530
Ile Arg Ala Val Asn Ala Glu Phe Ile
1535 1540
<210> 98
<211> 1764
<212> PRT
<213> 智人(homo sapiens)
<400> 98
Met Ser Ser Lys Ala Glu Lys Lys Gln Arg Leu Ser Gly Arg Gly Ser
1 5 10 15
Ser Gln Ala Ser Trp Ser Gly Arg Ala Thr Arg Ala Ala Val Ala Thr
20 25 30
Gln Glu Gln Gly Asn Ala Pro Ala Val Ser Glu Pro Glu Leu Gln Ala
35 40 45
Glu Leu Pro Lys Glu Glu Pro Glu Pro Arg Leu Glu Gly Pro Gln Ala
50 55 60
Gln Ser Glu Glu Ser Val Glu Pro Glu Ala Asp Val Lys Pro Leu Phe
65 70 75 80
Leu Ser Arg Ala Ala Leu Thr Gly Leu Ala Asp Ala Val Trp Thr Gln
85 90 95
Glu His Asp Ala Ile Leu Glu His Phe Ala Gln Asp Pro Thr Glu Ser
100 105 110
Ile Leu Thr Ile Phe Ile Asp Pro Cys Phe Gly Leu Lys Leu Glu Leu
115 120 125
Gly Met Pro Val Gln Thr Gln Asn Gln Leu Val Tyr Phe Ile Arg Gln
130 135 140
Ala Pro Val Pro Ile Thr Trp Glu Asn Phe Glu Ala Thr Val Gln Phe
145 150 155 160
Gly Thr Val Arg Gly Pro Tyr Ile Pro Ala Leu Leu Arg Leu Leu Gly
165 170 175
Gly Val Phe Ala Pro Gln Ile Phe Ala Asn Thr Gly Trp Pro Glu Ser
180 185 190
Ile Arg Asn His Phe Ala Ser His Leu His Lys Phe Leu Ala Cys Leu
195 200 205
Thr Asp Thr Arg Tyr Lys Leu Glu Gly His Thr Val Leu Tyr Ile Pro
210 215 220
Ala Glu Ala Met Asn Met Lys Pro Glu Met Val Ile Lys Asp Lys Glu
225 230 235 240
Leu Val Gln Arg Leu Glu Thr Ser Met Ile His Trp Thr Arg Gln Ile
245 250 255
Lys Glu Met Leu Ser Ala Gln Glu Thr Val Glu Thr Gly Glu Asn Leu
260 265 270
Gly Pro Leu Glu Glu Ile Glu Phe Trp Arg Asn Arg Cys Met Asp Leu
275 280 285
Ser Gly Ile Ser Lys Gln Leu Val Lys Lys Gly Val Lys His Val Glu
290 295 300
Ser Ile Leu His Leu Ala Lys Ser Ser Tyr Leu Ala Pro Phe Met Lys
305 310 315 320
Leu Ala Gln Gln Ile Gln Asp Gly Ser Arg Gln Ala Gln Ser Asn Leu
325 330 335
Thr Phe Leu Ser Ile Leu Lys Glu Pro Tyr Gln Glu Leu Ala Phe Met
340 345 350
Lys Pro Lys Asp Ile Ser Ser Lys Leu Pro Lys Leu Ile Ser Leu Ile
355 360 365
Arg Ile Ile Trp Val Asn Ser Pro His Tyr Asn Thr Arg Glu Arg Leu
370 375 380
Thr Ser Leu Phe Arg Lys Val Cys Asp Cys Gln Tyr His Phe Ala Arg
385 390 395 400
Trp Glu Asp Gly Lys Gln Gly Pro Leu Pro Cys Phe Phe Gly Ala Gln
405 410 415
Gly Pro Gln Ile Thr Arg Asn Leu Leu Glu Ile Glu Asp Ile Phe His
420 425 430
Lys Asn Leu His Thr Leu Arg Ala Val Arg Gly Gly Ile Leu Asp Val
435 440 445
Lys Asn Thr Cys Trp His Glu Asp Tyr Asn Lys Phe Arg Ala Gly Ile
450 455 460
Lys Asp Leu Glu Val Met Thr Gln Asn Leu Ile Thr Ser Ala Phe Glu
465 470 475 480
Leu Val Arg Asp Val Pro His Gly Val Leu Leu Leu Asp Thr Phe His
485 490 495
Arg Leu Ala Ser Arg Glu Ala Ile Lys Arg Thr Tyr Asp Lys Lys Ala
500 505 510
Val Asp Leu Tyr Met Leu Phe Asn Ser Glu Leu Ala Leu Val Asn Arg
515 520 525
Glu Arg Asn Lys Lys Trp Pro Asp Leu Glu Pro Tyr Val Ala Gln Tyr
530 535 540
Ser Gly Lys Ala Arg Trp Val His Ile Leu Arg Arg Arg Ile Asp Arg
545 550 555 560
Val Met Thr Cys Leu Ala Gly Ala His Phe Leu Pro Arg Ile Gly Thr
565 570 575
Gly Lys Glu Ser Val His Thr Tyr Gln Gln Met Val Gln Ala Ile Asp
580 585 590
Glu Leu Val Arg Lys Thr Phe Gln Glu Trp Thr Ser Ser Leu Asp Lys
595 600 605
Asp Cys Ile Arg Arg Leu Asp Thr Pro Leu Leu Arg Ile Ser Gln Glu
610 615 620
Lys Ala Gly Met Leu Asp Val Asn Phe Asp Lys Ser Leu Leu Ile Leu
625 630 635 640
Phe Ala Glu Ile Asp Tyr Trp Glu Arg Leu Leu Phe Glu Thr Pro His
645 650 655
Tyr Val Val Asn Val Ala Glu Arg Ala Glu Asp Leu Arg Ile Leu Arg
660 665 670
Glu Asn Leu Leu Leu Val Ala Arg Asp Tyr Asn Arg Ile Ile Ala Met
675 680 685
Leu Ser Pro Asp Glu Gln Ala Leu Phe Lys Glu Arg Ile Arg Leu Leu
690 695 700
Asp Lys Lys Ile His Pro Gly Leu Lys Lys Leu His Trp Ala Leu Lys
705 710 715 720
Gly Ala Ser Ala Phe Phe Ile Thr Glu Cys Arg Ile His Ala Ser Lys
725 730 735
Val Gln Met Ile Val Asn Glu Phe Lys Ala Ser Thr Leu Thr Ile Gly
740 745 750
Trp Arg Ala Gln Glu Met Ser Glu Lys Leu Leu Val Arg Ile Ser Gly
755 760 765
Lys Arg Val Tyr Arg Asp Leu Glu Phe Glu Glu Asp Gln Arg Glu His
770 775 780
Arg Ala Ala Val Gln Gln Lys Leu Met Asn Leu His Gln Asp Val Val
785 790 795 800
Thr Ile Met Thr Asn Ser Tyr Glu Val Phe Lys Asn Asp Gly Pro Glu
805 810 815
Ile Gln Gln Gln Trp Met Leu Tyr Met Ile Arg Leu Asp Arg Met Met
820 825 830
Glu Asp Ala Leu Arg Leu Asn Val Lys Trp Ser Leu Leu Glu Leu Ser
835 840 845
Lys Ala Ile Asn Gly Asp Gly Lys Thr Ser Pro Asn Pro Leu Phe Gln
850 855 860
Val Leu Val Ile Leu Lys Asn Asp Leu Gln Gly Ser Val Ala Gln Val
865 870 875 880
Glu Phe Ser Pro Thr Leu Gln Thr Leu Ala Gly Val Val Asn Asp Ile
885 890 895
Gly Asn His Leu Phe Ser Thr Ile Ser Val Phe Cys His Leu Pro Asp
900 905 910
Ile Leu Thr Lys Arg Lys Leu His Arg Glu Pro Ile Gln Thr Val Val
915 920 925
Glu Gln Asp Glu Asp Ile Lys Lys Ile Gln Thr Gln Ile Ser Ser Gly
930 935 940
Met Thr Asn Asn Ala Ser Leu Leu Gln Asn Tyr Leu Lys Thr Trp Asp
945 950 955 960
Met Tyr Arg Glu Ile Trp Glu Ile Asn Lys Asp Ser Phe Ile His Arg
965 970 975
Tyr Gln Arg Leu Asn Pro Pro Val Ser Ser Phe Val Ala Asp Ile Ala
980 985 990
Arg Tyr Thr Glu Val Ala Asn Asn Val Gln Lys Glu Glu Thr Val Thr
995 1000 1005
Asn Ile Gln Phe Val Leu Leu Asp Cys Ser His Leu Lys Phe Ser
1010 1015 1020
Leu Val Gln His Cys Asn Glu Trp Gln Asn Lys Phe Ala Thr Leu
1025 1030 1035
Leu Arg Glu Met Ala Ala Gly Arg Leu Leu Glu Leu His Thr Tyr
1040 1045 1050
Leu Lys Glu Asn Ala Glu Lys Ile Ser Arg Pro Pro Gln Thr Leu
1055 1060 1065
Glu Glu Leu Gly Val Ser Leu Gln Leu Val Asp Ala Leu Lys His
1070 1075 1080
Asp Leu Ala Asn Val Glu Thr Gln Ile Pro Pro Ile His Glu Gln
1085 1090 1095
Phe Ala Ile Leu Glu Lys Tyr Glu Val Pro Val Glu Asp Ser Val
1100 1105 1110
Leu Glu Met Leu Asp Ser Leu Asn Gly Glu Trp Val Val Phe Gln
1115 1120 1125
Gln Thr Leu Leu Asp Ser Lys Gln Met Leu Lys Lys His Lys Glu
1130 1135 1140
Lys Phe Lys Thr Gly Leu Ile His Ser Ala Asp Asp Phe Lys Lys
1145 1150 1155
Lys Ala His Thr Leu Leu Glu Asp Phe Glu Phe Lys Gly His Phe
1160 1165 1170
Thr Ser Asn Val Gly Tyr Met Ser Ala Leu Asp Gln Ile Thr Gln
1175 1180 1185
Val Arg Ala Met Leu Met Ala Met Arg Glu Glu Glu Asn Ser Leu
1190 1195 1200
Arg Ala Asn Leu Gly Ile Phe Lys Ile Glu Gln Pro Pro Ser Lys
1205 1210 1215
Asp Leu Gln Asn Leu Glu Lys Glu Leu Asp Ala Leu Gln Gln Ile
1220 1225 1230
Trp Glu Ile Ala Arg Asp Trp Glu Glu Asn Trp Asn Glu Trp Lys
1235 1240 1245
Thr Gly Arg Phe Leu Ile Leu Gln Thr Glu Thr Met Glu Thr Thr
1250 1255 1260
Ala His Gly Leu Phe Arg Arg Leu Thr Lys Leu Ala Lys Glu Tyr
1265 1270 1275
Lys Asp Arg Asn Trp Glu Ile Ile Glu Thr Thr Arg Ser Lys Ile
1280 1285 1290
Glu Gln Phe Lys Arg Thr Met Pro Leu Ile Ser Asp Leu Arg Asn
1295 1300 1305
Pro Ala Leu Arg Glu Arg His Trp Asp Gln Val Arg Asp Glu Ile
1310 1315 1320
Gln Arg Glu Phe Asp Gln Glu Ser Glu Ser Phe Thr Leu Glu Gln
1325 1330 1335
Ile Val Glu Leu Gly Met Asp Gln His Val Glu Lys Ile Gly Glu
1340 1345 1350
Ile Ser Ala Ser Ala Thr Lys Glu Leu Ala Ile Glu Val Ala Leu
1355 1360 1365
Gln Asn Ile Ala Lys Thr Trp Asp Val Thr Gln Leu Asp Ile Val
1370 1375 1380
Pro Tyr Lys Asp Lys Gly His His Arg Leu Arg Gly Thr Glu Glu
1385 1390 1395
Val Phe Gln Ala Leu Glu Asp Asn Gln Val Ala Leu Ser Thr Met
1400 1405 1410
Lys Ala Ser Arg Phe Val Lys Ala Phe Glu Lys Asp Val Asp His
1415 1420 1425
Trp Glu Arg Cys Leu Ser Leu Ile Leu Glu Val Ile Glu Met Ile
1430 1435 1440
Leu Thr Val Gln Arg Gln Trp Met Tyr Leu Glu Asn Ile Phe Leu
1445 1450 1455
Gly Glu Asp Ile Arg Lys Gln Leu Pro Asn Glu Ser Thr Leu Phe
1460 1465 1470
Asp Gln Val Asn Ser Asn Trp Lys Ala Ile Met Asp Arg Met Asn
1475 1480 1485
Lys Asp Asn Asn Ala Leu Arg Ser Thr His His Pro Gly Leu Leu
1490 1495 1500
Asp Thr Leu Ile Glu Met Asn Thr Ile Leu Glu Asp Ile Gln Lys
1505 1510 1515
Ser Leu Asp Met Tyr Leu Glu Thr Lys Arg His Ile Phe Pro Arg
1520 1525 1530
Phe Tyr Phe Leu Ser Asn Asp Asp Leu Leu Glu Ile Leu Gly Gln
1535 1540 1545
Ser Arg Asn Pro Glu Ala Val Gln Pro His Leu Lys Lys Cys Phe
1550 1555 1560
Asp Asn Ile Lys Leu Leu Arg Ile Gln Lys Val Gly Gly Pro Ser
1565 1570 1575
Ser Lys Trp Glu Ala Val Gly Met Phe Ser Gly Asp Gly Glu Tyr
1580 1585 1590
Ile Asp Phe Leu His Ser Val Phe Leu Glu Gly Pro Val Glu Ser
1595 1600 1605
Trp Leu Gly Asp Val Glu Gln Thr Met Arg Val Thr Leu Arg Asp
1610 1615 1620
Leu Leu Arg Asn Cys His Leu Ala Leu Arg Lys Phe Leu Asn Lys
1625 1630 1635
Arg Asp Lys Trp Val Lys Glu Trp Ala Gly Gln Val Val Ile Thr
1640 1645 1650
Ala Ser Gln Ile Gln Trp Thr Ala Asp Val Thr Lys Cys Leu Leu
1655 1660 1665
Thr Ala Lys Glu Arg Ala Asp Lys Lys Ile Leu Lys Val Met Lys
1670 1675 1680
Lys Asn Gln Val Ser Ile Leu Asn Lys Tyr Ser Glu Ala Ile Arg
1685 1690 1695
Gly Asn Leu Thr Lys Ile Met Arg Leu Lys Ile Val Ala Leu Val
1700 1705 1710
Thr Ile Glu Ile His Ala Arg Asp Val Leu Glu Lys Leu Tyr Lys
1715 1720 1725
Ser Gly Leu Met Asp Val Asn Ser Phe Asp Trp Leu Ser Gln Leu
1730 1735 1740
Arg Phe Tyr Trp Glu Lys Asp Leu Asp Asp Cys Val Ile Arg Gln
1745 1750 1755
Thr Asn Thr Gln Phe Gln
1760
<210> 99
<211> 1390
<212> PRT
<213> 智人(homo sapiens)
<400> 99
Met Gly Ala Thr Gly Arg Leu Glu Leu Thr Leu Ala Ala Pro Pro His
1 5 10 15
Pro Gly Pro Ala Phe Gln Arg Ser Lys Ala Arg Glu Thr Gln Gly Glu
20 25 30
Glu Glu Gly Ser Glu Met Gln Ile Ala Lys Ser Asp Ser Ile His His
35 40 45
Met Ser His Ser Gln Gly Gln Pro Glu Leu Pro Pro Leu Pro Ala Ser
50 55 60
Ala Asn Glu Glu Pro Ser Gly Leu Tyr Gln Thr Val Met Ser His Ser
65 70 75 80
Phe Tyr Pro Pro Leu Met Gln Arg Thr Ser Trp Thr Leu Ala Ala Pro
85 90 95
Phe Lys Glu Gln His His His Arg Gly Pro Ser Asp Ser Ile Ala Asn
100 105 110
Asn Tyr Ser Leu Met Ala Gln Asp Leu Lys Leu Lys Asp Leu Leu Lys
115 120 125
Val Tyr Gln Pro Ala Thr Ile Ser Val Pro Arg Asp Arg Thr Gly Gln
130 135 140
Gly Leu Pro Ser Ser Gly Asn Arg Ser Ser Ser Glu Pro Met Arg Lys
145 150 155 160
Lys Thr Lys Phe Ser Ser Arg Asn Lys Glu Asp Ser Thr Arg Ile Lys
165 170 175
Leu Ala Phe Lys Thr Ser Ile Phe Ser Pro Met Lys Lys Glu Val Lys
180 185 190
Thr Ser Leu Thr Phe Pro Gly Ser Arg Pro Met Ser Pro Glu Gln Gln
195 200 205
Leu Asp Val Met Leu Gln Gln Glu Met Glu Met Glu Ser Lys Glu Lys
210 215 220
Lys Pro Ser Glu Ser Asp Leu Glu Arg Tyr Tyr Tyr Tyr Leu Thr Asn
225 230 235 240
Gly Ile Arg Lys Asp Met Ile Ala Pro Glu Glu Gly Glu Val Met Val
245 250 255
Arg Ile Ser Lys Leu Ile Ser Asn Thr Leu Leu Thr Ser Pro Phe Leu
260 265 270
Glu Pro Leu Met Val Val Leu Val Gln Glu Lys Glu Asn Asp Tyr Tyr
275 280 285
Cys Ser Leu Met Lys Ser Ile Val Asp Tyr Ile Leu Met Asp Pro Met
290 295 300
Glu Arg Lys Arg Leu Phe Ile Glu Ser Ile Pro Arg Leu Phe Pro Gln
305 310 315 320
Arg Val Ile Arg Ala Pro Val Pro Trp His Ser Val Tyr Arg Ser Ala
325 330 335
Lys Lys Trp Asn Glu Glu His Leu His Thr Val Asn Pro Met Met Leu
340 345 350
Arg Leu Lys Glu Leu Trp Phe Ala Glu Phe Arg Asp Leu Arg Phe Val
355 360 365
Arg Thr Ala Glu Ile Leu Ala Gly Lys Leu Pro Leu Gln Pro Gln Glu
370 375 380
Phe Trp Asp Val Ile Gln Lys His Cys Leu Glu Ala His Gln Thr Leu
385 390 395 400
Leu Asn Lys Trp Ile Pro Thr Cys Ala Gln Leu Phe Thr Ser Arg Lys
405 410 415
Glu His Trp Ile His Phe Ala Pro Lys Ser Asn Tyr Asp Ser Ser Arg
420 425 430
Asn Ile Glu Glu Tyr Phe Ala Ser Val Ala Ser Phe Met Ser Leu Gln
435 440 445
Leu Arg Glu Leu Val Ile Lys Ser Leu Glu Asp Leu Val Ser Leu Phe
450 455 460
Met Ile His Lys Asp Gly Asn Asp Phe Lys Glu Pro Tyr Gln Glu Met
465 470 475 480
Lys Phe Phe Ile Pro Gln Leu Ile Met Ile Lys Leu Glu Val Ser Glu
485 490 495
Pro Ile Ile Val Phe Asn Pro Ser Phe Asp Gly Cys Trp Glu Leu Ile
500 505 510
Arg Asp Ser Phe Leu Glu Ile Ile Lys Asn Ser Asn Gly Ile Pro Lys
515 520 525
Leu Lys Tyr Ile Pro Leu Lys Phe Ser Phe Thr Ala Ala Ala Ala Asp
530 535 540
Arg Gln Cys Val Lys Ala Ala Glu Pro Gly Glu Pro Ser Met His Ala
545 550 555 560
Ala Ala Thr Ala Met Ala Glu Leu Lys Gly Tyr Asn Leu Leu Leu Gly
565 570 575
Thr Val Asn Ala Glu Glu Lys Leu Val Ser Asp Phe Leu Ile Gln Thr
580 585 590
Phe Lys Val Phe Gln Lys Asn Gln Val Gly Pro Cys Lys Tyr Leu Asn
595 600 605
Val Tyr Lys Lys Tyr Val Asp Leu Leu Asp Asn Thr Ala Glu Gln Asn
610 615 620
Ile Ala Ala Phe Leu Lys Glu Asn His Asp Ile Asp Asp Phe Val Thr
625 630 635 640
Lys Ile Asn Ala Ile Lys Lys Arg Arg Asn Glu Ile Ala Ser Met Asn
645 650 655
Ile Thr Val Pro Leu Ala Met Phe Cys Leu Asp Ala Thr Ala Leu Asn
660 665 670
His Asp Leu Cys Glu Arg Ala Gln Asn Leu Lys Asp His Leu Ile Gln
675 680 685
Phe Gln Val Asp Val Asn Arg Asp Thr Asn Thr Ser Ile Cys Asn Gln
690 695 700
Tyr Ser His Ile Ala Asp Lys Val Ser Glu Val Pro Ala Asn Thr Lys
705 710 715 720
Glu Leu Val Ser Leu Ile Glu Phe Leu Lys Lys Ser Ser Ala Val Thr
725 730 735
Val Phe Lys Leu Arg Arg Gln Leu Arg Asp Ala Ser Glu Arg Leu Glu
740 745 750
Phe Leu Met Asp Tyr Ala Asp Leu Pro Tyr Gln Ile Glu Asp Ile Phe
755 760 765
Asp Asn Ser Arg Asn Leu Leu Leu His Lys Arg Asp Gln Ala Glu Met
770 775 780
Asp Leu Ile Lys Arg Cys Ser Glu Phe Glu Leu Arg Leu Glu Gly Tyr
785 790 795 800
His Arg Glu Leu Glu Ser Phe Arg Lys Arg Glu Val Met Thr Thr Glu
805 810 815
Glu Met Lys His Asn Val Glu Lys Leu Asn Glu Leu Ser Lys Asn Leu
820 825 830
Asn Arg Ala Phe Ala Glu Phe Glu Leu Ile Asn Lys Glu Glu Glu Leu
835 840 845
Leu Glu Lys Glu Lys Ser Thr Tyr Pro Leu Leu Gln Ala Met Leu Lys
850 855 860
Asn Lys Val Pro Tyr Glu Gln Leu Trp Ser Thr Ala Tyr Glu Phe Ser
865 870 875 880
Ile Lys Ser Glu Glu Trp Met Asn Gly Pro Leu Phe Leu Leu Asn Ala
885 890 895
Glu Gln Ile Ala Glu Glu Ile Gly Asn Met Trp Arg Thr Thr Tyr Lys
900 905 910
Leu Ile Lys Thr Leu Ser Asp Val Pro Ala Pro Arg Arg Leu Ala Glu
915 920 925
Asn Val Lys Ile Lys Ile Asp Lys Phe Lys Gln Tyr Ile Pro Ile Leu
930 935 940
Ser Ile Ser Cys Asn Pro Gly Met Lys Asp Arg His Trp Gln Gln Ile
945 950 955 960
Ser Glu Ile Val Gly Tyr Glu Ile Lys Pro Thr Glu Thr Thr Cys Leu
965 970 975
Ser Asn Met Leu Glu Phe Gly Phe Gly Lys Phe Val Glu Lys Leu Glu
980 985 990
Pro Ile Gly Ala Ala Ala Ser Lys Glu Tyr Ser Leu Glu Lys Asn Leu
995 1000 1005
Asp Arg Met Lys Leu Asp Trp Val Asn Val Thr Phe Ser Phe Val
1010 1015 1020
Lys Tyr Arg Asp Thr Asp Thr Asn Ile Leu Cys Ala Ile Asp Asp
1025 1030 1035
Ile Gln Met Leu Leu Asp Asp His Val Ile Lys Thr Gln Thr Met
1040 1045 1050
Cys Gly Ser Pro Phe Ile Lys Pro Ile Glu Ala Glu Cys Arg Lys
1055 1060 1065
Trp Glu Glu Lys Leu Ile Arg Ile Gln Asp Asn Leu Asp Ala Trp
1070 1075 1080
Leu Lys Cys Gln Ala Thr Trp Leu Tyr Leu Glu Pro Ile Phe Ser
1085 1090 1095
Ser Glu Asp Ile Ile Ala Gln Met Pro Glu Glu Gly Arg Lys Phe
1100 1105 1110
Gly Ile Val Asp Ser Tyr Trp Lys Ser Leu Met Ser Gln Ala Val
1115 1120 1125
Lys Asp Asn Arg Ile Leu Val Ala Ala Asp Gln Pro Arg Met Ala
1130 1135 1140
Glu Lys Leu Gln Glu Ala Asn Phe Leu Leu Glu Asp Ile Gln Lys
1145 1150 1155
Gly Leu Asn Asp Tyr Leu Glu Lys Lys Arg Leu Phe Phe Pro Arg
1160 1165 1170
Phe Phe Phe Leu Ser Asn Asp Glu Leu Leu Glu Ile Leu Ser Glu
1175 1180 1185
Thr Lys Asp Pro Leu Arg Val Gln Pro His Leu Lys Lys Cys Phe
1190 1195 1200
Glu Gly Ile Ala Lys Leu Glu Phe Thr Asp Asn Leu Glu Ile Val
1205 1210 1215
Gly Met Ile Ser Ser Glu Lys Glu Thr Val Pro Phe Ile Gln Lys
1220 1225 1230
Ile Tyr Pro Ala Asn Ala Lys Gly Met Val Glu Lys Trp Leu Gln
1235 1240 1245
Gln Val Glu Gln Met Met Leu Ala Ser Met Arg Glu Val Ile Gly
1250 1255 1260
Leu Gly Ile Glu Ala Tyr Val Lys Val Pro Arg Asn His Trp Val
1265 1270 1275
Leu Gln Trp Pro Gly Gln Val Val Ile Cys Val Ser Ser Ile Phe
1280 1285 1290
Trp Thr Gln Glu Val Ser Gln Ala Leu Ala Glu Asn Thr Leu Leu
1295 1300 1305
Asp Phe Leu Lys Lys Ser Asn Asp Gln Ile Ala Gln Ile Val Gln
1310 1315 1320
Leu Val Arg Gly Lys Leu Ser Ser Gly Ala Arg Leu Thr Leu Gly
1325 1330 1335
Ala Leu Thr Val Ile Asp Val His Ala Arg Asp Val Val Ala Lys
1340 1345 1350
Leu Ser Glu Asp Arg Val Ser Asp Leu Asn Asp Phe Gln Trp Ile
1355 1360 1365
Ser Gln Leu Arg Tyr Tyr Trp Val Ala Lys Asp Val Gln Val Gln
1370 1375 1380
Ile Ile Thr Thr Glu Ala Leu
1385 1390
<210> 100
<211> 1941
<212> PRT
<213> 智人(homo sapiens)
<400> 100
Met Phe Arg Ile Gly Arg Arg Gln Leu Trp Lys His Ser Val Thr Arg
1 5 10 15
Val Leu Thr Gln Arg Leu Lys Gly Glu Lys Glu Ala Lys Arg Ala Leu
20 25 30
Leu Asp Ala Arg His Asn Tyr Leu Phe Ala Ile Val Ala Ser Cys Leu
35 40 45
Asp Leu Asn Lys Thr Glu Val Glu Asp Ala Ile Leu Glu Gly Asn Gln
50 55 60
Ile Glu Arg Ile Asp Gln Leu Phe Ala Val Gly Gly Leu Arg His Leu
65 70 75 80
Met Phe Tyr Tyr Gln Asp Val Glu Glu Ala Glu Thr Gly Gln Leu Gly
85 90 95
Ser Leu Gly Gly Val Asn Leu Val Ser Gly Lys Ile Lys Lys Pro Lys
100 105 110
Val Phe Val Thr Glu Gly Asn Asp Val Ala Leu Thr Gly Val Cys Val
115 120 125
Phe Phe Ile Arg Thr Asp Pro Ser Lys Ala Ile Thr Pro Asp Asn Ile
130 135 140
His Gln Glu Val Ser Phe Asn Met Leu Asp Ala Ala Asp Gly Gly Leu
145 150 155 160
Leu Asn Ser Val Arg Arg Leu Leu Ser Asp Ile Phe Ile Pro Ala Leu
165 170 175
Arg Ala Thr Ser His Gly Trp Gly Glu Leu Glu Gly Leu Gln Asp Ala
180 185 190
Ala Asn Ile Arg Gln Glu Phe Leu Ser Ser Leu Glu Gly Phe Val Asn
195 200 205
Val Leu Ser Gly Ala Gln Glu Ser Leu Lys Glu Lys Val Asn Leu Arg
210 215 220
Lys Cys Asp Ile Leu Glu Leu Lys Thr Leu Lys Glu Pro Thr Asp Tyr
225 230 235 240
Leu Thr Leu Ala Asn Asn Pro Glu Thr Leu Gly Lys Ile Glu Asp Cys
245 250 255
Met Lys Val Trp Ile Lys Gln Thr Glu Gln Val Leu Ala Glu Asn Asn
260 265 270
Gln Leu Leu Lys Glu Ala Asp Asp Val Gly Pro Arg Ala Glu Leu Glu
275 280 285
His Trp Lys Lys Arg Leu Ser Lys Phe Asn Tyr Leu Leu Glu Gln Leu
290 295 300
Lys Ser Pro Asp Val Lys Ala Val Leu Ala Val Leu Ala Ala Ala Lys
305 310 315 320
Ser Lys Leu Leu Lys Thr Trp Arg Glu Met Asp Ile Arg Ile Thr Asp
325 330 335
Ala Thr Asn Glu Ala Lys Asp Asn Val Lys Tyr Leu Tyr Thr Leu Glu
340 345 350
Lys Cys Cys Asp Pro Leu Tyr Ser Ser Asp Pro Leu Ser Met Met Asp
355 360 365
Ala Ile Pro Thr Leu Ile Asn Ala Ile Lys Met Ile Tyr Ser Ile Ser
370 375 380
His Tyr Tyr Asn Thr Ser Glu Lys Ile Thr Ser Leu Phe Val Lys Val
385 390 395 400
Thr Asn Gln Ile Ile Ser Ala Cys Lys Ala Tyr Ile Thr Asn Asn Gly
405 410 415
Thr Ala Ser Ile Trp Asn Gln Pro Gln Asp Val Val Glu Glu Lys Ile
420 425 430
Leu Ser Ala Ile Lys Leu Lys Gln Glu Tyr Gln Leu Cys Phe His Lys
435 440 445
Thr Lys Gln Lys Leu Lys Gln Asn Pro Asn Ala Lys Gln Phe Asp Phe
450 455 460
Ser Glu Met Tyr Ile Phe Gly Lys Phe Glu Thr Phe His Arg Arg Leu
465 470 475 480
Ala Lys Ile Ile Asp Ile Phe Thr Thr Leu Lys Thr Tyr Ser Val Leu
485 490 495
Gln Asp Ser Thr Ile Glu Gly Leu Glu Asp Met Ala Thr Lys Tyr Gln
500 505 510
Gly Ile Val Ala Thr Ile Lys Lys Lys Glu Tyr Asn Phe Leu Asp Gln
515 520 525
Arg Lys Met Asp Phe Asp Gln Asp Tyr Glu Glu Phe Cys Lys Gln Thr
530 535 540
Asn Asp Leu His Asn Glu Leu Arg Lys Phe Met Asp Val Thr Phe Ala
545 550 555 560
Lys Ile Gln Asn Thr Asn Gln Ala Leu Arg Met Leu Lys Lys Phe Glu
565 570 575
Arg Leu Asn Ile Pro Asn Leu Gly Ile Asp Asp Lys Tyr Gln Leu Ile
580 585 590
Leu Glu Asn Tyr Gly Ala Asp Ile Asp Met Ile Ser Lys Leu Tyr Thr
595 600 605
Lys Gln Lys Tyr Asp Pro Pro Leu Ala Arg Asn Gln Pro Pro Ile Ala
610 615 620
Gly Lys Ile Leu Trp Ala Arg Gln Leu Phe His Arg Ile Gln Gln Pro
625 630 635 640
Met Gln Leu Phe Gln Gln His Pro Ala Val Leu Ser Thr Ala Glu Ala
645 650 655
Lys Pro Ile Ile Arg Ser Tyr Asn Arg Met Ala Lys Val Leu Leu Glu
660 665 670
Phe Glu Val Leu Phe His Arg Ala Trp Leu Arg Gln Ile Glu Glu Ile
675 680 685
His Val Gly Leu Glu Ala Ser Leu Leu Val Lys Ala Pro Gly Thr Gly
690 695 700
Glu Leu Phe Val Asn Phe Asp Pro Gln Ile Leu Ile Leu Phe Arg Glu
705 710 715 720
Thr Glu Cys Met Ala Gln Met Gly Leu Glu Val Ser Pro Leu Ala Thr
725 730 735
Ser Leu Phe Gln Lys Arg Asp Arg Tyr Lys Arg Asn Phe Ser Asn Met
740 745 750
Lys Met Met Leu Ala Glu Tyr Gln Arg Val Lys Ser Lys Ile Pro Ala
