CN116568815A - Adeno-associated virus for ocular delivery of gene therapy - Google Patents

Adeno-associated virus for ocular delivery of gene therapy Download PDF

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Publication number
CN116568815A
CN116568815A CN202180067084.9A CN202180067084A CN116568815A CN 116568815 A CN116568815 A CN 116568815A CN 202180067084 A CN202180067084 A CN 202180067084A CN 116568815 A CN116568815 A CN 116568815A
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pro
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Inventor
J·布鲁德尔
X·王
W-H·李
E·菲恩贝格
S·尤思特
A·默瑟
Y·刘
O·达诺斯
A·R·特佩
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Bio Regeneration Co ltd
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Bio Regeneration Co ltd
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Priority claimed from PCT/US2021/054008 external-priority patent/WO2022076711A2/en
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Abstract

The present invention relates to recombinant adeno-associated viruses (rAAVs) having capsid proteins with tropism for ocular tissues. The rAAV has a capsid that enhances or increases ocular tissue transduction compared to a reference rAAV. Such rAAV can be used to deliver transgenes encoding therapeutic proteins for the treatment of ocular diseases.

Description

Adeno-associated virus for ocular delivery of gene therapy
1. Field of the invention
Disclosed herein are recombinant adeno-associated viruses (rAAV) having capsid proteins that target or have a tropism for ocular tissue and have enhanced delivery to ocular tissue, for example, relative to a reference capsid. In particular, rAAV vectors are provided having capsids that are AAV3B, aavrh.73, aavhu.26, aav.hu.51, AAV9s454.Tfr3 or other capsids that have been demonstrated to target one or more ocular tissues. Capsid proteins that direct the rAAV to target tissues and/or improve transduction of ocular tissues (including retinal tissue and RPE choroidal tissue) and deliver therapeutic agents for the treatment of retinal diseases, particularly non-infectious uveitis, are also provided.
2. Background art
The use of adeno-associated virus (AAV) as a gene delivery vehicle is a promising approach for dealing with many unmet patient needs. Tens of naturally occurring AAV capsids have been reported, and the natural diversity of AAV sequences in primate tissues has been exploited to identify more than one hundred variants distributed in the clade. AAV belongs to the parvoviral family and is a single stranded DNA virus with a relatively small genome and simple genetic components. In the absence of helper virus, AAV establishes a latent infection. AAV genomes typically have a Rep gene and Cap gene flanking an Inverted Terminal Repeat (ITR), which serve as replication and packaging signals generated by the vector. The capsid proteins form the capsid that carries the genomic DNA and can determine tissue tropism to deliver the DNA into the target cell.
Because of the low pathogenicity and the prospect of long-term targeted gene expression, recombinant AAV (rAAV) has been used as a gene transfer vector, with therapeutic sequences packaged into various capsids. Such vectors have been used in preclinical gene therapy studies, and there are currently over twenty gene therapy products in clinical development. Recombinant AAV, such as AAV2, has demonstrated desirable retinal cell transduction characteristics and clinical trials for the treatment of ocular diseases using recombinant AAV2 are underway. Depending on the indication to be treated, tropism for other ocular tissues is desirable. Attempts to enhance ocular tissue tropism of rAAV in human subjects have met with limited success.
There remains a need for rAAV vectors with enhanced ocular tissue (including specific ocular tissue) tropism, e.g., for delivering therapies in the treatment of eye-related disorders (e.g., non-infectious uveitis). There is also a need for rAAV vectors with enhanced tissue specific targeting and/or enhanced tissue specific transduction to deliver therapies.
3. Summary of the invention
Recombinant AAV particles having capsid proteins that direct rAAV to target tissue are provided. The capsid proteins facilitate ocular tissue targeting and/or cellular uptake and/or integration of the rAAV genome, including targeting rAAV particles to anterior segment tissue (cornea, iris, ciliary body, schlemm's canal, and/or trabecular meshwork) or posterior segment tissue (such as retina or RPE-choroidal tissue) or optic nerve (orbital or cranial segment), and delivering therapeutic agents for treating ocular disorders. The rAAV may have a transgene encoding a therapeutic protein for treating an ocular disorder, and methods of administering the rAAV for delivery to ocular tissue to treat an ocular disease or disorder are provided. In embodiments, the rAAV has capsids of the following AAV serotypes: AAV serotype 1 (AAV 1; SEQ ID NO: 59); AAV serotype 2 (AAV 2; SEQ ID NO: 60); AAV serotype 3 (AAV 3; SEQ ID NO: 61), AAV serotype 3B (AAV 3B; SEQ ID NO: 74), AAV serotype 4 (AAV 4; SEQ ID NO: 62); AAV serotype 5 (AAV 5; SEQ ID NO: 63); AAV serotype 6 (AAV 6; SEQ ID NO: 64); AAV serotype 7 (AAV 7; SEQ ID NO: 65); AAV serotype 8 (AAV 8; SEQ ID NO: 66); AAV serotype 9 (AAV 9; SEQ ID NO: 67); AAV serotype 9e (AAV 9e; SEQ ID NO: 68); AAV serotype rh.10 (AAVrh.10; SEQ ID NO: 69); AAV serotype rh.20 (AAV.rh.20; SEQ ID NO: 70); AAV serotype hu.37 (aavhu.37; 71), AAV serotype rh39 (aavrh.39; 73), AAV serotype rh73 (aavrh.73; SEQ ID NO. 75), AAV serotype rh.74 (AAVrh.74; SEQ ID NO. 72 or SEQ ID NO. 96), AAV serotype hu.51 (AAVhu.51; SEQ ID NO. 76), AAV serotype hu.21 (AAVhu.21; SEQ ID NO. 77), AAV serotype hu.12 (AAVhu.12; SEQ ID NO. 78), AAV serotype hu.26 (AAVhu.26; SEQ ID NO. 79), AAV serotype rh.24 (AAVrh.24; SEQ ID NO. 87), AAV serotype hu.38 (AAVhu.38; SEQ ID NO. 88), AAV serotype rh.72 (AAVhu.72; SEQ ID NO. 89), AAV serotype hu.56 (AAVhu.56; SEQ ID NO. 86), AAV serotype cy.5; SEQ ID NO. 90), AAV serotype cy.6 (Vcy.6; SEQ ID NO. 6), AAV hu.92, AAV hu.7, SEQ ID NO. 92, AAV hu.85, AAV7, AAV hu.75), AAV serotype hu.6 (SEQ ID NO. 9) and AAV hu.75), AAV serotype hu.8 (SEQ ID NO. 85, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 7) have one of the amino acid sequence of the AAV type human being inserted into the capsid (SEQ ID NO. 7 ) or the capsid (SEQ ID NO. 7), SEQ ID NO. 6, SEQ ID NO. 7, or SEQ ID NO. 7, and SEQ, hu, and, SEQ, hu, human, human, human: 66 for numbering see fig. 7), aav9.Y443f (amino acid sequence SEQ ID NO:67 for numbering see fig. 7), aav9.y6f (amino acid sequence SEQ ID NO:66, see fig. 7 for numbering) (see fig. 7 or table 10).
In certain embodiments, the rAAV has a capsid of AAV3B serotype, aavrh.73 serotype, aav.hu.26 serotype, aavhu.51, AAVrh64R1 serotype, or aav9.s454.tfr3. Certain rAAV capsids have a tropism for particular ocular tissues and can be used to target particular ocular tissues. In embodiments, rAAV with AAV3B or aavrh.73 capsids may be administered for targeting the iris, retina, RPE choroid, or sclera, and in certain embodiments, the ciliary body, schlemm's canal, trabecular meshwork, or optic nerve (orbital and/or cranial segments). In embodiments, rAAV with AAV3B or aavrh.73 capsids can be used to target retinal and/or RPE choroidal tissues. In other embodiments, rAAV with aavrh.73 capsids can be used to target iris tissue, and in other embodiments, aavhu.26 capsids can be used to target ciliary body or trabecular meshwork. In embodiments, the ciliary body and/or trabecular meshwork is targeted for the treatment of glaucoma. AAV1 capsids can be used to target trabecular meshwork or sclera, and AAV7 can be used to target trabecular meshwork. In certain embodiments, the rAAV is administered in the absence of hyaluronic acid. rAAV may be delivered by intravitreal, suprachoroidal or intracameral administration, and in certain embodiments, may be administered to specific ocular tissues, such as the retina, retinal pigment epithelial cells, choroid, sclera, or ciliary body.
Also provided are engineered capsid proteins that facilitate transduction of a rAAV in one or more tissues (including one or more cell types) following systemic, intravenous, intracameral, suprachoroidal, or intravitreal administration, wherein the capsid proteins comprise a peptide inserted into a surface-exposed Variable Region (VR) of the capsid, e.g., into VR-I, VR-IV or VR-VIII, or following a first amino acid of VP2, e.g., immediately following residue 138 of AAV9 capsid (amino acid sequence SEQ ID NO: 67) or immediately following a corresponding residue of another AAV capsid, or alternatively engineered with one or more amino acid substitutions described herein, and the transduction of an AAV with an engineered capsid in at least one tissue (e.g., anterior segment or posterior segment or both) following such administration is increased as compared to transduction of an AAV with a corresponding non-engineered capsid. In certain embodiments, transduction is measured by detection of a transgene (such as GFP fluorescence). In particular embodiments, rAAV-transduced eye tissue (including anterior or posterior transduced eye tissue, including anterior or posterior segment) with an engineered capsid is 1.1-fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher than the transduction of a reference AAV (parental AAV serotype without an insert).
In certain embodiments, rAAV incorporating the engineered capsids described herein are provided, including rAAV having a genome comprising a transgene of therapeutic interest. Packaging cells for producing a rAAV described herein are provided. Also provided are methods of treatment by delivering the engineered rAAV described herein and pharmaceutical compositions comprising the engineered rAAV described herein. Also provided are methods of making rAAV having the engineered capsids described herein.
The invention is illustrated by the following examples describing the construction of engineered capsids and screening for capsid tropism for ocular tissues following IV or IVT administration using barcoded rAAV in mice and NHPs.
3.1. Description of the embodiments
1. A method of delivering a transgene to an ocular tissue cell, the method comprising contacting the cell with a rAAV vector comprising a transgene encoding an ocular disease therapeutic operably linked to one or more regulatory elements that promote expression of the ocular disease therapeutic in the ocular tissue cell, wherein the rAAV has the following capsids: AAV1 (SEQ ID NO: 59); AAV2 (SEQ D NO: 60); AAV3 SEQ ID NO:61 A) is provided; AAV3B (SEQ ID NO: 74); AAV4 (SEQ ID NO: 62); AAV5 (SEQ ID NO: 63); AAV6 (SEQ ID NO: 64); AAV7 (SEQ ID NO: 65); AAV8 (SEQ ID NO: 66); AAV9 (SEQ ID NO: 67); AAV9e (SEQ ID NO: 68); AAVrh.10 (SEQ ID NO: 69); AAVrh.20 (SEQ ID NO: 70); AAVhu.37 (SEQ ID NO: 71); AAVrh39 (SEQ ID NO: 73); AAV rh73 (SEQ ID NO: 75); AAVrh.74 (SEQ ID NO:72 or SEQ ID NO: 96); AAVhu.51 (SEQ ID NO: 76); AAVhu.21 (SEQ ID NO: 77); AAVhu.12 (SEQ ID NO: 78); AAVhu.26 (SEQ ID NO: 79); AAVrh.24 (SEQ ID NO: 87); AAVhu.38 (SEQ ID NO: 88); AAVrh.72 (SEQ ID NO: 89); AAVhu.56 (SEQ ID NO: 86); AAVcy.5 (SEQ ID NO: 90); AAVcy.6 (SEQ ID NO: 91); AAVrh.46 (SEQ ID NO: 92); AAVrh.13 (SEQ ID NO: 85); AAVrh.64.R1 (SEQ ID NO: 107); AAV9.S454-TFR3 (SEQ D NO: 42); AAV8.BBB (SEQ ID NO: 26); AAV8.BBB. LD (SEQ D NO: 27); AAV8.Y703F (Y703F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering); AAV9.Y443F (Y443F substitution in amino acid sequence SEQ ID NO:67, see FIG. 7 for numbering); or AAV9.Y6F (Y6F substitution in amino acid sequence SEQ D NO:66, see FIG. 7 for numbering).
2. A method of delivering a transgene to ocular tissue or ocular tissue target cells or cellular matrix thereof in a subject in need thereof, the method comprising administering to the subject a rAAV vector comprising a transgene encoding an ocular disease therapeutic operably linked to one or more regulatory elements that promote expression of the ocular disease therapeutic in the ocular tissue, wherein rAAV has capsid AAV1 (SEQ ID NO: 59); AAV2 (SEQ ID NO: 60); AAV3 SEQ ID NO:61 A) is provided; AAV3B (SEQ ID NO: 74); AAV4 (SEQ D NO: 62); AAV5 (SEQ ID NO: 63); AAV6 (SEQ ID NO: 64); AAV7 (SEQ ID NO: 65); AAV8 (SEQ ID NO: 66); AAV9 (SEQ ID NO: 67); AAV9e (SEQ ID NO: 68); AAVrh.10 (SEQ ID NO: 69); AAVrh.20 (SEQ ID NO: 70); AAVhu.37 (SEQ ID NO: 71); AAVrh39 (SEQ ID NO: 73); AAVrh73 (SEQ ID NO: 75); AAVrh.74 (SEQ ID NO:72 or SEQ ID NO: 96); AAVhu.51 (SEQ ID NO: 76); AAVhu.21 (SEQ ID NO: 77); AAVhu.12 (SEQ ID NO: 78); AAVhu.26 (SEQ ID NO: 79); AAVrh.24 (SEQ ID NO: 87); AAVhu.38 (SEQ ID NO: 88); AAVrh.72 (SEQ ID NO: 89); AAVhu.56 (SEQ ID NO: 86); AAVcy.5 (SEQ ID NO: 90); AAVcy.6 (SEQ ID NO: 91); AAVrh.46 (SEQ ID NO: 92); AAVrh.13 (SEQ ID NO: 85); AAVrh.64.R1 (SEQ ID NO: 107); AAV9.S454-TFR3 (SEQ ID NO: 42); AAV8.BBB (SEQ ID NO: 26); AAV8.BBB. LD (SEQ ID NO: 27); AAV8.Y703F (Y703F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering); AAV9.Y443F (Y443F substitution in amino acid sequence SEQ ID NO:67, see FIG. 7 for numbering); or AAV9.Y6F (Y6F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering).