755 760 765
Ala Ile Glu Gln Leu Ile Val Pro His Leu Ala Lys Val Asp Glu Ala
770 775 780
Leu Gln Pro Gly Leu Ala Ala Leu Thr Trp Thr Ser Leu Asn Ile Glu
785 790 795 800
Ala Tyr Leu Glu Asn Thr Phe Ala Lys Ile Lys Asp Leu Glu Leu Leu
805 810 815
Leu Asp Arg Val Asn Asp Leu Ile Glu Phe Arg Ile Asp Ala Ile Leu
820 825 830
Glu Glu Met Ser Ser Thr Pro Leu Cys Gln Leu Pro Gln Glu Glu Pro
835 840 845
Leu Thr Cys Glu Glu Phe Leu Gln Met Thr Lys Asp Leu Cys Val Asn
850 855 860
Gly Ala Gln Ile Leu His Phe Lys Ser Ser Leu Val Glu Glu Ala Val
865 870 875 880
Asn Glu Leu Val Asn Met Leu Leu Asp Val Glu Val Leu Ser Glu Glu
885 890 895
Glu Ser Glu Lys Ile Ser Asn Glu Asn Ser Val Asn Tyr Lys Asn Glu
900 905 910
Ser Ser Ala Lys Arg Glu Glu Gly Asn Phe Asp Thr Leu Thr Ser Ser
915 920 925
Ile Asn Ala Arg Ala Asn Ala Leu Leu Leu Thr Thr Val Thr Arg Lys
930 935 940
Lys Lys Glu Thr Glu Met Leu Gly Glu Glu Ala Arg Glu Leu Leu Ser
945 950 955 960
His Phe Asn His Gln Asn Met Asp Ala Leu Leu Lys Val Thr Arg Asn
965 970 975
Thr Leu Glu Ala Ile Arg Lys Arg Ile His Ser Ser His Thr Ile Asn
980 985 990
Phe Arg Asp Ser Asn Ser Ala Ser Asn Met Lys Gln Asn Ser Leu Pro
995 1000 1005
Ile Phe Arg Ala Ser Val Thr Leu Ala Ile Pro Asn Ile Val Met
1010 1015 1020
Ala Pro Ala Leu Glu Asp Val Gln Gln Thr Leu Asn Lys Ala Val
1025 1030 1035
Glu Cys Ile Ile Ser Val Pro Lys Gly Val Arg Gln Trp Ser Ser
1040 1045 1050
Glu Leu Leu Ser Lys Lys Lys Ile Gln Glu Arg Lys Met Ala Ala
1055 1060 1065
Leu Gln Ser Asn Glu Asp Ser Asp Ser Asp Val Glu Met Gly Glu
1070 1075 1080
Asn Glu Leu Gln Asp Thr Leu Glu Ile Ala Ser Val Asn Leu Pro
1085 1090 1095
Ile Pro Val Gln Thr Lys Asn Tyr Tyr Lys Asn Val Ser Glu Asn
1100 1105 1110
Lys Glu Ile Val Lys Leu Val Ser Val Leu Ser Thr Ile Ile Asn
1115 1120 1125
Ser Thr Lys Lys Glu Val Ile Thr Ser Met Asp Cys Phe Lys Arg
1130 1135 1140
Tyr Asn His Ile Trp Gln Lys Gly Lys Glu Glu Ala Ile Lys Thr
1145 1150 1155
Phe Ile Thr Gln Ser Pro Leu Leu Ser Glu Phe Glu Ser Gln Ile
1160 1165 1170
Leu Tyr Phe Gln Asn Leu Glu Gln Glu Ile Asn Ala Glu Pro Glu
1175 1180 1185
Tyr Val Cys Val Gly Ser Ile Ala Leu Tyr Thr Ala Asp Leu Lys
1190 1195 1200
Phe Ala Leu Thr Ala Glu Thr Lys Ala Trp Met Val Val Ile Gly
1205 1210 1215
Arg His Cys Asn Lys Lys Tyr Arg Ser Glu Met Glu Asn Ile Phe
1220 1225 1230
Met Leu Ile Glu Glu Phe Asn Lys Lys Leu Asn Arg Pro Ile Lys
1235 1240 1245
Asp Leu Asp Asp Ile Arg Ile Ala Met Ala Ala Leu Lys Glu Ile
1250 1255 1260
Arg Glu Glu Gln Ile Ser Ile Asp Phe Gln Val Gly Pro Ile Glu
1265 1270 1275
Glu Ser Tyr Ala Leu Leu Asn Arg Tyr Gly Leu Leu Ile Ala Arg
1280 1285 1290
Glu Glu Ile Asp Lys Val Asp Thr Leu His Tyr Ala Trp Glu Lys
1295 1300 1305
Leu Leu Ala Arg Ala Gly Glu Val Gln Asn Lys Leu Val Ser Leu
1310 1315 1320
Gln Pro Ser Phe Lys Lys Glu Leu Ile Ser Ala Val Glu Val Phe
1325 1330 1335
Leu Gln Asp Cys His Gln Phe Tyr Leu Asp Tyr Asp Leu Asn Gly
1340 1345 1350
Pro Met Ala Ser Gly Leu Lys Pro Gln Glu Ala Ser Asp Arg Leu
1355 1360 1365
Ile Met Phe Gln Asn Gln Phe Asp Asn Ile Tyr Arg Lys Tyr Ile
1370 1375 1380
Thr Tyr Thr Gly Gly Glu Glu Leu Phe Gly Leu Pro Ala Thr Gln
1385 1390 1395
Tyr Pro Gln Leu Leu Glu Ile Lys Lys Gln Leu Asn Leu Leu Gln
1400 1405 1410
Lys Ile Tyr Thr Leu Tyr Asn Ser Val Ile Glu Thr Val Asn Ser
1415 1420 1425
Tyr Tyr Asp Ile Leu Trp Ser Glu Val Asn Ile Glu Lys Ile Asn
1430 1435 1440
Asn Glu Leu Leu Glu Phe Gln Asn Arg Cys Arg Lys Leu Pro Arg
1445 1450 1455
Ala Leu Lys Asp Trp Gln Ala Phe Leu Asp Leu Lys Lys Ile Ile
1460 1465 1470
Asp Asp Phe Ser Glu Cys Cys Pro Leu Leu Glu Tyr Met Ala Ser
1475 1480 1485
Lys Ala Met Met Glu Arg His Trp Glu Arg Ile Thr Thr Leu Thr
1490 1495 1500
Gly His Ser Leu Asp Val Gly Asn Glu Ser Phe Lys Leu Arg Asn
1505 1510 1515
Ile Met Glu Ala Pro Leu Leu Lys Tyr Lys Glu Glu Ile Glu Asp
1520 1525 1530
Ile Cys Ile Ser Ala Val Lys Glu Arg Asp Ile Glu Gln Lys Leu
1535 1540 1545
Lys Gln Val Ile Asn Glu Trp Asp Asn Lys Thr Phe Thr Phe Gly
1550 1555 1560
Ser Phe Lys Thr Arg Gly Glu Leu Leu Leu Arg Gly Asp Ser Thr
1565 1570 1575
Ser Glu Ile Ile Ala Asn Met Glu Asp Ser Leu Met Leu Leu Gly
1580 1585 1590
Ser Leu Leu Ser Asn Arg Tyr Asn Met Pro Phe Lys Ala Gln Ile
1595 1600 1605
Gln Lys Trp Val Gln Tyr Leu Ser Asn Ser Thr Asp Ile Ile Glu
1610 1615 1620
Ser Trp Met Thr Val Gln Asn Leu Trp Ile Tyr Leu Glu Ala Val
1625 1630 1635
Phe Val Gly Gly Asp Ile Ala Lys Gln Leu Pro Lys Glu Ala Lys
1640 1645 1650
Arg Phe Ser Asn Ile Asp Lys Ser Trp Val Lys Ile Met Thr Arg
1655 1660 1665
Ala His Glu Val Pro Ser Val Val Gln Cys Cys Val Gly Asp Glu
1670 1675 1680
Thr Leu Gly Gln Leu Leu Pro His Leu Leu Asp Gln Leu Glu Ile
1685 1690 1695
Cys Gln Lys Ser Leu Thr Gly Tyr Leu Glu Lys Lys Arg Leu Cys
1700 1705 1710
Phe Pro Arg Phe Phe Phe Val Ser Asp Pro Ala Leu Leu Glu Ile
1715 1720 1725
Leu Gly Gln Ala Ser Asp Ser His Thr Ile Gln Ala His Leu Leu
1730 1735 1740
Asn Val Phe Asp Asn Ile Lys Ser Val Lys Phe His Glu Lys Ile
1745 1750 1755
Tyr Asp Arg Ile Leu Ser Ile Ser Ser Gln Glu Gly Glu Thr Ile
1760 1765 1770
Glu Leu Asp Lys Pro Val Met Ala Glu Gly Asn Val Glu Val Trp
1775 1780 1785
Leu Asn Ser Leu Leu Glu Glu Ser Gln Ser Ser Leu His Leu Val
1790 1795 1800
Ile Arg Gln Ala Ala Ala Asn Ile Gln Glu Thr Gly Phe Gln Leu
1805 1810 1815
Thr Glu Phe Leu Ser Ser Phe Pro Ala Gln Val Gly Leu Leu Gly
1820 1825 1830
Ile Gln Met Ile Trp Thr Arg Asp Ser Glu Glu Ala Leu Arg Asn
1835 1840 1845
Ala Lys Phe Asp Lys Lys Ile Met Gln Lys Thr Asn Gln Ala Phe
1850 1855 1860
Leu Glu Leu Leu Asn Thr Leu Ile Asp Val Thr Thr Arg Asp Leu
1865 1870 1875
Ser Ser Thr Glu Arg Val Lys Tyr Glu Thr Leu Ile Thr Ile His
1880 1885 1890
Val His Gln Arg Asp Ile Phe Asp Asp Leu Cys His Met His Ile
1895 1900 1905
Lys Ser Pro Met Asp Phe Glu Trp Leu Lys Gln Cys Arg Phe Tyr
1910 1915 1920
Phe Asn Glu Asp Ser Asp Lys Met Met Ile His Ile Thr Asp Val
1925 1930 1935
Ala Phe Ile
1940
<210> 101
<211> 1433
<212> PRT
<213> 智人(homo sapiens)
<400> 101
Met Thr Phe Arg Ala Thr Asp Ser Glu Phe Asp Leu Thr Asn Ile Glu
1 5 10 15
Glu Tyr Ala Glu Asn Ser Ala Leu Ser Arg Leu Asn Asn Ile Lys Ala
20 25 30
Lys Gln Arg Val Ser Tyr Val Thr Ser Thr Glu Asn Glu Ser Asp Thr
35 40 45
Gln Ile Leu Thr Phe Arg His Ile Thr Lys Ala Gln Glu Lys Thr Arg
50 55 60
Lys Arg Gln Gln Pro Ile Lys Leu Glu Pro Leu Pro Val Leu Lys Val
65 70 75 80
Tyr Gln Asp His Lys Gln Pro Glu Tyr Ile His Glu Gln Asn Arg Phe
85 90 95
Gln Leu Met Thr Ala Gly Ile Ile Lys Arg Pro Val Ser Ile Ala Lys
100 105 110
Lys Ser Phe Ala Thr Ser Ser Thr Gln Phe Leu Glu His Gln Asp Ala
115 120 125
Val Lys Lys Met Gln Ile His Arg Pro Tyr Val Glu Val Phe Ser Pro
130 135 140
Ser Pro Pro Lys Leu Pro His Thr Gly Ile Gly Lys Arg Gly Leu Phe
145 150 155 160
Gly Thr Arg Ser Ser Ala Tyr Pro Lys Tyr Thr Phe His Asp Arg Glu
165 170 175
Glu Val Val Lys Ala Asn Ile Arg Asp Pro Leu Gln Ile Ile Lys Ile
180 185 190
Ile Arg Glu Asn Glu His Leu Gly Phe Leu Tyr Met Ile Pro Ala Val
195 200 205
Pro Arg Ser Ser Ile Glu Tyr Asp Thr Tyr Asn Leu Lys Val Val Ser
210 215 220
Tyr Glu Asn Ile Asn Lys Asn Asp Tyr Tyr Thr Ile Ser Gln Arg Ala
225 230 235 240
Val Thr His Ile Tyr Asn Glu Asp Ile Glu Phe Ile Glu Ile Asp Arg
245 250 255
Trp Glu Gln Glu Tyr Leu Tyr His Arg Glu Leu Thr Lys Ile Pro Ile
260 265 270
Phe Ser Leu Phe Arg Lys Trp Lys Ala Phe Ser Val Trp Arg Lys Asn
275 280 285
Val Arg Ser Lys Lys Ile Thr Gly Cys Gln Lys Ser Leu Gln Lys Asn
290 295 300
Leu Phe Ile Val Asn Pro His Leu Arg Pro Ala Leu Leu Lys Ile Asn
305 310 315 320
Glu Leu Cys Tyr His Leu Ser Phe Met Gly Leu Cys Tyr Ile Glu Lys
325 330 335
Cys His Thr Tyr Thr Leu Gln Glu Phe Lys Ala Ala Gln Val Ile Arg
340 345 350
Leu Ala Glu Val Thr Glu Arg Leu Gly Glu Phe Arg Asn Glu Ala Lys
355 360 365
Tyr Val Val Arg Arg Ala Cys Arg Phe Ala Leu Arg Ala Ala Gly Phe
370 375 380
Val Pro Asp Asp Cys Ala Phe Gly Pro Phe Glu Asp Tyr His Lys Val
385 390 395 400
Gln Ser Ser Gly Ser Phe Ile Asn Thr Pro His Glu Leu Pro Thr Tyr
405 410 415
Gly Asp Ser Glu Lys Met Thr Tyr Thr Glu Gln Ala Ser Lys Arg His
420 425 430
Tyr Cys Met Arg Leu Thr Cys Phe Ile Arg Leu Asn Asp Tyr Leu Ile
435 440 445
Glu Asn Thr Met His Ile Leu Thr Val Asn Ala Val Asn Ser Leu Leu
450 455 460
Asn His Leu Thr Asp Lys Leu Lys Arg Thr Pro Ser Ala Asp Val Ile
465 470 475 480
Gln Lys Trp Ile Thr Glu Glu Lys Pro Glu Val Pro Asp Lys Lys Gly
485 490 495
Thr Leu Met Val Glu Lys Gln Glu Glu Asp Glu Ser Leu Ile Pro Met
500 505 510
Phe Leu Thr Glu Leu Met Leu Thr Val Gln Ser Leu Leu Phe Glu Pro
515 520 525
Ser Leu Glu Asp Phe Leu Asp Gly Ile Leu Gly Ala Val Asn His Cys
530 535 540
Gln Asn Thr Val Leu Ser Val Pro Asn Leu Val Pro Asp Ser Tyr Phe
545 550 555 560
Asp Ala Phe Thr Ser Pro Tyr Ile Asn Asn Lys Leu Glu Gly Lys Thr
565 570 575
Cys Gly Thr Gly Pro Ser Leu Ala Ala Val Phe Glu Asp Asp Lys Asn
580 585 590
Phe His Thr Ile Ile Ser Gln Ile Lys Glu Thr Ile Gln Ala Ala Phe
595 600 605
Glu Ser Ala Arg Ile Tyr Ala Ala Thr Phe Glu Lys Phe Gln Ile Phe
610 615 620
Phe Lys Glu Asn Glu Ser Leu Asp Leu Gln Ala Leu Lys Leu Gln Glu
625 630 635 640
Pro Asp Ile Asn Phe Phe Ser Glu Gln Leu Glu Lys Tyr His Lys Gln
645 650 655
His Lys Asp Ala Val Ala Leu Arg Pro Thr Arg Asn Val Gly Leu Leu
660 665 670
Leu Ile Asp Thr Arg Leu Leu Arg Glu Lys Leu Ile Pro Ser Pro Leu
675 680 685
Arg Cys Leu Glu Val Leu Asn Phe Met Leu Pro Arg Gln Ser Lys Lys
690 695 700
Lys Val Asp Ala Ile Ile Phe Glu Ala Gln Asp Ala Glu Tyr Lys Leu
705 710 715 720
Glu Phe Val Pro Thr Thr Thr Thr Glu Tyr Val His Ser Leu Leu Phe
725 730 735
Leu Asp Glu Ile Gln Glu Arg Ile Glu Ser Leu Glu Asp Glu Gly Asn
740 745 750
Ile Val Thr Gln Met Tyr Lys Leu Met Glu Gln Tyr Gln Val Pro Thr
755 760 765
Pro Pro Glu Asp Phe Ala Val Phe Ala Thr Met Lys Pro Ser Ile Val
770 775 780
Ala Val Arg Asn Ala Ile Asp Lys Ser Val Gly Asp Arg Glu Ser Ser
785 790 795 800
Ile Lys Gln Phe Cys Val His Leu Gly Ser Asp Leu Glu Glu Leu Asn
805 810 815
Asn Glu Val Asn Glu Val Lys Leu Gln Ala Gln Asp Pro Gln Ile Leu
820 825 830
Asp Ile Ser Ala Asp Gln Asp Lys Ile Arg Leu Ile Leu Asn Asn Leu
835 840 845
Gln Ser Val Leu Ala Asp Leu Gln Lys Arg Ala Phe Gln Tyr Lys Ser
850 855 860
Tyr Gln Lys Asn Phe Lys Val Glu Val Ser Lys Phe Glu Ala Leu Glu
865 870 875 880
Glu Val Ser Ala Glu Leu Lys Leu Lys Gln Leu Leu Trp Asp Ser Phe
885 890 895
Ser Glu Trp Asp Lys Leu Gln Gln Glu Trp Leu Lys Ser Lys Phe Asp
900 905 910
Cys Leu Asp Pro Glu Val Leu Asn Gly Gln Val Ser Lys Tyr Ala Lys
915 920 925
Phe Val Thr Gln Leu Glu Lys Gly Leu Pro Pro Asn Ser Val Val Pro
930 935 940
Gln Leu Lys Tyr Lys Val Glu Lys Met Lys Glu Lys Leu Pro Val Ile
945 950 955 960
Ile Asp Leu Arg Asn Pro Thr Leu Lys Ala Arg His Trp Ala Ala Ile
965 970 975
Glu Gln Thr Val Asp Ala Thr Leu Val Asp Ala Glu Ile Pro Leu Thr
980 985 990
Leu Glu Arg Leu Ser Gln Leu His Val Phe Asp Phe Gly Gln Glu Ile
995 1000 1005
Gln Asp Ile Ser Gly Gln Ala Ser Gly Glu Ala Ala Leu Glu Ala
1010 1015 1020
Ile Leu Lys Lys Val Glu Asp Ser Trp Lys Thr Thr Glu Phe Val
1025 1030 1035
Ile Leu Pro His Arg Asp Ser Lys Asp Val Phe Ile Leu Gly Gly
1040 1045 1050
Thr Asp Asp Ile Gln Val Leu Leu Asp Asp Ser Thr Ile Asn Val
1055 1060 1065
Ala Thr Leu Ala Ser Ser Arg Tyr Leu Gly Pro Leu Lys Thr Arg
1070 1075 1080
Val Asp Glu Trp Gln Lys Gln Leu Ala Leu Phe Asn Gln Thr Leu
1085 1090 1095
Glu Glu Trp Leu Thr Cys Gln Arg Asn Trp Leu Tyr Leu Glu Ser
1100 1105 1110
Ile Phe Asn Ala Pro Asp Ile Gln Arg Gln Leu Pro Ala Glu Ala
1115 1120 1125
Lys Met Phe Leu Gln Val Asp Lys Ser Trp Lys Glu Ile Met Arg
1130 1135 1140
Lys Val Asn Arg Leu Pro Asn Ala Leu Arg Ala Ala Thr Gln Pro
1145 1150 1155
Gly Leu Leu Glu Thr Phe Gln Asn Asn Asn Ala Leu Leu Asp Gln
1160 1165 1170
Ile Gln Lys Cys Leu Glu Ala Tyr Leu Glu Ser Lys Arg Val Ile
1175 1180 1185
Phe Pro Arg Phe Tyr Phe Leu Ser Asn Asp Glu Leu Leu Glu Ile
1190 1195 1200
Leu Ala Gln Thr Arg Asn Pro Gln Ala Val Gln Pro His Leu Arg
1205 1210 1215
Lys Cys Phe Asp Ser Ile Ser Lys Leu Glu Phe Ala Leu Met Pro
1220 1225 1230
Pro Ala Glu Gly Lys Ile Pro Gly Ile Asp Gly Glu Pro Glu Lys
1235 1240 1245
Val Tyr Thr Asn Asp Ile Leu Ala Met Leu Ser Pro Glu Gly Glu
1250 1255 1260
Arg Val Ser Leu Gly Lys Gly Leu Lys Ala Arg Gly Asn Val Glu
1265 1270 1275
Glu Trp Leu Gly Lys Val Glu Glu Ala Met Phe Thr Ser Leu Arg
1280 1285 1290
Arg Leu Cys Lys Ala Ala Ile Ala Asp Tyr Gln Gly Lys Leu Arg
1295 1300 1305
Thr Asp Trp Val Val Ala Gly His Pro Ser Gln Val Ile Leu Thr
1310 1315 1320
Val Ser Gln Ile Met Trp Cys Arg Asp Leu Thr Glu Cys Leu Glu
1325 1330 1335
Thr Glu His Ser Asn His Ile Gln Ala Leu Lys Asn Phe Glu Lys
1340 1345 1350
Val Asn Phe Glu Arg Leu Asn Ala Leu Ala Ala Ile Val Gln Gly
1355 1360 1365
Ser Leu Pro Lys Leu His Arg Asn Ile Leu Thr Ala Leu Ile Thr
1370 1375 1380
Ile Asp Val His Ala Arg Asp Ile Val Thr Glu Leu Val Gln Ser
1385 1390 1395
Lys Val Glu Thr Val Glu Ser Phe Asp Trp Gln Arg Gln Leu Arg
1400 1405 1410
Tyr Tyr Trp Asp Ile Asp Leu Asp Asn Cys Val Ala Arg Met Ala
1415 1420 1425
Leu Ser Gln Tyr Thr
1430
<210> 102
<211> 1289
<212> PRT
<213> 智人(homo sapiens)
<400> 102
Met Ser Ser Glu Gln Asp Lys Ser Ala Ser Lys Glu Lys Ser Lys Lys
1 5 10 15
Pro Val Arg Phe Leu Pro Gln Leu Ser Met Glu Lys Leu Ala Ser Lys
20 25 30
Glu Lys Phe Lys Ala Pro Ala Arg Ala Leu Pro Gln Leu Ser Met Val
35 40 45
Ser Thr Lys Pro His Trp Gln Gln Ala Ala Pro Ser Phe His Leu Ser
50 55 60
Val Lys Gln Asp Asp Glu Ser Pro Glu Pro Phe Ser Val Lys Asn Glu
65 70 75 80
Gln Ser His Ala Glu Tyr Met Glu Arg Phe Gly Lys Lys Gly Lys Leu
85 90 95
Pro His Gln Val Asp Asp Ser Tyr Val Gly Pro Ser Thr Ser Lys Ser
100 105 110
Lys Gly Lys Ser Pro His Lys Glu Arg Glu Asn Phe Arg Ser Thr Leu
115 120 125
Val Asn Val Ile Met Gln Gln Asp Ala Asp Leu Asp Ser Ala Val Pro
130 135 140
Asp Gly Ser Thr Ile Pro Lys Pro Thr Ala Ser Ala Ile Glu Lys Asp
145 150 155 160
Ile Leu Arg Tyr Tyr Tyr Tyr Ile His His Gly Ile Asp Thr Asp His
165 170 175
Val Ala Pro Met Glu Asp Ser Trp Leu Glu His Val Leu Asp Leu Val
180 185 190
Pro Gln His Leu Lys Val Phe Thr Asp Ser Ile Val Thr Leu Ser Asp
195 200 205
Glu Met Arg Glu Asp Tyr Leu Leu Ser Val Arg Lys Ser Ile Val Asp
210 215 220
Phe Val Leu Lys Asp Pro Arg Glu Lys Gly Asp Asp Lys Lys Thr Asp
225 230 235 240
Glu Leu Pro Ala His Arg Ala Glu Met Glu Ile Leu Pro Lys Pro Trp
245 250 255
Arg Lys Ser Phe Leu Ala Ala Ser Ser Tyr Ile Arg Asp His Leu Asn
260 265 270
Ala Met Asn Pro Thr Met Leu Ala Val Leu Asp Leu Trp His Thr Asn
275 280 285
Phe Lys Lys Leu Arg Leu Val Asp Ile Lys Glu Phe His Asn Cys Gln
290 295 300
Asp Ala Leu Glu Leu Ser Ser Phe Gln Asn Ile Ile Met Arg His Met
305 310 315 320
Asp Ser Ala Lys Glu Thr Leu Leu Lys Met Trp Phe Pro Glu Val Gln
325 330 335
Asn Ile Tyr Tyr Gln Gly Asn Lys Lys Lys Gln Leu Pro Thr Gly Asp
340 345 350
Ser Ser Ala Lys Leu Glu Ser Phe Phe Asn Cys Ala Ala Ala Leu Met
355 360 365
Thr Leu Gln Leu Gln Asp Leu Thr Leu Val Ser Met Gln Asp Phe Thr
370 375 380
Asp Leu Ile Ala Gln Pro Pro Asp Ser Val Arg Ala Phe Glu His Pro
385 390 395 400
Gly Phe Ile Met Arg Leu Ile Leu Asp Asn Asp Thr Ile Lys Phe Glu
405 410 415
Pro Glu Leu Ser Asp Tyr Ile Asp Ile Phe Leu Asn Val Tyr Asp Val
420 425 430
Met Ile Lys Ala Val Ser Phe Val Pro Arg Val Glu Thr Lys Leu Tyr
435 440 445
Ser Lys Trp Glu Ser Lys Ser Lys Pro Thr Thr Leu Lys Pro Ile Ile
450 455 460
Leu Asn Glu Ile Val Asp Ala His Lys Glu Lys Ile Lys Glu Val Ile
465 470 475 480
Met Lys Glu Ser Val Ala Pro Thr Glu His Leu Arg Leu Tyr Asp Lys
485 490 495
Tyr Asp Phe Leu Ile Thr Arg Lys Ala Glu Arg Asp Val Asp Asn Phe
500 505 510
Leu Ala Glu Asn His Ser Tyr Glu Lys Ile Ile Asp Glu Ile Cys Lys
515 520 525
Tyr Gln Lys Leu Ile Glu Glu Ile Gln Tyr Thr Ser Ile Lys Thr Ile
530 535 540
Arg Leu Gly Met Phe Glu Met His Cys Glu Glu Leu Ile Arg Ala Leu
545 550 555 560
Val Lys Arg Ala Asp Ile Ile Cys Gly Lys Leu Leu Ala Lys Met Phe
565 570 575
Arg Asp His Gln Glu Val Asn Thr Arg Leu Cys Asp Glu Phe Glu Arg
580 585 590
Ile Ala Glu Lys Ala Leu Ser Thr Pro Pro Asn Thr Ala Glu Leu Met
595 600 605
Glu Met Lys Ala Tyr Ile Gln Lys Val Glu Val Thr Asp Met Ile Glu
610 615 620
Leu Glu Gln Arg Leu Val Asp Ser Lys Asn Cys Leu Ala Phe Leu Ile
625 630 635 640
Glu Tyr Val Asn Phe Ser Pro Ala Asp Met Arg Leu Asn Asn Ser Val
645 650 655
Phe Gln Trp Tyr Gly Arg Met Gly Glu Ile Phe Glu Glu His Arg Lys
660 665 670
Ile Ile Lys Glu Lys Ile Glu Gln Tyr Gln Glu Gly Leu Lys Leu Arg
675 680 685
Cys Glu Arg Phe Val Glu Glu Leu Glu Ser Tyr Ala Lys Gln Ser Glu
690 695 700
Glu Phe Tyr Ser Phe Gly Asp Leu Gln Asp Val Gln Arg Tyr Leu Lys
705 710 715 720
Lys Ala Gln Ile Leu Asn Gly Lys Leu Asp Leu Ala Ala Asp Lys Ile
725 730 735
Glu Gln Phe Asn Ala Glu Glu Glu Ala Phe Gly Trp Leu Pro Ser Val
740 745 750
Tyr Pro Gln Arg Lys Lys Ile Gln Asp Gly Leu Asn Pro Tyr Leu Arg
755 760 765
Leu Tyr Glu Thr Ala Val Glu Phe Ser Ser Asn Tyr Arg Ala Trp Thr
770 775 780
Glu Gly Pro Tyr His Lys Val Asn Pro Asp Gln Val Glu Ala Asp Ile
785 790 795 800
Gly Asn Tyr Trp Arg Gly Leu Tyr Lys Leu Glu Lys Thr Phe His Asp
805 810 815
Ser Pro Tyr Ala Leu Ala Met Thr Lys Lys Val Arg Ser Lys Val Glu
820 825 830
Asp Phe Lys Gln His Ile Pro Leu Ile Gln Val Ile Cys Asn Pro Gly
835 840 845
Leu Arg Pro Arg His Trp Glu Ala Met Ser Ala Ile Val Gly Tyr Pro
850 855 860
Leu Gln Pro Ser Asp Asp Ser Thr Val Ser Ser Phe Leu Asp Met Asn
865 870 875 880
Leu Glu Pro Tyr Ile Asp Arg Phe Glu Gly Ile Ser Glu Ala Ala Ser
885 890 895
Lys Glu Tyr Ser Leu Glu Lys Ala Met Glu Lys Met Ile Thr Glu Trp
900 905 910
Asp Ala Val Glu Phe Val Ile His Ser Tyr Arg Glu Thr Gly Thr Phe
915 920 925
Ile Leu Ala Ser Val Asp Glu Ile Gln Met Leu Leu Asp Asp His Ile
930 935 940
Ile Lys Thr Gln Thr Met Arg Gly Ser Pro Phe Ile Lys Pro Tyr Glu
945 950 955 960
Lys Gln Met Arg Glu Trp Glu Gly Lys Leu Leu Leu Leu Gln Glu Ile
965 970 975
Leu Asp Glu Trp Leu Lys Val Gln Ala Thr Trp Leu Tyr Leu Glu Pro
980 985 990
Ile Phe Ser Ser Pro Asp Ile Met Ser Gln Met Pro Glu Glu Gly Arg
995 1000 1005
Arg Phe Thr Ala Val Asp Lys Thr Trp Arg Asp Ile Met Arg Ser
1010 1015 1020
Val Met Gln Asp Lys His Val Leu Thr Val Val Thr Ile Asp Arg
1025 1030 1035
Met Leu Glu Arg Leu Lys Lys Ser Asn Glu Leu Leu Glu Leu Ile
1040 1045 1050
Leu Lys Gly Leu Asn Glu Tyr Leu Glu Lys Lys Arg Leu Phe Phe
1055 1060 1065
Pro Arg Phe Phe Phe Leu Ser Asn Asp Glu Leu Leu Glu Ile Leu
1070 1075 1080
Ser Glu Thr Lys Asp Pro Thr Arg Val Gln Pro His Leu Lys Lys
1085 1090 1095
Cys Phe Glu Gly Ile Ala Lys Val Glu Phe Thr Glu Thr Leu Asp
1100 1105 1110
Ile Thr His Met Lys Ser Ser Glu Gly Glu Val Val Glu Leu Ile
1115 1120 1125
Glu Ile Ile Ser Thr Ala Lys Ala Arg Gly Gln Val Glu Lys Trp
1130 1135 1140
Leu Val Glu Leu Glu Arg Val Met Ile Asn Ser Ile His Lys Val
1145 1150 1155
Thr Gly Asp Ala Thr Phe Ala Tyr Thr Lys Tyr Glu Arg Ile Asn
1160 1165 1170
Trp Val Arg Asp Trp Pro Gly Gln Thr Val Leu Cys Val Ser Gln
1175 1180 1185
Ile Phe Trp Thr Lys Glu Val Gln Thr Ala Ile Pro Met Gly Ile
1190 1195 1200
Lys Ala Leu Glu Gln Tyr Leu Lys Thr Cys Asn Arg Gln Ile Asp
1205 1210 1215
Asp Ile Val Thr Leu Val Arg Gly Lys Leu Ser Met Gln Asn Arg
1220 1225 1230
Val Thr Leu Gly Ala Leu Val Val Leu Asp Val His Ala Arg Asp
1235 1240 1245
Val Leu Ser Ser Leu Val Lys Lys Asn Ile Ser Asp Asp Ser Asp
1250 1255 1260
Phe Glu Trp Leu Ser Gln Leu Arg Tyr Tyr Trp Gln Glu Asn His
1265 1270 1275
Leu Glu Thr Lys Met Ile Asn Ala Gly Leu Arg
1280 1285
<210> 103
<211> 1807
<212> PRT
<213> 智人(homo sapiens)
<400> 103
Met Met Lys Leu Tyr Ile Asp Asn Ala Ala Pro Asp Lys Leu Lys Gly
1 5 10 15
Leu Cys Ile Phe Phe Val Arg Cys Arg Asn Asp Val Ala Ile Asn Val
20 25 30
Lys Thr Ile Gln Glu Glu Ala Leu Phe Thr Val Leu Asp Ala Ser Lys
35 40 45
Gly Leu Leu Asn Gly Ile Arg Asp Met Leu Ala Asn Ile Phe Leu Pro
50 55 60
Ala Val Leu Ala Thr Asn Asn Trp Gly Ala Leu Asn Gln Ser Lys Gln
65 70 75 80
Gly Glu Ser Glu Lys His Ile Phe Thr Glu Thr Ile Asn Arg Tyr Leu
85 90 95
Ser Phe Leu Asp Gly Ala Arg Ile Ser Ile Glu Gly Thr Val Lys Leu
100 105 110
Lys Thr Ile Asp Asn Val Asn Phe Ser Lys Leu His Thr Phe Glu Glu
115 120 125
Val Thr Ala Ala Ala Ser Asn Ser Glu Thr Val His Gln Leu Glu Glu
130 135 140
Val Leu Met Val Trp Tyr Lys Gln Ile Glu Gln Val Leu Ile Glu Ser
145 150 155 160
Glu Gln Met Arg Lys Glu Ala Gly Asp Ser Gly Pro Leu Thr Glu Leu
165 170 175
Glu His Trp Lys Arg Met Ser Ala Lys Phe Asn Tyr Ile Ile Glu Gln
180 185 190
Ile Lys Gly Pro Ser Cys Lys Ala Val Ile Asn Val Leu Asn Val Ala
195 200 205
His Ser Lys Leu Leu Lys Asn Trp Arg Asp Leu Asp Ala Arg Ile Thr
210 215 220
Asp Thr Ala Asn Glu Ser Lys Asp Asn Val Arg Tyr Leu Tyr Thr Leu
225 230 235 240
Glu Lys Val Cys Gln Pro Leu Tyr Asn His Asp Leu Val Ser Met Ala
245 250 255
His Gly Ile Gln Asn Leu Ile Asn Ala Ile Arg Met Ile His Gly Val
260 265 270
Ser Arg Tyr Tyr Asn Thr Ser Glu Arg Met Thr Ser Leu Phe Ile Lys
275 280 285
Val Thr Asn Gln Met Val Thr Ala Cys Lys Ala Tyr Ile Thr Asp Gly
290 295 300
Gly Leu Asn His Val Trp Asp Gln Glu Thr Pro Val Val Leu Lys Lys
305 310 315 320
Ile Gln Asp Cys Ile Phe Leu Phe Lys Glu Tyr Gln Ala Ser Phe His
325 330 335
Lys Thr Arg Lys Leu Ile Ser Glu Ser Ser Gly Glu Lys Ser Phe Glu
340 345 350
Val Ser Glu Met Tyr Ile Phe Gly Lys Phe Glu Ala Phe Cys Lys Arg
355 360 365
Leu Glu Lys Ile Thr Glu Met Ile Thr Val Val Gln Thr Tyr Ser Thr
370 375 380
Leu Ser Asn Ser Thr Ile Glu Gly Ile Asp Ile Met Ala Ile Lys Phe
385 390 395 400
Arg Asn Ile Tyr Gln Gly Val Lys Lys Lys Gln Tyr Asp Ile Leu Asp
405 410 415
Pro Arg Arg Thr Glu Phe Asp Thr Asp Phe Leu Asp Phe Met Thr Lys
420 425 430
Ile Asn Gly Leu Glu Val Gln Ile Gln Ala Phe Met Asn Ser Ser Phe
435 440 445
Gly Lys Ile Leu Ser Ser Gln Gln Ala Leu Gln Leu Leu Gln Arg Phe
450 455 460
Gln Lys Leu Asn Ile Pro Cys Leu Gly Leu Glu Ile Asn His Thr Ile
465 470 475 480
Glu Arg Ile Leu Gln Tyr Tyr Val Ala Glu Leu Asp Ala Thr Lys Lys
485 490 495
Leu Tyr His Ser Gln Lys Asp Asp Pro Pro Leu Ala Arg Asn Met Pro
500 505 510
Pro Ile Ala Gly Lys Ile Leu Trp Val Arg Gln Leu Tyr Arg Arg Ile
515 520 525
Ser Glu Pro Ile Asn Tyr Phe Phe Lys Asn Ser Asp Ile Leu Ser Ser
530 535 540
Pro Asp Gly Lys Ala Val Ile Arg Gln Tyr Asn Lys Ile Ser Tyr Val
545 550 555 560
Leu Val Glu Phe Glu Val Val Tyr His Thr Ala Trp Ile Arg Glu Ile
565 570 575
Ser Gln Leu His Tyr Ala Leu Gln Ala Thr Leu Phe Val Arg His Pro
580 585 590
Glu Thr Gly Lys Leu Leu Val Asn Phe Asp Pro Lys Ile Leu Glu Val
595 600 605
Val Arg Glu Thr Lys Cys Met Ile Lys Met Lys Leu Asp Val Pro Glu
610 615 620
Gln Ala Lys Arg Leu Leu Lys Leu Glu Ser Lys Leu Lys Ala Asp Lys
625 630 635 640
Leu Tyr Leu Gln Gly Leu Leu Gln Tyr Tyr Asp Glu Leu Cys Gln Glu
645 650 655
Val Pro Ser Val Phe Val Asn Leu Met Thr Pro Lys Met Lys Lys Val
660 665 670
Glu Ser Val Leu Arg Gln Gly Leu Thr Val Leu Thr Trp Ser Ser Leu
675 680 685
Thr Leu Glu Ser Phe Phe Gln Glu Val Glu Leu Val Leu Asp Met Phe
690 695 700
Asn Gln Leu Leu Lys Lys Ile Ser Asp Leu Cys Glu Met His Ile Asp
705 710 715 720
Thr Val Leu Lys Glu Ile Ala Lys Thr Val Leu Ile Ser Leu Pro Glu
725 730 735
Ser Gly Ala Thr Lys Val Glu Asp Met Leu Thr Leu Asn Glu Thr Tyr
740 745 750
Thr Lys Glu Trp Ala Asp Ile Leu Asn His Lys Ser Lys His Val Glu
755 760 765
Glu Ala Val Arg Glu Leu Ile Ser Ile Phe Glu Gln Ile Tyr Glu Val
770 775 780
Lys Tyr Thr Gly Lys Val Gly Lys Gln Ser Glu Gln Arg Lys His Val
785 790 795 800
Val Phe Gly Ser Glu Thr Gly Glu Gly Glu Asn Asn Asp Tyr Glu Ala
805 810 815
Asn Ile Val Asn Glu Phe Asp Thr His Asp Lys Glu Asp Glu Phe Lys
820 825 830
Lys Glu Cys Lys Glu Val Phe Ala Phe Phe Ser His Gln Leu Leu Asp
835 840 845
Ser Leu Gln Lys Ala Thr Arg Leu Ser Leu Asp Thr Met Lys Arg Arg
850 855 860
Ile Phe Val Ala Ser Leu Tyr Gly Arg Lys Gln Ser Glu Asp Ile Ile
865 870 875 880
Ser Phe Ile Lys Ser Glu Val His Leu Ala Ile Pro Asn Val Val Met
885 890 895
Ile Pro Ser Leu Asp Asp Ile Gln Gln Ala Ile Asn Arg Met Ile Gln
900 905 910
Leu Thr Leu Glu Val Ser Arg Gly Val Ala His Trp Gly Gln Gln Gln
915 920 925
Ile Arg Pro Ile Lys Ser Val Ile Pro Ser Pro Thr Thr Thr Asp Val
930 935 940
Thr His Gln Asn Thr Gly Lys Leu Leu Lys Lys Glu Glu Arg Ser Phe
945 950 955 960
Glu Glu Ala Ile Pro Ala Arg Lys Leu Lys Asn Phe Tyr Pro Gly Val
965 970 975
Ala Glu His Lys Asp Ile Ser Lys Leu Val Leu Leu Leu Ser Ser Ser
980 985 990
Val Asn Ser Leu Arg Lys Ala Ala His Glu Ala Leu Gln Asp Phe Gln
995 1000 1005
Lys Tyr Lys Thr Leu Trp Thr Glu Asp Arg Asp Val Lys Val Lys
1010 1015 1020
Glu Phe Leu Ala Asn Asn Pro Ser Leu Thr Glu Ile Arg Ser Glu
1025 1030 1035
Ile Leu His Tyr Ala Thr Phe Glu Gln Glu Ile Asp Glu Leu Lys
1040 1045 1050
Pro Ile Ile Val Val Gly Ala Leu Glu Leu His Thr Glu Pro Met
1055 1060 1065
Lys Leu Ala Leu Ser Ile Glu Ala Lys Ala Trp Lys Met Leu Leu
1070 1075 1080
Cys Arg Tyr Leu Asn Glu Glu Tyr Lys Lys Lys Met Ser Tyr Met
1085 1090 1095
Ile Ala Phe Ile Asn Glu Tyr Leu Lys Lys Leu Ser Arg Pro Ile
1100 1105 1110
Arg Asp Leu Asp Asp Val Arg Phe Ala Met Glu Ala Leu Ser Cys
1115 1120 1125
Ile Arg Asp Asn Glu Ile Gln Met Asp Met Thr Leu Gly Pro Ile
1130 1135 1140
Glu Glu Ala Tyr Ala Ile Leu Asn Arg Phe Glu Val Glu Val Thr
1145 1150 1155
Lys Glu Glu Ser Glu Ala Val Asp Thr Leu Arg Tyr Ser Phe Asn
1160 1165 1170
Lys Leu Gln Ser Lys Ala Val Ser Val Gln Glu Asp Leu Val Gln
1175 1180 1185
Val Gln Pro Lys Phe Lys Ser Asn Leu Leu Glu Ser Val Glu Val
1190 1195 1200
Phe Arg Glu Asp Val Ile Asn Phe Ala Glu Ala Tyr Glu Leu Glu
1205 1210 1215
Gly Pro Met Val Pro Asn Ile Pro Pro Gln Glu Ala Ser Asn Arg
1220 1225 1230
Leu Gln Ile Phe Gln Ala Ser Phe Asp Asp Leu Trp Arg Lys Phe
1235 1240 1245
Val Thr Tyr Ser Ser Gly Glu Gln Leu Phe Gly Leu Pro Val Thr
1250 1255 1260
Asp Tyr Glu Val Leu His Lys Thr Arg Lys Glu Leu Asn Leu Leu
1265 1270 1275
Gln Lys Leu Tyr Gly Leu Tyr Asp Thr Val Met Ser Ser Ile Ser
1280 1285 1290
Gly Tyr Tyr Glu Ile Leu Trp Gly Asp Val Asp Ile Glu Lys Ile
1295 1300 1305
Asn Ala Glu Leu Leu Glu Phe Gln Asn Arg Cys Arg Lys Leu Pro
1310 1315 1320
Lys Gly Leu Lys Asp Trp Gln Ala Phe Leu Asp Leu Lys Lys Arg
1325 1330 1335
Ile Asp Asp Phe Ser Glu Ser Cys Pro Leu Leu Glu Met Met Thr
1340 1345 1350
Asn Lys Ala Met Lys Gln Arg His Trp Asp Arg Ile Ser Glu Leu
1355 1360 1365
Thr Gly Thr Pro Phe Asp Val Glu Ser Asp Ser Phe Cys Leu Arg
1370 1375 1380
Asn Ile Met Glu Ala Pro Leu Leu Lys His Lys Asp Asp Ile Glu
1385 1390 1395
Asp Ile Cys Ile Ser Ala Ile Lys Glu Lys Asp Ile Glu Ala Lys
1400 1405 1410
Leu Thr Gln Val Ile Glu Asn Trp Thr Asn Gln Asn Leu Ser Phe
1415 1420 1425
Ala Ala Phe Lys Gly Lys Gly Glu Leu Leu Leu Lys Gly Thr Glu
1430 1435 1440
Ser Gly Glu Ile Ile Thr Leu Met Glu Asp Ser Leu Met Val Leu
1445 1450 1455
Gly Ser Leu Leu Ser Asn Arg Tyr Asn Ala Pro Phe Lys Lys Asn
1460 1465 1470
Ile Gln Asn Trp Val Tyr Lys Leu Ser Thr Ser Ser Asp Ile Ile
1475 1480 1485
Glu Glu Trp Leu Val Val Gln Asn Leu Trp Val Tyr Leu Glu Ala
1490 1495 1500
Val Phe Val Gly Gly Asp Ile Ala Lys Gln Leu Pro Gln Glu Ala
1505 1510 1515
Lys Arg Phe Gln Asn Ile Asp Lys Ser Trp Ile Lys Ile Met Gln
1520 1525 1530
Arg Ala His Glu Asn Pro Asn Val Ile Asn Cys Cys Val Gly Asp
1535 1540 1545
Glu Thr Met Gly Gln Leu Leu Pro His Leu His Glu Gln Leu Glu
1550 1555 1560
Val Cys Gln Lys Ser Leu Thr Gly Tyr Leu Glu Lys Lys Arg Leu
1565 1570 1575
Leu Phe Pro Arg Phe Phe Phe Val Ser Asp Pro Val Leu Leu Glu
1580 1585 1590
Ile Leu Gly Gln Ala Ser Asp Ser His Thr Ile Gln Pro His Leu
1595 1600 1605
Pro Ala Val Ser Asp Asn Ile Asn Glu Val Thr Phe His Ala Lys
1610 1615 1620
Asp Tyr Asp Arg Ile Met Ala Val Ile Ser Arg Glu Gly Glu Lys
1625 1630 1635
Ile Val Leu Asp Asn Ser Val Met Ala Lys Gly Pro Val Glu Ile
1640 1645 1650
Trp Leu Leu Asp Leu Leu Lys Met Gln Met Ser Ser Leu His Asn
1655 1660 1665
Ile Ile Arg Ser Ala Phe Tyr Gln Ile Ser Asp Ser Gly Phe Gln
1670 1675 1680
Leu Leu Pro Phe Leu Ser His Phe Pro Ala Gln Val Gly Leu Leu
1685 1690 1695
Gly Ile Gln Met Leu Trp Thr His Asp Ser Glu Glu Ala Leu Arg
1700 1705 1710
Asn Ala Lys Asp Asp Arg Lys Ile Met Gln Val Thr Asn Gln Lys
1715 1720 1725
Phe Leu Asp Ile Leu Asn Thr Leu Ile Ser Gln Thr Thr His Asp
1730 1735 1740
Leu Ser Lys Phe Asp Arg Val Lys Phe Glu Thr Leu Ile Thr Ile
1745 1750 1755
His Val His Gln Arg Asp Ile Phe Asp Asp Leu Val Lys Met His
1760 1765 1770
Ile Lys Ser Pro Thr Asp Phe Glu Trp Leu Lys Gln Ser Arg Phe
1775 1780 1785
Tyr Phe Lys Glu Asp Leu Asp Gln Thr Val Val Ser Ile Thr Asp
1790 1795 1800
Val Asp Phe Ile
1805
<210> 104
<211> 1831
<212> PRT
<213> 智人(homo sapiens)
<400> 104
Met Arg Leu Ala Glu Glu Arg Ala Ala Leu Ala Ala Glu Asn Ala Asp
1 5 10 15
Gly Glu Pro Gly Ala Asp Arg Arg Leu Arg Leu Leu Gly Thr Tyr Val
20 25 30
Ala Met Ser Leu Arg Pro Ala Ala Gly Ala Trp Glu Arg Cys Ala Gly
35 40 45
Ser Ala Glu Ala Glu Gln Leu Leu Gln Ala Phe Leu Gly Arg Asp Ala
50 55 60
Ala Glu Gly Pro Arg Pro Leu Leu Val Val Arg Pro Gly Pro Arg Gly
65 70 75 80
Leu Ala Ile Arg Pro Gly Leu Glu Val Gly Pro Glu Ser Gly Leu Ala
85 90 95
Gly Ala Lys Ala Leu Phe Phe Leu Arg Thr Gly Pro Glu Pro Pro Gly
100 105 110
Pro Asp Ser Phe Arg Gly Ala Val Val Cys Gly Asp Leu Pro Ala Ala
115 120 125
Pro Leu Glu His Leu Ala Ala Leu Phe Ser Glu Val Val Leu Pro Val
130 135 140
Leu Ala Asn Glu Lys Asn Arg Leu Asn Trp Pro His Met Ile Cys Glu
145 150 155 160
Asp Val Arg Arg His Ala His Ser Leu Gln Cys Asp Leu Ser Val Ile
165 170 175
Leu Glu Gln Val Lys Gly Lys Thr Leu Leu Pro Leu Pro Ala Gly Ser
180 185 190
Glu Lys Met Glu Phe Ala Asp Ser Lys Ser Glu Thr Val Leu Asp Ser
195 200 205
Ile Asp Lys Ser Val Ile Tyr Ala Ile Glu Ser Ala Val Ile Lys Trp
210 215 220
Ser Tyr Gln Val Gln Val Val Leu Lys Arg Glu Ser Ser Gln Pro Leu
225 230 235 240
Leu Gln Gly Glu Asn Pro Thr Pro Lys Val Glu Leu Glu Phe Trp Lys
245 250 255
Ser Arg Tyr Glu Asp Leu Lys Tyr Ile Tyr Asn Gln Leu Arg Thr Ile
260 265 270
Thr Val Arg Gly Met Ala Lys Leu Leu Asp Lys Leu Gln Ser Ser Tyr
275 280 285
Phe Pro Ala Phe Lys Ala Met Tyr Arg Asp Val Val Ala Ala Leu Ala
290 295 300
Glu Ala Gln Asp Ile His Val His Leu Ile Pro Leu Gln Arg His Leu
305 310 315 320
Glu Ala Leu Glu Asn Ala Glu Phe Pro Glu Val Lys Pro Gln Leu Arg
325 330 335
Pro Leu Leu His Val Val Cys Leu Ile Trp Ala Thr Cys Lys Ser Tyr
340 345 350
Arg Ser Pro Gly Arg Leu Thr Val Leu Leu Gln Glu Ile Cys Asn Leu
355 360 365
Leu Ile Gln Gln Ala Ser Asn Tyr Leu Ser Pro Glu Asp Leu Leu Arg
370 375 380
Ser Glu Val Glu Glu Ser Gln Arg Lys Leu Gln Val Val Ser Asp Thr
385 390 395 400
Leu Ser Phe Phe Lys Gln Glu Phe Gln Asp Arg Arg Glu Asn Leu His
405 410 415
Thr Tyr Phe Lys Glu Asn Gln Glu Val Lys Glu Trp Asp Phe Gln Ser
420 425 430
Ser Leu Val Phe Val Arg Leu Asp Gly Phe Leu Gly Gln Leu His Val
435 440 445
Val Glu Gly Leu Leu Lys Thr Ala Leu Asp Phe His Lys Leu Gly Lys
450 455 460
Val Glu Phe Ser Gly Val Arg Gly Asn Ala Leu Ser Gln Gln Val Gln
465 470 475 480
Gln Met His Glu Glu Phe Gln Glu Met Tyr Arg Leu Leu Ser Gly Ser
485 490 495
Ser Ser Asp Cys Leu Tyr Leu Gln Ser Thr Asp Phe Glu Asn Asp Val
500 505 510
Ser Glu Phe Asn Gln Lys Val Glu Asp Leu Asp Arg Arg Leu Gly Thr
515 520 525
Ile Phe Ile Gln Ala Phe Asp Asp Ala Pro Gly Leu Glu His Ala Phe
530 535 540
Lys Leu Leu Asp Ile Ala Gly Asn Leu Leu Glu Arg Pro Leu Val Ala
545 550 555 560
Arg Asp Thr Ser Asp Lys Tyr Leu Val Leu Ile Gln Met Phe Asn Lys
565 570 575
Asp Leu Asp Ala Val Arg Met Ile Tyr Ser Gln His Val Gln Glu Glu
580 585 590
Ala Glu Leu Gly Phe Ser Pro Val His Lys Asn Met Pro Thr Val Ala
595 600 605
Gly Gly Leu Arg Trp Ala Gln Glu Leu Arg Gln Arg Ile Gln Gly Pro
610 615 620
Phe Ser Asn Phe Gly Arg Ile Thr His Pro Cys Met Glu Ser Ala Glu
625 630 635 640
Gly Lys Arg Met Gln Gln Lys Tyr Glu Asp Met Leu Ser Leu Leu Glu
645 650 655
Lys Tyr Glu Thr Arg Leu Tyr Glu Asp Trp Cys Arg Thr Val Ser Glu
660 665 670
Lys Ser Gln Tyr Asn Leu Ser Gln Pro Leu Leu Lys Arg Asp Pro Glu
675 680 685
Thr Lys Glu Ile Thr Ile Asn Phe Asn Pro Gln Leu Ile Ser Val Leu
690 695 700
Lys Glu Met Ser Tyr Leu Glu Pro Arg Glu Met Lys His Met Pro Glu
705 710 715 720
Thr Ala Ala Ala Met Phe Ser Ser Arg Asp Phe Tyr Arg Gln Leu Val
725 730 735
Ala Asn Leu Glu Leu Met Ala Asn Trp Tyr Asn Lys Val Met Lys Thr
740 745 750
Leu Leu Glu Val Glu Phe Pro Leu Val Glu Glu Glu Leu Gln Asn Ile
755 760 765
Asp Leu Arg Leu Arg Ala Ala Glu Glu Thr Leu Asn Trp Lys Thr Glu
770 775 780
Gly Ile Cys Asp Tyr Val Thr Glu Ile Thr Ser Ser Ile His Asp Leu
785 790 795 800
Glu Gln Arg Ile Gln Lys Thr Lys Asp Asn Val Glu Glu Ile Gln Asn
805 810 815
Ile Met Lys Thr Trp Val Thr Pro Ile Phe Lys Thr Lys Asp Gly Lys
820 825 830
Arg Glu Ser Leu Leu Ser Leu Asp Asp Arg His Asp Arg Met Glu Lys
835 840 845
Tyr Tyr Asn Leu Ile Lys Glu Ser Gly Leu Lys Ile His Ala Leu Val
850 855 860
Gln Glu Asn Leu Gly Leu Phe Ser Ala Asp Pro Thr Ser Asn Ile Trp
865 870 875 880
Lys Thr Tyr Val Asn Ser Ile Asp Asn Leu Leu Leu Asn Gly Phe Phe
885 890 895
Leu Ala Ile Glu Cys Ser Leu Lys Tyr Leu Leu Glu Asn Thr Glu Cys
900 905 910
Lys Ala Gly Leu Thr Pro Ile Phe Glu Ala Gln Leu Ser Leu Ala Ile
915 920 925
Pro Glu Leu Val Phe Tyr Pro Ser Leu Glu Ser Gly Val Lys Gly Gly
930 935 940
Phe Cys Asp Ile Val Glu Gly Leu Ile Thr Ser Ile Phe Arg Ile Pro
945 950 955 960
Ser Leu Val Pro Arg Leu Ser Pro Gln Asn Gly Ser Pro His Tyr Gln
965 970 975
Val Asp Leu Asp Gly Ile Pro Asp Leu Ala Asn Met Arg Arg Thr Leu
980 985 990
Met Glu Arg Val Gln Arg Met Met Gly Leu Cys Cys Gly Tyr Gln Ser
995 1000 1005
Thr Phe Ser Gln Tyr Ser Tyr Leu Tyr Val Glu Asp Arg Lys Glu
1010 1015 1020
Val Leu Gly Gln Phe Leu Leu Tyr Gly His Ile Leu Thr Pro Glu
1025 1030 1035
Glu Ile Glu Asp His Val Glu Asp Gly Ile Pro Glu Asn Pro Pro
1040 1045 1050
Leu Leu Ser Gln Phe Lys Val Gln Ile Asp Ser Tyr Glu Thr Leu
1055 1060 1065
Tyr Glu Glu Val Cys Arg Leu Glu Pro Ile Lys Val Phe Asp Gly
1070 1075 1080
Trp Met Lys Ile Asp Ile Arg Pro Phe Lys Ala Ser Leu Leu Asn
1085 1090 1095
Ile Ile Lys Arg Trp Ser Leu Leu Phe Lys Gln His Leu Val Asp
1100 1105 1110
His Val Thr His Ser Leu Ala Asn Leu Asp Ala Phe Ile Lys Lys
1115 1120 1125
Ser Glu Ser Gly Leu Leu Lys Lys Val Glu Lys Gly Asp Phe Gln
1130 1135 1140
Gly Leu Val Glu Ile Met Gly His Leu Met Ala Val Lys Glu Arg
1145 1150 1155
Gln Ser Asn Thr Asp Glu Met Phe Glu Pro Leu Lys Gln Thr Ile
1160 1165 1170
Glu Leu Leu Lys Thr Tyr Glu Gln Glu Leu Pro Glu Thr Val Phe
1175 1180 1185
Lys Gln Leu Glu Glu Leu Pro Glu Lys Trp Asn Asn Ile Lys Lys
1190 1195 1200
Val Ala Ile Thr Val Lys Gln Gln Val Ala Pro Leu Gln Ala Asn
1205 1210 1215
Glu Val Thr Leu Leu Arg Gln Arg Cys Thr Ala Phe Asp Ala Glu
1220 1225 1230
Gln Gln Gln Phe Trp Glu Gln Phe His Lys Glu Ala Pro Phe Arg
1235 1240 1245
Phe Asp Ser Ile His Pro His Gln Met Leu Asp Ala Arg His Ile
1250 1255 1260
Glu Ile Gln Gln Met Glu Ser Thr Met Ala Ser Ile Ser Glu Ser
1265 1270 1275
Ala Ser Leu Phe Glu Val Asn Val Pro Asp Tyr Lys Gln Leu Arg
1280 1285 1290
Gln Cys Arg Lys Glu Val Cys Gln Leu Lys Glu Leu Trp Asp Thr
1295 1300 1305
Ile Gly Met Val Thr Ser Ser Ile His Ala Trp Glu Thr Thr Pro
1310 1315 1320
Trp Arg Asn Ile Asn Val Glu Ala Met Glu Leu Glu Cys Lys Gln
1325 1330 1335
Phe Ala Arg His Ile Arg Asn Leu Asp Lys Glu Val Arg Ala Trp
1340 1345 1350
Asp Ala Phe Thr Gly Leu Glu Ser Thr Val Trp Asn Thr Leu Ser
1355 1360 1365
Ser Leu Arg Ala Val Ala Glu Leu Gln Asn Pro Ala Ile Arg Glu
1370 1375 1380
Arg His Trp Arg Gln Leu Met Gln Ala Thr Gly Val Ser Phe Thr
1385 1390 1395
Met Asp Gln Asp Thr Thr Leu Ala His Leu Leu Gln Leu Gln Leu
1400 1405 1410
His His Tyr Glu Asp Glu Val Arg Gly Ile Val Asp Lys Ala Ala
1415 1420 1425
Lys Glu Met Gly Met Glu Lys Thr Leu Lys Glu Leu Gln Thr Thr
1430 1435 1440
Trp Ala Gly Met Glu Phe Gln Tyr Glu Pro His Pro Arg Thr Asn
1445 1450 1455
Val Pro Leu Leu Cys Ser Asp Glu Asp Leu Ile Glu Val Leu Glu
1460 1465 1470
Asp Asn Gln Val Gln Leu Gln Asn Leu Val Met Ser Lys Tyr Val
1475 1480 1485
Ala Phe Phe Leu Glu Glu Val Ser Gly Trp Gln Lys Lys Leu Ser
1490 1495 1500
Thr Val Asp Ala Val Ile Ser Ile Trp Phe Glu Val Gln Arg Thr
1505 1510 1515
Trp Thr His Leu Glu Ser Ile Phe Thr Gly Ser Glu Asp Ile Arg
1520 1525 1530
Ala Gln Leu Pro Gln Asp Ser Lys Arg Phe Glu Gly Ile Asp Ile
1535 1540 1545
Asp Phe Lys Glu Leu Ala Tyr Asp Ala Gln Lys Ile Pro Asn Val
1550 1555 1560
Val Gln Thr Thr Asn Lys Pro Gly Leu Tyr Glu Lys Leu Glu Asp
1565 1570 1575
Ile Gln Gly Arg Leu Cys Leu Cys Glu Lys Ala Leu Ala Glu Tyr
1580 1585 1590
Leu Asp Thr Lys Arg Leu Ala Phe Pro Arg Phe Tyr Phe Leu Ser
1595 1600 1605
Ser Ser Asp Leu Leu Asp Ile Leu Ser Asn Gly Thr Ala Pro Gln
1610 1615 1620
Gln Val Gln Arg His Leu Ser Lys Leu Phe Asp Asn Met Ala Lys
1625 1630 1635
Met Arg Phe Gln Leu Asp Ala Ser Gly Glu Pro Thr Lys Thr Ser
1640 1645 1650
Leu Gly Met Tyr Ser Lys Glu Glu Glu Tyr Val Ala Phe Ser Glu
1655 1660 1665
Pro Cys Asp Cys Ser Gly Gln Val Glu Ile Trp Leu Asn His Val
1670 1675 1680
Leu Gly His Met Lys Ala Thr Val Arg His Glu Met Thr Glu Gly
1685 1690 1695
Val Thr Ala Tyr Glu Glu Lys Pro Arg Glu Gln Trp Leu Phe Asp
1700 1705 1710
His Pro Ala Gln Val Ala Leu Thr Cys Thr Gln Ile Trp Trp Thr
1715 1720 1725
Thr Glu Val Gly Met Ala Phe Ala Arg Leu Glu Glu Gly Tyr Glu
1730 1735 1740
Ser Ala Met Lys Asp Tyr Tyr Lys Lys Gln Val Ala Gln Leu Lys
1745 1750 1755
Thr Leu Ile Thr Met Leu Ile Gly Gln Leu Ser Lys Gly Asp Arg
1760 1765 1770
Gln Lys Ile Met Thr Ile Cys Thr Ile Asp Val His Ala Arg Asp
1775 1780 1785
Val Val Ala Lys Met Ile Ala Gln Lys Val Asp Asn Ala Gln Ala
1790 1795 1800
Phe Leu Trp Leu Ser Gln Leu Arg His Arg Trp Asp Asp Glu Val
1805 1810 1815
Lys His Cys Phe Ala Asn Ile Cys Asp Ala Gln Phe Leu
1820 1825 1830
<210> 105
<211> 1793
<212> PRT
<213> 智人(homo sapiens)
<400> 105
Met Val Pro Glu Glu Val Glu Val Glu Ile Asp Glu Ile Pro Val Leu
1 5 10 15
Ser Glu Glu Gly Glu Glu Glu Glu Glu Thr Tyr Ser Gln Lys Val Glu
20 25 30
Ser Val Asp Lys Val Arg Ala Lys Arg Val Ser Leu Arg Thr Glu Ser
35 40 45
Leu Gly Gln Pro Leu Asn Arg Glu Asp Glu Glu Met Asp Lys Glu Ile
50 55 60
Ser Glu Lys Leu Pro Ser Lys Arg Thr Ala Lys His Ile Met Glu Lys
65 70 75 80
Met His Leu His Met Leu Cys Thr Pro Leu Pro Glu Glu Phe Leu Asp
85 90 95
Gln Asn Val Val Phe Phe Leu Arg Asn Thr Lys Glu Ala Ile Ser Glu
100 105 110
Ala Thr Asp Met Lys Glu Ala Met Glu Ile Met Pro Glu Thr Leu Glu
115 120 125
Tyr Gly Ile Ile Asn Ala Asn Val Leu His Phe Leu Lys Asn Ile Ile
130 135 140
Cys Gln Val Phe Leu Pro Ala Leu Ser Phe Asn Gln His Arg Thr Ser
145 150 155 160
Thr Thr Val Gly Val Thr Ser Gly Glu Val Ser Asn Ser Ser Glu His
165 170 175
Glu Ser Asp Leu Pro Pro Met Pro Gly Glu Ala Val Glu Tyr His Ser
180 185 190
Ile Gln Leu Ile Arg Asp Glu Phe Leu Met Asn Val Gln Lys Phe Ala
195 200 205
Ser Asn Ile Gln Arg Thr Met Gln Gln Leu Glu Gly Glu Ile Lys Leu
210 215 220
Glu Met Pro Ile Ile Ser Val Glu Gly Glu Val Ser Asp Leu Ala Ala
225 230 235 240
Asp Pro Glu Thr Val Asp Ile Leu Glu Gln Cys Val Ile Asn Trp Leu
245 250 255
Asn Gln Ile Ser Thr Ala Val Glu Ala Gln Leu Lys Lys Thr Pro Gln
260 265 270