3. The method of embodiment 1 or 2, wherein the capsid is an AAV3B serotype, an aavrh.73 serotype, an aav.hu.26 serotype, an aavhu.51, an AAVrh64R1 serotype, or an aav9.s454.tfr3 capsid.
4. The method of any one of embodiments 1-3, wherein the ocular tissue or ocular tissue target cell is a corneal tissue or cell, an iris tissue or cell, a ciliary body tissue or cell, a schlemm's canal tissue or cell, a trabecular meshwork tissue or cell, a retinal tissue or cell, an RPE-choroidal tissue or cell, or an optic nerve cell.
5. The method of embodiment 4, wherein the ocular tissue or ocular tissue target cell is a retinal tissue or cell or an RPE-choroidal tissue or cell.
6. The method of embodiment 5, wherein the capsid is an AAV3B or aavrh.73 capsid.
7. The method of embodiments 1-6, wherein the ocular disease is non-infectious uveitis.
8. The method of embodiments 1-4, wherein the ocular disease is glaucoma.
9. The method of embodiment 8, wherein the rAAV targets the trabecular meshwork and/or the schlemm's canal.
10. The method of embodiment 8 or 9, wherein the capsid is an AAV1 capsid, AAV2, AAV7 capsid, AAV3B capsid, aav.hu.26 capsid, or AAV9.s454-TFR3 capsid.
11. The method of any one of embodiments 1-10, wherein the rAAV vector is administered intravitreally, suprachoroidal or intracamerally.
12. The method of any one of embodiments 1-10, wherein the rAAV vector is administered systemically.
13. The method of any one of embodiments 1-12, wherein the rAAV vector provided is administered in the absence of hyaluronic acid.
14. A pharmaceutical composition for delivering a transgene to an ocular tissue cell, the composition comprising a rAAV vector comprising a transgene encoding an ocular disease therapeutic operably linked to one or more regulatory elements that promote expression of the ocular disease therapeutic in the ocular tissue cell, wherein the rAAV has the following capsids: AAV1 (SEQ ID NO: 59); AAV2 (SEQ ID NO: 60); AAV3 SEQ ID NO:61 A) is provided; AAV3B (SEQ ID NO: 74); AAV4 (SEQ ID NO: 62); AAV5 (SEQ ID NO: 63); AAV6 (SEQ ID NO: 64); AAV7 (SEQ ID NO: 65); AAV8 (SEQ ID NO: 66); AAV9 (SEQ ID NO: 67); AAV9e (SEQ ID NO: 68); AAVrh.10 (SEQ ID NO: 69); AAVrh.20 (SEQ ID NO: 70); AAVhu.37 (SEQ ID NO: 71); AAVrh39 (SEQ ID NO: 73); AAVrh73 (SEQ ID NO: 75); AAVrh.74 (SEQ ID NO:72 or SEQ ID NO: 96); AAVhu.51 (SEQ ID NO: 76); AAVhu.21 (SEQ ID NO: 77); AAVhu.12 (SEQ ID NO: 78); AAVhu.26 (SEQ ID NO: 79); AAVrh.24 (SEQ ID NO: 87); AAVhu.38 (SEQ ID NO: 88); AAVrh.72 (SEQ ID NO: 89); AAVhu.56 (SEQ ID NO: 86); AAVcy.5 (SEQ ID NO: 90); AAVcy.6 (SEQ ID NO: 91); AAVrh.46 (SEQ ID NO: 92); AAVrh.13 (SEQ ID NO: 85); AAVrh.64.R1 (SEQ ID NO: 107); AAV9.S454-TFR3 (SEQ ID NO: 42); AAV8.BBB (SEQ ID NO: 26); AAV8.BBB. LD (SEQ ID NO: 27); AAV8.Y703F (Y703F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering); AAV9.Y443F (Y443F substitution in amino acid sequence SEQ ID NO:67, see FIG. 7 for numbering); or AAV9.Y6F (Y6F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering).
15. The pharmaceutical composition of embodiment 14, wherein the capsid is an AAV3B serotype, an aavrh.73 serotype, an aav.hu.26 serotype, an aavhu.51, an AAVrh64R1 serotype, or an aav9.s454.tfr3 capsid.
16. The pharmaceutical composition according to embodiment 14 or 15, wherein the ocular tissue or ocular tissue target cell is a corneal tissue or cell, an iris tissue or cell, a ciliary body tissue or cell, a schlemm's canal tissue or cell, a trabecular meshwork tissue or cell, a retinal tissue or cell, an RPE-choroidal tissue or cell, or an optic nerve cell.
17. The pharmaceutical composition according to embodiment 16, wherein the ocular tissue or ocular tissue target cell is a retinal tissue or cell or an RPE-choroidal tissue or cell.
18. The pharmaceutical composition of embodiment 17, wherein the capsid is an AAV3B or aavrh.73 capsid.
19. The pharmaceutical composition according to embodiments 14 to 18, wherein the ocular disease is non-infectious uveitis.
20. The pharmaceutical composition according to embodiments 14 to 18, wherein the ocular disease is glaucoma.
21. The pharmaceutical composition of embodiment 20, wherein the rAAV targets the trabecular meshwork and/or the schlemm's canal.
22. The pharmaceutical composition of embodiment 20 or 21, wherein the capsid is an AAV3B serotype, an aavrh.73 serotype, an aav.hu.26 serotype, an aavhu.51, an AAVrh64R1 serotype, or an aav9.s454.tfr3 capsid.
23. The pharmaceutical composition of any one of embodiments 14-22, wherein the rAAV vector is administered intravitreally, suprachoroidal or intracamerally.
24. The method of any one of embodiments 14-22, wherein the rAAV vector is administered systemically.
25. The method of embodiments 14-24, wherein the rAAV vector provided is administered in the absence of hyaluronic acid.
26. The method or pharmaceutical composition of any one of embodiments 1-25, wherein the rAAV exhibits at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater transduction in a target tissue as compared to a reference AAV capsid.
27. The method or pharmaceutical composition of any one of embodiments 1-26, wherein the abundance of a transgenic RNA in a target tissue is 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the abundance of a transgenic RNA from a reference AAV capsid.
28. The method or pharmaceutical composition of embodiments 26 or 27, wherein the reference AAV capsid is AAV2, AAV8, or AAV9.
29. A method of treating an ocular disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 14-22 or 25.
30. The method of a pharmaceutical composition according to any one of embodiments 1 to 29, wherein the ocular disease therapeutic agent is a VEGF fusion protein, such as aflibercept; an anti-VEGF antibody or antigen-binding fragment thereof, such as cervacizumab, ranibizumab, bevacizumab, or bloc-racetam mab; an anti-kallikrein antibody or antigen binding fragment thereof, such as lenalimumab; anti-IL 6 or anti-IL 6R antibodies or antigen binding fragments thereof, such as saxaglib, sha Lilu mab, steuximab, clazab mab, cet Lu Kushan antibody, olobulab, gli Lin Zushan antibody (gerilimzumab), or tolizumab; an anti-TNF antibody or antigen-binding fragment thereof, such as adalimumab, infliximab, golimumab, or pegylated cetuximab; TNF receptor fusion proteins such as etanercept; an anti-C3 antibody or antigen-binding fragment thereof, such as eculizumab, lei Fuli bead mab or terstuzumab (tesidolumab); or an anti-C5 antibody or antigen-binding fragment thereof, such as NGM621.
31. A nucleic acid comprising a nucleotide sequence encoding a rAAV capsid protein of any of the above embodiments, or encoding an amino acid sequence sharing at least 80% identity therewith.
32. A packaging cell capable of expressing the nucleic acid of embodiment 31 to produce an AAV vector comprising a capsid protein encoded by the nucleotide sequence.
4. Description of the drawings
FIG. 1 depicts sequence comparisons of capsid amino acid sequences, including the VR-IV loop (AAV 9 VR-IV) of type 9 adeno-associated virus from residues L447 to R476, (where residues 451-459 are bracketed) to correspond to regions of other AAVs. The figure discloses the sequence of the SEQ ID NOs respectively in the appearance sequence: 49. 51-54, 50 and 55-58.
FIG. 2 depicts a protein model of AAV capsid structure showing capsid variable regions VR-IV, VR-V and VR-VIII. Boxes highlight the loop regions of VR-IV, which provide the surface exposed amino acids represented in the model.
FIG. 3 depicts the high packaging efficiency (titer) expressed in genome copy number/mL (GC/mL) of wild-type AAV9 and eight (8) candidate modified rAAV9 vectors (1090, 1091, 1092, 1093, 1094, 1095, 1096, and 1097), each containing FLAG inserts immediately following different loci within AAV9 VR-IV, from residues I451 through Q458, respectively. All vectors were packaged in 10mL cultures with luciferase transgene; error bars represent standard error of the mean.
FIG. 4 shows surface exposure of the 1VR-IV ring FLAG insert in each of the eight (8) candidate modified rAAV9 vectors (1090, 1091, 1092, 1093, 1094, 1095, 1096, and 1097), as demonstrated by immunoprecipitation of the packaging vector through binding to the anti-FLAG resin.
FIGS. 5A-5B depict transduction efficiency in Lec2 cells transduced with capsid vectors carrying a luciferase gene (as a transgene) packaged into each of wild-type AAV9 (9-luc) or eight (8) candidate modified (insert FLAG peptide) rAAV9 vectors (1090, 1091, 1092, 1093, 1094, 1095, 1096 and 1097); transduction activity was expressed as percent luciferase activity, 100% at 9-luc activity (FIG. 5A), or as relative light units per microgram of protein (RLU) (FIG. 5B).
Figures 6A-6E the bar graph depicted in figure 6A shows that insertion following S454 of AAV9 of different peptide lengths and compositions may affect production efficiency of AAV particles in packaging cells. Ten peptides of different composition and length were inserted after S454 within AAV9 VR-IV. Five days after transfection, qPCR was performed on the supernatant of the harvested transfected suspension HEK293 cells. The results depicted in the bar graph demonstrate that the nature of the insertion affects the ability of AAV particles to be produced and secreted by HEK293 cells and is expressed by total yield (titer). (error bars represent standard error of average length of peptide, noted on Y-axis in brackets.) fig. 6B-6E depict fluorescence images of transduced cell cultures of the following cell lines: (6B) Lec2 cell line, (6C) HT-22 cell line, (6D) hCMEC/D3 cell line and (6E) C2C12 cell line. AAV9 wild-type and S454 insertion homing peptide capsids containing GFP transgene were used to transduce the cell line. The P1 vector is not included in the image due to very low transduction efficiency, and the P8 vector is not included in the image due to low titer. Aav9.s454.flag showed low transduction levels in each cell type tested.
FIG. 7 depicts alignment of AAV 1-9e, AAV3B, rh, rh20, rh39, rh73, rh74 version 1 and version 2, hu12, hu21, hu26, hu37, hu51 and hu53 capsid sequences having insertion sites for heterologous peptides after the initiation codon of VP2 and within or near variable region 1 (VR-I), variable region 4 (VR-IV) and variable region 8 (VR-VIII), all highlighted in gray; the specific insertion site within the variable region eight (VR-VIII) of each capsid protein is denoted by the symbol "#" (following amino acid residue 588 according to the amino acid numbering of AAV 9). Fig. 7 shows the sequences SEQ ID NO: 59. 60, 61, 94, 74, 62, 95, 63, 64, 65, 66, 67, 68, 69, 70, 73, 75, 72, 96, 78, 77, 79, 71, 76, 80.
Figure 8 depicts copy number of GFP (green fluorescent protein) transgene in mouse brain cells after administration of the following AAV vectors: AAV9; PHP.eB, also referred to herein as AAV9e (AAV 9 with the peptide TLAVPFK (SEQ ID NO: 20) inserted between positions 588 and 589) and modification A587D/A588G); AAV9 having TLAAPFK (SEQ ID NO: 1) between 588 and 589; PHP.S (AAV 9 with peptide QAVRTSL (SEQ ID NO: 16) inserted between positions 588 and 589); AAV 9. Php.sh (AAV 9 with peptide QAVRTSH (SEQ ID NO: 17) inserted between positions 588 and 589).
Figures 9A-9C depict the amino acid sequences of recombinant AAV3B vectors comprising the following peptide insertions: inserts LALGETTRPA (SEQ ID NO: 9) are shown in bold between N588 and T589 of VR-III (FIG. 9A, SEQ ID NO: 97), A267 and S268 (FIG. 9B, SEQ ID NO: 98), and LALGETTRPA (SEQ ID NO: 9) between G454 and T455 of VR-IV (FIG. 9C, SEQ ID NO: 99).
FIGS. 10A-10C depict the amino acid sequence of a recombinant AAVrh73 vector comprising the following peptide insertions: inserts LALGETTRPA (SEQ ID NO: 9) are shown in bold between N590 and T591 of VR-III (FIG. 10A,SEQ ID NO:100), between T270 and N271 (FIG. 10B,SEQ ID NO:101), and LALGETTRPA (SEQ ID NO: 9) between G456 and G457 of VR-IV (FIG. 10C,SEQ ID NO:102).