Gly Lys Gly Pro Leu Ala Glu Ile Glu Phe Trp Arg Glu Arg Asn Ala
275 280 285
Thr Leu Ser Ala Leu His Glu Gln Thr Lys Leu Pro Ile Val Arg Lys
290 295 300
Val Leu Asp Val Ile Lys Glu Ser Asp Ser Met Leu Val Ala Asn Leu
305 310 315 320
Gln Pro Val Phe Thr Glu Leu Phe Lys Phe His Thr Glu Ala Ser Asp
325 330 335
Asn Val Arg Phe Leu Ser Thr Val Glu Arg Tyr Phe Lys Asn Ile Thr
340 345 350
His Gly Ser Gly Phe His Val Val Leu Asp Thr Ile Pro Ala Met Met
355 360 365
Ser Ala Leu Arg Met Val Trp Ile Ile Ser Arg His Tyr Asn Lys Asp
370 375 380
Glu Arg Met Ile Pro Leu Met Glu Arg Ile Ala Trp Glu Ile Ala Glu
385 390 395 400
Arg Val Cys Arg Val Val Asn Leu Arg Thr Leu Phe Lys Glu Asn Arg
405 410 415
Ala Ser Ala Gln Ser Lys Thr Leu Glu Ala Arg Asn Thr Leu Arg Leu
420 425 430
Trp Lys Lys Ala Tyr Phe Asp Thr Arg Ala Lys Ile Glu Ala Ser Gly
435 440 445
Arg Glu Asp Arg Trp Glu Phe Asp Arg Lys Arg Leu Phe Glu Arg Thr
450 455 460
Asp Tyr Met Ala Thr Ile Cys Gln Asp Leu Ser Asp Val Leu Gln Ile
465 470 475 480
Leu Glu Glu Phe Tyr Asn Ile Phe Gly Pro Glu Leu Lys Ala Val Thr
485 490 495
Gly Asp Pro Lys Arg Ile Asp Asp Val Leu Cys Arg Val Asp Gly Leu
500 505 510
Val Thr Pro Met Glu Asn Leu Thr Phe Asp Pro Phe Ser Ile Lys Ser
515 520 525
Ser Gln Phe Trp Lys Tyr Val Met Asp Glu Phe Lys Ile Glu Val Leu
530 535 540
Ile Asp Ile Ile Asn Lys Ile Phe Val Gln Asn Leu Glu Asn Pro Pro
545 550 555 560
Leu Tyr Lys Asn His Pro Pro Val Ala Gly Ala Ile Tyr Trp Glu Arg
565 570 575
Ser Leu Phe Phe Arg Ile Lys His Thr Ile Leu Arg Phe Gln Glu Val
580 585 590
Gln Glu Ile Leu Asp Ser Asp Arg Gly Gln Glu Val Lys Gln Lys Tyr
595 600 605
Leu Glu Val Gly Arg Thr Met Lys Glu Tyr Glu Asp Arg Lys Tyr Glu
610 615 620
Gln Trp Met Glu Val Thr Glu Gln Val Leu Pro Ala Leu Met Lys Lys
625 630 635 640
Ser Leu Leu Thr Lys Ser Ser Ile Ala Thr Glu Glu Pro Ser Thr Leu
645 650 655
Glu Arg Gly Ala Val Phe Ala Ile Asn Phe Ser Pro Ala Leu Arg Glu
660 665 670
Ile Ile Asn Glu Thr Lys Tyr Leu Glu Gln Leu Gly Phe Thr Val Pro
675 680 685
Glu Leu Ala Arg Asn Val Ala Leu Gln Glu Asp Lys Phe Leu Arg Tyr
690 695 700
Thr Ala Gly Ile Gln Arg Met Leu Asp His Tyr His Met Leu Ile Gly
705 710 715 720
Thr Leu Asn Asp Ala Glu Ser Val Leu Leu Lys Asp His Ser Gln Glu
725 730 735
Leu Leu Arg Val Phe Arg Ser Gly Tyr Lys Arg Leu Asn Trp Asn Ser
740 745 750
Leu Gly Ile Gly Asp Tyr Ile Thr Gly Cys Lys Gln Ala Ile Gly Lys
755 760 765
Phe Glu Ser Leu Val His Gln Ile His Lys Asn Ala Asp Asp Ile Ser
770 775 780
Ser Arg Leu Thr Leu Ile Glu Ala Ile Asn Leu Phe Lys Tyr Pro Ala
785 790 795 800
Ala Lys Ser Glu Glu Glu Leu Pro Gly Val Lys Glu Phe Phe Glu His
805 810 815
Ile Glu Arg Glu Arg Ala Ser Asp Val Asp His Met Val Arg Trp Tyr
820 825 830
Leu Ala Ile Gly Pro Leu Leu Thr Lys Val Glu Gly Leu Val Val His
835 840 845
Thr Asn Thr Gly Lys Ala Pro Lys Leu Ala Ser Tyr Tyr Lys Tyr Trp
850 855 860
Glu Lys Lys Ile Tyr Glu Val Leu Thr Lys Leu Ile Leu Lys Asn Leu
865 870 875 880
Gln Ser Phe Asn Ser Leu Ile Leu Gly Asn Val Pro Leu Phe His Thr
885 890 895
Glu Thr Ile Leu Thr Ala Pro Glu Ile Ile Leu His Pro Asn Thr Asn
900 905 910
Glu Ile Asp Lys Met Cys Phe His Cys Val Arg Asn Cys Val Glu Ile
915 920 925
Thr Lys His Phe Val Arg Trp Met Asn Gly Ser Cys Ile Glu Cys Pro
930 935 940
Pro Gln Lys Gly Glu Glu Glu Glu Val Val Ile Ile Asn Phe Tyr Asn
945 950 955 960
Asp Ile Ser Leu Asn Pro Gln Ile Ile Glu Gln Ala Val Met Ile Pro
965 970 975
Gln Asn Val His Arg Ile Leu Ile Asn Leu Met Lys Tyr Leu Gln Lys
980 985 990
Trp Lys Arg Tyr Arg Pro Leu Trp Lys Leu Asp Lys Ala Ile Val Met
995 1000 1005
Glu Lys Phe Ala Ala Lys Lys Pro Pro Cys Val Ala Tyr Asp Glu
1010 1015 1020
Lys Leu Gln Phe Tyr Ser Lys Ile Ala Tyr Glu Val Met Arg His
1025 1030 1035
Pro Leu Ile Lys Asp Glu His Cys Ile Arg Leu Gln Leu Arg His
1040 1045 1050
Leu Ala Asn Thr Val Gln Glu Asn Ala Lys Ser Trp Val Ile Ser
1055 1060 1065
Leu Gly Lys Leu Leu Asn Glu Ser Ala Lys Glu Glu Leu Tyr Asn
1070 1075 1080
Leu His Glu Glu Met Glu His Leu Ala Lys Asn Leu Arg Lys Ile
1085 1090 1095
Pro Asn Thr Leu Glu Asp Leu Lys Phe Val Leu Ala Thr Ile Ala
1100 1105 1110
Glu Ile Arg Ser Lys Ser Leu Val Met Glu Leu Arg Tyr Arg Asp
1115 1120 1125
Val Gln Glu Arg Tyr Arg Thr Met Ala Met Tyr Asn Leu Phe Pro
1130 1135 1140
Pro Asp Ala Glu Lys Glu Leu Val Asp Lys Ile Glu Ser Ile Trp
1145 1150 1155
Ser Asn Leu Phe Asn Asp Ser Val Asn Val Glu His Ala Leu Gly
1160 1165 1170
Asp Ile Lys Arg Thr Phe Thr Glu Leu Thr Arg Gly Glu Ile Met
1175 1180 1185
Asn Tyr Arg Val Gln Ile Glu Glu Phe Ala Lys Arg Phe Tyr Ser
1190 1195 1200
Glu Gly Pro Gly Ser Val Gly Asp Asp Leu Asp Lys Gly Val Glu
1205 1210 1215
Leu Leu Gly Val Tyr Glu Arg Glu Leu Ala Arg His Glu Lys Ser
1220 1225 1230
Arg Gln Glu Leu Ala Asn Ala Glu Lys Leu Phe Asp Leu Pro Ile
1235 1240 1245
Thr Met Tyr Pro Glu Leu Leu Lys Val Gln Lys Glu Met Ser Gly
1250 1255 1260
Leu Arg Met Ile Tyr Glu Leu Tyr Glu Gly Leu Lys Val Ala Lys
1265 1270 1275
Glu Glu Trp Ser Gln Thr Leu Trp Ile Asn Leu Asn Val Gln Ile
1280 1285 1290
Leu Gln Glu Gly Ile Glu Gly Phe Leu Arg Ala Leu Arg Lys Leu
1295 1300 1305
Pro Arg Pro Val Arg Gly Leu Ser Val Thr Tyr Tyr Leu Glu Ala
1310 1315 1320
Lys Met Lys Ala Phe Lys Asp Ser Ile Pro Leu Leu Leu Asp Leu
1325 1330 1335
Lys Asn Glu Ala Leu Arg Asp Arg His Trp Lys Glu Leu Met Glu
1340 1345 1350
Lys Thr Ser Val Phe Phe Glu Met Thr Glu Thr Phe Thr Leu Glu
1355 1360 1365
Asn Met Phe Ala Met Glu Leu His Lys His Thr Asp Val Leu Asn
1370 1375 1380
Glu Ile Val Thr Ala Ala Ile Lys Glu Val Ala Ile Glu Lys Ala
1385 1390 1395
Val Lys Glu Ile Leu Asp Thr Trp Glu Asn Met Lys Phe Thr Val
1400 1405 1410
Val Lys Tyr Cys Lys Gly Thr Gln Glu Arg Gly Tyr Ile Leu Gly
1415 1420 1425
Ser Val Asp Glu Ile Ile Gln Ser Leu Asp Asp Asn Thr Phe Asn
1430 1435 1440
Leu Gln Ser Ile Ser Gly Ser Arg Phe Val Gly Pro Phe Leu Gln
1445 1450 1455
Thr Val His Lys Trp Glu Lys Thr Leu Ser Leu Ile Gly Glu Val
1460 1465 1470
Ile Glu Ile Trp Met Leu Val Gln Arg Lys Trp Met Tyr Leu Glu
1475 1480 1485
Ser Ile Phe Ile Gly Gly Asp Ile Arg Ser Gln Leu Pro Glu Glu
1490 1495 1500
Ala Lys Lys Phe Asp Asn Ile Asp Lys Val Phe Lys Arg Ile Met
1505 1510 1515
Gly Glu Thr Leu Lys Asp Pro Val Ile Lys Arg Cys Cys Glu Ala
1520 1525 1530
Pro Asn Arg Leu Ser Asp Leu Gln Asn Val Ser Glu Gly Leu Glu
1535 1540 1545
Lys Cys Gln Lys Ser Leu Asn Asp Tyr Leu Asp Ser Lys Arg Asn
1550 1555 1560
Ala Phe Pro Arg Phe Phe Phe Ile Ser Asp Asp Glu Leu Leu Ser
1565 1570 1575
Ile Leu Gly Ser Ser Asp Pro Leu Cys Val Gln Glu His Met Ile
1580 1585 1590
Lys Met Tyr Asp Asn Ile Ala Ser Leu Arg Phe Asn Asp Gly Asp
1595 1600 1605
Ser Gly Glu Lys Leu Val Ser Ala Met Ile Ser Ala Glu Gly Glu
1610 1615 1620
Val Met Glu Phe Arg Lys Ile Leu Arg Ala Glu Gly Arg Val Glu
1625 1630 1635
Asp Trp Met Thr Ala Val Leu Asn Glu Met Arg Arg Thr Asn Arg
1640 1645 1650
Leu Ile Thr Lys Glu Ala Ile Phe Arg Tyr Cys Glu Asp Arg Ser
1655 1660 1665
Arg Val Asp Trp Met Leu Leu Tyr Gln Gly Met Val Val Leu Ala
1670 1675 1680
Ala Ser Gln Val Trp Trp Thr Trp Glu Val Glu Asp Val Phe His
1685 1690 1695
Lys Ala Gln Lys Gly Glu Lys Gln Ala Met Lys Asn Tyr Gly Arg
1700 1705 1710
Lys Met His Arg Gln Ile Asp Glu Leu Val Thr Arg Ile Thr Met
1715 1720 1725
Pro Leu Ser Lys Asn Asp Arg Lys Lys Tyr Asn Thr Val Leu Ile
1730 1735 1740
Ile Asp Val His Ala Arg Asp Ile Val Asp Ser Phe Ile Arg Gly
1745 1750 1755
Ser Ile Leu Glu Ala Arg Glu Phe Asp Trp Glu Ser Gln Leu Arg
1760 1765 1770
Phe Tyr Trp Asp Arg Glu Pro Asp Glu Leu Asn Ile Arg Gln Cys
1775 1780 1785
Thr Gly Thr Phe Gly
1790
<210> 106
<211> 1854
<212> PRT
<213> 智人(homo sapiens)
<400> 106
Met Ala Ala Gln Val Ala Ala Arg Glu Ala Arg Asp Phe Arg Glu Ala
1 5 10 15
Pro Thr Leu Arg Leu Thr Ser Gly Ala Gly Leu Glu Ala Val Gly Ala
20 25 30
Val Glu Leu Glu Glu Glu Glu Glu Asn Glu Glu Glu Ala Ala Ala Arg
35 40 45
Arg Ala Arg Ser Phe Ala Gln Asp Ala Arg Val Arg Phe Leu Gly Gly
50 55 60
Arg Leu Ala Met Met Leu Gly Phe Thr Glu Glu Lys Trp Ser Gln Tyr
65 70 75 80
Leu Glu Ser Glu Asp Asn Arg Gln Val Leu Gly Glu Phe Leu Glu Ser
85 90 95
Thr Ser Pro Ala Cys Leu Val Phe Ser Phe Ala Ala Ser Gly Arg Leu
100 105 110
Ala Ala Ser Gln Glu Ile Pro Arg Asp Ala Asn His Lys Leu Val Phe
115 120 125
Ile Ser Lys Lys Ile Thr Glu Ser Ile Gly Val Asn Asp Phe Ser Gln
130 135 140
Val Val Leu Phe Gly Glu Leu Pro Ala Leu Ser Leu Gly His Val Ser
145 150 155 160
Ala Phe Leu Asp Glu Ile Leu Val Pro Val Leu Ser Asn Lys Asn Asn
165 170 175
His Lys Ser Trp Ser Cys Phe Thr Ser Gln Asp Met Glu Tyr His Ile
180 185 190
Glu Val Met Lys Lys Lys Met Tyr Ile Phe Arg Gly Lys Met Ser Arg
195 200 205
Arg Thr Leu Leu Pro Ile Pro Thr Val Ala Gly Lys Met Asp Leu Asp
210 215 220
Gln Asn Cys Ser Glu Asn Lys Pro Pro Ser Asn Glu Arg Ile Ile Leu
225 230 235 240
His Ala Ile Glu Ser Val Val Ile Glu Trp Ser His Gln Ile Gln Glu
245 250 255
Ile Ile Glu Arg Asp Ser Val Gln Arg Leu Leu Asn Gly Leu His Leu
260 265 270
Ser Pro Gln Ala Glu Leu Asp Phe Trp Met Met Arg Arg Glu Asn Leu
275 280 285
Ser Cys Ile Tyr Asp Gln Leu Gln Ala Pro Val Val Leu Lys Met Val
290 295 300
Lys Ile Leu Thr Thr Lys Gln Ser Ser Tyr Phe Pro Thr Leu Lys Asp
305 310 315 320
Ile Phe Leu Ala Val Glu Asn Ala Leu Leu Glu Ala Gln Asp Val Glu
325 330 335
Leu Tyr Leu Arg Pro Leu Arg Arg His Ile Gln Cys Leu Gln Glu Thr
340 345 350
Glu Phe Pro Gln Thr Arg Ile Leu Ile Ala Pro Leu Phe His Thr Ile
355 360 365
Cys Leu Ile Trp Ser His Ser Lys Phe Tyr Asn Thr Pro Ala Arg Val
370 375 380
Ile Val Leu Leu Gln Glu Phe Cys Asn Leu Phe Ile Asn Gln Ala Thr
385 390 395 400
Ala Tyr Leu Ser Pro Glu Asp Leu Leu Arg Gly Glu Ile Glu Glu Ser
405 410 415
Leu Glu Lys Val Gln Val Ala Val Asn Ile Leu Lys Thr Phe Lys Asn
420 425 430
Ser Phe Phe Asn Tyr Arg Lys Lys Leu Ala Ser Tyr Phe Met Gly Arg
435 440 445
Lys Leu Arg Pro Trp Asp Phe Gln Ser His Leu Val Phe Cys Arg Phe
450 455 460
Asp Lys Phe Leu Asp Arg Leu Ile Lys Ile Glu Asp Ile Phe Ala Thr
465 470 475 480
Thr Leu Glu Phe Glu Lys Leu Glu Arg Leu Glu Phe Gly Gly Thr Lys
485 490 495
Gly Ala Ile Leu Asn Gly Gln Val His Glu Met Ser Glu Glu Leu Met
500 505 510
Glu Leu Cys Lys Leu Phe Lys Gln Ser Thr Tyr Asp Pro Ser Asp Cys
515 520 525
Thr Asn Met Glu Phe Glu Ser Asp Tyr Val Ala Phe Lys Ser Lys Thr
530 535 540
Leu Glu Phe Asp Arg Arg Leu Gly Thr Ile Ile Cys Glu Ala Phe Phe
545 550 555 560
Asn Cys Asn Gly Leu Glu Ala Ala Phe Lys Leu Leu Thr Ile Phe Gly
565 570 575
Asn Phe Leu Glu Lys Pro Val Val Met Glu Ile Phe Ser Leu His Tyr
580 585 590
Ser Thr Leu Val His Met Phe Asn Thr Glu Leu Asp Val Cys Lys Gln
595 600 605
Leu Tyr Asn Glu His Met Lys Gln Ile Glu Cys Gly His Val Val Leu
610 615 620
Asn Lys Asn Met Pro Phe Thr Ser Gly Asn Met Lys Trp Ala Gln Gln
625 630 635 640
Val Leu Gln Arg Leu Gln Met Phe Trp Ser Asn Phe Ala Ser Leu Arg
645 650 655
Tyr Leu Phe Leu Gly Asn Pro Asp His Ala Leu Val Tyr Gln Lys Tyr
660 665 670
Val Glu Met Thr Thr Leu Leu Asp Gln Phe Glu Ser Arg Ile Tyr Asn
675 680 685
Glu Trp Lys Ser Asn Val Asp Glu Ile Cys Glu Phe Asn Leu Asn Gln
690 695 700
Pro Leu Val Lys Phe Ser Ala Ile Asn Gly Leu Leu Cys Val Asn Phe
705 710 715 720
Asp Pro Lys Leu Val Ala Val Leu Arg Glu Val Lys Tyr Leu Leu Met
725 730 735
Leu Lys Lys Gln Asp Ile Pro Asp Ser Ala Leu Ala Ile Phe Lys Lys
740 745 750
Arg Asn Thr Ile Leu Lys Tyr Ile Gly Asn Leu Asp Leu Leu Val Gln
755 760 765
Gly Tyr Asn Lys Leu Lys Gln Thr Leu Leu Glu Val Glu Tyr Pro Leu
770 775 780
Ile Glu Asp Glu Leu Arg Ala Ile Asp Glu Gln Leu Thr Ala Ala Thr
785 790 795 800
Thr Trp Leu Thr Trp Gln Asp Asp Cys Trp Gly Tyr Ile Glu Arg Val
805 810 815
Arg Ala Ala Thr Ser Glu Leu Glu His Arg Val Glu Arg Thr Gln Lys
820 825 830
Asn Val Lys Val Ile Gln Gln Thr Met Arg Gly Trp Ala Arg Cys Val
835 840 845
Leu Pro Pro Arg Arg Glu His Arg Arg Glu Ala Ala Phe Thr Leu Glu
850 855 860
Asp Lys Gly Asp Leu Phe Thr Lys Lys Tyr Lys Leu Ile Gln Gly Asp
865 870 875 880
Gly Cys Lys Ile His Asn Leu Val Glu Glu Asn Arg Lys Leu Phe Lys
885 890 895
Ala Asn Pro Ser Leu Asp Thr Trp Lys Ile Tyr Val Glu Phe Ile Asp
900 905 910
Asp Ile Val Val Glu Gly Phe Phe Gln Ala Ile Met His Asp Leu Asp
915 920 925
Phe Phe Leu Lys Asn Thr Glu Lys Gln Leu Lys Pro Ala Pro Phe Phe
930 935 940
Gln Ala Gln Met Ile Leu Leu Pro Pro Glu Ile Val Phe Lys Pro Ser
945 950 955 960
Leu Asp Arg Glu Ala Gly Asp Gly Phe Tyr Asp Leu Val Glu Glu Met
965 970 975
Leu Cys Asn Ser Phe Arg Met Ser Ala Gln Met Asn Arg Ile Ala Thr
980 985 990
His Leu Glu Ile Lys Asn Tyr Gln Asn Asp Met Asp Asn Met Leu Gly
995 1000 1005
Leu Ala Glu Val Arg Gln Glu Ile Met Asn Arg Val Val Asn Val
1010 1015 1020
Ile Asn Lys Val Leu Asp Phe Arg Asn Thr Leu Glu Thr His Thr
1025 1030 1035
Tyr Leu Trp Val Asp Asp Arg Ala Glu Phe Met Lys His Phe Leu
1040 1045 1050
Leu Tyr Gly His Ala Val Ser Ser Asp Glu Met Asp Ala His Ala
1055 1060 1065
Asn Glu Glu Ile Pro Glu Gln Pro Pro Thr Leu Glu Gln Phe Lys
1070 1075 1080
Glu Gln Ile Asp Ile Tyr Glu Ala Leu Tyr Val Gln Met Ser Lys
1085 1090 1095
Phe Glu Asp Phe Arg Val Phe Asp Ser Trp Phe Lys Val Asp Met
1100 1105 1110
Lys Pro Phe Lys Val Ser Leu Leu Thr Ile Ile Lys Lys Trp Ser
1115 1120 1125
Trp Met Phe Gln Glu His Leu Leu Arg Phe Val Ile Asp Ser Leu
1130 1135 1140
Asn Glu Leu Gln Glu Phe Ile Lys Glu Thr Asp Ser Gly Leu Gln
1145 1150 1155
Arg Glu Leu Asn Glu Gly Asp His Asp Gly Leu Val Asp Ile Met
1160 1165 1170
Val His Leu Leu Ala Val Arg Ser Arg Gln Arg Ala Thr Asp Glu
1175 1180 1185
Leu Phe Glu Pro Leu Lys Glu Thr Ile Thr Leu Leu Glu Ser Tyr
1190 1195 1200
Gly Gln Lys Met Pro Glu Gln Val Tyr Ile Gln Leu Glu Glu Leu
1205 1210 1215
Pro Glu Arg Trp Glu Thr Thr Lys Lys Ile Ala Ala Thr Val Arg
1220 1225 1230
His Glu Val Ser Pro Leu His Asn Ala Glu Val Thr Leu Ile Arg
1235 1240 1245
Lys Lys Cys Ile Leu Phe Asp Ala Lys Gln Ala Glu Phe Arg Glu
1250 1255 1260
Arg Phe Arg His Tyr Ala Pro Leu Gly Phe Asn Ala Glu Asn Pro
1265 1270 1275
Tyr Thr Ala Leu Asp Lys Ala Asn Glu Glu Leu Glu Ala Leu Glu
1280 1285 1290
Glu Glu Met Leu Gln Met Gln Glu Ser Thr Arg Leu Phe Glu Val
1295 1300 1305
Ala Leu Pro Glu Tyr Lys Gln Met Lys Gln Cys Arg Lys Glu Ile
1310 1315 1320
Lys Leu Leu Lys Gly Leu Trp Asp Val Ile Ile Tyr Val Arg Arg
1325 1330 1335
Ser Ile Asp Asn Trp Thr Lys Thr Gln Trp Arg Gln Ile His Val
1340 1345 1350
Glu Gln Met Asp Val Glu Leu Arg Arg Phe Ala Lys Glu Ile Trp
1355 1360 1365
Ser Leu Asn Lys Glu Val Arg Val Trp Asp Ala Tyr Thr Gly Leu
1370 1375 1380
Glu Gly Thr Val Lys Asp Met Thr Ala Ser Leu Arg Ala Ile Thr
1385 1390 1395
Glu Leu Gln Ser Pro Ala Leu Arg Asp Arg His Trp His Gln Leu
1400 1405 1410
Met Lys Ala Ile Gly Val Lys Phe Leu Ile Asn Glu Ala Thr Thr
1415 1420 1425
Leu Ala Asp Leu Leu Ala Leu Arg Leu His Arg Val Glu Asp Asp
1430 1435 1440
Val Arg Arg Ile Val Asp Lys Ala Val Lys Glu Leu Gly Thr Glu
1445 1450 1455
Lys Val Ile Thr Glu Ile Ser Gln Thr Trp Ala Thr Met Lys Phe
1460 1465 1470
Ser Tyr Glu Val His Tyr Arg Thr Gly Ile Pro Leu Leu Lys Ser
1475 1480 1485
Asp Glu Gln Leu Phe Glu Thr Leu Glu His Asn Gln Val Gln Leu
1490 1495 1500
Gln Thr Leu Leu Gln Ser Lys Tyr Val Glu Tyr Phe Ile Glu Gln
1505 1510 1515
Val Leu Ser Trp Gln Asn Lys Leu Asn Ile Ala Asp Leu Val Ile
1520 1525 1530
Phe Thr Trp Met Glu Val Gln Arg Thr Trp Ser His Leu Glu Ser
1535 1540 1545
Ile Phe Val Cys Ser Glu Asp Ile Arg Ile Gln Leu Val Lys Asp
1550 1555 1560
Ala Arg Arg Phe Asp Gly Val Asp Ala Glu Phe Lys Glu Leu Met
1565 1570 1575
Phe Lys Thr Ala Lys Val Glu Asn Val Leu Glu Ala Thr Cys Arg
1580 1585 1590
Pro Asn Leu Tyr Glu Lys Leu Lys Asp Leu Gln Ser Arg Leu Ser
1595 1600 1605
Leu Cys Glu Lys Ala Leu Ala Glu Tyr Leu Glu Thr Lys Arg Ile
1610 1615 1620
Ala Phe Pro Arg Phe Tyr Phe Val Ser Ser Ala Asp Leu Leu Asp
1625 1630 1635
Ile Leu Ser Lys Gly Ala Gln Pro Lys Gln Val Thr Cys His Leu
1640 1645 1650
Ala Lys Leu Phe Asp Ser Ile Ala Asp Leu Gln Phe Glu Asp Asn
1655 1660 1665
Gln Asp Val Ser Ala His Arg Ala Val Gly Met Tyr Ser Lys Glu
1670 1675 1680
Lys Glu Tyr Val Pro Phe Gln Ala Glu Cys Glu Cys Val Gly His
1685 1690 1695
Val Glu Thr Trp Leu Leu Gln Leu Glu Gln Thr Met Gln Glu Thr
1700 1705 1710
Val Arg His Ser Ile Thr Glu Ala Ile Val Ala Tyr Glu Glu Lys
1715 1720 1725
Pro Arg Glu Leu Trp Ile Phe Asp Phe Pro Ala Gln Val Ala Leu
1730 1735 1740
Thr Ser Ser Gln Ile Trp Trp Thr Thr Asp Val Gly Ile Ala Phe
1745 1750 1755
Ser Arg Leu Glu Glu Gly Tyr Glu Thr Ala Leu Lys Asp Phe His
1760 1765 1770
Lys Lys Gln Ile Ser Gln Leu Asn Thr Leu Ile Thr Leu Leu Leu
1775 1780 1785
Gly Glu Leu Pro Pro Gly Asp Arg Gln Lys Ile Met Thr Ile Cys
1790 1795 1800
Thr Ile Asp Val His Ala Arg Asp Val Val Ala Lys Leu Ile Ser
1805 1810 1815
Gln Lys Val Val Ser Pro Gln Ala Phe Thr Trp Leu Ser Gln Leu
1820 1825 1830
Arg His Arg Trp Glu Asp Thr Gln Lys His Cys Phe Val Asn Ile
1835 1840 1845
Cys Asp Ala Gln Phe Gln
1850
<210> 107
<211> 1214
<212> PRT
<213> 智人(homo sapiens)
<400> 107
Met Ser Asp Ala Asn Lys Ala Ala Ile Ala Ala Glu Lys Glu Ala Leu
1 5 10 15
Asn Leu Lys Leu Pro Pro Ile Val His Leu Pro Glu Asn Ile Gly Val
20 25 30
Asp Thr Pro Thr Gln Ser Lys Leu Leu Lys Tyr Arg Arg Ser Lys Glu
35 40 45
Gln Gln Gln Lys Ile Asn Gln Leu Val Ile Asp Gly Ala Lys Arg Asn
50 55 60
Leu Asp Arg Thr Leu Gly Lys Arg Thr Pro Leu Leu Pro Pro Pro Asp
65 70 75 80
Tyr Pro Gln Thr Met Thr Ser Glu Met Lys Lys Lys Gly Phe Asn Tyr
85 90 95
Ile Tyr Met Lys Gln Cys Val Glu Ser Ser Pro Leu Val Pro Ile Gln
100 105 110
Gln Glu Trp Leu Asp His Met Leu Arg Leu Ile Pro Glu Ser Leu Lys
115 120 125
Glu Gly Lys Glu Arg Glu Glu Leu Leu Glu Ser Leu Ile Asn Glu Val
130 135 140
Ser Ser Asp Phe Glu Asn Ser Met Lys Arg Tyr Leu Val Gln Ser Val
145 150 155 160
Leu Val Lys Pro Pro Val Lys Ser Leu Glu Asp Glu Gly Gly Pro Leu
165 170 175
Pro Glu Ser Pro Val Gly Leu Asp Tyr Ser Asn Pro Trp His Ser Ser
180 185 190
Tyr Val Gln Ala Arg Asn Gln Ile Phe Ser Asn Leu His Ile Ile His
195 200 205
Pro Thr Met Lys Met Leu Leu Asp Leu Gly Tyr Thr Thr Phe Ala Asp
210 215 220
Thr Val Leu Leu Asp Phe Thr Gly Ile Arg Ala Lys Gly Pro Ile Asp
225 230 235 240
Cys Glu Ser Leu Lys Thr Asp Leu Ser Ile Gln Thr Arg Asn Ala Glu
245 250 255
Glu Lys Ile Met Asn Thr Trp Tyr Pro Lys Val Ile Asn Leu Phe Thr
260 265 270
Lys Lys Glu Ala Leu Glu Gly Val Lys Pro Glu Lys Leu Asp Ala Phe
275 280 285
Tyr Ser Cys Val Ser Thr Leu Met Ser Asn Gln Leu Lys Asp Leu Leu
290 295 300
Arg Arg Thr Val Glu Gly Phe Val Lys Leu Phe Asp Pro Lys Asp Gln
305 310 315 320
Gln Arg Leu Pro Ile Phe Lys Ile Glu Leu Thr Phe Asp Asp Asp Lys
325 330 335
Met Glu Phe Tyr Pro Thr Phe Gln Asp Leu Glu Asp Asn Val Leu Ser
340 345 350
Leu Val Glu Arg Ile Ala Glu Ala Leu Gln Asn Val Gln Thr Ile Pro
355 360 365
Ser Trp Leu Ser Gly Thr Ser Thr Pro Val Asn Leu Asp Thr Glu Leu
370 375 380
Pro Glu His Val Leu His Trp Ala Val Asp Thr Leu Lys Ala Ala Val
385 390 395 400
His Arg Asn Leu Glu Gly Ala Arg Lys His Tyr Glu Thr Tyr Val Glu
405 410 415
Lys Tyr Asn Trp Leu Leu Asp Gly Thr Ala Val Glu Asn Ile Glu Thr
420 425 430
Phe Gln Thr Glu Asp His Thr Phe Asp Glu Tyr Thr Glu Phe Ile Glu
435 440 445
Lys Phe Leu Ser Leu Ala Ser Glu Ile Met Leu Leu Pro Gln Trp Ile
450 455 460
His Tyr Thr Met Val Arg Leu Asp Cys Glu Asp Leu Lys Thr Gly Leu
465 470 475 480
Thr Asn Lys Ala Lys Ala Phe Ala Asn Ile Leu Leu Asn Asp Ile Ala
485 490 495
Ser Lys Tyr Arg Lys Glu Asn Glu Cys Ile Cys Ser Glu Phe Glu Ala
500 505 510
Ile Lys Glu His Ala Leu Lys Val Pro Glu Thr Thr Glu Glu Met Met
515 520 525
Asp Leu Ile Ser Tyr Val Glu Lys Ala Arg Thr Val Gly Ile Glu Glu