FIGS. 11A-11C depict the amino acid sequences of recombinant AAV8 vectors comprising the following peptide insertions: the inserts LALGETTRPA (SEQ ID NO: 9) are shown in bold between N590 and T591 of VR-III (FIG. 11A), A269 and T270 (FIG. 11B), and LALGETTRPA (SEQ ID NO: 9) between T453 and T454 of VR-IV (FIG. 11C).
Figures 12A-12B depict an in vitro transwell assay of AAV vector crossing the Blood Brain Barrier (BBB) cell layer (figure 12A), and the results demonstrate that AAV. Hdyn (represented by the inverted triangle) crosses the assayed BBB cell layer faster than AAV9 (square), and more quickly and to a greater extent than AAV2 (circle) (figure 12B).
Fig. 13 depicts the results of a Next Generation Sequencing (NGS) analysis of brain gDNA from mice to which engineered capsid and natural capsid collection have been administered intravenously, revealing the relative abundance of the different capsids in the collection in mouse tissue. Three different pools were injected into mice. The dashed lines indicate which carriers are pooled together. Parental AAV9 was included as a control in each set (set 1: bc01, set 2: bc31, set 3: bc01). The bar codes for each shell in the collection are listed in tables 4A-4C.
FIGS. 14A-14H depict in vivo transduction profiles of AAV.hDyn in female C57B1/6 mice, showing increased copy number/μg gDNA in brain (FIG. 14A), liver (FIG. 14B), heart (FIG. 14C), lung (FIG. 14D), kidney (FIG. 14E), skeletal muscle (FIG. 14F), sciatic nerve (FIG. 14G) and ovary (FIG. 14H) of the mice that were initially subjected to the experiment or mice injected with AAV9 or AAV.hDyn, wherein AAV.hDyn shows increased brain biodistribution compared to AAV 9.
Figures 15A-15C depict the distribution of GFP from aav. Hdyn throughout the brain, with immunohistochemical staining images of brain sections from striatum (figure 15A), hippocampus (figure 15B) and cortex (figure 15C) revealing the overall transduction of the brain by the modified vector.
Fig. 16A and B depict the anatomy of the eye. Fig. 16A depicts a cross-section of the anterior portion of the eye, and fig. 16B depicts the anatomy of the entire eye.
Figures 17A and 17B depict in vivo transduction assays of gDNA (figure 17A) and RNA (figure 17B) isolated from eyes of NHPs, wherein a collection of engineered and native capsids was administered to the eyes of these NHPs by IVT, revealing the relative abundance of the different capsids in the collection in the cell type of the eyes of NHPs. Parental aav2.7m8 was included as a control in each set and used to calculate relative abundance.
Fig. 18A-18C show graphs of relative abundance of rAAV DNA and RNA expressed from transgenes through capsid plus barcode (relative to AAV 9) following IVT administration in eye tissue, cornea (fig. 18A), iris (fig. 18B) or lens (fig. 18C) of NHP for the nine most abundant capsids and control AAV8 and AAV 9. Ordinary one-way ANOVA with respect to post-use Dunnett multiple comparisons of AAV9 (#). P < 0.0001; p < 0.001; p < 0.01; p < 0.05 (). No RNA transcribed from the transgene was detected in the cornea or lens tissue
Figures 19A-19C show graphs of the relative abundance (relative to AAV 9) of rAAV DNA and RNA expressed from the transgenes through capsid plus barcode following IVT use in the ciliary body (figure 19A), schlemm's canal (figure 19B), or trabecular meshwork (figure 19C) of NHP for the nine most abundant capsids and control AAV8 and AAV 9. Ordinary one-way ANOVA with respect to post-use Dunnett multiple comparisons of AAV9 (#). P < 0.0001; p < 0.001; p < 0.01; p < 0.05 ().
Figures 20A-20C show graphs of relative abundance of rAAV DNA and RNA expressed from transgenes through capsid plus barcode (relative to AAV 9) following IVT administration in the retina (figure 20A), RPE-choroid (figure 20B) or sclera (figure 20C) of NHP for the nine most abundant capsids and control AAV8 and AAV 9. Ordinary one-way ANOVA with respect to post-use Dunnett multiple comparisons of AAV9 (#). P < 0.0001; p < 0.001; p < 0.01; p < 0.05 ().
Figures 21A and 21B show graphs of relative abundance (relative to AAV 9) of rAAV DNA and RNA expressed from the transgenes through capsid plus barcode following IVT administration in the optic nerve (orbital segment) or optic nerve (cranial segment) of NHP (figure 21A) or optic nerve (cranial segment) (figure 21B) for the nine most abundant capsids and control AAV8 and AAV 9. Ordinary one-way ANOVA with respect to post-use Dunnett multiple comparisons of AAV9 (#). P < 0.0001; p < 0.001; p < 0.01; p < 0.05 (). RNA transcribed from the transgene was not detected in optic nerve samples of the orbital or cranial segments.
Fig. 22A and 22B show graphs of relative abundance (relative to AAV 9) of rAAV DNA and RNA expressed from the capsid plus barcode transgene following IVT administration in mouse (fig. 22A) or NHP (fig. 22B) retinal tissue for the nine most abundant capsids and control AAV8 and AAV 9. Ordinary one-way ANOVA with respect to post-use Dunnett multiple comparisons of AAV9 (#). P < 0.0001; p < 0.001; p < 0.01; p < 0.05 ().
Figures 23A and 23B show graphs of relative abundance of rAAV DNA and RNA expressed by the transgenes barcoded by the capsids (relative to AAV 9) relative to AAV8 or AAV9 following IVT administration in mice (figure 23A) or in the NHP (figure 23B) RPE-choroid for the nine most abundant capsids and controls AAV8 and AAV 9. Ordinary one-way ANOVA with respect to post-use Dunnett multiple comparisons of AAV9 (#). P < 0.0001; p < 0.001; p < 0.01; p < 0.05 ().
Figure 24 shows a comparison of the biodistribution of the vectors in the rAAV vector collection following IVT injection in cynomolgus monkeys and mice.
5. Detailed description of the preferred embodiments
The inventors have identified capsids of adeno-associated viruses (AAV) that promote targeting of recombinant AAV (rAAV) particles to ocular tissues, including transduction of the rAAV genome, cellular uptake, integration, and expression of transgenes delivered in the rAAV particles, to a greater extent than rAAV with reference capsids such as AAV2, AAV8, or AAV9 capsids. Thus, recombinant AAV particles having capsid proteins that direct rAAV to target tissue are provided. The capsid proteins facilitate ocular tissue targeting and/or cellular uptake and/or integration of the rAAV genome, including targeting rAAV particles to anterior segment tissue (cornea, iris, ciliary body, schlemm's canal, and/or trabecular meshwork) or posterior segment tissue (such as retina or RPE-choroidal tissue) or optic nerve (orbital or cranial segment), and delivering therapeutic agents for treating ocular disorders. Including rAAV having capsid proteins engineered to include amino acid sequences that confer and/or enhance desired properties, such as ocular tissue targeting, transduction, and integration of the rAAV genome relative to a parent, non-engineered capsid, or reference capsid. The rAAV may have a transgene encoding a therapeutic protein for treating an ocular disorder, and methods of administering the rAAV for delivery to ocular tissue to treat an ocular disease or disorder are provided.
In embodiments, the rAAV has capsids of the following serotypes: AAV serotype 1 (SEQ ID NO: 59); AAV serotype 2 (SEQ ID NO: 60); AAV serotype 3 (SEQ ID NO: 61), AAV serotype 3B (AAV 3B) (SEQ ID NO: 74), AAV serotype 4 (SEQ ID NO: 62); AAV serotype 5 (SEQ ID NO: 63); AAV serotype 6 (SEQ ID NO: 64); AAV7 capsid (SEQ ID NO: 65); AAV8 capsid (SEQ ID NO: 66); AAV serotype 9 (SEQ ID NO: 67); AAV serotype 9e (SEQ ID NO: 68); AAV serotype rh10 (SEQ ID NO: 69); AAV serotype rh20 (SEQ ID NO: 70); and AAV serotype hu.37 (SEQ ID NO: 71), AAV serotype rh39 (SEQ ID NO: 73), AAV serotype rh73 (SEQ ID NO: 75), AAV serotype rh74 (SEQ ID No. 72 or SEQ ID No. 96), AAV serotype hu51 (AAV. Hu51) (SEQ ID No. 76), AAV serotype hu21 (AAV. Hu21) (SEQ ID No. 77), AAV serotype hu12 (AAV. Hu12) (SEQ ID No. 78), AAV serotype hu26 (AAV. Hu26) (SEQ ID No. 79), AAV serotype rh 24 (SEQ ID No. 87), AAV serotype hu 38 (SEQ ID No. 88), AAV serotype rh.72 (SEQ ID No. 89), AAV serotype hu 56 (SEQ ID No. 86), AAV serotype cy.5 (SEQ ID No. 90), AAV serotype cy.6 (SEQ ID No. 91), AAV serotype rh.46 (SEQ ID No. 92), AAV serotype rh.13 (SEQ ID No. 85) or AAV serotype rh.64.r1 (SEQ ID No. 107), or said capsid having one or more substitutions in the amino acid sequence of the capsid (S) relative to the present disclosure of insertion and/or the amino acid of the capsid (SEQ ID No. 26, v_8) (SEQ ID No. 8) of the amino acid sequence of any amino acid amino speeds between drum, or v drum: 66 for numbering see fig. 7), aav9.Y443f (at amino acid sequence SEQ ID NO:67 for numbering see fig. 7), aav9.y6f (at amino acid sequence SEQ ID NO:66, see fig. 7 for numbering) (see fig. 7 or table 10).
Also provided are recombinant vectors comprising the capsid proteins, and pharmaceutical compositions thereof, nucleic acids encoding the capsid proteins, and methods of making and using the capsid proteins and rAAV vectors with ocular targeting capsids for targeted delivery, improved transduction and/or treatment of ocular disorders associated with targeted ocular tissues. In particular, compositions comprising rAAV and methods of using capsid proteins to target rAAV to ocular tissues including iris, cornea, ciliary body, schlemm's canal, trabecular meshwork, RPE-choroid, retina, and optic nerve, and to facilitate delivery of therapeutic agents for treating ocular disorders are provided.
In other embodiments, provided are rAAV vectors comprising a transgene and methods of treating an ocular disease or disorder as an ophthalmic disease therapeutic agent, wherein the capsid is AAV3B serotype, aavrh.73 serotype, aav.hu.26 serotype, aavhu.51, AAVrh64R1 serotype, or AAV9.s454.tfr3 capsid or other capsid shown herein having a tropism for ocular tissues including cornea, iris, lens ciliary body, schlemm's canal, trabecular meshwork, retina, RPE-choroid, sclera, or optic nerve. In one embodiment, the ocular disorder is non-infectious uveitis. In one embodiment, the ocular disorder is glaucoma. Also provided are compositions comprising rAAV comprising peptide inserts that target or home to a target tissue (such as the retina) and methods of use thereof.
AAV "serotype" as used throughout refers to an AAV having an immunologically distinct capsid, naturally occurring capsid, or engineered capsid.
5.1. Definition of the definition
The term "AAV" or "adeno-associated virus" refers to a dependent parvovirus (Dependorparvovirus) in the genus Parvoviridae. The AAV may be an AAV derived from a naturally occurring "wild type" virus, from a rAAV genome packaged into a capsid comprising a capsid protein encoded by a naturally occurring cap gene, and/or from a rAAV genome packaged into a capsid comprising a capsid protein encoded by a non-naturally occurring capsid cap gene. Examples of the latter include rAAV with capsid proteins comprising peptides inserted into the amino acid sequence of naturally occurring capsids.
The term "rAAV" refers to "recombinant AAV". In some embodiments, the recombinant AAV has an AAV genome in which part or all of the rep and cap genes have been replaced with heterologous sequences.
The term "rep-cap helper plasmid" refers to a plasmid that provides viral rep and cap gene functions and facilitates AAV production from a rAAV genome lacking functional rep and/or cap gene sequences.
The term "cap gene" refers to a nucleic acid sequence encoding a capsid protein that forms or aids in the formation of a viral capsid. For AAV, the capsid protein may be VP1, VP2 or VP3.
The term "rep gene" refers to a nucleic acid sequence that encodes a viral replication and production of the desired nonstructural proteins.
As used herein, the terms "nucleic acid" and "nucleotide sequence" include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), combinations of DNA and RNA molecules or hybrid DNA/RNA molecules, and analogs of DNA or RNA molecules. Such analogs can be generated using, for example, nucleotide analogs including, but not limited to, inosine or tritylated bases. Such analogs may also include DNA or RNA molecules that contain modified backbones that impart beneficial properties to the molecule, such as, for example, nuclease resistance or increased ability to cross cell membranes. The nucleic acid or nucleotide sequence may be single-stranded, double-stranded, may contain single-stranded and double-stranded portions, and may contain triple-stranded portions, but is preferably double-stranded DNA.
As used herein, the terms "subject," "host," and "patient" are used interchangeably. As used herein, a subject is a mammal, such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or primate (e.g., monkey and human), or in certain embodiments is a human.
As used herein, the term "therapeutic agent" refers to any agent that can be used to treat, manage, or ameliorate symptoms associated with a disease or disorder associated with a function to be provided by a transgene. As used herein, a "therapeutically effective amount" refers to an amount of an agent that provides at least one therapeutic benefit in the treatment or control of a disease or disorder of interest (e.g., the amount of a product expressed by a transgene) when administered to a subject suffering from the disease or disorder. Furthermore, a therapeutically effective amount with respect to an agent of the present invention refers to an amount of the agent that provides at least one therapeutic benefit in the treatment or management of a disease or disorder, alone or in combination with other therapies.
As used herein, the term "prophylactic agent" refers to any agent that can be used to prevent, delay or slow the progression of a disease or disorder, wherein the disease or disorder is associated with a function that a transgene will provide. As used herein, a "prophylactically effective amount" refers to an amount of a prophylactic agent (e.g., an amount of a product expressed by a transgene) that, when administered to a subject susceptible to a disease or disorder of interest, provides at least one prophylactic benefit in preventing or delaying the disease or disorder of interest. A prophylactically effective amount may also refer to an amount sufficient to prevent or delay the onset of a disease or disorder of interest; or an amount of an agent that slows the progression of the disease or disorder of interest; an amount sufficient to delay or minimize the onset of the disease or disorder of interest; or an amount sufficient to prevent or delay recurrence or spread thereof. A prophylactically effective amount may also refer to an amount of an agent sufficient to prevent or delay the exacerbation of a symptom of a disease or disorder of interest. Further, a prophylactically effective amount with respect to the prophylactic agents of the present invention refers to an amount of prophylactic agent that provides at least one prophylactic benefit in the prevention or delay of a disease or disorder, alone or in combination with other agents.
The prophylactic agents of the invention can be administered to a subject "susceptible" to a disease or disorder of interest. A subject "susceptible" to a disease or disorder is a subject that exhibits symptoms associated with the development of the disease or disorder, or has the genetic makeup, environmental exposure, or other risk factor of such a disease or disorder, but the symptoms have not yet reached levels that can be diagnosed as a disease or disorder. For example, patients with a family history of diseases associated with the deleted gene (to be provided by the transgene) may be suitable as a susceptible person. Furthermore, patients who still have dormant tumors after removal of the primary tumor may be suitable as a predisposition to tumor recurrence.
As used herein, the "central nervous system" ("CNS") refers to the nervous tissue that the circulatory agent reaches after crossing the blood brain barrier and includes, for example, the brain, optic nerve, cranial nerve and spinal cord. The CNS also includes cerebrospinal fluid, which fills the central ducts and ventricles of the spinal cord.
AAV "serotype" as used throughout refers to an AAV having an immunologically distinct capsid, naturally occurring capsid, or engineered capsid.
5.2. Eye targeting capsid and rAAV
5.2.1 AAV capsids with ocular tissue tropism
The capsids identified herein have tropism that allows transduction and expression of the transgene in ocular tissues, including specific ocular tissues of the anterior or posterior segment of the eye, including cornea, iris, lens, ciliary body, schlemm's canal, trabecular meshwork, retina, RPE-choroid, sclera, or optic nerve. The target tissue may also be a "retinal cell" type that includes one or more cell types found in or near the retina, including amacrine cells, bipolar cells, horizontal cells, miller glial cells, photoreceptor cells (e.g., rod and cone cells), retinal ganglion cells, retinal pigment epithelium, and the like, particularly human photoreceptor cells (e.g., human cone and/or rod cells), human horizontal cells, human bipolar cells, human amacrine cells, and human retinal ganglion cells (e.g., dwarf cells, umbrella cells, bilayer cells, giant retinal ganglion cells, photosensitive ganglion cells, and/or miller glial cells), endothelial cells in the inner limiting membrane, and/or human retinal pigment epithelium in the outer limiting membrane.
In particular embodiments, methods of delivering transgenes to ocular tissue, methods of treating ocular diseases, and pharmaceutical compositions comprising rAAV comprising transgenes encoding ocular therapeutic agents are provided, wherein the AAV has the following capsids: AAV serotype 1 (SEQ ID NO: 59); AAV serotype 2 (SEQ ID NO: 60); AAV serotype 3 (SEQ ID NO: 61), AAV serotype 3B (AAV 3B) (SEQ ID NO: 74), AAV serotype 4 (SEQ ID NO: 62); AAV serotype 5 (SEQ ID NO: 63); AAV serotype 6 (SEQ ID NO: 64); AAV7 capsid (SEQ ID NO: 65); AAV8 capsid (SEQ ID NO: 66); AAV serotype 9 (SEQ ID NO: 67); AAV serotype 9e (SEQ ID NO: 68); AAV serotype rh10 (SEQ ID NO: 69); AAV serotype rh20 (SEQ ID NO: 70); and AAV serotype hu.37 (SEQ ID NO: 71), AAV serotype rh39 (SEQ ID NO: 73), AAV serotype rh73 (SEQ ID NO: 75), AAV serotype rh74 (SEQ ID NO:72 or SEQ ID NO: 96), AAV serotype hu51 (AAV.hu51) (SEQ ID NO: 76), AAV serotype hu21 (AAV.hu21) (SEQ ID NO: 77), AAV serotype hu12 (AAV.hu12) (SEQ ID NO: 78), AAV serotype hu26 (AAV.hu26) (SEQ ID NO: 79), AAV serotype rh.24 (SEQ ID NO: 87), AAV serotype hu.38 (SEQ ID NO: 88), AAV serotype rh.72 (SEQ ID NO: 89), AAV serotype hu.56 (SEQ ID NO: 86), AAV serotype cy.5 (SEQ ID NO: 90), AAV serotype cy.6 (SEQ ID NO: 91), AAV serotype rh.46 (SEQ ID NO: 92), AAV serotype rh.85 (SEQ ID NO: 85) or AAV serotype 7 (SEQ ID NO: 7) or a variant thereof, see FIG. 7 or a variant thereof.
In particular embodiments, the capsid is an AAV3B serotype, an aavrh.73 serotype, an aav.hu.26 serotype, an aavhu.51, an AAVrh64R1 serotype, or an aav9.s454.tfr3 capsid.
Certain rAAV capsids have a tropism for particular ocular tissues and can be used to target particular ocular tissues. In embodiments, rAAV with AAV3B or aavrh.73 capsids may be administered for targeting the iris, retina, RPE choroid, or sclera, and in certain embodiments, the ciliary body, schlemm's canal, trabecular meshwork, or optic nerve (orbital and/or cranial segments). In embodiments, rAAV with AAV3B or aavrh.73 capsids can be used to target retinal and/or RPE choroidal tissues. In other embodiments, rAAV with aavrh.73 capsids can be used to target iris tissue, and in other embodiments, aavhu.26 capsids can be used to target ciliary body or trabecular meshwork. AAV1 capsids can be used to target trabecular meshwork or sclera, and AAV7 can be used to target trabecular meshwork.
The rAAV particles having an ocular tissue targeting capsid described herein have enhanced targeting, transduction, genomic integration, transgenic mRNA transcription, and/or transgenic expression in ocular tissue as compared to a reference rAAV particle having a reference capsid, e.g., AAV2, AAV8, or AAV9 capsid. The enhancement may be in the whole eye tissue, or may be in particular in anterior segment tissue, posterior segment tissue or optic nerve. In embodiments, the enhancement is in the iris, retina, RPE choroid, sclera, ciliary body, schlemm's canal, trabecular meshwork, or optic nerve. The enhancement may be evaluated as known in the art, for example, in examples 15-18 herein. In embodiments, rAAV particles having an ocular tissue-targeting capsid exhibit at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher transduction or genomic copies in a target tissue as compared to a reference AAV capsid (which may be AAV2, AAV8, or AAV 9), wherein the target tissue is ocular tissue, anterior ocular tissue, posterior ocular tissue, iris, retina, RPE choroid, sclera, ciliary body, schlemm's canal, trabecular meshwork, or optic nerve. In embodiments, rAAV particles having an eye tissue-targeting capsid exhibit at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher expression of a transgenic mRNA or transgenic protein in a target tissue compared to the abundance of a transgenic RNA or protein from a reference AAV capsid (which may be AAV2, AAV8, or AAV 9), wherein the target tissue is eye tissue, anterior eye tissue, posterior eye tissue, iris, retina, RPE choroid, sclera, ciliary body, schlemm's canal, trabecular meshwork, or optic nerve.
5.2.2 engineered rAAV vectors with peptide insertion
Another aspect relates to capsid proteins modified by insertion of a peptide and/or one or more amino acid substitutions to confer or enhance ocular cell homing properties, including enhanced transduction, AAV genome copy abundance or integration, transgenic mRNA levels, or transgenic protein expression, and rAAV particles comprising the capsid proteins. The modified capsid may target cells of the retina, including non-long process cells, bipolar cells, horizontal cells, miller glia cells, photoreceptor cells (e.g., rod cells and cone cells), retinal ganglion cells, retinal pigment epithelium, etc., particularly human photoreceptor cells (e.g., human cone cells and/or rod cells), human horizontal cells, human bipolar cells, human non-long process cells, and human retinal ganglion cells (e.g., dwarf cells, umbrella cells, bilayer cells, giant retinal ganglion cells, photosensitive ganglion cells and/or miller glia cells), endothelial cells in the inner limiting membrane, and/or human retinal pigment epithelium in the outer limiting membrane. The modified capsids may target other ocular tissues including anterior segment tissues including iris, cornea, ciliary body, schlemm's canal, trabecular meshwork, and posterior segment tissues such as retina or RPE-choroid and optic nerve.
In embodiments, modified capsids and rAAV particles comprising the capsids are provided, as set forth in table 10 or described herein, including aav9.s454-TFR3 (SEQ ID NO: 42), aav8.bbb (a 269S substitution (SEQ ID NO: 26)), aav8.bbb.ld (a 296S,498_nnn/aaa_500; SEQ ID NO: 27)), aav8.y703f (amino acid sequence SEQ ID NO:66 for numbering see fig. 7), aav9.Y443f (amino acid sequence SEQ ID NO:67 for numbering see fig. 7), aav9.y6f (amino acid sequence SEQ ID NO:66, see fig. 7 for numbering).
In specific embodiments, the peptide for targeting ocular tissue is inserted into or consists of at least 4, 5, 6, 7, 8, 9 or 10 consecutive amino acids of RTIGPSV (SEQ ID NO: 12). In a particularly interesting embodiment, the peptide insertion comprises or consists of the amino acid sequence RTIGPSV (SEQ ID NO: 12).
One aspect relates to capsid proteins of recombinant adeno-associated viruses (rAAV) that are engineered to target ocular tissue cells. In some embodiments, the rAAV can comprise a peptide insertion, wherein the peptide insertion is surface exposed when packaged as an AAV particle. For example, the peptide insertion may be RTIGPSV (SEQ ID NO: 12) or LALGETTRPA (SEQ ID NO: 9) or any other peptide, such as the peptides in Table 5, including SEQ ID NO:1-20, at least RTIGPSV (SEQ ID NO: 12) or LALGETTRPA (SEQ ID NO: 9) or SEQ ID NO:1-20, 4, 5, 6, 7, 8, 9 or 10 consecutive amino acids or consists thereof. In some embodiments, peptide insertion occurs within the Variable Region IV (VRIV) of the AAV9 (SEQ ID NO: 118) capsid (i.e., between two amino acids without deletion of any capsid amino acids), or within the corresponding region of another type of AAV capsid, particularly AAV3B, AAVrh73, AAV.hu.26, AAV hu.51, or AAVrh64R1 (see alignment in Table 10 and FIG. 7). In some embodiments, peptide insertion occurs within the variable region VIII (VR-VIII) of the AAV9 capsid (i.e., between two amino acids without deletion of any capsid amino acids), or within a corresponding region of the capsid of another AAV type (see exemplary alignment in fig. 7).
In various embodiments, the rAAV capsid and/or the insertion peptide directs the rAAV particle to a target tissue (more specifically, an eye including anterior or posterior segment tissue), and/or facilitates rAAV uptake, transduction, and/or genomic integration. Also provided are nucleic acids encoding the engineered capsid proteins and variants thereof, packaging cells for expressing the nucleic acids to produce a rAAV vector, pharmaceutical compositions further comprising a transgenic rAAV vector and a rAAV vector, and methods of delivering the transgene to a target cell type or target tissue of a subject in need thereof using the rAAV vector.
In various embodiments, the rAAV capsid specifically recognizes and/or facilitates transduction of ocular tissue or, for example, one or more specific cell types, such as within a target tissue or cellular matrix thereof. In particular, the capsids target rAAV to ocular tissues including iris, cornea, ciliary body, schlemm's canal, trabecular meshwork, RPE choroid, and optic nerve, especially retina.
A capsid having a peptide inserted at a plurality of positions suitable for insertion of the peptide in and near the VR-IV loop of an AAV9 capsid (see fig. 2) and corresponding regions on the VR-IV loop of other AAV-type capsids is provided. Although previous studies analyzed potential locations in various AAVs, none identified AAV9 VR-IV as suitable for this purpose (consider, for example, wu et al 2000, "Mutational Analysis of the Adeno-Associated Virus Type 2 (AAV 2) Capsid Gene and Construction of AAV2 Vectors with Altered Tropism," J of Virology 74 (18): 8635-8647; lochrie et al 2006, "Adeno-associated viruses (AAV) capsid genes isolated from rat and mouse liver genomic DNA define two new AAV species distantly related to AAV-5," Virology 353:68-82; shi and Bartlett,2003, "RGD Inclusion in VP3 Proyides Adeno-Associated Virus Type (AAV 2) -Based Vectors with a Heparan Sulfate-Independent Cell Entry Mechanism," Molecular Therapy 7 (4): 515525-; nicklin et al 2001, "Efficient and Selective AAV2-Mediated Gene Transfer Directed to Human Vascular Endothelial Cells" Molecular Therapy (2): 174-181; grifman et al 2001, "Incorporation of Tumor-Targeting Peptides into Recombinant Adeno-associated Virus Capsids," Molecular Therapy (6): 964-975; gired et al 1999 Genetic capsid modifications allow efficient re-targeting of Adeno-2; media 3): 1052-203, and "2003-203, etc., and" viron et al, 37-203; virology 52208, j.of Virology 75 (19): 9493-9501).