530 535 540
Leu Ile Leu Arg Ile Gln Glu Ser Lys Arg Gln Met Ser Tyr Phe Leu
545 550 555 560
Asp Val Phe Leu Phe Pro Gln Glu Asp Leu Ala Leu Asn Ala Thr Val
565 570 575
Leu Met Trp Pro Arg Lys Ile Asn Pro Ile Phe Asp Glu Asn Asp Glu
580 585 590
Leu Ile Glu Asn Ala Lys His Lys Lys Glu Asn Glu Leu Met Ala Lys
595 600 605
Arg Glu Lys Leu Ile Leu Glu Ile Glu Lys Glu Ser Arg Arg Met Glu
610 615 620
Glu Phe Thr Glu Phe Ala Glu Leu Glu Arg Met Gln Gln Tyr Val Thr
625 630 635 640
Asp Val Arg Gln Leu Gln Lys Arg Ile Gln Glu Ser Glu Glu Ala Val
645 650 655
Gln Phe Ile Asn Lys Glu Glu Glu Leu Phe Lys Trp Glu Leu Thr Lys
660 665 670
Tyr Pro Glu Leu Asp Lys Leu Lys Val Asn Ile Glu Pro Tyr Gln Lys
675 680 685
Phe Phe Asn Phe Val Leu Lys Trp Gln Arg Ser Glu Lys Arg Trp Met
690 695 700
Asp Gly Gly Phe Leu Asp Leu Asn Gly Glu Ser Met Glu Ala Asp Val
705 710 715 720
Glu Glu Phe Ser Arg Glu Ile Phe Lys Thr Leu Lys Phe Phe Gln Thr
725 730 735
Lys Leu Lys Lys Glu Leu Gln Glu Lys Arg Lys Ala Ala Arg Lys Arg
740 745 750
Ser Leu Glu Glu Glu Lys Ile Glu Glu Glu Pro Lys Asp Asn Ala Thr
755 760 765
Ile Thr Met Cys Arg Met Arg Ala Arg His Trp Lys Gln Ile Ser Glu
770 775 780
Ile Val Gly Tyr Asp Leu Thr Pro Asp Ser Gly Thr Thr Leu Arg Lys
785 790 795 800
Val Leu Lys Leu Asn Leu Thr Pro Tyr Leu Glu Gln Phe Glu Val Ile
805 810 815
Ser Ala Gly Ala Ser Lys Glu Phe Ser Leu Glu Lys Ala Met Asn Thr
820 825 830
Met Ile Gly Thr Trp Glu Asp Ile Ala Phe His Ile Ser Leu Tyr Arg
835 840 845
Asp Thr Gly Val Cys Ile Leu Ser Ser Val Asp Glu Ile Gln Ala Ile
850 855 860
Leu Asp Asp Gln Ile Ile Lys Thr Gln Thr Met Arg Gly Ser Pro Phe
865 870 875 880
Ile Lys Pro Phe Glu His Glu Ile Lys Ala Trp Glu Asp Arg Leu Ile
885 890 895
Arg Ile Gln Glu Thr Ile Asp Glu Trp Leu Lys Val Gln Ala Gln Trp
900 905 910
Leu Tyr Leu Glu Pro Ile Phe Cys Ser Glu Asp Ile Met Gln Gln Met
915 920 925
Pro Glu Glu Gly Arg Gln Phe Gln Thr Val Asp Arg His Trp Arg Asp
930 935 940
Ile Met Lys Phe Cys Ala Lys Asp Pro Lys Val Leu Ala Ala Thr Ser
945 950 955 960
Leu Thr Gly Leu Leu Glu Lys Leu Gln Asn Cys Asn Glu Leu Leu Glu
965 970 975
Lys Ile Met Lys Gly Leu Asn Ala Tyr Leu Glu Lys Lys Arg Leu Phe
980 985 990
Phe Pro Arg Phe Phe Phe Leu Ser Asn Asp Glu Met Leu Glu Ile Leu
995 1000 1005
Ser Glu Thr Lys Asp Pro Leu Arg Val Gln Pro His Leu Lys Lys
1010 1015 1020
Cys Phe Glu Gly Ile Ala Lys Leu Glu Phe Leu Pro Asn Leu Asp
1025 1030 1035
Ile Lys Ala Met Tyr Ser Ser Glu Gly Glu Arg Val Glu Leu Ile
1040 1045 1050
Ala Leu Ile Ser Thr Ser Ala Ala Arg Gly Ala Val Glu Lys Trp
1055 1060 1065
Leu Ile Gln Val Glu Asp Leu Met Leu Arg Ser Val His Asp Val
1070 1075 1080
Ile Ala Ala Ala Arg Leu Ala Tyr Pro Glu Ser Ala Arg Arg Asp
1085 1090 1095
Trp Val Arg Glu Trp Pro Gly Gln Val Val Leu Cys Ile Ser Gln
1100 1105 1110
Met Phe Trp Thr Ser Glu Thr Gln Glu Val Ile Ser Gly Gly Thr
1115 1120 1125
Glu Gly Leu Lys Lys Tyr Tyr Lys Glu Leu Gln Asn Gln Leu Asn
1130 1135 1140
Glu Ile Val Glu Leu Val Arg Gly Lys Leu Ser Lys Gln Thr Arg
1145 1150 1155
Thr Thr Leu Gly Ala Leu Val Thr Ile Asp Val His Ala Arg Asp
1160 1165 1170
Val Val Met Asp Met Ile Lys Met Gly Val Ser His Asp Thr Asp
1175 1180 1185
Phe Leu Trp Leu Ala Gln Leu Arg Tyr Tyr Trp Glu Asn Glu Asn
1190 1195 1200
Ala Arg Val Arg Ile Ile Asn Cys Asn Val Lys
1205 1210
<210> 108
<211> 200
<212> PRT
<213> 智人(homo sapiens)
<400> 108
Met Gly Arg Arg Ser Gln Trp Ile Trp Ala Met Arg Cys Gln Met Leu
1 5 10 15
Val Pro Val Leu Ser Leu His Ile Gly Leu Ala Arg Ala Leu Gly Cys
20 25 30
Gly Cys Ile Ala Ser Lys Ile Glu Cys Leu Ile Arg Cys Asn Ala Pro
35 40 45
Phe Pro Leu Leu Asp Ala Val Gly Ser Val Ala Ser Gln Glu Leu Gln
50 55 60
Ser Leu Thr Gly Thr Val Gly Val Thr Ser Gly Ala Ala Ala Tyr Pro
65 70 75 80
Arg Trp Asn Leu Ala Arg Ala Arg Ala Pro Pro His Leu Pro Gly Thr
85 90 95
Gln Asp Pro Leu Arg Arg Val Arg Asp Pro Thr Pro Ile Val Ala Ser
100 105 110
Ser Pro Gly Arg Arg Arg Gly Ser Trp Ser Gly Gly Tyr Gly Gln Glu
115 120 125
Ala Ser Glu Pro Gly Val Val Gly Leu Cys Cys Ala Val Leu Pro Ile
130 135 140
His Pro Ser Leu Ala Leu Ala Gly Val Gly Gly Pro Asp Leu Arg Arg
145 150 155 160
Phe Gln Glu Gly Pro Gln Arg Pro Ser Asp His Gly Ala Ala Glu Lys
165 170 175
His Met Glu Thr Phe Ile Pro Ile Asp Leu Thr Thr Glu Asn Gln Glu
180 185 190
Met Asp Lys Glu Glu Thr Lys Thr
195 200
<210> 109
<211> 1794
<212> PRT
<213> 智人(homo sapiens)
<400> 109
Met Thr Met Ala Pro Asp Val Arg Leu Glu Tyr Leu Glu Glu Val Ala
1 5 10 15
Ser Ile Val Leu Lys Phe Lys Pro Asp Lys Trp Ser Lys Leu Ile Gly
20 25 30
Ala Glu Glu Asn Val Ala Leu Phe Thr Glu Phe Phe Glu Lys Pro Asp
35 40 45
Val Gln Val Leu Val Leu Thr Leu Asn Ala Ala Gly Met Ile Ile Pro
50 55 60
Cys Leu Gly Phe Pro Gln Ser Leu Lys Ser Lys Gly Val Tyr Phe Ile
65 70 75 80
Lys Thr Lys Ser Glu Asn Ile Asn Lys Asp Asn Tyr Arg Ala Arg Leu
85 90 95
Leu Tyr Gly Asp Ile Ser Pro Thr Pro Val Asp Gln Leu Ile Ala Val
100 105 110
Val Glu Glu Val Leu Ser Ser Leu Leu Asn Gln Ser Glu Asn Met Ala
115 120 125
Gly Trp Pro Gln Val Val Ser Glu Asp Ile Val Lys Gln Val His Arg
130 135 140
Leu Lys Asn Glu Met Phe Val Met Ser Gly Lys Ile Lys Gly Lys Thr
145 150 155 160
Leu Leu Pro Ile Pro Glu His Leu Gly Ser Leu Asp Gly Thr Leu Glu
165 170 175
Ser Met Glu Arg Ile Pro Ser Ser Leu Asp Asn Leu Leu Leu His Ala
180 185 190
Ile Glu Thr Thr Ile Ile Asp Trp Ser His Gln Ile Arg Asp Val Leu
195 200 205
Ser Lys Asp Ser Ala Gln Ala Leu Leu Asp Gly Leu His Pro Leu Pro
210 215 220
Gln Val Glu Phe Glu Phe Trp Asp Ala Arg Leu Leu Asn Leu Lys Cys
225 230 235 240
Ile His Glu Gln Leu Asn Arg Pro Lys Val Asn Lys Ile Val Glu Ile
245 250 255
Leu Glu Lys Ala Lys Ser Cys Tyr Trp Pro Ala Leu Gln Asn Val Tyr
260 265 270
Thr Asn Val Thr Glu Gly Leu Lys Glu Ala Asn Asp Ile Val Leu Tyr
275 280 285
Leu Lys Pro Leu Arg Ile Leu Leu Glu Glu Met Glu Gln Ala Asp Phe
290 295 300
Thr Met Leu Pro Thr Phe Ile Ala Lys Val Leu Asp Thr Ile Cys Phe
305 310 315 320
Ile Trp Ala Thr Ser Glu Tyr Tyr Asn Thr Pro Ala Arg Ile Ile Val
325 330 335
Ile Leu Gln Glu Phe Cys Asn Gln Ile Ile Glu Met Thr Arg Thr Phe
340 345 350
Leu Ser Pro Glu Glu Val Leu Lys Gly Leu Gln Gly Glu Ile Glu Glu
355 360 365
Val Leu Ser Gly Ile Ser Leu Ala Val Asn Val Leu Lys Glu Leu Tyr
370 375 380
Gln Thr Tyr Asp Phe Cys Cys Val Asn Met Lys Leu Phe Phe Lys Asp
385 390 395 400
Lys Glu Pro Val Pro Trp Glu Phe Pro Ser Ser Leu Ala Phe Ser Arg
405 410 415
Ile Asn Ser Phe Phe Gln Arg Ile Gln Thr Ile Glu Glu Leu Tyr Lys
420 425 430
Thr Ala Ile Glu Phe Leu Lys Leu Glu Lys Ile Glu Leu Gly Gly Val
435 440 445
Arg Gly Asn Leu Leu Gly Ser Leu Val Thr Arg Ile Tyr Asp Glu Val
450 455 460
Phe Glu Leu Val Lys Val Phe Ala Asp Cys Lys Tyr Asp Pro Leu Asp
465 470 475 480
Pro Gly Asp Ser Asn Phe Asp Arg Asp Tyr Ala Asp Phe Glu Ile Lys
485 490 495
Ile Gln Asp Leu Asp Arg Arg Leu Ala Thr Ile Phe Cys Gln Gly Phe
500 505 510
Asp Asp Cys Ser Cys Ile Lys Ser Ser Ala Lys Leu Leu Tyr Met Cys
515 520 525
Gly Gly Leu Met Glu Arg Pro Leu Ile Leu Ala Glu Val Ala Pro Arg
530 535 540
Tyr Ser Val Met Leu Glu Leu Phe Asp Ala Glu Leu Asp Asn Ala Lys
545 550 555 560
Ile Leu Tyr Asp Ala Gln Met Ala Ala Ser Glu Glu Gly Asn Ile Pro
565 570 575
Leu Ile His Lys Asn Met Pro Pro Val Ala Gly Gln Leu Lys Trp Ser
580 585 590
Leu Glu Leu Gln Glu Arg Leu Glu Val Ser Met Lys His Leu Lys His
595 600 605
Val Glu His Pro Val Met Ser Gly Ala Glu Ala Lys Leu Thr Tyr Gln
610 615 620
Lys Tyr Asp Glu Met Met Glu Leu Leu Arg Cys His Arg Glu Lys Ile
625 630 635 640
Tyr Gln Gln Trp Val Ala Gly Val Asp Gln Asp Cys His Phe Asn Leu
645 650 655
Gly Gln Pro Leu Ile Leu Arg Asp Ala Ala Ser Asn Leu Ile His Val
660 665 670
Asn Phe Ser Lys Ala Leu Val Ala Val Leu Arg Glu Val Lys Tyr Leu
675 680 685
Asn Phe Gln Gln Gln Lys Glu Ile Pro Asp Ser Ala Glu Ser Leu Phe
690 695 700
Ser Glu Asn Glu Thr Phe Arg Lys Phe Val Gly Asn Leu Glu Leu Ile
705 710 715 720
Val Gly Trp Tyr Asn Glu Ile Lys Thr Ile Val Lys Ala Val Glu Phe
725 730 735
Leu Leu Ile Lys Ser Glu Leu Glu Ala Ile Asp Val Lys Leu Leu Ser
740 745 750
Ala Glu Thr Thr Leu Phe Trp Asn Gly Glu Gly Val Phe Gln Tyr Ile
755 760 765
Gln Glu Val Arg Glu Ile Leu His Asn Leu Gln Asn Arg Met Gln Lys
770 775 780
Ala Lys Gln Asn Ile Glu Gly Ile Ser Gln Ala Met Lys Asp Trp Ser
785 790 795 800
Ala Asn Pro Leu Phe Glu Arg Lys Asp Asn Lys Lys Glu Ala Leu Leu
805 810 815
Asp Leu Asp Gly Arg Ile Ala Asn Leu Asn Lys Arg Tyr Ala Ala Val
820 825 830
Arg Asp Ala Gly Val Lys Ile Gln Ala Met Val Ala Glu Asn Ala Glu
835 840 845
Leu Phe Arg Ala Asp Thr Leu Ser Leu Pro Trp Lys Asp Tyr Val Ile
850 855 860
Tyr Ile Asp Asp Met Val Leu Asp Glu Phe Asp Gln Phe Ile Arg Lys
865 870 875 880
Ser Leu Ser Phe Leu Met Asp Asn Met Val Ile Asp Glu Ser Ile Ala
885 890 895
Pro Leu Phe Glu Ile Arg Met Glu Leu Asp Glu Asp Gly Leu Thr Phe
900 905 910
Asn Pro Thr Leu Glu Val Gly Ser Asp Arg Gly Phe Leu Ala Leu Ile
915 920 925
Glu Gly Leu Val Asn Asp Ile Tyr Asn Val Ala Arg Leu Ile Pro Arg
930 935 940
Leu Ala Lys Asp Arg Met Asn Tyr Lys Met Asp Leu Glu Asp Asn Thr
945 950 955 960
Asp Leu Ile Glu Met Arg Glu Glu Val Ser Ser Leu Val Ile Asn Ala
965 970 975
Met Lys Glu Ala Glu Glu Tyr Gln Asp Ser Phe Glu Arg Tyr Ser Tyr
980 985 990
Leu Trp Thr Asp Asn Leu Gln Glu Phe Met Lys Asn Phe Leu Ile Tyr
995 1000 1005
Gly Cys Ala Val Thr Ala Glu Asp Leu Asp Thr Trp Thr Asp Asp
1010 1015 1020
Thr Ile Pro Lys Thr Pro Pro Thr Leu Ala Gln Phe Gln Glu Gln
1025 1030 1035
Ile Asp Ser Tyr Glu Lys Leu Tyr Glu Glu Val Ser Lys Cys Glu
1040 1045 1050
Asn Thr Lys Val Phe His Gly Trp Leu Gln Cys Asp Cys Arg Pro
1055 1060 1065
Phe Lys Gln Ala Leu Leu Ser Thr Ile Arg Arg Trp Gly Phe Met
1070 1075 1080
Phe Lys Arg His Leu Ser Asn His Val Thr Asn Ser Leu Ala Asp
1085 1090 1095
Leu Glu Ala Phe Met Lys Val Ala Arg Met Gly Leu Thr Lys Pro
1100 1105 1110
Leu Lys Glu Gly Asp Tyr Asp Gly Leu Val Glu Val Met Gly His
1115 1120 1125
Leu Met Lys Val Lys Glu Arg Gln Ala Ala Thr Asp Asn Met Phe
1130 1135 1140
Glu Pro Leu Lys Gln Thr Ile Glu Leu Leu Lys Thr Tyr Gly Glu
1145 1150 1155
Glu Met Pro Glu Glu Ile His Leu Lys Leu Gln Glu Leu Pro Glu
1160 1165 1170
His Trp Ala Asn Thr Lys Lys Leu Ala Ile Gln Val Lys Leu Thr
1175 1180 1185
Val Ala Pro Leu Gln Ala Asn Glu Val Ser Ile Leu Arg Arg Lys
1190 1195 1200
Cys Gln Gln Phe Glu Leu Lys Gln His Glu Phe Arg Glu Arg Phe
1205 1210 1215
Arg Arg Glu Ala Pro Phe Ser Phe Ser Asp Pro Asn Pro Tyr Lys
1220 1225 1230
Ser Leu Asn Lys Val Phe Leu Leu Lys Gly Ile Met Glu Ala Leu
1235 1240 1245
Ser Lys Ser Gly Gly Leu Phe Glu Val Pro Val Pro Asp Tyr Lys
1250 1255 1260
Gln Leu Lys Ala Cys His Arg Glu Val Arg Leu Leu Lys Glu Leu
1265 1270 1275
Trp Asp Met Val Val Val Val Asn Thr Ser Ile Glu Asp Trp Lys
1280 1285 1290
Thr Thr Lys Trp Lys Asp Ile Asn Val Glu Gln Met Asp Ile Asp
1295 1300 1305
Cys Lys Lys Phe Ala Lys Asp Met Arg Ser Leu Asp Lys Glu Met
1310 1315 1320
Lys Thr Trp Asp Ala Phe Val Gly Leu Asp Asn Thr Val Lys Asn
1325 1330 1335
Val Ile Thr Ser Leu Arg Ala Val Ser Glu Leu Gln Asn Pro Ala
1340 1345 1350
Ile Arg Glu Arg His Trp Gln Gln Leu Met Gln Ala Thr Gln Val
1355 1360 1365
Lys Phe Lys Met Ser Glu Glu Thr Thr Leu Ala Asp Leu Leu Gln
1370 1375 1380
Leu Asn Leu His Ser Tyr Glu Asp Glu Val Arg Asn Ile Val Asp
1385 1390 1395
Lys Ala Val Lys Glu Ser Gly Met Glu Lys Val Leu Lys Ala Leu
1400 1405 1410
Asp Ser Thr Trp Ser Met Met Glu Phe Gln His Glu Pro His Pro
1415 1420 1425
Arg Thr Gly Thr Met Met Leu Lys Ser Ser Glu Val Leu Val Glu
1430 1435 1440
Thr Leu Glu Asp Asn Gln Val Gln Leu Gln Asn Leu Met Met Ser
1445 1450 1455
Lys Tyr Leu Ala His Phe Leu Lys Glu Val Thr Ser Trp Gln Gln
1460 1465 1470
Lys Leu Ser Thr Ala Asp Ser Val Ile Ser Ile Trp Phe Glu Val
1475 1480 1485
Gln Arg Thr Trp Ser His Leu Glu Ser Ile Phe Ile Gly Ser Glu
1490 1495 1500
Asp Ile Arg Thr Gln Leu Pro Gly Asp Ser Gln Arg Phe Asp Asp
1505 1510 1515
Ile Asn Gln Glu Phe Lys Ala Leu Met Glu Asp Ala Val Lys Thr
1520 1525 1530
Pro Asn Val Val Glu Ala Thr Ser Lys Pro Gly Leu Tyr Asn Lys
1535 1540 1545
Leu Glu Ala Leu Lys Lys Ser Leu Ala Ile Cys Glu Lys Ala Leu
1550 1555 1560
Ala Glu Tyr Leu Glu Thr Lys Arg Leu Ala Phe Pro Arg Phe Tyr
1565 1570 1575
Phe Val Ser Ser Ala Asp Leu Leu Asp Ile Leu Ser Asn Gly Asn
1580 1585 1590
Asp Pro Val Glu Val Ser Arg His Leu Ser Lys Leu Phe Asp Ser
1595 1600 1605
Leu Cys Lys Leu Lys Phe Arg Leu Asp Ala Ser Asp Lys Pro Leu
1610 1615 1620
Lys Val Gly Leu Gly Met Tyr Ser Lys Glu Asp Glu Tyr Met Val
1625 1630 1635
Phe Asp Gln Glu Cys Asp Leu Ser Gly Gln Val Glu Val Trp Leu
1640 1645 1650
Asn Arg Val Leu Asp Arg Met Cys Ser Thr Leu Arg His Glu Ile
1655 1660 1665
Pro Glu Ala Val Val Thr Tyr Glu Glu Lys Pro Arg Glu Gln Trp
1670 1675 1680
Ile Leu Asp Tyr Pro Ala Gln Ile Trp Trp Thr Thr Glu Val Gly
1685 1690 1695
Leu Ala Phe Ala Arg Leu Glu Glu Gly Tyr Glu Asn Ala Ile Lys
1700 1705 1710
Asp Tyr Asn Lys Lys Gln Ile Ser Gln Leu Asn Val Leu Ile Thr
1715 1720 1725
Leu Leu Ile Gly Asn Leu Asn Ala Gly Asp Arg Met Lys Ile Met
1730 1735 1740
Thr Ile Cys Thr Ile Asp Val His Ala Arg Asp Val Val Ala Lys
1745 1750 1755
Met Ile Val Glu Ser Ser Gln Ala Phe Thr Trp Gln Ala Gln Leu
1760 1765 1770
Arg His Arg Trp Asp Glu Glu Lys Arg His Cys Phe Ala Asn Ile
1775 1780 1785
Cys Asp Ala Gln Ile Gln
1790
<210> 110
<211> 736
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 110
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly
145 150 155 160
Lys Thr Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro
180 185 190
Ala Thr Pro Ala Ala Val Gly Pro Thr Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ala
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Ala Ser Thr Gly Ala Ser Asn Asp Asn His
260 265 270
Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe
275 280 285
His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn
290 295 300
Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln
305 310 315 320
Val Lys Glu Val Thr Thr Asn Asp Gly Val Thr Thr Ile Ala Asn Asn
325 330 335
Leu Thr Ser Thr Val Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu Pro
340 345 350
Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala
355 360 365
Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly
370 375 380
Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro
385 390 395 400
Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe
405 410 415
Glu Glu Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp
420 425 430
Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Asn Arg
435 440 445
Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn Lys Asp Leu Leu Phe Ser
450 455 460
Arg Gly Ser Pro Ala Gly Met Ser Val Gln Pro Lys Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Lys Thr Asp Asn
485 490 495
Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala Ser Lys Tyr Asn Leu Asn
500 505 510
Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr Ala Met Ala Ser His Lys
515 520 525
Asp Asp Glu Asp Lys Phe Phe Pro Met Ser Gly Val Met Ile Phe Gly
530 535 540
Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn Pro Val Ala Thr Glu Arg
565 570 575
Phe Gly Thr Val Ala Val Asn Phe Gln Ser Ser Ser Thr Asp Pro Ala
580 585 590
Thr Gly Asp Val His Ala Met Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys Asn Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Ala Glu Phe Ser Ala Thr Lys Phe Ala Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Val Gln Tyr Thr Ser Asn
690 695 700
Tyr Ala Lys Ser Ala Asn Val Asp Phe Thr Val Asp Asn Asn Gly Leu
705 710 715 720
Tyr Thr Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Pro Leu
725 730 735
<210> 111
<211> 735
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 111
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Arg Gln Ala Ala Thr
580 585 590
Ala Asp Val Asn Thr Gln Gly Val Leu Pro Gly Met Val Trp Gln Asp
595 600 605
Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr
610 615 620
Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys
625 630 635 640
His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asn
645 650 655
Pro Ser Thr Thr Phe Ser Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln
660 665 670
Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys
675 680 685
Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr
690 695 700
Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr
705 710 715 720
Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 112
<211> 736
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 112
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Val Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Arg Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Ile Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Gly
130 135 140
Ala Val Asp Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Val Gly
145 150 155 160
Lys Ser Gly Lys Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro
180 185 190
Ala Ala Pro Thr Ser Leu Gly Ser Asn Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Lys Leu Ser Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Arg Gly Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Asn Arg Thr
435 440 445
Gln Gly Thr Thr Ser Gly Thr Thr Asn Gln Ser Arg Leu Leu Phe Ser
450 455 460
Gln Ala Gly Pro Gln Ser Met Ser Leu Gln Ala Arg Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Leu Ser Lys Thr Ala Asn Asp Asn
485 490 495
Asn Asn Ser Asn Phe Pro Trp Thr Ala Ala Ser Lys Tyr His Leu Asn
500 505 510
Gly Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Asp Asp Glu Glu Lys Phe Phe Pro Met His Gly Asn Leu Ile Phe Gly
530 535 540
Lys Glu Gly Thr Thr Ala Ser Asn Ala Glu Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln
565 570 575
Tyr Gly Thr Val Ala Asn Asn Leu Gln Ser Ser Asn Thr Ala Pro Thr
580 585 590
Thr Gly Thr Val Asn His Gln Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys His Pro Pro Pro Gln Ile Met Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Thr Thr Phe Ser Pro Ala Lys Phe Ala Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 113
<211> 734
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 113
Met Thr Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser Glu
1 5 10 15
Gly Val Arg Glu Trp Trp Ala Leu Gln Pro Gly Ala Pro Lys Pro Lys
20 25 30
Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro Gly
35 40 45
Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro Val
50 55 60
Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp Gln
65 70 75 80
Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala Asp
85 90 95
Ala Glu Phe Gln Gln Arg Leu Gln Gly Asp Thr Ser Phe Gly Gly Asn
100 105 110
Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro Leu
115 120 125
Gly Leu Val Glu Gln Ala Gly Glu Thr Ala Pro Gly Lys Lys Arg Pro
130 135 140
Leu Ile Glu Ser Pro Gln Gln Pro Asp Ser Ser Thr Gly Ile Gly Lys
145 150 155 160
Lys Gly Lys Gln Pro Ala Lys Lys Lys Leu Val Phe Glu Asp Glu Thr
165 170 175
Gly Ala Gly Asp Gly Pro Pro Glu Gly Ser Thr Ser Gly Ala Met Ser
180 185 190
Asp Asp Ser Glu Met Arg Ala Ala Ala Gly Gly Ala Ala Val Glu Gly
195 200 205
Gly Gln Gly Ala Asp Gly Val Gly Asn Ala Ser Gly Asp Trp His Cys
210 215 220
Asp Ser Thr Trp Ser Glu Gly His Val Thr Thr Thr Ser Thr Arg Thr
225 230 235 240
Trp Val Leu Pro Thr Tyr Asn Asn His Leu Tyr Lys Arg Leu Gly Glu
245 250 255
Ser Leu Gln Ser Asn Thr Tyr Asn Gly Phe Ser Thr Pro Trp Gly Tyr
260 265 270
Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln
275 280 285