Thus, provided are rAAV vectors carrying peptide insertions of RTIGPSV (SEQ ID NO: 12), LGETTRP (SEQ ID NO: 8) or LALGETTRPA (SEQ ID NO: 9) or other peptides (e.g., SEQ ID NO:1-20 peptides) at insertion points, in particular within the surface exposed variable region of the capsid shell, in particular within or near the variable region IV of the capsid protein. In some embodiments, the rAAV capsid protein comprises a peptide insertion immediately following (i.e., linked by a peptide bond at the C-terminus of) an amino acid residue corresponding to one of amino acids 451 to 461 of an AAV9 capsid protein (amino acid sequence SEQ ID NO:67, and see fig. 7 for alignment of capsid protein amino acid sequences with respect to other AAV serotypes), wherein the peptide insertion is surface exposed when the capsid protein is packaged as an AAV particle. For example, in particular embodiments, an AAV3B capsid protein comprises an RTIGPSV (SEQ ID NO: 12) peptide insertion (i.e., a peptide linkage through the C-terminus of the amino acid residues) immediately following the amino acid residue corresponding to one of amino acids 449 through 459 of AAV3B (SEQ ID NO: 74) or amino acids 452 through 461 of AAVrh73 capsid protein (SEQ ID NO: 75), wherein the peptide insertion is surface exposed when the capsid protein is packaged as an AAV particle. Peptide insertions should not be deleted of any residue of the AAV capsid protein. Typically, peptide insertion occurs in the variable (poorly conserved) regions of the capsid proteins and in the surface exposed loops, as compared to other serotypes.
Peptide insertion described as insertion "at" a given site refers to an insertion immediately following, i.e., a peptide bond with a carboxyl group of a residue typically found at that site in a wild-type virus. For example, an insertion at Q588 in AAV9 indicates that peptide insertion occurs between Q588 and the contiguous amino acid (A589) in the AAV9 wild-type capsid protein sequence (SEQ ID NO: 67). In embodiments, there is no amino acid residue deletion at or near the insertion point (within 5, 10, 15 residues or within the structural loop that serves as the insertion site). In a particular embodiment, the capsid protein is an AAV3B capsid protein or an AAVrh73 capsid protein, and the insertion occurs immediately after at least one of amino acid residues 449 to 459 or 451 to 461, respectively. In specific embodiments, peptide insertion occurs immediately after amino acid residues Q449, G450, T451, T452, S453, G454, T455, T456, N457, Q458, or S459 of the AAV3B capsid or Q452, S453, T454, G455, G456, T457, a458, G459, T460, or Q461 of the AAVrh73 capsid. In certain embodiments, the peptide is inserted between residues S454 and G455 of the AAV9 capsid protein, between residues G454 and T455 of the AAV3B capsid protein, between residues G457 and T458 of AAVrh73, or between residues S454 and G455 of an AAV capsid protein that corresponds to a protein other than AAV9 capsid protein (amino acid sequence SEQ ID NO: 67). In other embodiments, the capsid protein is from at least one AAV type selected from AAV serotype 1 (AAV 1), serotype 2 (AAV 2), serotype 3 (AAV 3), serotype 3B (AAV 3B), serotype 4 (AAV 4), serotype 5 (AAV 5), serotype 6 (AAV 6), serotype 7 (AAV 7), serotype 8 (AAV 8), serotype rh8 (AAVrh 8), serotype 9e (AAV 9 e), serotype rh10 (AAVrh 1 0), serotype rh20 (AAVrh 20), serotype rh39 (AAVrh 39), serotype rh73 (AAVrh 73), serotype hu.37 (aavhu.37), serotype rh74 (AAVrh 74, versions 1 and 2), serotype hu51 (aav.hu51), serotype hu21 (aav.hu21), serotype hu12 (aav.hu12) or serotype hu26 (aav.hu26), (see fig. 7), and the insertion occurs at least one amino acid 461 to amino acid residues corresponding to amino acid number 451. An alignment of these different AAV serotypes as shown in fig. 7 indicates "corresponding" amino acid residues in the different capsid amino acid sequences such that the "corresponding" amino acid residues are aligned in the same position in the alignment as residues in the reference sequence. In some embodiments, peptide insertion occurs immediately after one of the following amino acid residues: 450-459 of the AAV1 capsid (SEQ ID NO: 59) in the sequence depicted in FIG. 7; 449-458 of AAV2 capsid (SEQ ID NO: 60); 449-459 of AAV3 capsid (SEQ ID NO: 61); 449-459 of AAV3B capsid (SEQ ID NO: 74), 443-453 of AAV4 capsid (SEQ ID NO: 62); 442-445 of AAV5 capsid (SEQ ID NO: 63); 450-459 of AAV6 capsid (SEQ ID NO: 64); 451-461 of AAV7 capsid (SEQ ID NO: 65); 451-461 of AAV8 capsid (SEQ ID NO: 66); 451-461 of AAV9 capsid (SEQ ID NO: 67); 452-461 of AAV9e capsid (SEQ ID NO: 68); 452-461 of AAVrh10 capsid (SEQ ID NO: 69); 452-461 of AAVrh20 capsid (SEQ ID NO: 70); 452-461 of AAVhu.37 (SEQ ID NO: 71); 452-461 of AAVrh 73; 452-461 of AAVrh74 (SEQ ID NO:72 or SEQ ID NO: 96); 452-461 of AAVrh39 (SEQ ID NO: 73), 449-458 of AAVhu12 (SEQ ID NO: 78), 449-458 of AAVhu21 (SEQ ID NO: 77), 449-458 of AAVhu26 (SEQ ID NO: 79) or 449-458 of AAVhu51 (SEQ ID NO: 76). In certain embodiments, the rAAV capsid protein comprises a peptide insertion immediately after (i.e., C-terminal to) amino acid 588 of an AAV9 capsid protein (having the amino acid sequence of SEQ ID NO:67 and see fig. 7), wherein the peptide insertion is surface exposed when the capsid protein is packaged as an AAV particle. In particular embodiments, the rAAV capsid protein comprises a peptide insertion, particularly LALGETTRPA (SEQ ID NO: 9) immediately after amino acid 588 of the AAV3B capsid protein or immediately after amino acid 590 of the AAVrh73 capsid protein. In other embodiments, the rAAV capsid protein has a peptide insertion that does not immediately follow amino acid 588 of AAV9 or corresponds to amino acid 588 of AAV 9.
In other embodiments, when the peptide is a targeting peptide, it comprises RTIGPSV (SEQ ID NO: 12), or at least 10 contiguous amino acids, or just 10 contiguous amino acids, or a functional fragment thereof, from at least one AAV type selected from AAV serotype 1 (AAV 1), serotype 2 (AAV 2), serotype 3 (AAV 3), serotype 3B (AAV 3B), serotype 4 (AAV 4), serotype 5 (AAV 5), serotype 6 (AAV 6), serotype 7 (AAV 7), serotype 8 (AAV 8), serotype rh8 (AAVrh 8), serotype 9e (AAV 9 e), serotype rh10 (AAVrh 10), serotype rh20 (AAVrh 20), serotype rh39 (AAVrh 39), serotype hu.37 (aavhu.37), serotype rh73 (AAVrh 73), serotype rh74 (AAVrh 74, 1 and 2), serotype hu51 (aav.hu51), serotype hu21 (aav.hu21), serotype hu12 (aav.26) and the peptide is inserted at the point of the surface of the capsid (AAV) and the peptide is exposed at any of the surface (aav.26). In a specific embodiment, the peptide is inserted in 138 of AAV1 capsid (SEQ ID NO: 59); 262-272;450-459; or 585-593; 138 of AAV2 capsid (SEQ ID NO: 60); 262-272;449-458; or 584-592; 138 of AAV3 capsid (SEQ ID NO: 61); 262-272;449-459; or 585-593; 138 of AAV3B capsid (SEQ ID NO: 74); 262-272;449-459; or 585-593; 137 of AAV4 capsid (SEQ ID NO: 62); 256-262;443-453; or 583-591; 137 of AAV5 capsid (SEQ ID NO: 63); 252-262;442-445; or 574-582; 138 of AAV6 capsid (SEQ ID NO: 64); 262-272;450-459;585-593; 138 of AAV7 capsid (SEQ ID NO: 65); 263-273;451-461;586-594; 138 of AAV8 capsid (SEQ ID NO: 66); 263-274;452-461;587-595; 138 of AAV9 capsid (SEQ ID NO: 67); 262-273;452-461;585-593; 138 of AAV9e capsid (SEQ ID NO: 68); 262-273;452-461;585-593; 138 of AAVrh10 capsid (SEQ ID NO: 69); 263-274;452-461;587-595; 138 of AAVrh20 capsid (SEQ ID NO: 70); 263-274;452-461;587-595; 138 of AAVrh73 capsid (SEQ ID NO: 75); 263-274;452-461;587-595; 138 of the AAVrh74 capsid (SEQ ID NO:72 or SEQ ID NO: 96); 263-274;452-461;587-595, AAVhu37 capsid (SEQ ID NO: 71) 138;263-274;452-461;587-595; 138 of AAVrh39 capsid (SEQ ID NO: 734); 263-274;452-461;587-595; 138 of AAVhu12 capsid (SEQ ID NO: 78); 264-271;449-458;584-592; 449-458 of AAVhu21 capsid (SEQ ID NO: 77); 584-592; 449-458 of AAVhu26 capsid (SEQ ID NO: 79); 584-592; and 449-458 of AAVhu51 capsid (SEQ ID NO: 76); 584-592 (numbered as in fig. 7).
In some embodiments, the capsid protein is from an AAV other than serotype AAV2. In some embodiments, peptide insertion does not occur immediately after an amino acid residue corresponding to amino acid 570 or 611 of the AAV2 capsid protein. In some embodiments, peptide insertion does not occur between amino acid residues corresponding to amino acids 587-588 of the AAV2 capsid protein (see US 2014/0294771 by Schaffer et al).
AAV vectors comprising the engineered capsids are also provided. In some embodiments, the AAV vector is non-replicating and does not include nucleotide sequences encoding rep or cap proteins (these are provided by packaging cells in the manufacture of rAAV vectors). In some embodiments, the AAV-based vector comprises components from one or more AAV serotypes. In some embodiments, an AAV-based vector provided herein comprises a capsid component from one or more of the following: AAV1, AAV2, AAV3B, AAV, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, aav.rh8, aav.rh10, aav.rh20, aav.rh39, aav.rh73, aav.rh74, aav.rhm4-1, aav.hu.26, aav.hu37, aav.ank80, aav.ank80l65, 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, hsc13, aav.14, aav.hsc15, or a combination of two or more thereof. In some embodiments, an AAV-based vector provided herein comprises components from one or more of the following: AAV1, AAV2, AAV3B, AAV, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, aav.rh8, aav.rh10, aav.rh20, aav.rh39, aav.rh73, aav.rh74, aav.rhm4-1, aav.hu.26, 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, hsc13, aav.14, aav.hsc15 or a combination of two or more thereof. In some embodiments, the rAAV particle comprises a capsid protein having at least 80% or more identity (e.g., 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, etc., i.e., at most 100% identity) to, e.g., VP1, VP2, and/or VP3 sequences of an AAV capsid serotype selected from the group consisting of: AAV1, AAV2, AAV3B, AAV, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, aav.rh8, aav.rh10, aav.rh20, aav.rh39, aav.rh73, aav.rh74, aav.rhm4-1, aav.hu.26, aav.hu37, aav.ank80, aav.ank80l65, 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, hsc13, aav.14, aav.hsc15 or a pseudotyped or modified or pseudotyped thereof. These engineered AAV vectors may comprise a genome comprising a transgene encoding a therapeutic protein.
In a particular embodiment, the recombinant AAV used in the compositions and methods herein is Anc80 or Anc80L65 (see, e.g., zinn et al 2015, cell Rep.12 (6): 1056-1068, which is incorporated by reference in its entirety). In particular embodiments, the recombinant AAV used in the compositions and methods herein is aav.7m8 (including variants thereof) (see, e.g., US9,193,956;US 9,458,517;US 9,587,282;US 2016/0376323 and WO 2018/075798, each incorporated herein by reference in its entirety). In particular embodiments, the AAV used in the compositions and methods herein is any AAV disclosed in US9,585,971, such as AAV-php.b. In particular embodiments, the AAV used in the compositions and methods herein is an AAV2/Rec2 or AAV2/Rec3 vector having hybrid capsid sequences derived from AAV8 and serotypes cy5, rh20 or rh39 (see, e.g., issa et al, 2013, PLoS One 8 (4): e60361, which is incorporated herein by reference in relation to these vectors). In particular embodiments, the AAV used in the compositions and methods herein is an AAV disclosed in any one of the following (each of which is incorporated herein by reference in its entirety): US 7,282,199; US 7,906,111; US 8,524,446; US 8,999,678; US 8,628,966; US 8,927,514; US 8,734,809; US9,284,357; US9,409,953; US9,169,299; US9,193,956; US9,458,517; US9,587,282; US 2015/0374803; US 2015/0126688; US 2017/0067908; US 2013/0224836; US 2016/0215024; US 2017/0051257; PCT/US2015/034799; and PCT/EP2015/053335. In some embodiments, the rAAV particle has a capsid protein that has at least 80% or more identity (e.g., 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, etc., that is, up to 100% identity) to VP1, VP2, and/or VP3 sequences of AAV capsids disclosed in any one of the following patents and patent applications: U.S. patent nos. 7,282,199, 7,906,111, 8,524,446, 8,999,678, 8,628,966, 8,927,514, 8,734,809, US9,284,357, 9,409,953, 9,169,299, 9,193,956, 9,458,517, and 9,587,282; U.S. patent application publication nos. 2015/0374803, 2015/0126888, 2017/0067908, 2013/0224836, 2016/0215024, 2017/0051257; and international patent application numbers PCT/US2015/034799, PCT/EP2015/053335, each of which is incorporated herein by reference in its entirety.