Arg Leu Ile Asn Asn Asn Trp Gly Met Arg Pro Lys Ala Met Arg Val
290 295 300
Lys Ile Phe Asn Ile Gln Val Lys Glu Val Thr Thr Ser Asn Gly Glu
305 310 315 320
Thr Thr Val Ala Asn Asn Leu Thr Ser Thr Val Gln Ile Phe Ala Asp
325 330 335
Ser Ser Tyr Glu Leu Pro Tyr Val Met Asp Ala Gly Gln Glu Gly Ser
340 345 350
Leu Pro Pro Phe Pro Asn Asp Val Phe Met Val Pro Gln Tyr Gly Tyr
355 360 365
Cys Gly Leu Val Thr Gly Asn Thr Ser Gln Gln Gln Thr Asp Arg Asn
370 375 380
Ala Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly
385 390 395 400
Asn Asn Phe Glu Ile Thr Tyr Ser Phe Glu Lys Val Pro Phe His Ser
405 410 415
Met Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile
420 425 430
Asp Gln Tyr Leu Trp Gly Leu Gln Ser Thr Thr Thr Gly Thr Thr Leu
435 440 445
Asn Ala Gly Thr Ala Thr Thr Asn Phe Thr Lys Leu Arg Pro Thr Asn
450 455 460
Phe Ser Asn Phe Lys Lys Asn Trp Leu Pro Gly Pro Ser Ile Lys Gln
465 470 475 480
Gln Gly Phe Ser Lys Thr Ala Asn Gln Asn Tyr Lys Ile Pro Ala Thr
485 490 495
Gly Ser Asp Ser Leu Ile Lys Tyr Glu Thr His Ser Thr Leu Asp Gly
500 505 510
Arg Trp Ser Ala Leu Thr Pro Gly Pro Pro Met Ala Thr Ala Gly Pro
515 520 525
Ala Asp Ser Lys Phe Ser Asn Ser Gln Leu Ile Phe Ala Gly Pro Lys
530 535 540
Gln Asn Gly Asn Thr Ala Thr Val Pro Gly Thr Leu Ile Phe Thr Ser
545 550 555 560
Glu Glu Glu Leu Ala Ala Thr Asn Ala Thr Asp Thr Asp Met Trp Gly
565 570 575
Asn Leu Pro Gly Gly Asp Gln Ser Asn Ser Asn Leu Pro Thr Val Asp
580 585 590
Arg Leu Thr Ala Leu Gly Ala Val Pro Gly Met Val Trp Gln Asn Arg
595 600 605
Asp Ile Tyr Tyr Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp
610 615 620
Gly His Phe His Pro Ser Pro Leu Ile Gly Gly Phe Gly Leu Lys His
625 630 635 640
Pro Pro Pro Gln Ile Phe Ile Lys Asn Thr Pro Val Pro Ala Asn Pro
645 650 655
Ala Thr Thr Phe Ser Ser Thr Pro Val Asn Ser Phe Ile Thr Gln Tyr
660 665 670
Ser Thr Gly Gln Val Ser Val Gln Ile Asp Trp Glu Ile Gln Lys Glu
675 680 685
Arg Ser Lys Arg Trp Asn Pro Glu Val Gln Phe Thr Ser Asn Tyr Gly
690 695 700
Gln Gln Asn Ser Leu Leu Trp Ala Pro Asp Ala Ala Gly Lys Tyr Thr
705 710 715 720
Glu Pro Arg Ala Ile Gly Thr Arg Tyr Leu Thr His His Leu
725 730
<210> 114
<211> 724
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 114
Met Ser Phe Val Asp His Pro Pro Asp Trp Leu Glu Glu Val Gly Glu
1 5 10 15
Gly Leu Arg Glu Phe Leu Gly Leu Glu Ala Gly Pro Pro Lys Pro Lys
20 25 30
Pro Asn Gln Gln His Gln Asp Gln Ala Arg Gly Leu Val Leu Pro Gly
35 40 45
Tyr Asn Tyr Leu Gly Pro Gly Asn Gly Leu Asp Arg Gly Glu Pro Val
50 55 60
Asn Arg Ala Asp Glu Val Ala Arg Glu His Asp Ile Ser Tyr Asn Glu
65 70 75 80
Gln Leu Glu Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala Asp
85 90 95
Ala Glu Phe Gln Glu Lys Leu Ala Asp Asp Thr Ser Phe Gly Gly Asn
100 105 110
Leu Gly Lys Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro Phe
115 120 125
Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Thr Gly Lys Arg Ile
130 135 140
Asp Asp His Phe Pro Lys Arg Lys Lys Ala Arg Thr Glu Glu Asp Ser
145 150 155 160
Lys Pro Ser Thr Ser Ser Asp Ala Glu Ala Gly Pro Ser Gly Ser Gln
165 170 175
Gln Leu Gln Ile Pro Ala Gln Pro Ala Ser Ser Leu Gly Ala Asp Thr
180 185 190
Met Ser Ala Gly Gly Gly Gly Pro Leu Gly Asp Asn Asn Gln Gly Ala
195 200 205
Asp Gly Val Gly Asn Ala Ser Gly Asp Trp His Cys Asp Ser Thr Trp
210 215 220
Met Gly Asp Arg Val Val Thr Lys Ser Thr Arg Thr Trp Val Leu Pro
225 230 235 240
Ser Tyr Asn Asn His Gln Tyr Arg Glu Ile Lys Ser Gly Ser Val Asp
245 250 255
Gly Ser Asn Ala Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr
260 265 270
Phe Asp Phe Asn Arg Phe His Ser His Trp Ser Pro Arg Asp Trp Gln
275 280 285
Arg Leu Ile Asn Asn Tyr Trp Gly Phe Arg Pro Arg Ser Leu Arg Val
290 295 300
Lys Ile Phe Asn Ile Gln Val Lys Glu Val Thr Val Gln Asp Ser Thr
305 310 315 320
Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp
325 330 335
Asp Asp Tyr Gln Leu Pro Tyr Val Val Gly Asn Gly Thr Glu Gly Cys
340 345 350
Leu Pro Ala Phe Pro Pro Gln Val Phe Thr Leu Pro Gln Tyr Gly Tyr
355 360 365
Ala Thr Leu Asn Arg Asp Asn Thr Glu Asn Pro Thr Glu Arg Ser Ser
370 375 380
Phe Phe Cys Leu Glu Tyr Phe Pro Ser Lys Met Leu Arg Thr Gly Asn
385 390 395 400
Asn Phe Glu Phe Thr Tyr Asn Phe Glu Glu Val Pro Phe His Ser Ser
405 410 415
Phe Ala Pro Ser Gln Asn Leu Phe Lys Leu Ala Asn Pro Leu Val Asp
420 425 430
Gln Tyr Leu Tyr Arg Phe Val Ser Thr Asn Asn Thr Gly Gly Val Gln
435 440 445
Phe Asn Lys Asn Leu Ala Gly Arg Tyr Ala Asn Thr Tyr Lys Asn Trp
450 455 460
Phe Pro Gly Pro Met Gly Arg Thr Gln Gly Trp Asn Leu Gly Ser Gly
465 470 475 480
Val Asn Arg Ala Ser Val Ser Ala Phe Ala Thr Thr Asn Arg Met Glu
485 490 495
Leu Glu Gly Ala Ser Tyr Gln Val Pro Pro Gln Pro Asn Gly Met Thr
500 505 510
Asn Asn Leu Gln Gly Ser Asn Thr Tyr Ala Leu Glu Asn Thr Met Ile
515 520 525
Phe Asn Ser Gln Pro Ala Asn Pro Gly Thr Thr Ala Thr Tyr Leu Glu
530 535 540
Gly Asn Met Leu Ile Thr Ser Glu Ser Glu Thr Gln Pro Val Asn Arg
545 550 555 560
Val Ala Tyr Asn Val Gly Gly Gln Met Ala Thr Asn Asn Gln Ser Ser
565 570 575
Thr Thr Ala Pro Ala Thr Gly Thr Tyr Asn Leu Gln Glu Ile Val Pro
580 585 590
Gly Ser Val Trp Met Glu Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp
595 600 605
Ala Lys Ile Pro Glu Thr Gly Ala His Phe His Pro Ser Pro Ala Met
610 615 620
Gly Gly Phe Gly Leu Lys His Pro Pro Pro Met Met Leu Ile Lys Asn
625 630 635 640
Thr Pro Val Pro Gly Asn Ile Thr Ser Phe Ser Asp Val Pro Val Ser
645 650 655
Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Thr Val Glu Met Glu
660 665 670
Trp Glu Leu Lys Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln
675 680 685
Tyr Thr Asn Asn Tyr Asn Asp Pro Gln Phe Val Asp Phe Ala Pro Asp
690 695 700
Ser Thr Gly Glu Tyr Arg Thr Thr Arg Pro Ile Gly Thr Arg Tyr Leu
705 710 715 720
Thr Arg Pro Leu
<210> 115
<211> 736
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 115
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Phe Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly
145 150 155 160
Lys Thr Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro
180 185 190
Ala Thr Pro Ala Ala Val Gly Pro Thr Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ala
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Ala Ser Thr Gly Ala Ser Asn Asp Asn His
260 265 270
Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe
275 280 285
His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn
290 295 300
Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln
305 310 315 320
Val Lys Glu Val Thr Thr Asn Asp Gly Val Thr Thr Ile Ala Asn Asn
325 330 335
Leu Thr Ser Thr Val Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu Pro
340 345 350
Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala
355 360 365
Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly
370 375 380
Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro
385 390 395 400
Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe
405 410 415
Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp
420 425 430
Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Asn Arg
435 440 445
Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn Lys Asp Leu Leu Phe Ser
450 455 460
Arg Gly Ser Pro Ala Gly Met Ser Val Gln Pro Lys Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Lys Thr Asp Asn
485 490 495
Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala Ser Lys Tyr Asn Leu Asn
500 505 510
Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr Ala Met Ala Ser His Lys
515 520 525
Asp Asp Lys Asp Lys Phe Phe Pro Met Ser Gly Val Met Ile Phe Gly
530 535 540
Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn Pro Val Ala Thr Glu Arg
565 570 575
Phe Gly Thr Val Ala Val Asn Leu Gln Ser Ser Ser Thr Asp Pro Ala
580 585 590
Thr Gly Asp Val His Val Met Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Ala Glu Phe Ser Ala Thr Lys Phe Ala Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Val Gln Tyr Thr Ser Asn
690 695 700
Tyr Ala Lys Ser Ala Asn Val Asp Phe Thr Val Asp Asn Asn Gly Leu
705 710 715 720
Tyr Thr Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Pro Leu
725 730 735
<210> 116
<211> 737
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 116
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asn Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Ala Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Ser Val Gly Ser Gly Thr Val Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn
210 215 220
Ala Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Ser Glu Thr Ala Gly Ser Thr Asn Asp Asn
260 265 270
Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Lys Leu Arg Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Thr Asn Asp Gly Val Thr Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Ile Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn
370 375 380
Gly Ser Gln Ser Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr Ser
405 410 415
Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ala
435 440 445
Arg Thr Gln Ser Asn Pro Gly Gly Thr Ala Gly Asn Arg Glu Leu Gln
450 455 460
Phe Tyr Gln Gly Gly Pro Ser Thr Met Ala Glu Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Phe Arg Gln Gln Arg Val Ser Lys Thr Leu Asp
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Asp Arg Phe Phe Pro Ser Ser Gly Val Leu Ile
530 535 540
Phe Gly Lys Thr Gly Ala Thr Asn Lys Thr Thr Leu Glu Asn Val Leu
545 550 555 560
Met Thr Asn Glu Glu Glu Ile Arg Pro Thr Asn Pro Val Ala Thr Glu
565 570 575
Glu Tyr Gly Ile Val Ser Ser Asn Leu Gln Ala Ala Asn Thr Ala Ala
580 585 590
Gln Thr Gln Val Val Asn Asn Gln Gly Ala Leu Pro Gly Met Val Trp
595 600 605
Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro
610 615 620
His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly
625 630 635 640
Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro
645 650 655
Ala Asn Pro Pro Glu Val Phe Thr Pro Ala Lys Phe Ala Ser Phe Ile
660 665 670
Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu
675 680 685
Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser
690 695 700
Asn Phe Glu Lys Gln Thr Gly Val Asp Phe Ala Val Asp Ser Gln Gly
705 710 715 720
Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn
725 730 735
Leu
<210> 117
<211> 738
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 117
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 118
<211> 736
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 118
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 119
<211> 736
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 119
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Asp Gly Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 120
<211> 738
<212> PRT
<213> 腺相关病毒
<400> 120
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Gln Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala
580 585 590
Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Asp
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 121
<211> 738
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 121
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Thr Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Gln Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala
580 585 590
Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 122
<211> 738
<212> PRT
<213> 腺相关病毒hu.37 (Adeno-associated virus hu.37)
<400> 122
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Gln Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Ala Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Arg Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Thr Asn Thr Gly
580 585 590
Pro Ile Val Gly Asn Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 123
<211> 738
<212> PRT
<213> 腺相关病毒rh.74型式1 (Adeno-associated virus rh.74 version 1)
<400> 123
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asn Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Ser Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Asn Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala
580 585 590
Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Thr Lys Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 124
<211> 738
<212> PRT
<213> 腺相关病毒rh.39 (Adeno-associated virus rh.39)
<400> 124
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Gln Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Ala Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Arg Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Thr Asn Thr Gly
580 585 590
Pro Ile Val Gly Asn Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 125
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 125
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Thr Leu Ala Ala
580 585 590
Pro Phe Lys Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 126
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 126
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Thr Leu Ala Ala
260 265 270
Pro Phe Lys Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp
275 280 285
Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp
290 295 300
Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu
305 310 315 320
Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Asp Asn Asn
325 330 335
Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe
340 345 350
Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Glu
355 360 365
Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr
370 375 380
Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly Arg Ser Ser
385 390 395 400
Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn
405 410 415
Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser
420 425 430
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
435 440 445
Gln Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 127
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 127
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Thr Leu Ala Ala Pro Phe Lys Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 128
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 128
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Lys Met Gln Val
580 585 590
Pro Phe Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 129
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 129
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Lys Met Gln Val
260 265 270
Pro Phe Gln Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp
275 280 285
Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp
290 295 300
Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu
305 310 315 320
Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Asp Asn Asn
325 330 335
Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe
340 345 350
Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Glu
355 360 365
Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr
370 375 380
Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly Arg Ser Ser
385 390 395 400
Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn
405 410 415
Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser
420 425 430
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
435 440 445
Gln Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 130
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 130
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Lys Met Gln Val Pro Phe Gln Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 131
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 131
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Gln Gln Ala Ala
580 585 590
Pro Ser Phe Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 132
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 132
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Gln Gln Ala Ala
260 265 270
Pro Ser Phe Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp
275 280 285
Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp
290 295 300
Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu
305 310 315 320
Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Asp Asn Asn
325 330 335
Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe
340 345 350
Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Glu
355 360 365
Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr
370 375 380
Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly Arg Ser Ser
385 390 395 400
Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn
405 410 415
Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser
420 425 430
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
435 440 445
Gln Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 133
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 133
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gln Gln Ala Ala Pro Ser Phe Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 134
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 134
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Arg Tyr Asn Ala
580 585 590
Pro Phe Lys Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 135
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 135
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Arg Tyr Asn Ala
260 265 270
Pro Phe Lys Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp
275 280 285
Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp
290 295 300
Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu
305 310 315 320
Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Asp Asn Asn
325 330 335
Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe
340 345 350
Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Glu
355 360 365
Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr
370 375 380
Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly Arg Ser Ser
385 390 395 400
Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn
405 410 415
Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser
420 425 430
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
435 440 445
Gln Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 136
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 136
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Arg Tyr Asn Ala Pro Phe Lys Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 137
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 137
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Leu Lys Leu Pro
580 585 590
Pro Ile Val Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 138
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 138
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Leu Lys Leu Pro
260 265 270
Pro Ile Val Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp
275 280 285
Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp
290 295 300
Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu
305 310 315 320
Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Asp Asn Asn
325 330 335
Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe
340 345 350
Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Glu
355 360 365
Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr
370 375 380
Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly Arg Ser Ser
385 390 395 400
Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn
405 410 415
Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser
420 425 430
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
435 440 445
Gln Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 139
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 139
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Leu Lys Leu Pro Pro Ile Val Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 140