In some embodiments, the rAAV particles comprise any AAV capsids disclosed in U.S. patent No. 9,840,719 and WO 2015/01393, such as aav.rh74 and RHM4-1, each of which is incorporated herein by reference in its entirety. In some embodiments, the rAAV particle comprises any AAV capsid disclosed in WO 2014/172669, such as AAV rh.74, which is incorporated herein by reference in its entirety. In some embodiments, the rAAV particle comprises a capsid of AAV2/5, such as Georgiadis et al, 2016,Gene Therapy 23:857-862 and Georgiaadis et al, 2018,Gene Therapy 25:450, each of which is incorporated by reference in its entirety. In some embodiments, the rAAV particle comprises any AAV capsid disclosed in WO 2017/070491, such as AAV2tYF, which is incorporated herein by reference in its entirety. In some embodiments, the rAAV particle comprises a capsid of AAVLK03 or AAV3B, such as Puzzo et al, 2017, sci.Transl.med.29 (9): 418, which is incorporated by reference in its entirety. In some embodiments, the rAAV particle comprises U.S. patent No. 8,628,966; US 8,927,514; any AAV capsid disclosed in US 9,923,120 and WO 2016/049230, such as HSC1, HSC2, HSC3, HSC4, HSC5, HSC6, HSC7, HSC8, HSC9, HSC10, HSC11, HSC12, HSC13, HSC14, HSC15, or HSC16, are each incorporated herein by reference in its entirety.
In some embodiments, the rAAV particle has a capsid protein disclosed in the following documents: international application publication nos. WO2003/052051 (see, e.g., SEQ ID No. 2 of the '051 publication), WO 2005/033321 (see, e.g., SEQ ID nos. 123 and 88 of the' 321 publication), WO 03/042397 (see, e.g., SEQ ID nos. 2, 81, 85 and 97 of the '397 publication), WO 2006/068888 (see, e.g., SEQ ID nos. 1 and 3-6 of the' 888 publication), WO 2006/110689 (see, e.g., SEQ ID nos. 5-38 of the '689 publication), WO2009/104964 (see, e.g., SEQ ID nos. 1-5, 7, 9, 20, 22, 24 and 31 of the' 964 publication), WO2010/127097 (see, e.g., SEQ ID nos. 5-38 of the '097 publication), and WO 2015/191508 (see, e.g., SEQ ID nos. 80-294 of the' 924), the respective disclosures of which are incorporated herein by reference in their entirety. In some embodiments, the rAAV particle has a capsid protein that has at least 80% or more identity (e.g., 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, etc., that is, at most 100% identity) to VP1, VP2, and/or VP3 sequences of AAV capsids disclosed in the following documents: international application publication nos. WO2003/052051 (see, e.g., SEQ ID No. 2 of the '051 publication nos. 2), WO 2005/033321 (see, e.g., SEQ ID nos. 123 and 88 of the' 321 publication nos. 123 and 88), WO 03/042397 (see, e.g., SEQ ID nos. 2, 81, 85 and 97 of the '397 publication nos. 2, 81, 85 and 97), WO 2006/068888 (see, e.g., SEQ ID nos. 1 and 3-6 of the' 888 publication nos. 1, 3-6), WO 2006/110689 (see, e.g., SEQ ID nos. 5-38 of the '689 publication), WO2009/104964 (see, e.g., SEQ ID nos. 1-5, 7, 9, 20, 22, 24 and 31 of the' 964 publication nos. 1-5, 7), W02010/127097 (see, e.g., SEQ ID nos. 5-38 of the '097 publication nos. 80-294), and us application nos. 20150023924 (see, e.g., SEQ ID nos. 1 and 5-10 of the' 924).
In further embodiments, the rAAV particle comprises a pseudotyped AAV capsid. In some embodiments, the pseudotyped AAV capsid is a rAAV2/8 or rAAV2/9 pseudotyped AAV capsid. Methods for producing and using pseudotyped rAAV particles are known in the art (see, e.g., duan et al, J. Virol.,75:7662-7671 (2001); halbert et al, J. Virol.,74:1524-1532 (2000); zolotukhin et al, methods 28:158-167 (2002); and Auricchio et al, hum. Molecular. Genet.10:3075-3081, (2001)).
In certain embodiments, single stranded AAV (ssAAV) may be used. In certain embodiments, self-complementing vectors, such as scAAV (see, e.g., wu,2007,Human Gene Therapy,18 (2): 171-82; mccarty et al 2001,Gene Therapy,8 (16): 1248-1254;US 6,596,535;US 7,125,717; and US 7,456,683, each of which is incorporated herein by reference in its entirety), may be used.
Typically, peptide insertions are sequences of consecutive amino acids from a heterologous protein or domain thereof. The peptide to be inserted is typically long enough to preserve a particular biological function, property or characteristic of the protein or domain from which it is derived. The peptide to be inserted is typically short enough to allow the capsid protein to form a shell, similar or substantially similar to the native capsid protein without the insertion. In preferred embodiments, the peptide insertion is about 4 to about 30 amino acid residues in length and about 4 to about 20, about 4 to about 15, about 5 to about 10, or about 7 amino acids in length. The peptide sequence for insertion is at least 4 amino acids in length and may be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in length. In some embodiments, the peptide sequence is 16, 17, 18, 19, or 20 amino acids in length. In embodiments, the peptide is no more than 7 amino acids, 10 amino acids, or 12 amino acids in length.
"peptide insertion from a heterologous protein" in an AAV capsid protein refers to an amino acid sequence that has been introduced into the capsid protein and is not native to any AAV serotype capsid. Non-limiting examples include peptides of human proteins in AAV capsid proteins.
The inventors have also surprisingly found specific peptides that can be used to re-target AAV vectors to specific tissues, organs or cells; in particular, peptides are provided that cause the rAAV vector to target ocular tissues. Without being bound by any one theory, peptides inserted into the AAV capsid variable region loop, e.g., RTIGPSV (SEQ ID NO: 12) peptides, have been shown to enhance transduction efficiency in ocular tissues. Such peptides may provide enhanced transport of AAV particles, encapsulating transgenes across endothelial cell matrix.
The insertion sites for the peptides described herein immediately following the amino acid residues of the AAV capsids shown below (see also fig. 7) are summarized below:
AAV1:138;262-272;450-459;595-593; and in particular embodiments, between 453-454 (SEQ ID NO: 59).
AAV2:138;262-272;449-458;584-592; and in particular embodiments between 452-453 (SEQ ID NO: 60).
AAV3:138;262-272;449-459;585-593; and in particular embodiments between 452-453 (SEQ ID NO: 61).
AAV3B:138;262-272;449-459;585-593; and in particular embodiments between 452-453 (SEQ ID NO: 74).
AAV4:137, respectively; 256-262;443-453;583-591; and in particular embodiments, between 446 and 447 (SEQ ID NO: 62).
AAV5:137, respectively; 252-262;442-445;574-582; and in particular embodiments between 445 and 446 (SEQ ID NO: 63).
AAV6:138;262-272;450-459;585-593; and in particular embodiments between 452-453 (SEQ ID NO: 64).
AAV7:138;263-273;451-461;586-594; and in particular embodiments, between 453-454 (SEQ ID NO: 65).
AAV8:138;263-274;451-461;587-595; and in particular embodiments, between 453-454 (SEQ ID NO: 66).
AAV9:138;262-273;452-461;585-593; and in particular embodiments, between 454-455 (SEQ ID NO: 67).
AAV9e:138;262-273;452-461;585-593; and in particular embodiments between 454-455 (SEQ ID NO: 68).
AAVrh10:138;263-274;452-461;587-595; and in particular embodiments, between 454 and 455 (SEQ ID NO: 69).
AAVth20:138;263-274;452-461;587-595; and in particular embodiments between 454-455 (SEQ ID NO: 70).
AAVrh39:138;263-274;452-461;587-595; and in particular embodiments, between 454-455 (SEQ ID NO: 73).
AAV.hu12：138；263-274；452-461；584-595
AAV.hu21：138；264-271；449-458；584-592
AAV.hu26：138；264-271；449-458；584-592
AAV.hu51：138；264-271；449-458；584-592
AAVrh73:138;263-274;452-461;587-595; and in particular embodiments between 456 and 457 (SEQ ID NO: 75).
AAVrh74:138;263-274;452-461;587-595; and in particular embodiments between 454 and 455 (SEQ ID NO.123 or SEQ ID NO: 144).
Aavhu.37:138;263-274;452-461;587-595; and in particular embodiments between 454 and 455 (SEQ ID NO. 122)
In particular embodiments, peptide insertion occurs between amino acid residues 588-589 of the AAV9 capsid or between corresponding residues of another AAV type capsid, as determined by amino acid sequence alignment (e.g., as shown in fig. 7). In particular embodiments, peptide insertion occurs immediately after amino acid residues I451 to L461, S268, and Q588 of the AAV9 capsid sequence or immediately after the corresponding residues of another AAV capsid sequence (fig. 7).
In some embodiments, one or more peptides from one or more homing domains can be inserted into a single system. In some embodiments, the capsid is selected and/or further modified to reduce recognition of AAV particles by the subject's immune system, such as to avoid pre-existing antibodies in the subject. In some embodiments. In some embodiments, the capsid is selected and/or further modified to enhance the desired tropism/targeting.
Method for producing rAAV molecule
Another aspect of the invention relates to the manufacture of the molecules disclosed herein. In some embodiments, the molecules according to the invention are prepared by: providing nucleotides comprising a nucleic acid sequence encoding any of the capsid protein molecules herein; and producing the corresponding rAAV particle using a packaging cell system, wherein the capsid shell is comprised of capsid proteins. In some embodiments, the nucleic acid sequence encodes a sequence that has at least 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.9% identity to a sequence of a capsid protein molecule described herein and retains (or substantially retains) the biological function of the capsid protein (in some embodiments comprises having an insert peptide from a heterologous protein or domain thereof). In some embodiments, the nucleic acid encodes a sequence that has at least 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.9% identity to the sequence of an AAV9 capsid protein (SEQ ID NO:67 and see fig. 7), while retaining (or substantially retaining) the biological function of the AAV9 capsid protein. In some embodiments, the nucleic acid encodes a sequence that has at least 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.9% identity to the sequence of the following proteins, while retaining (or substantially retaining) the biological function of the AAV9 capsid protein: AAV1 capsid protein (SEQ ID NO: 59); AAV2 capsid protein (SEQ ID NO: 60); AAV3 capsid protein (SEQ ID NO: 61); AAV3B capsid protein (SEQ ID NO: 74); AAV4 capsid protein (SEQ ID NO: 62); AAV5 capsid protein (SEQ ID NO: 63); AAV6 capsid protein (SEQ ID NO: 64); AAV7 capsid protein (SEQ ID NO: 65); AAV8 capsid protein (SEQ ID NO: 66); AAV9e capsid protein (SEQ ID NO: 68); AAVrh.10 capsid protein (SEQ ID NO: 69); AAVrh.20 capsid protein (SEQ ID NO: 70); AAVhu.37 capsid protein (SEQ ID NO: 71); AAVrh39 capsid protein (SEQ ID NO: 73); AAVrh73 capsid protein (SEQ ID NO: 75); AAVrh.74 capsid protein (SEQ ID NO:72 or SEQ ID NO: 96); AAVhu.51 capsid protein (SEQ ID NO: 76); AAVhu.21 capsid protein (SEQ ID NO: 77); AAVhu.12 capsid protein (SEQ ID NO: 78); AAVhu.26 capsid protein (SEQ ID NO: 79); AAVrh.24 capsid protein (SEQ ID NO: 87); AAVhu.38 capsid protein (SEQ ID NO: 88); AAVrh.72 capsid protein (SEQ ID NO: 89); AAVhu.56 capsid protein (SEQ ID NO: 86); AAVcy.5 capsid protein (SEQ ID NO: 90); AAVcy.6 capsid protein (SEQ ID NO: 91); AAVrh.46 capsid protein (SEQ ID NO: 92); AAVrh.13 capsid protein (SEQ ID NO: 85); AAVrh.64.R1 capsid protein (SEQ ID NO: 107); AAV9.S454-TFR3 capsid protein (SEQ ID NO: 42); AAV8.BBB capsid protein (SEQ ID NO: 26); AAV8.BBB.LD capsid protein (SEQ ID NO: 27); AAV8.Y703F capsid protein (Y703F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering); AAV9.Y443F capsid protein (Y443F substitution in amino acid sequence SEQ ID NO:67, see FIG. 7 for numbering); or AAV9.Y6F capsid protein (Y6F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering).
Capsid proteins, capsids, and rAAV particles can be produced by techniques known in the art. In some embodiments, the viral genome comprises at least one inverted terminal repeat sequence to allow packaging into a vector. In some embodiments, the viral genome further comprises a cap gene and/or a rep gene for expressing and splicing the cap gene. In other embodiments, the cap and rep genes are provided by packaging cells and are not present in the viral genome.
In some embodiments, nucleic acid encoding an engineered capsid protein is cloned into an AAV Rep-Cap helper plasmid to replace an existing capsid gene. This plasmid, when introduced together in a host cell, facilitates packaging of the rAAV genome into engineered capsid proteins as a capsid shell. The packaging cell may be any cell type having genes required to promote AAV genome replication, capsid assembly and packaging. Non-limiting examples include 293 cells or derivatives thereof, HELA cells or insect cells.
Standard techniques can be used for recombinant DNA, oligonucleotide synthesis and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques may be performed according to manufacturer specifications or as commonly done in the art or as described herein. The foregoing techniques and procedures may generally be performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout the present specification. See, e.g., sambrook et al, molecular Cloning: a Laboratory Manual (2 nd edition, cold Spring Harbor Laboratory Press, cold Spring Harbor, n.y. (1989)), which is incorporated herein by reference for any purpose. Unless specifically defined otherwise, nomenclature used in connection with the analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein, and the laboratory procedures and techniques therefor, are those well known and commonly employed in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. Nucleic acid sequences of AAV-based viral vectors and methods of making recombinant AAV and AAV capsids are described, for example, in US 7,282,199; US 7,790,449; US 8,318,480; US 8,962,332; and PCT/EP2014/076466, each of which is incorporated herein by reference in its entirety.
In embodiments, a rAAV provided herein comprises a recombinant AAV genome comprising an expression cassette flanking an ITR sequence, such as an AAV2 or AAV9 ITR sequence, wherein the expression cassette comprises a nucleotide sequence encoding a therapeutic protein for treating an ocular indication. In embodiments, the therapeutic protein is a VEGF fusion protein, such as aflibercept; an anti-VEGF antibody or antigen-binding fragment thereof, such as cervacizumab, ranibizumab, bevacizumab, or bloc-racetam mab; an anti-kallikrein antibody or antigen binding fragment thereof, such as lenalimumab; anti-IL 6 or anti-IL 6R antibodies or antigen binding fragments thereof, such as saxaglib, sha Lilu mab, steuximab, cladazazumab, west Lu Kushan antibody, olozumab, gli Lin Zushan antibody, or tolizumab; an anti-TNF antibody or antigen-binding fragment thereof, such as adalimumab, infliximab, golimumab, or pegylated cetuximab; TNF receptor fusion proteins such as etanercept; an anti-C3 antibody or antigen-binding fragment thereof, such as eculizumab, lei Fuli bead mab or terstuzumab; or an anti-C5 antibody or antigen-binding fragment thereof, such as NGM621.
In some embodiments, the rAAV provides a transgenic delivery vector useful for therapeutic and prophylactic applications, as discussed in more detail below. In some embodiments, the rAAV vector further comprises regulatory control elements known to those of skill in the art to affect expression of RNA and/or protein products encoded by nucleic acids (transgenes) within target cells of the subject. Regulatory control elements may be tissue specific, i.e. active (or substantially more active or significantly more active) only in the target cells/tissues. In particular embodiments, the AAV vector comprises a regulatory sequence (e.g., a promoter) operably linked to a transgene that allows expression in a target tissue. The promoter may be a constitutive promoter, such as a CB7 promoter. Additional promoters include: cytomegalovirus (CMV) promoter, rous Sarcoma Virus (RSV) promoter, MMT promoter, EF-1. Alpha. Promoter, UB6 promoter, chicken beta-actin promoter, CAG promoter, RPE65 promoter or opsin promoter. In some embodiments, inducible promoters, such as hypoxia-inducible or rapamycin-inducible promoters, are used, particularly where it may be desirable to shut down transgene expression.
In particular embodiments, an AAV3B serotype, aavrh.73 serotype, aav.hu.26 serotype, aavhu.51, AAVrh64R1 serotype, or AAV9.s454.tfr3 capsid vector comprising a viral genome comprising an expression cassette for expression of a transgene and flanking ITRs under the control of regulatory elements and an engineered viral capsid described herein or having at least 95%, 96%, 97%, 98%, 99% or 99.9% identity to an amino acid sequence of an AAV3B, aavrh.73, aav.hu.26, aavhu.51, AAVrh64R1, or AAV9.s454.tfr3 capsid protein (SEQ ID NOs: 74, 75, 79, 76, 107 and 42, respectively; see fig. 7) is provided while retaining the biological function of the AAV3B serotype, aavrh.73 serotype, aavrh.26 serotype, aavhu.51, AAVrh64R1, or aav9.s454.capsid. In certain embodiments, the encoded AAV3B serotype, aavrh.73 serotype, aav.hu.26 serotype, aavhu.51, AAVrh64R1 serotype, or AAV9.s454.tfr3 capsid has a sequence relative to an additional 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, or 30 amino acid substituted AAV3B serotype, aavrh.73 serotype, aav.hu.26 serotype, aavhu.51, AAVrh64R1 serotype, or AAV9.s454.tfr3 capsid.
The recombinant adenovirus may be a first generation vector with an E1 deletion, with or without an E3 deletion, and with an expression cassette inserted into either deletion region. The recombinant adenovirus may be a second generation vector containing all or part of the deletions of the E2 and E4 regions. Helper-dependent adenoviruses retain only adenovirus inverted terminal repeats and packaging signals (phi). Transgenes are typically inserted between the packaging signal and the 3' itr, with or without stuffer sequences to keep the genome near the wild-type size of about 36 kb. Exemplary protocols for the production of adenovirus vectors can be found in Alba et al, 2005, "Gutless adenovirus: last generation adenovirus for Gene Therapy, "Gene Therapy 12: S18-S27, which are incorporated herein by reference in their entirety.
rAAV vectors for delivery of transgenes to a target tissue, cell or organ have tropism for that particular target tissue, cell or organ (particularly the eye and tissues within the eye). Tissue-specific promoters may also be used. Constructs may also include expression control elements (e.g., introns such as chicken beta-actin intron, mouse adenovirus (MVM) intron, human factor IX intron (e.g., FIX truncated intron 1), beta-globin splice donor/immunoglobulin heavy chain splice acceptor intron, adenovirus splice donor/immunoglobulin splice acceptor intron, SV40 late splice donor/splice acceptor (19S/16S) intron, and hybrid adenovirus splice donor/IgG splice acceptor introns, as well as polyA signals such as rabbit beta-globin polyA signal, human growth hormone (hGH) polyA signal, SV40 late polyA signal, synthetic PolyA (SPA) signal, and bovine growth hormone (bGH) polyA signal see, e.g., powell and Rivera-Soto,2015, discov. Med.,. 19 (102): 49-57.
In certain embodiments, the nucleic acid sequences disclosed herein may be codon optimized, e.g., by any codon optimization technique known to those of skill in the art (see, e.g., a review by Quax et al, 2015,Mol Cell 59:149-161).
In particular embodiments, the constructs described herein comprise the following components: (1) AAV2 inverted terminal repeats flanking the expression cassette; (2) Control elements, including constitutive promoters or eye tissue specific promoters, optionally, intron sequences, such as chicken gamma-actin intron and poly a signal; and (3) providing (e.g., encoding) a transgene of a nucleic acid or protein product of interest. In embodiments, the protein of interest is a therapeutic protein, including, for example, a VEGF fusion protein, such as aflibercept; an anti-VEGF antibody or antigen-binding fragment thereof, such as cervacizumab, ranibizumab, bevacizumab, or bloc-racetam mab; an anti-kallikrein antibody or antigen binding fragment thereof, such as lenalimumab; anti-IL 6 or anti-IL 6R antibodies or antigen binding fragments thereof, such as saxaglib, sha Lilu mab, steuximab, cladazazumab, west Lu Kushan antibody, olozumab, gli Lin Zushan antibody, or tolizumab; an anti-TNF antibody or antigen-binding fragment thereof, such as adalimumab, infliximab, golimumab, or pegylated cetuximab; TNF receptor fusion proteins such as etanercept; an anti-C3 antibody or antigen-binding fragment thereof, such as eculizumab, lei Fuli bead mab or terstuzumab; or an anti-C5 antibody or antigen-binding fragment thereof, such as NGM621.
The viral vectors provided herein can be made using host cells, e.g., mammalian host cells, including host cells from humans, monkeys, mice, rats, rabbits, or hamsters. Non-limiting examples include: a549, WEHI, 10T1/2, BHK, MDCK, COS1, COS7, BSC 1, BSC 40, BMT 10, VERO, W138, heLa, 293, saos, C2C12, L, HT1080, hepG2, primary fibroblasts, hepatocytes and myoblasts. Typically, host cells are stably transformed with sequences encoding the transgene and related elements (i.e., the vector genome) and genetic components such as replication and capsid genes (e.g., rep and cap genes of AAV) for the production of the virus in the host cell. For a method of producing a recombinant AAV vector having an AAV8 capsid, see section IV of the detailed description of U.S. patent No. 7,282,199B2, which is incorporated herein by reference in its entirety. The genomic copy titre of the vector may be determined, for example, byAnalysis to determine. The virus particles can be recovered, for example, by CsCl2 sedimentation. Alternatively, baculovirus expression systems in insect cells can be used to produce AAV vectors. For reviews, see Apnte-Ubillus et al 2018, appl. Microbiol. Biotechnol. 102:1045-1054, which is incorporated herein by reference in its entirety for manufacturing techniques.
An in vitro assay (e.g., a cell culture assay) can be used to measure transgene expression from the vectors described herein, thereby indicating, for example, the efficacy of the vector. For example, the number of the cells to be processed,cell line (Lonza), a cell line derived from human embryonic retinal cells or retinal pigment epithelial cells, e.g., retinal pigment epithelial cell line hTERT RPE-1 (obtainable fromObtained) can be used to assess transgene expression. Alternatively, a source derived fromCell lines of the liver or other cell types, such as but not limited to HuH-7, HEK293, fibrosarcoma HT-1080, HKB-11 and CAP cells. Once expressed, assays known in the art can be used to determine the characteristics of the expressed product (i.e., transgene product), including the determination of glycosylation and tyrosine sulfation pattern.
5.4. Therapeutic and prophylactic use
Another aspect relates to therapies comprising administering a transgene to a subject in need thereof by a rAAV vector according to the invention to delay, prevent, treat, and/or control an ocular disease or disorder and/or ameliorate one or more symptoms associated with the ocular disease or disorder. A subject in need thereof includes a subject having a disease or disorder, or a subject susceptible to a disease or disorder, e.g., a subject at risk of developing or having a recurrence of a disease or disorder. In general, rAAV carrying a particular transgene may be used in connection with a given disease or disorder in a subject, wherein the native gene of the subject corresponding to the transgene is deficient in providing the correct gene product or the correct amount of gene product. The transgene may then provide a copy of the gene that is defective in the subject.
For subjects having a genetic mutation in the corresponding native gene, the transgene may include a cDNA that restores protein function. In some embodiments, the cDNA comprises related RNA for genome engineering, such as genome editing by homologous recombination. In some embodiments, the transgene encodes a therapeutic RNA, such as shRNA, artificial miRNA, or an element that affects splicing.
In embodiments, the transgene comprises a nucleotide.
AAV vectors can be selected or engineered as described herein to target an appropriate tissue or cell type, including ocular tissue, to deliver a transgene for therapeutic or prophylactic use.
In particular aspects, the rAAV described herein can be used to deliver targeted to ocular tissue or targeted to an ocular tissue cell type, including a cell matrix associated with a target cell type, associated with a disorder or disease to be treated/prevented. A disease or disorder associated with a particular tissue or cell type is a disease or disorder that affects the particular tissue or cell type to a large extent as compared to other tissue or cell types of the body, or is a disease or disorder in which the effects or symptoms of the disorder appear in the particular tissue or cell type. Methods of delivering a transgene to a target tissue of a subject in need thereof include administering a rAAV to the subject, wherein the capsid has a tropism for tissue cell types, including enhanced transduction, genomic integration, transgenic mRNA and protein expression in ocular tissue, including as compared to a rAAV having a reference capsid such as AAV2, AAV8, or AAV 9.
For diseases or conditions associated with the retina or eye, the rAAV vector has a capsid with ocular tropism, thereby directing the rAAV to target the eye or ocular tissue of the subject, including, in embodiments, across the blood-ocular barrier. The term "retinal cell" refers to one or more cell types found in or near the retina, including amacrine cells, bipolar cells, horizontal cells, miller glial cells, photoreceptor cells (e.g., rod cells and cone cells), retinal ganglion cells (e.g., dwarfism cells, umbrella cells, bilayer cells, giant retinal ganglion cells and photosensitive ganglion cells), retinal pigment epithelium, endothelial cells of the inner limiting membrane, and the like. Ocular tissues include anterior segment tissues including iris, cornea, lens, ciliary body, schlemm's canal and trabecular meshwork; and posterior segment tissues such as the retina or RPE-choroid and optic nerve (see fig. 16A and 16B).
In further embodiments, methods and compositions are provided wherein a rAAV comprising a recombinant genome comprising a transgene encoding an ocular therapeutic agent has a capsid that is eosinophilic for transduction and/or transgene expression in ocular tissue (including anterior and/or posterior segments), wherein the capsid has the following serotypes: AAV serotype 1 (AAV 1; SEQ ID NO: 59); AAV serotype 2 (AAV 2; SEQ ID NO: 60); AAV serotype 3 (AAV 3; SEQ ID NO: 61), AAV serotype 3B (AAV 3B; SEQ ID NO: 74), AAV serotype 4 (AAV 4; SEQ ID NO: 62); AAV serotype 5 (AAV 5; SEQ ID NO: 63); AAV serotype 6 (AAV 6; SEQ ID NO: 64); AAV serotype 7 (AAV 7; SEQ ID NO: 65); AAV serotype 8 (AAV 8; SEQ ID NO: 66); AAV serotype 9 (AAV 9; SEQ ID NO: 67); AAV serotype 9e (AAV 9e; SEQ ID NO: 68); AAV serotype rh.10 (AAVrh.10; SEQ ID NO: 69); AAV serotype rh.20 (AAV.rh.20; SEQ ID NO: 70); AAV serotype hu.37 (aavhu.37; 71), AAV serotype rh39 (aavrh.39; 73), AAV serotype rh73 (aavrh.73; SEQ ID NO. 75), AAV serotype rh.74 (AAVrh.74; SEQ ID NO. 72 or SEQ ID NO. 96), AAV serotype hu.51 (AAVhu.51; SEQ ID NO. 76), AAV serotype hu.21 (AAVhu.21; SEQ ID NO. 77), AAV serotype hu.12 (AAVhu.12; SEQ ID NO. 78), AAV serotype hu.26 (AAVhu.26; SEQ ID NO. 79), AAV serotype rh.24 (AAVrh.24; SEQ ID NO. 87), AAV serotype hu.38 (AAVhu.38; SEQ ID NO. 88), AAV serotype rh.72 (AAVhu.72; SEQ ID NO. 89), AAV serotype hu.56 (AAVhu.56; SEQ ID NO. 86), AAV serotype cy.5 (AAV.90), AAV serotype cy.6 (Vcy.6; SEQ ID NO. 6), AAV hu.92, AAV.46, AAV serotype hu.85 (SEQ ID NO. 6), AAV.296, and one of the amino acid sequence of the AAV serotype has been inserted into the amino acid sequence of the AAV capsid (SEQ ID NO. 7 ) or the one of the AAV capsid (SEQ ID NO. 7), AAV capsid (SEQ ID NO. 7, SEQ ID NO. 6, 7) or the amino acid sequence of which has the amino acid sequence of the AAV capsid (SEQ ID NO. 7, and 7). 66 for numbering see fig. 7), aav9.Y443f (at amino acid sequence SEQ ID NO:67 for numbering see fig. 7), aav9.y6f (at amino acid sequence SEQ ID NO:66, see fig. 7 for numbering) (see fig. 7 or table 10). In certain embodiments, the rAAV has a capsid of AAV3B serotype, aavrh.73 serotype, aav.hu.26 serotype, aavhu.51, AAVrh64R1 serotype, or aav9.s454.tfr3. In particular embodiments, the rAAV is administered in the absence of hyaluronic acid, including where the rAAV has not been previously incubated or mixed with hyaluronic acid (including hyaluronic acid at a concentration of 0.1%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.6%, 0.75%, or 1.0% by volume).