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 140
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Pro Phe Ile Lys
580 585 590
Pro Phe Glu Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 141
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 141
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Pro Phe Ile Lys
260 265 270
Pro Phe Glu Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp
275 280 285
Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp
290 295 300
Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu
305 310 315 320
Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Asp Asn Asn
325 330 335
Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe
340 345 350
Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Glu
355 360 365
Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr
370 375 380
Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly Arg Ser Ser
385 390 395 400
Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn
405 410 415
Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser
420 425 430
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
435 440 445
Gln Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 142
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 142
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Pro Phe Ile Lys Pro Phe Glu Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 143
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 143
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Thr Leu Ser Leu
580 585 590
Pro Trp Lys Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 144
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 144
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Thr Leu Ser Leu
260 265 270
Pro Trp Lys Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp
275 280 285
Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp
290 295 300
Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu
305 310 315 320
Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Asp Asn Asn
325 330 335
Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe
340 345 350
Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Glu
355 360 365
Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr
370 375 380
Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly Arg Ser Ser
385 390 395 400
Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn
405 410 415
Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser
420 425 430
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
435 440 445
Gln Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 145
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 145
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Thr Leu Ser Leu Pro Trp Lys Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 146
<211> 745
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 146
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Leu Gly
580 585 590
Glu Thr Thr Arg Pro Thr Ala Pro Gln Ile Gly Thr Val Asn Ser Gln
595 600 605
Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Thr Phe Asn
660 665 670
Gln Ser Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Thr Ser Val
705 710 715 720
Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 147
<211> 745
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 147
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Leu Gly Glu
260 265 270
Thr Thr Arg Pro Thr Asn Asp Asn Thr Tyr Phe Gly Tyr Ser Thr Pro
275 280 285
Trp Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg
290 295 300
Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg
305 310 315 320
Leu Ser Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Gln Asn
325 330 335
Glu Gly Thr Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Ile Gln Val
340 345 350
Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His
355 360 365
Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln
370 375 380
Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser Gln Ala Val Gly Arg Ser
385 390 395 400
Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly
405 410 415
Asn Asn Phe Gln Phe Thr Tyr Thr Phe Glu Asp Val Pro Phe His Ser
420 425 430
Ser Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile
435 440 445
Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Gln Thr Thr Gly Gly Thr
450 455 460
Ala Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro Asn Thr Met
465 470 475 480
Ala Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln
485 490 495
Arg Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn Phe Ala Trp
500 505 510
Thr Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Ala Asn
515 520 525
Pro Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg Phe Phe
530 535 540
Pro Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala Ala Arg Asp
545 550 555 560
Asn Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu Glu Ile Lys
565 570 575
Thr Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ala Asp Asn
580 585 590
Leu Gln Gln Gln Asn Thr Ala Pro Gln Ile Gly Thr Val Asn Ser Gln
595 600 605
Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Thr Phe Asn
660 665 670
Gln Ser Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Thr Ser Val
705 710 715 720
Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 148
<211> 745
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 148
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Leu Gly Glu Thr Thr Arg Pro Thr Gly Gly Thr
450 455 460
Ala Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro Asn Thr Met
465 470 475 480
Ala Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln
485 490 495
Arg Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn Phe Ala Trp
500 505 510
Thr Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Ala Asn
515 520 525
Pro Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg Phe Phe
530 535 540
Pro Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala Ala Arg Asp
545 550 555 560
Asn Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu Glu Ile Lys
565 570 575
Thr Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ala Asp Asn
580 585 590
Leu Gln Gln Gln Asn Thr Ala Pro Gln Ile Gly Thr Val Asn Ser Gln
595 600 605
Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Thr Phe Asn
660 665 670
Gln Ser Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Thr Ser Val
705 710 715 720
Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 149
<211> 747
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 149
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Leu Ala
580 585 590
Leu Gly Glu Thr Thr Arg Pro Thr Ala Pro Gln Ile Gly Thr Val Asn
595 600 605
Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr
610 615 620
Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe
625 630 635 640
His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro
645 650 655
Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Thr
660 665 670
Phe Asn Gln Ser Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly
675 680 685
Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys
690 695 700
Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Thr
705 710 715 720
Ser Val Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg
725 730 735
Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 150
<211> 747
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 150
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Leu Ala Leu
260 265 270
Gly Glu Thr Thr Arg Pro Thr Asn Asp Asn Thr Tyr Phe Gly Tyr Ser
275 280 285
Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser
290 295 300
Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro
305 310 315 320
Lys Arg Leu Ser Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr
325 330 335
Gln Asn Glu Gly Thr Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Ile
340 345 350
Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr Val Leu Gly Ser
355 360 365
Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile
370 375 380
Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser Gln Ala Val Gly
385 390 395 400
Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg
405 410 415
Thr Gly Asn Asn Phe Gln Phe Thr Tyr Thr Phe Glu Asp Val Pro Phe
420 425 430
His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro
435 440 445
Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Gln Thr Thr Gly
450 455 460
Gly Thr Ala Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro Asn
465 470 475 480
Thr Met Ala Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg
485 490 495
Gln Gln Arg Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn Phe
500 505 510
Ala Trp Thr Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu
515 520 525
Ala Asn Pro Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg
530 535 540
Phe Phe Pro Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala Ala
545 550 555 560
Arg Asp Asn Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu Glu
565 570 575
Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ala
580 585 590
Asp Asn Leu Gln Gln Gln Asn Thr Ala Pro Gln Ile Gly Thr Val Asn
595 600 605
Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr
610 615 620
Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe
625 630 635 640
His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro
645 650 655
Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Thr
660 665 670
Phe Asn Gln Ser Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly
675 680 685
Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys
690 695 700
Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Thr
705 710 715 720
Ser Val Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg
725 730 735
Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 151
<211> 747
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 151
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Leu Ala Leu Gly Glu Thr Thr Arg Pro Thr Gly
450 455 460
Gly Thr Ala Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro Asn
465 470 475 480
Thr Met Ala Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg
485 490 495
Gln Gln Arg Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn Phe
500 505 510
Ala Trp Thr Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu
515 520 525
Ala Asn Pro Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg
530 535 540
Phe Phe Pro Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala Ala
545 550 555 560
Arg Asp Asn Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu Glu
565 570 575
Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ala
580 585 590
Asp Asn Leu Gln Gln Gln Asn Thr Ala Pro Gln Ile Gly Thr Val Asn
595 600 605
Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr
610 615 620
Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe
625 630 635 640
His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro
645 650 655
Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Thr
660 665 670
Phe Asn Gln Ser Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly
675 680 685
Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys
690 695 700
Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Thr
705 710 715 720
Ser Val Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg
725 730 735
Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 152
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> /注释="人工序列的描述：合成"
多肽
<400> 152
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Thr Leu Ala Val Pro Phe Lys Gly Gln Asn
450 455 460
Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val
465 470 475 480
Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val
485 490 495
Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly
500 505 510
Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly
515 520 525
Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu
530 535 540
Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val
545 550 555 560
Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr
565 570 575
Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln
580 585 590
Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 153
<211> 747
<212> PRT
<213> 腺相关病毒(Adeno-associated virus)
<400> 153
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Gln Glu Gln Leu
580 585 590
Glu Arg Ala Leu Asn Ser Ser Ala Gln Ala Gln Thr Gly Trp Val Gln
595 600 605
Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr
610 615 620
Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe
625 630 635 640
His Pro Ser Pro Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro
645 650 655
Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala
660 665 670
Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly
675 680 685
Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys
690 695 700
Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn
705 710 715 720
Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg
725 730 735
Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 154
<211> 738
<212> PRT
<213> 腺相关病毒rh.74型式2 (Adeno-associated virus rh.74 version 2)
<400> 154
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asn Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Ser Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Asn Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala
580 585 590
Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
Claims (73)
1.一种重组腺相关病毒(rAAV)衣壳蛋白，所述衣壳蛋白包含来自非AAV蛋白的异源蛋白的具有至少4个且至多12个邻接氨基酸的肽插入物，所述肽插入物紧接在对应于图8的AAV9衣壳蛋白的氨基酸138或氨基酸451至461中的一者的氨基酸残基之后，其中当所述衣壳蛋白被包装为AAV颗粒时，所述肽插入物经表面暴露。
2.一种重组腺相关病毒(rAAV)衣壳蛋白，所述衣壳蛋白包含具有至少4个且至多12个邻接氨基酸的肽插入物，所述肽插入物来自选自由以下组成的组的异源蛋白或结构域：
(i)神经组织归巢蛋白或结构域，条件是所述肽插入物不包含序列TLAVPFK(SEQ IDNO:27)；
(ii)轴丝或细胞质动力蛋白归巢结构域；
(iii)骨归巢结构域；
(iv)肾归巢结构域；
(v)肌肉归巢结构域；
(vi)内皮细胞归巢结构域；
(vii)整联蛋白受体结合结构域；
(viii)转铁蛋白受体结合结构域，条件是所述肽插入物不包含序列RTIGPSV(SEQ IDNO:19)和CRTIGPSVC(SEQ ID NO:20)二者；
(ix)肿瘤细胞靶向结构域；或
(x)视网膜细胞归巢蛋白或结构域，条件是所述肽插入物不包含序列LGETTRP(SEQ IDNO:15)和LALGETTRP(SEQ ID NO:16)二者；
其中当所述衣壳蛋白被包装为AAV颗粒时，所述肽插入物经表面暴露。
3.如权利要求1或2所述的rAAV衣壳蛋白，其中所述衣壳蛋白来自至少一种选自以下的AAV类型：AAV 1型(AAV1)、血清型2(AAV2)、血清型3(AAV3)、血清型4(AAV4)、血清型5(AAV5)、血清型6(AAV6)、血清型7(AAV7)、血清型8(AAV8)、血清型rh8(AAVrh8)、血清型9(AAV9)、血清型9e(AAV9e)、血清型rh10(AAVrh10)、血清型rh20(AAVrh20)、血清型hu.37(AVVhu.37)、血清型rh39(AAVrh39)和血清型rh74(AAVrh74)。
4.如权利要求1-3中任一项所述的rAAV衣壳蛋白，其中所述肽插入物紧接在图8中所描绘序列中的以下位置内的氨基酸残基中的一者之后出现：
(a)AAV1衣壳氨基酸序列(SEQ ID NO.110)的450-459；
(b)AAV2衣壳氨基酸序列(SEQ ID NO.111)的449-458；
(c)AAV3衣壳氨基酸序列(SEQ ID NO.112)的449-459；
(d)AAV4衣壳氨基酸序列(SEQ ID NO.113)的443-453；
(e)AAV5衣壳氨基酸序列(SEQ ID NO.114)的442-445；
(f)AAV6衣壳氨基酸序列(SEQ ID NO.115)的450-459；
(g)AAV7衣壳氨基酸序列(SEQ ID NO.116)的451-461；
(h)AAV8衣壳氨基酸序列(SEQ ID NO.117)的451-461；
(i)AAV9衣壳氨基酸序列(SEQ ID NO.118)的451-461；
(j)AAV9e衣壳氨基酸序列(SEQ ID NO.119)的452-461；
(k)AAVrh10衣壳氨基酸序列(SEQ ID NO.120)的452-461；
(l)AAVrh20衣壳氨基酸序列(SEQ ID NO.121)的452-461；
(m)AAVhu.37衣壳氨基酸序列(SEQ ID NO.122)的452-461；
(n)AAVrh74衣壳氨基酸序列(SEQ ID NO.123或SEQ ID NO.154)的452-461；或
(o)AAVrh39衣壳氨基酸序列(SEQ ID NO.124)的452-461。
5.如权利要求4所述的rAAV衣壳蛋白，其中所述肽插入物出现于对应于所述AAV9衣壳的氨基酸I451、N452、G453、S454、G455、Q456、N457、Q458、Q459、T460或L461中的一者的氨基酸残基之后。
6.如权利要求1、3-5中任一项所述的rAAV衣壳蛋白，其中所述异源蛋白是归巢结构域、中和抗体表位或纯化标签。
7.如权利要求6所述的rAAV衣壳蛋白，其中所述归巢结构域是
(i)神经组织归巢结构域；
(ii)轴丝或细胞质动力蛋白归巢结构域；
(iii)骨归巢结构域；
(iv)肾归巢结构域；
(v)肌肉归巢结构域；
(vi)内皮细胞归巢结构域；
(vii)整联蛋白受体结合结构域；
(viii)转铁蛋白受体结合结构域；
(ix)肿瘤细胞靶向结构域；或
(x)视网膜细胞归巢结构域。
8.如权利要求7所述的rAAV衣壳蛋白，其中所述肽插入物包含具有以下氨基酸序列的动力蛋白肽的至少4个邻接氨基酸或由其组成或是所述动力蛋白肽的7个邻接氨基酸：SITLVKSTQTV(SEQ ID NO:21)、TILSRSTQTG(SEQ ID NO:22)、VVMVGEKPITITQ HSVETEG(SEQID NO:25)、RSSEEDKSTQTT(SEQ ID NO:26)、KMQVPFQ(SEQ ID NO:1)、LKLPPIV(SEQ ID NO:5)、PFI KPFE(SEQ ID NO:6)、TLSLPWK(SEQ ID NO:7)、QQAAPSF(SEQ ID NO:3)、RYNAPFK(SEQ ID NO:4)、TLAVPFK(SEQ I D NO:27)或TLAAPFK(SEQ ID NO:2)。
9.如权利要求7所述的rAAV衣壳蛋白，其中来自所述转铁蛋白受体结合结构域的所述肽插入物是氨基酸序列RTIGPSV(SEQ ID NO:19)或CRTIGPSVC(SEQ ID NO:20)的至少4个邻接氨基酸或7个氨基酸。
10.如权利要求7所述的rAAV衣壳蛋白，其中来自所述视网膜细胞归巢结构域的所述肽插入物是氨基酸序列TLAAPFK(SEQ ID NO:2)、LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQID NO:16)的至少4个邻接氨基酸或7个氨基酸。
11.如权利要求10所述的rAAV衣壳蛋白，其中所述AAV衣壳蛋白是AAV8衣壳蛋白或AAV9衣壳蛋白。
12.如权利要求7所述的rAAV衣壳蛋白，其中来自所述纯化标签的所述肽插入物是具有氨基酸序列YPYDVPDYA(SEQ ID NO:86)的血凝素(HA)表位或具有氨基酸序列DYKDDDDK(SEQID NO:52)的FLAG标签的至少4个邻接氨基酸或7个邻接氨基酸。
13.如权利要求2或3所述的rAAV衣壳蛋白，其中所述神经组织归巢蛋白或所述视网膜细胞归巢蛋白是人轴丝动力蛋白(HAD)重链尾部。
14.如权利要求13所述的rAAV衣壳蛋白，其中所述肽插入物包含至少4个且至多15个来自所述HAD重链尾部的二聚化结构域的邻接氨基酸。
15.如权利要求14所述的rAAV衣壳蛋白，其中所述肽插入物包含至少4个且至多15个来自由以下(描绘于图7中)组成的组的邻接氨基酸：
(a)(DYH1_人UniProtKB-Q9P2D7的aa 1-1542)(SEQ ID NO.97)；
(b)(DYH2_人UniProtKB-Q9P225的aa 1-1764)(SEQ ID NO.98)；
(c)(DYH3_人UniProtKB-Q8TD57的aa 1-1390)(SEQ ID NO.99)；
(d)(DYH5_人UniProtKB-Q8TE73的aa 1-1941)(SEQ ID NO.100)；
(e)(DYH6_人UniProtKB-Q9C0G6的aa 1-1433)(SEQ ID NO.101)；
(f)(DYH7_人UniProtKB-Q8WXX0的aa 1-1289)(SEQ ID NO.102)；
(g)(DYH8_人UniProtKB-Q96JB1的aa 1-1807)(SEQ ID NO.103)；
(h)(DYH9_人UniProtKB-Q9NYC9的aa 1-1831)(SEQ ID NO.104)；
(i)(DYH10_人UniProtKB-Q8IVF4的aa 1-1793)(SEQ ID NO.105)；
(j)(DYH11_人UniProtKB-Q96DT5的aa 1-1854)(SEQ ID NO.106)；
(k)(DYH12_人UniProtKB-Q6ZR08的aa 1-1214)(SEQ ID NO.107)；
(l)(DYH14_人UniProtKB-Q0VDD8的aa 1-200)(SEQ ID NO.108)；或
(m)(DYH17_人UniProtKB-Q9UFH2的aa 1-1794)(SEQ ID NO.109)。
16.如权利要求15所述的rAAV衣壳蛋白，其中所述肽插入物包含至少4个且至多15个来自所述动力蛋白重链序列(图7)中的任一者的残基1-200的邻接氨基酸。
17.如权利要求15所述的rAAV衣壳蛋白，其中所述肽插入物包含7个来自图7的所述动力蛋白重链序列中的任一者的邻接氨基酸。
18.如权利要求16所述的rAAV衣壳蛋白，其中所述肽插入物包含7个来自所述动力蛋白重链序列(图7)中的任一者的残基1-200的邻接氨基酸。
19.如权利要求2或3所述的rAAV衣壳蛋白，其中所述肽插入物包含以下肽中的一者的至少4个邻接氨基酸：
(a)KMQVPFQ(SEQ ID NO:1)；
(b)TLAAPFK(SEQ ID NO:2)；
(c)QQAAPSF(SEQ ID NO:3)；
(d)RYNAPFK(SEQ ID NO:4)；
(e)LKLPPIV(SEQ ID NO:5)；
(f)PFIKPFE(SEQ ID NO:6)；或
(g)TLSLPWK(SEQ ID NO:7)。
20.如权利要求2或3所述的rAAV衣壳蛋白，其中所述肽插入物由以下肽中的一者组成：
(a)KMQVPFQ(SEQ ID NO:1)；
(b)TLAAPFK(SEQ ID NO:2)；
(c)QQAAPSF(SEQ ID NO:3)；
(d)RYNAPFK(SEQ ID NO:4)；
(e)LKLPPIV(SEQ ID NO:5)；
(f)PFIKPFE(SEQ ID NO:6)；或
(g)TLSLPWK(SEQ ID NO:7)。
21.如权利要求20所述的rAAV衣壳蛋白，其中所述肽插入物是氨基酸序列TLAAPFK(SEQID NO:2)。
22.如权利要求2或3所述的rAAV衣壳蛋白，其中所述神经组织归巢蛋白是小鼠轴丝动力蛋白(MAD)重链尾部。
23.如权利要求2或3所述的rAAV衣壳蛋白，其中所述神经组织归巢结构域是结合先天性修复受体且并非红细胞生成性的EPO(促红细胞生成素)结构域或所述结构域的构象类似物。
24.如权利要求23所述的rAAV衣壳蛋白，其中所述肽插入物是至少4个且至多11个来自QEQLERALNSS(SEQ ID NO:8)的邻接氨基酸。
25.如权利要求24所述的rAAV衣壳蛋白，其中所述肽插入物具有氨基酸序列QEQLERALNSS(SEQ ID NO:8)。
26.如权利要求2或3所述的rAAV衣壳蛋白，其中所述神经组织归巢蛋白是具有SRL(丝氨酸-精氨酸-赖氨酸)基序的脑归巢结构域。
27.如权利要求26所述的rAAV衣壳蛋白，其中来自所述脑归巢结构域的所述肽插入物具有氨基酸序列LSSRLDA(SEQ ID NO:10)或CLSSRLDAC(SEQ ID NO:11)的至少4个邻接氨基酸或是所述氨基酸序列。
28.如权利要求2或3所述的rAAV衣壳蛋白，其中所述轴丝或细胞质动力蛋白归巢结构域是动力蛋白轻链归巢结构域。
29.如权利要求28所述的rAAV衣壳蛋白，其中来自所述动力蛋白轻链归巢结构域的所述肽插入物是SITLVKSTQTV(SEQ ID NO:21)、TILSRSTQTG(SEQ ID NO:22)、VVMVGEKPITITQHSVETEG(SEQ ID NO:25)或RSSEEDKSTQTT(SEQ ID NO:26)中的一者的至少4个且至多12个邻接氨基酸。
30.如权利要求2或3所述的rAAV衣壳蛋白，其中所述骨归巢蛋白是羟磷灰石(HA)结合结构域。
31.如权利要求30所述的rAAV衣壳蛋白，其中来自所述羟磷灰石(HA)结合结构域的所述肽插入物是序列DDDDDDDD(SEQ ID NO:9)的至少6个氨基酸残基。
32.如权利要求2或3所述的rAAV衣壳蛋白，其中所述肾归巢结构域包含氨基酸序列CLPVASC(SEQ ID NO:12)。
33.如权利要求32所述的rAAV衣壳蛋白，其中来自所述肾归巢结构域肽的所述肽插入物是氨基酸序列LPVAS(SEQ ID NO:13)或CLPVASC(SEQ ID NO:12)。
34.如权利要求2或3所述的rAAV衣壳蛋白，其中来自所述肌肉归巢结构域的所述肽插入物包含氨基酸序列ASSLNIA(SEQ ID NO:14)或由其组成。
35.如权利要求2或3所述的rAAV衣壳蛋白，其中所述肽插入物包含氨基酸序列QAVRTSL(SEQ ID NO:23)或QAVRTSH(SEQ ID NO:24)或由其组成。
36.如权利要求2或3所述的rAAV衣壳蛋白，其中来自所述内皮细胞归巢结构域的所述肽插入物包含氨基酸序列SIGYPLP(SEQ ID NO:28)或由其组成。
37.如权利要求2或3所述的rAAV衣壳蛋白，其中来自所述整联蛋白结合结构域的所述肽插入物具有氨基酸序列CDCRGDCFC(SEQ ID NO:29)。
38.如权利要求2或3所述的rAAV衣壳蛋白，其中所述转铁蛋白受体结合结构域是转铁蛋白结构域或其构象类似物或铁模拟物。
39.如权利要求38所述的rAAV衣壳蛋白，其中来自所述转铁蛋白结构域的所述肽插入物是来自序列HAIYPRH(SEQ ID NO:17)或THRPPMWSPVWP(SEQ ID NO:18)的至少4个邻接氨基酸或7个邻接氨基酸。
40.如权利要求39所述的rAAV衣壳蛋白，其中所述肽插入物包含氨基酸序列HAIYPRH(SEQ ID NO:17)或THRPPMWSPVWP(SEQ ID NO:18)或由其组成。
41.如权利要求2或3所述的rAAV衣壳蛋白，其中来自所述肿瘤细胞靶向结构域的所述肽插入物包含氨基酸序列NGRAHA(SEQ ID NO:30)或由其组成。