Typically, when the rAAV vector has tropism for ocular tissues, the vector is administered by in vivo injection, such as directly into the eye. For example, a rAAV comprising peptide inserts for increasing tropism to eye, retina or RPE-choroidal tissues may be injected intravitreally, intracamerally or suprachoroidal. In some embodiments, the rAAV with ocular tissue tropism is administered by intraocular injection, e.g., through the pars plana into the vitreous or aqueous humor of the eye. In some embodiments, the rAAV for increasing ocular tissue tropism is administered by peribulbar injection or subconjunctival injection. In some embodiments, the rAAV having ocular tissue tropism is administered by injection through the suprachoroidal space (i.e., in the space between the sclera and the choroid). One advantage of rAAV vectors with ocular tissue tropism is that subjects can avoid surgery, e.g., avoid surgical implantation of therapeutic agents, but instead deliver by injection. In certain embodiments, the therapeutic agent is delivered by a rAAV vector described herein by intracameral, intravitreal, or suprachoroidal injection to provide a therapeutically effective amount for treating a disease or disorder associated with the eye, particularly a disease or disorder associated with the eye of a subject. In further embodiments, the treatment is effected in a single intracameral, intravitreal or suprachoroidal injection, no more than two intracameral, intravitreal or suprachoroidal injections, no more than three intracameral, intravitreal or suprachoroidal injections, no more than four intracameral, intravitreal or suprachoroidal injections, no more than five intracameral, intravitreal or suprachoroidal injections, or no more than six intracameral, intravitreal or suprachoroidal injections.
The disease/condition associated with the eye or retina is referred to as an "ocular disease". Non-limiting examples of ocular diseases include anterior ischemic optic neuropathy; acute macular optic neuropathy; barde-Bie Deer (barset-Biedl) syndrome; behcet's (Behcet) disease; retinal branch vein occlusion; central retinal vein occlusion; no choroidal disease; choroidal neovascularization; choroidal retinal degeneration; cone-rod malnutrition; dyschromatopsia (e.g., achromatopsia, erythroblindness, green blindness, and blue blindness); congenital stationary night blindness; diabetic uveitis; disorders of the outer retinal membrane; hereditary macular degeneration; histoplasmosis; macular degeneration (e.g., acute macular degeneration, non-exudative age-related macular degeneration, exudative age-related macular degeneration); diabetic retinopathy; oedema (e.g., macular oedema, cystoid macular oedema, diabetic macular oedema); glaucoma; leber (Leber) congenital amaurosis; leber (Leber) hereditary optic neuropathy; macular telangiectasia; multifocal choroiditis; diabetic retinal dysfunction without retinopathy; ocular trauma; eye tumors; proliferative Vitreoretinopathy (PVR); retinopathy of prematurity; retinal cleavage; retinitis pigmentosa; retinal artery occlusive disease, retinal detachment, stargardt disease (yellow spotted fundus); sympathogenic ophthalmia; spreading grape membranes; uveal inflammatory retinopathy; hermaphroditic (Usher) syndrome; woget-salix-original field (Vogt Koyanagi-Harada (VKH)) syndrome; or posterior ocular conditions associated with ocular laser or photodynamic therapy.
In particular embodiments, the disease or condition is non-infectious uveitis, neuromyelitis optica, macular degeneration, including dry age-related macular degeneration, macular edema, diabetic retinopathy, or glaucoma.
In particular embodiments, the rAAV targets (including transduction and transgene expression) one or more specific ocular tissues, including anterior or posterior segment tissues, and in more particular embodiments, the rAAV targets the cornea, iris or lens, or ciliary body, schlemm's canal or trabecular meshwork, or retina, retinal pigment epithelium (RPE-) choroid, or sclera, or optic nerve. In particular embodiments, rAAV with AAV3B or aavrh.73 capsids may be administered for targeting the iris, retina, RPE choroid, or sclera, and in certain embodiments, the ciliary body, schlemm's canal, trabecular meshwork, or optic nerve (orbital and/or cranial segments). In embodiments, rAAV with AAV3B or aavrh.73 capsids can be used to target retinal and/or RPE choroidal tissues. In other embodiments, rAAV with aavrh.73 capsids can be used to target iris tissue, and in other embodiments, aavhu.26 capsids can be used to target ciliary body or trabecular meshwork. AAV1 capsids can be used to target trabecular meshwork or sclera, and AAV7 can be used to target trabecular meshwork.
In certain embodiments, the transgene comprises a nucleotide sequence encoding an ocular disease therapeutic agent that is a VEGF fusion protein, such as aflibercept; an anti-VEGF antibody or antigen-binding fragment thereof, such as cervacizumab, ranibizumab, bevacizumab, or bloc-racetam mab; an anti-kallikrein antibody or antigen binding fragment thereof, such as lenalimumab; anti-IL 6 or anti-IL 6R antibodies or antigen binding fragments thereof, such as saxaglib, sha Lilu mab, steuximab, cladazazumab, west Lu Kushan antibody, olozumab, gli Lin Zushan antibody, or tolizumab; an anti-TNF antibody or antigen-binding fragment thereof, such as adalimumab, infliximab, golimumab, or pegylated cetuximab; TNF receptor fusion proteins such as etanercept; an anti-C3 antibody or antigen-binding fragment thereof, such as eculizumab, lei Fuli bead mab or terstuzumab; or an anti-C5 antibody or antigen-binding fragment thereof, such as NGM621, or LKA-651, sorazuki mab, GSK933776, rankanemab, atorvastatin Su Shan, cal Luo Tuo ximab, AND-007, or ine Li Zhushan antibodies. The gene therapy construct encoding the antibody or antigen binding fragment thereof is designed such that both the heavy and light chains are expressed. The coding sequences for the heavy and light chains may be engineered in a single construct, wherein the heavy and light chains are separated by a cleavable linker or IRES (e.g., furin-T2A linker, etc.) in order to express separate heavy and light chain polypeptides. In certain embodiments, the coding sequence encodes a Fab or F (ab') 2 Or scFv. In certain embodiments, the full length heavy and light chains of the antibody are expressed. In other embodiments, the construct expresses an scFv in which the heavy and light chain variable domains are linked via a flexible, non-cleavable linker. The nucleotide sequence encoding the therapeutic protein is operably linked to a regulatory element to facilitate expression of the therapeutic protein in the ocular tissue of interest.
The rAAV vectors of the invention may also facilitate delivery, particularly targeted delivery, of oligonucleotides, drugs, imaging agents, inorganic nanoparticles, liposomes, antibodies to a target cell or tissue. rAAV vectors may also facilitate delivery of non-coding DNA, RNA, or oligonucleotides to a target tissue, particularly targeted delivery.
The agent may be provided as a pharmaceutically acceptable composition as known in the art and/or as described herein. Furthermore, rAAV molecules of the invention may be administered alone or in combination with other prophylactic and/or therapeutic agents.
The dosages and frequency of administration provided herein are covered by the terms therapeutically effective and prophylactically effective. The dosage and frequency will generally vary depending upon the particular therapeutic or prophylactic agent being administered, the severity and type of the disease, the route of administration, and the age, weight, response and past medical history of the patient, and will be determined at the discretion of the practitioner and the circumstances of each patient. One skilled in the art can select an appropriate regimen by taking such factors into account and by following the dosages reported in the literature and recommended in the Physics' Desk Reference (56 th edition, 2002), for example. The prophylactic and/or therapeutic agent may be repeatedly administered. Several aspects of the procedure may vary, such as the timing of administration of the prophylactic or therapeutic agent, and whether such agents are administered alone or as a mixture.
The amount of the agent of the invention that will be effective can be determined by standard clinical techniques. The effective dose can be inferred from dose-response curves obtained from in vitro or animal model test systems. For any agent used in the methods of the invention, a therapeutically effective dose can be estimated initially from cell culture assays. Doses may be formulated in animal models to achieve a method comprising IC as determined in cell culture 50 (i.e., the concentration of test compound that achieves half-maximal inhibition of symptoms). Such information may be used to more accurately determine useful doses in humans. The level in the plasma may be measured, for example, by high performance liquid chromatography.
The prophylactic and/or therapeutic agents and combinations thereof may be tested in a suitable animal model system prior to use in humans. Such animal model systems include, but are not limited to, rats, mice, chickens, cattle, monkeys, pigs, dogs, rabbits, etc. Any animal system known in the art may be used. Such model systems are widely used and are well known to the skilled artisan. In some embodiments, animal model systems for ocular disorders based on rats, mice, or other small mammals other than primates are used.
Once the prophylactic and/or therapeutic agents of the invention have been tested in animal models, they can be tested in clinical trials to determine their efficacy. Establishing a clinical trial will be performed according to common methods known to those skilled in the art and may establish the optimal dosage and route of administration and toxicity profile of the agents of the invention. For example, clinical trials can be designed to test the efficacy and toxicity of the rAAV molecules of the invention in human patients.
Toxicity and efficacy of the prophylactic and/or therapeutic agents of the invention can be determined in cell culture or experimental animals by standard pharmaceutical procedures, e.g., to determine LD 50 (50% lethal dose to population) and ED 50 (a therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD 50 /ED 50 . Preventive and/or therapeutic agents exhibiting a large therapeutic index are preferred. While prophylactic and/or therapeutic agents exhibiting toxic side effects may be used, care should be taken to design a delivery system that targets such agents to the site of the affected tissue in order to minimize potential damage to uninfected cells and thereby reduce side effects.
rAAV will typically be administered for a time and in an amount effective to obtain the desired therapeutic and/or prophylactic benefit. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage and/or timing of a prophylactic and/or therapeutic agent for use in a human. The dosage of such agents includes ED 50 In a circulating concentration range with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
Therapeutically effective dose-through of rAAV vectors for patientsOften from about 0.1m1 to about 100m1 contains a concentration of about 1x10 9 Up to about 1x10 16 A genome, or about 1x10 10 Up to about 1x10 15 Genome of about 1x10 12 Up to about 1x10 16 Genome of about 1x10 14 Up to about 1x10 16 Genome of about 1x10 11 Up to about 1x10 13 Individual genomes, or about 1x10 12 Up to about 1x10 14 Solutions of the individual genomes. Expression levels of the transgene may be monitored to determine/adjust dosages, frequencies, timing, etc.
Treatment of a subject with a therapeutically or prophylactically effective amount of an agent of the invention may comprise a monotherapy or may comprise a series of therapies. For example, a pharmaceutical composition comprising an agent of the invention may be administered once or may be administered 2, 3 or 4 times, e.g. at intervals of one week, one month, 2 months or three months.
The rAAV molecules of the invention may be administered alone or in combination with other prophylactic and/or therapeutic agents. Each prophylactic or therapeutic agent may be administered simultaneously or sequentially at different time points in any order; however, if not administered simultaneously, they should be administered in close enough time to provide the desired therapeutic or prophylactic effect. Each therapeutic agent may be administered alone in any suitable form or by any suitable route.
In various embodiments, the different prophylactic and/or therapeutic agents are administered less than 1 hour apart, about 1 hour to about 2 hours apart, about 2 hours to about 3 hours apart, about 3 hours to about 4 hours apart, about 4 hours to about 5 hours apart, about 5 hours to about 6 hours apart, about 6 hours to about 7 hours apart, about 7 hours to about 8 hours apart, about 8 hours to about 9 hours apart, about 9 hours to about 10 hours apart, about 10 hours to about 11 hours apart, about 11 hours to about 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart. In certain embodiments, two or more agents are administered in the same visit to the patient.
Methods of administering the agents described herein include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous, including infusion or bolus injection), epidural administration, and absorption through epithelial or mucosal skin or mucosal lining (e.g., intranasal, oral, rectal and intestinal mucosa, etc.). In particular embodiments, such as where transgene expression is expected in the eye, the vector is administered via intravitreal, intraocular, suprachoroidal or intracameral injection. In particular embodiments, the vector is applied directly to the target tissue, for example directly to the retina or ciliary body.
In certain embodiments, the agents of the invention are administered intravenously and may be administered with other bioactive agents.
In another specific embodiment, the agents of the invention may be delivered in a sustained release formulation, for example, wherein the formulation provides for prolonged release and thus prolonged half-life of the administered agent. Controlled release systems suitable for use include, but are not limited to, diffusion controlled, solvent controlled, and chemical controlled systems. The diffusion control system comprises, for example, a reservoir device in which the molecules of the invention are enclosed within the device such that release of the molecules is controlled by permeation through the diffusion barrier. Common reservoir devices include, for example, membranes, capsules, microcapsules, liposomes, and hollow fibers. Monolithic (matrix) devices are a second type of diffusion control system in which dual antigen binding molecules are dispersed or dissolved in a rate controlling matrix (e.g., a polymer matrix). The agents of the present invention may be uniformly dispersed throughout the rate controlling matrix and the release rate is controlled by diffusion through the matrix. Polymers suitable for use in the monolithic matrix device include naturally occurring polymers, synthetic polymers, and synthetically modified natural