42.如权利要求2或3所述的rAAV衣壳蛋白，其中所述肽插入物是来自TLAAPFK(SEQ IDNO:2)、TLAVPFK(SEQ ID NO:27)、RTIGPSV(SEQ ID NO:19)、CRTIGPSVC(SEQ ID NO:20)、LGETTRP(SEQ ID NO:15)和LALGETTRP(SEQ ID NO:16)中的一者的至少4个邻接氨基酸或7个邻接氨基酸。
43.如权利要求2或13-42中任一项所述的rAAV衣壳蛋白，其中所述肽插入物紧接在以下氨基酸残基(如图8中所描绘)中的一者之后出现：
(a)AAV1衣壳氨基酸序列(SEQ ID NO.110)的138、262-272；450-459；或585-593；
(b)AAV2衣壳氨基酸序列(SEQ ID NO.111)的138、262-272；449-458；或584-592；
(c)AAV3衣壳氨基酸序列(SEQ ID NO.112)的138、262-272；449-459；或585-593；
(d)AAV4衣壳氨基酸序列(SEQ ID NO.113)的137、256-262；443-453；或583-591；
(e)AAV5衣壳氨基酸序列(SEQ ID NO.114)的137、252-262；442-445；或574-582；
(f)AAV6衣壳氨基酸序列(SEQ ID NO.115)的138、262-272；450-459；585-593；
(g)AAV7衣壳氨基酸序列(SEQ ID NO.116)的138、263-273；451-461；586-594；
(h)AAV8衣壳氨基酸序列(SEQ ID NO.117)的138、263-274；452-461；587-595；
(i)AAV9衣壳氨基酸序列(SEQ ID NO.118)的138、262-273；452-461；585-593；
(j)AAV9e衣壳氨基酸序列(SEQ ID NO.119)的138、262-273；452-461；585-593；
(k)AAVrh10衣壳氨基酸序列(SEQ ID NO.120)的138、263-274；452-461；587-595；
(l)AAVrh20衣壳氨基酸序列(SEQ ID NO.121)的138、263-274；452-461；587-595；
(m)AAVhu37衣壳氨基酸序列(SEQ ID NO.122)的138、263-274；452-461；587-595；
(n)AAVrh74衣壳氨基酸序列(SEQ ID NO.123或SEQ ID NO.154)的138、263-274；452-461；587-595；或
(o)AAVrh39衣壳氨基酸序列(SEQ ID NO.124)的138、263-274；452-461；587-595。
44.如权利要求43所述的rAAV衣壳蛋白，所述rAAV衣壳蛋白包含插入所述AAV9衣壳的氨基酸残基588-589之间或紧接在对应于AAV9衣壳的氨基酸138的氨基酸残基之后的氨基酸序列TLAAPFK(SEQ ID NO:2)(参见图8)。
45.如权利要求43所述的rAAV衣壳蛋白，所述rAAV衣壳蛋白包含插入所述AAV9衣壳的I451至L461、S268或Q588中的一者之后的氨基酸序列TLAAPFK(SEQ ID NO:2)(图8)。
46.如权利要求43所述的rAAV衣壳蛋白，所述rAAV衣壳蛋白包含介于所述AAV9衣壳的氨基酸残基588-589之间的氨基酸序列QEQLERALNSS(SEQ ID NO:8)(图8)。
47.如权利要求43所述的rAAV衣壳蛋白，所述rAAV衣壳蛋白包含插入一个或多个选自所述AAV9衣壳的I451至L461或S268的位置处的氨基酸序列QEQLERALNSS(SEQ ID NO:8)(图8)。
48.如权利要求43所述的rAAV衣壳蛋白，其中所述肽插入物包含紧接在所述AAV9衣壳蛋白的氨基酸残基262-273中的一者之后的氨基酸序列TLAVPFK(SEQ ID NO:27)。
49.如权利要求43所述的rAAV衣壳蛋白，其中所述肽插入物包含介于所述AAV8衣壳蛋白的氨基酸残基269与270之间的氨基酸序列LGETTRP(SEQ ID NO:15)。
50.如权利要求49所述的rAAV衣壳蛋白，其中所述肽插入物具有氨基酸序列LALGETTRP(SEQ ID NO:16)。
51.如权利要求43所述的rAAV衣壳蛋白，其中所述肽插入物包含介于所述AAV8衣壳蛋白的氨基酸残基590与591之间的氨基酸序列LGETTRP(SEQ ID NO:15)。
52.如权利要求51所述的rAAV衣壳蛋白，其中所述肽插入物具有氨基酸序列LALGETTRP(SEQ ID NO:16)。
53.如权利要求43所述的rAAV衣壳蛋白，其中所述肽插入物包含紧接在所述AAV8衣壳蛋白的氨基酸残基453和454中的一者之后的氨基酸序列LGETTRP(SEQ ID NO:15)。
54.如权利要求53所述的rAAV衣壳蛋白，其中所述肽插入物包含氨基酸序列LALGETTRP(SEQ ID NO:16)。
55.如权利要求2或13-43中任一项所述的rAAV衣壳蛋白，其中所述衣壳是AAV9并且所述肽插入物出现于AAV9的氨基酸残基454至455之间(图8)。
56.如权利要求2或13-43中任一项所述的rAAV衣壳蛋白，其中所述肽插入物紧接在对应于所述AAV9衣壳的I451至L461、S268或Q588中的一者的酸残基之后出现(图8)。
57.如权利要求43所述的rAAV衣壳蛋白，其中所述肽插入物紧接在AAV9衣壳蛋白的氨基酸451至461中的一者之后出现。
58.如权利要求2或13-43中任一项所述的rAAV衣壳蛋白，其中所述肽插入物出现于AAV衣壳第八可变区(VR-VIII)中。
59.如前述权利要求中任一项所述的rAAV衣壳蛋白，条件是所述衣壳蛋白并非所述AAV2衣壳蛋白。
60.一种重组AAV衣壳蛋白，所述重组AAV衣壳蛋白相对于野生型或未工程改造衣壳蛋白包含一个或多个氨基酸取代，其中所述rAAV衣壳蛋白是具有A269S氨基酸取代的AAV8衣壳蛋白或是具有S263G/S269R/A273T取代或W503R或Q474A取代或另一AAV类型衣壳的衣壳蛋白中的相应取代的AAV9衣壳蛋白。
61.如实施方案60所述的rAAV衣壳蛋白，所述rAAV衣壳蛋白还包含对于AAV8衣壳蛋白的498-NNN/AAA-500或对于AAV9衣壳蛋白的496-NNN/AAA-498或另一AAV类型衣壳的衣壳蛋白中的相应取代。
62.一种核酸，所述核酸包含编码前述权利要求中任一项所述的rAAV衣壳蛋白或编码与其共有至少80％同一性的氨基酸序列的核苷酸序列。
63.如权利要求62所述的核酸，所述核酸编码前述权利要求中任一项所述的rAAV衣壳蛋白。
64.一种包装细胞，所述包装细胞能够表达权利要求62或63所述的核酸以产生包含由所述核苷酸序列编码的所述衣壳蛋白的AAV载体。
65.一种rAAV载体，所述rAAV载体包含权利要求1-61中任一项所述的衣壳蛋白。
66.如权利要求65所述的rAAV载体，所述rAAV载体还包含转基因。
67.一种药物组合物，所述药物组合物包含权利要求65或66所述的rAAV载体和药学上可接受的载体。
68.一种将转基因递送至细胞的方法，所述方法包括使所述细胞与权利要求65或66所述的rAAV载体接触；或权利要求65或66所述的rAAV载体用于将转基因递送至细胞，其中使所述细胞与所述载体接触。
69.一种将转基因递送至有需要的受试者的靶组织的方法，所述方法包括向所述受试者施用权利要求65或66所述的rAAV载体，其中所述肽插入物是归巢肽；或权利要求65或66所述的rAAV载体，所述rAAV载体用于将转基因递送至有需要的受试者的靶组织，其中将所述载体施用于所述受试者。
70.根据权利要求69所述的方法或使用的rAAV载体，其中所述rAAV载体全身性、静脉内、鞘内、鼻内、腹膜内、玻璃体内、经由腰部穿刺或经由小脑延髓池施用。
71.根据权利要求70所述的方法或使用的rAAV载体，其中所述靶组织是：
(i)神经组织，并且所述载体包含来自所述神经组织归巢结构域的肽插入物；
(ii)骨，并且所述载体包含来自所述骨归巢结构域的肽插入物；
(iii)肾，并且所述载体包含来自所述肾归巢结构域的肽插入物；
(iv)肌肉，并且所述载体包含来自所述肌肉归巢结构域的肽插入物；
(v)内皮细胞，并且所述载体包含来自所述内皮细胞归巢结构域的肽插入物；
(vi)整联蛋白受体，并且所述载体包含来自所述整联蛋白受体结合结构域的肽插入物；
(vii)肿瘤细胞上的转铁蛋白受体，并且所述载体包含来自所述转铁蛋白受体结合结构域的肽插入物；
(viii)肿瘤细胞，并且所述载体包含来自所述肿瘤细胞靶向结构域的肽插入物；或
(ix)视网膜细胞，并且所述载体包含来自所述视网膜细胞归巢结构域的肽插入物。
72.如权利要求71所述的方法或使用的rAAV载体，其中所述靶组织是视网膜细胞并且所述肽插入物包含氨基酸序列TLAAPFK(SEQ ID NO:2)、LGETTRP(SEQ ID NO:15)或LALGETTRP(SEQ ID NO:16)。
73.如权利要求72所述的方法或使用的rAAV载体，其中所述靶组织是视网膜细胞并且所述肽插入物包含氨基酸序列TLAAPFK(SEQ ID NO:2)。
Applications Claiming Priority (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962829608P | 2019-04-04 | 2019-04-04 | |
| US62/829,608 | 2019-04-04 | ||
| US201962833516P | 2019-04-12 | 2019-04-12 | |
| US62/833,516 | 2019-04-12 | ||
| US201962839368P | 2019-04-26 | 2019-04-26 | |
| US62/839,368 | 2019-04-26 | ||
| US201962924107P | 2019-10-21 | 2019-10-21 | |
| US62/924,107 | 2019-10-21 | ||
| US202062963512P | 2020-01-20 | 2020-01-20 | |
| US62/963,512 | 2020-01-20 | ||
| PCT/US2020/026485 WO2020206189A1 (en) | 2019-04-04 | 2020-04-02 | Recombinant adeno-associated viruses and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114127089A true CN114127089A (zh) | 2022-03-01 |
Family
ID=70416587
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202080031981.XA Pending CN114127089A (zh) | 2019-04-04 | 2020-04-02 | 重组腺相关病毒及其用途 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20220186256A1 (zh) |
| EP (1) | EP3947420A1 (zh) |
| JP (1) | JP2022528416A (zh) |
| CN (1) | CN114127089A (zh) |
| CA (1) | CA3135798A1 (zh) |
| IL (1) | IL286911A (zh) |
| MX (1) | MX2021011963A (zh) |
| TW (1) | TW202102526A (zh) |
| WO (1) | WO2020206189A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113121651A (zh) * | 2021-04-19 | 2021-07-16 | 信念医药科技(上海)有限公司 | 新型低中和抗体腺相关病毒衣壳蛋白 |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11149256B2 (en) | 2018-09-26 | 2021-10-19 | California Institute Of Technology | Adeno-associated virus compositions for targeted gene therapy |
| WO2021230987A1 (en) | 2020-05-13 | 2021-11-18 | Voyager Therapeutics, Inc. | Redirection of tropism of aav capsids |
| EP4225777A2 (en) * | 2020-10-07 | 2023-08-16 | RegenxBio Inc. | Adeno-associated viruses for ocular delivery of gene therapy |
| WO2022076750A2 (en) * | 2020-10-07 | 2022-04-14 | Regenxbio Inc. | Recombinant adeno-associated viruses for cns or muscle delivery |
| US20240059743A1 (en) * | 2020-12-16 | 2024-02-22 | Chidren's Medical Research Institute | Aav capsids and vectors |
| CN114805594B (zh) * | 2021-01-19 | 2024-01-26 | 中国人民解放军军事科学院军事医学研究院 | 一种能够透过生物屏障且聚集核周的动力蛋白结合肽及其应用 |
| CN114805595B (zh) * | 2021-01-19 | 2024-01-26 | 中国人民解放军军事科学院军事医学研究院 | 具有生物屏障透过性和核内聚集特性的动力蛋白结合肽及其应用 |
| WO2022156531A1 (zh) * | 2021-01-19 | 2022-07-28 | 中国人民解放军军事科学院军事医学研究院 | 一种能够透过生物屏障的动力蛋白结合肽及其应用 |
| US20240115734A1 (en) * | 2021-02-09 | 2024-04-11 | Affinia Therapeutics Inc. | Recombinant aavs with improved tropism and specificity |
| CN113121653B (zh) * | 2021-04-19 | 2021-11-19 | 上海信致医药科技有限公司 | 肌肉和视网膜特异性的新型腺相关病毒衣壳蛋白 |
| EP4346767A1 (en) * | 2021-06-03 | 2024-04-10 | Dyno Therapeutics, Inc. | Capsid variants and methods of using the same |
| WO2023283962A1 (en) * | 2021-07-16 | 2023-01-19 | Huigene Therapeutics Co., Ltd. | Modified aav capsid for gene therapy and methods thereof |
| WO2023060113A1 (en) | 2021-10-05 | 2023-04-13 | Regenxbio Inc. | Compositions and methods for recombinant aav production |
| WO2023060269A1 (en) * | 2021-10-07 | 2023-04-13 | Regenxbio Inc. | Recombinant adeno-associated viruses for targeted delivery |
| WO2023060272A2 (en) * | 2021-10-07 | 2023-04-13 | Regenxbio Inc. | Recombinant adeno-associated viruses for cns tropic delivery |
| WO2023108507A1 (en) * | 2021-12-15 | 2023-06-22 | National Institute Of Biological Sciences, Beijing | Recombinant aav vectors and use thereof |
| WO2023121177A1 (ko) * | 2021-12-21 | 2023-06-29 | (주)큐리진 | 면역 회피성 항종양 아데노바이러스 |
| WO2023178220A1 (en) | 2022-03-16 | 2023-09-21 | Regenxbio Inc. | Compositions and methods for recombinant aav production |
| WO2023183623A1 (en) | 2022-03-25 | 2023-09-28 | Regenxbio Inc. | Dominant-negative tumor necrosis factor alpha adeno-associated virus gene therapy |
| WO2023201277A1 (en) * | 2022-04-14 | 2023-10-19 | Regenxbio Inc. | Recombinant adeno-associated viruses for cns tropic delivery |
| WO2023205610A2 (en) | 2022-04-18 | 2023-10-26 | Regenxbio Inc. | Hybrid aav capsids |
| WO2023230657A1 (en) * | 2022-05-31 | 2023-12-07 | Mount Spec Investments Pty Ltd | Modified adeno-associated virus capsid proteins and methods thereof |
| WO2023242633A2 (en) * | 2022-06-14 | 2023-12-21 | Vectory B.V. | Recombinant aav capsid proteins |
| WO2024016003A2 (en) * | 2022-07-14 | 2024-01-18 | The Broad Institute, Inc. | Aav capsids that enable cns-wide gene delivery through interactions with the transferrin receptor |
| WO2024026494A1 (en) * | 2022-07-29 | 2024-02-01 | Regeneron Pharmaceuticals, Inc. | Viral particles retargeted to transferrin receptor 1 |
| WO2024044725A2 (en) | 2022-08-24 | 2024-02-29 | Regenxbio Inc. | Recombinant adeno-associated viruses and uses thereof |
| CN116693633B (zh) * | 2023-02-21 | 2023-12-22 | 广州派真生物技术有限公司 | 腺相关病毒突变体及其应用 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006119150A2 (en) * | 2005-04-29 | 2006-11-09 | Beth Israel Deaconess Medical Center | Compositions and methods for targeting of viral vectors |
| WO2008145401A2 (en) * | 2007-05-31 | 2008-12-04 | Medigene Ag | Mutated parvovirus structural proteins as vaccines |
| WO2012145601A2 (en) * | 2011-04-22 | 2012-10-26 | The Regents Of The University Of California | Adeno-associated virus virions with variant capsid and methods of use thereof |
| WO2013170078A1 (en) * | 2012-05-09 | 2013-11-14 | Oregon Health & Science University | Adeno associated virus plasmids and vectors |
| WO2017212019A1 (en) * | 2016-06-09 | 2017-12-14 | Centre National De La Recherche Scientifique (Cnrs) | Raav with chemically modified capsid |
Family Cites Families (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3378250D1 (en) | 1982-04-22 | 1988-11-24 | Ici Plc | Continuous release formulations |
| US5128326A (en) | 1984-12-06 | 1992-07-07 | Biomatrix, Inc. | Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same |
| AU6430190A (en) | 1989-10-10 | 1991-05-16 | Pitman-Moore, Inc. | Sustained release composition for macromolecular proteins |
| WO1991006287A1 (en) | 1989-11-06 | 1991-05-16 | Enzytech, Inc. | Protein microspheres and methods of using them |
| US5912015A (en) | 1992-03-12 | 1999-06-15 | Alkermes Controlled Therapeutics, Inc. | Modulated release from biocompatible polymers |
| ATE252894T1 (de) | 1995-01-05 | 2003-11-15 | Univ Michigan | Oberflächen-modifizierte nanopartikel und verfahren für ihre herstellung und verwendung |
| CA2230494A1 (en) | 1995-08-31 | 1997-03-06 | Alkermes Controlled Therapeutics Inc. | Composition for sustained release of an agent |
| US5622699A (en) | 1995-09-11 | 1997-04-22 | La Jolla Cancer Research Foundation | Method of identifying molecules that home to a selected organ in vivo |
| US5989463A (en) | 1997-09-24 | 1999-11-23 | Alkermes Controlled Therapeutics, Inc. | Methods for fabricating polymer-based controlled release devices |
| SE512663C2 (sv) | 1997-10-23 | 2000-04-17 | Biogram Ab | Inkapslingsförfarande för aktiv substans i en bionedbrytbar polymer |
| AU781958C (en) | 1999-08-09 | 2006-03-30 | Targeted Genetics Corporation | Enhancement of expression of a single-stranded, heterologous nucleotide sequence from recombinant viral vectors by designing the sequence such that it forms intrastrand base pairs |
| CA2449412C (en) | 2000-11-30 | 2013-04-02 | Uab Research Foundation | Receptor-mediated uptake of peptides that bind the human transferrin receptor |
| NZ532635A (en) | 2001-11-13 | 2007-05-31 | Univ Pennsylvania | A method of identifying unknown adeno-associated virus (AAV) sequences and a kit for the method |
| PT1453547T (pt) | 2001-12-17 | 2016-12-28 | Univ Pennsylvania | Sequências do vírus adeno-associado (aav) do serotipo 8, vetores contendo as mesmas, e utilizações destas |
| ES2648241T3 (es) | 2003-09-30 | 2017-12-29 | The Trustees Of The University Of Pennsylvania | Clados de virus adenoasociados (AAV), secuencias, vectores que contienen el mismo, y usos de los mismos |
| US7183969B2 (en) | 2004-12-22 | 2007-02-27 | Raytheon Company | System and technique for calibrating radar arrays |
| ES2525067T3 (es) | 2005-04-07 | 2014-12-17 | The Trustees Of The University Of Pennsylvania | Método de incremento de la función de un vector de AAV |
| JP4495210B2 (ja) | 2005-06-09 | 2010-06-30 | パナソニック株式会社 | 振幅誤差補償装置及び直交度誤差補償装置 |
| US20100203083A1 (en) * | 2007-05-31 | 2010-08-12 | Medigene Ag | Mutated structural protein of a parvovirus |
| US8642314B2 (en) | 2008-02-19 | 2014-02-04 | Amsterdam Molecular Therapeutics (Amt) B.V. | Optimization of expression of parvoviral rep and cap proteins in insect cells |
| PL2425000T3 (pl) | 2009-04-30 | 2019-08-30 | The Trustees Of The University Of Pennsylvania | Kompozycje do kierowania komórek przewodzących do dróg oddechowych zawierające konstrukty wirusów związanych z adenowirusami |
| US8734809B2 (en) | 2009-05-28 | 2014-05-27 | University Of Massachusetts | AAV's and uses thereof |
| US8927514B2 (en) | 2010-04-30 | 2015-01-06 | City Of Hope | Recombinant adeno-associated vectors for targeted treatment |
| US8628966B2 (en) | 2010-04-30 | 2014-01-14 | City Of Hope | CD34-derived recombinant adeno-associated vectors for stem cell transduction and systemic therapeutic gene transfer |
| WO2012057363A1 (ja) | 2010-10-27 | 2012-05-03 | 学校法人自治医科大学 | 神経系細胞への遺伝子導入のためのアデノ随伴ウイルスビリオン |
| US9409953B2 (en) | 2011-02-10 | 2016-08-09 | The University Of North Carolina At Chapel Hill | Viral vectors with modified transduction profiles and methods of making and using the same |
| EP3795581A3 (en) | 2011-08-24 | 2021-06-09 | The Board of Trustees of the Leland Stanford Junior University | New avv capsid proteins for nucleic acid transfer |
| AU2014244167A1 (en) | 2013-03-13 | 2015-10-08 | The Children's Hospital Of Philadelphia | Adeno-associated virus vectors and methods of use thereof |
| CA2904396A1 (en) * | 2013-03-15 | 2014-09-18 | The University Of North Carolina At Chapel Hill | Methods and compositions for dual glycan binding aav vectors |
| KR102268473B1 (ko) | 2013-04-20 | 2021-06-25 | 더 리서치 인스티튜트 앳 네이션와이드 칠드런스 하스피탈 | 엑손 2-표적 U7snRNA 폴리뉴클레오티드 작제물의 재조합형 아데노 부속 바이러스 전달 |
| WO2015013313A2 (en) | 2013-07-22 | 2015-01-29 | The Children's Hospital Of Philadelphia | Variant aav and compositions, methods and uses for gene transfer to cells, organs and tissues |
| WO2015038958A1 (en) | 2013-09-13 | 2015-03-19 | California Institute Of Technology | Selective recovery |
| HUE052676T2 (hu) | 2013-10-11 | 2021-05-28 | Massachusetts Eye & Ear Infirmary | Eljárások õsi vírusszekvenciák elõrejelzésére és alkalmazásaik |
| US10746742B2 (en) | 2014-04-25 | 2020-08-18 | Oregon Health & Science University | Methods of viral neutralizing antibody epitope mapping |
| WO2015191508A1 (en) | 2014-06-09 | 2015-12-17 | Voyager Therapeutics, Inc. | Chimeric capsids |
| ES2856090T3 (es) | 2014-09-24 | 2021-09-27 | Hope City | Variantes de vectores de virus adenoasociados para la edición genómica de alta eficacia y sus métodos |
| WO2016119150A1 (zh) | 2015-01-28 | 2016-08-04 | 宇龙计算机通信科技(深圳)有限公司 | 具有多摄像头的移动终端的拍摄方法和移动终端 |
| JP6665466B2 (ja) | 2015-09-26 | 2020-03-13 | 日亜化学工業株式会社 | 半導体発光素子及びその製造方法 |
| WO2017070491A1 (en) | 2015-10-23 | 2017-04-27 | Applied Genetic Technologies Corporation | Ophthalmic formulations |
| WO2018075798A1 (en) | 2016-10-19 | 2018-04-26 | Adverum Biotechnologies, Inc. | Modified aav capsids and uses thereof |
| MX2019009720A (es) * | 2017-02-15 | 2019-10-07 | Univ North Carolina Chapel Hill | Metodos y composiciones para la transferencia de genes a traves de la vasculatura. |
| CA3054687A1 (en) * | 2017-02-28 | 2018-09-07 | Adverum Biotechnologies, Inc. | Modified aav capsids and uses thereof |
-
2020
- 2020-04-01 TW TW109111391A patent/TW202102526A/zh unknown
- 2020-04-02 EP EP20721074.1A patent/EP3947420A1/en active Pending
- 2020-04-02 WO PCT/US2020/026485 patent/WO2020206189A1/en unknown
- 2020-04-02 MX MX2021011963A patent/MX2021011963A/es unknown
- 2020-04-02 CA CA3135798A patent/CA3135798A1/en active Pending
- 2020-04-02 CN CN202080031981.XA patent/CN114127089A/zh active Pending
- 2020-04-02 US US17/600,418 patent/US20220186256A1/en active Pending
- 2020-04-02 JP JP2021559079A patent/JP2022528416A/ja active Pending
-
2021
- 2021-10-03 IL IL286911A patent/IL286911A/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006119150A2 (en) * | 2005-04-29 | 2006-11-09 | Beth Israel Deaconess Medical Center | Compositions and methods for targeting of viral vectors |
| WO2008145401A2 (en) * | 2007-05-31 | 2008-12-04 | Medigene Ag | Mutated parvovirus structural proteins as vaccines |
| WO2012145601A2 (en) * | 2011-04-22 | 2012-10-26 | The Regents Of The University Of California | Adeno-associated virus virions with variant capsid and methods of use thereof |
| WO2013170078A1 (en) * | 2012-05-09 | 2013-11-14 | Oregon Health & Science University | Adeno associated virus plasmids and vectors |
| WO2017212019A1 (en) * | 2016-06-09 | 2017-12-14 | Centre National De La Recherche Scientifique (Cnrs) | Raav with chemically modified capsid |
Non-Patent Citations (1)
| Title |
|---|
| HILDEGARD BUNING 等: ""Capsid Modifications for Targeting and Improving the Efficacy of AAV Vectors"", MOLECULAR THERAPY METHOD & CLINICAL DEVELOPMENT, vol. 12, no. 1, 1 March 2019 (2019-03-01), pages 256 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113121651A (zh) * | 2021-04-19 | 2021-07-16 | 信念医药科技(上海)有限公司 | 新型低中和抗体腺相关病毒衣壳蛋白 |
| CN113121651B (zh) * | 2021-04-19 | 2023-11-17 | 信念医药科技(上海)有限公司 | 低中和抗体腺相关病毒衣壳蛋白 |
Also Published As
| Publication number | Publication date |
|---|---|
| TW202102526A (zh) | 2021-01-16 |
| JP2022528416A (ja) | 2022-06-10 |
| EP3947420A1 (en) | 2022-02-09 |
| IL286911A (en) | 2021-10-31 |
| WO2020206189A1 (en) | 2020-10-08 |
| WO2020206189A9 (en) | 2021-06-03 |
| US20220186256A1 (en) | 2022-06-16 |
| CA3135798A1 (en) | 2020-10-08 |
| MX2021011963A (es) | 2022-03-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114127089A (zh) | 重组腺相关病毒及其用途 | |
| US20230381341A1 (en) | Adeno-associated viruses for ocular delivery of gene therapy | |
| RU2664471C2 (ru) | Способы и композиции для лечения болезней мозга | |
| WO2022076750A2 (en) | Recombinant adeno-associated viruses for cns or muscle delivery | |
| CN112703198A (zh) | 用于跨血脑屏障递送试剂的方法和组合物 | |
| US20230042103A1 (en) | Engineered nucleic acid regulatory element and methods of uses thereof | |
| CA3033125A1 (en) | Methods and compositions for targeted gene transfer | |
| CN113874385A (zh) | 突变的腺相关病毒衣壳蛋白、包含该蛋白的aav颗粒和肝定向aav载体基因治疗 | |
| KR20210040984A (ko) | 점액다당류증 iva의 치료 | |
| US20230374541A1 (en) | Recombinant adeno-associated viruses for cns or muscle delivery | |
| WO2023178053A1 (en) | Modified muscle-specific promoters | |
| CN116670152A (zh) | 具有组织特异性靶向基序的新型组合物和含有其的组合物 | |
| TW202305124A (zh) | 具有腦特異性靶向模體的新穎構成物及含有其之組成物 | |
| WO2023201277A1 (en) | Recombinant adeno-associated viruses for cns tropic delivery | |
| WO2023060269A1 (en) | Recombinant adeno-associated viruses for targeted delivery | |
| WO2023060272A2 (en) | Recombinant adeno-associated viruses for cns tropic delivery | |
| CN116568815A (zh) | 用于基因疗法的眼部递送的腺相关病毒 | |
| WO2024044725A2 (en) | Recombinant adeno-associated viruses and uses thereof | |
| CA3219795A1 (en) | Recombinant tert-encoding viral genomes and vectors | |
| CN115279400A (zh) | 用于跨血脑屏障递送免疫治疗剂以治疗脑癌的方法和组合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |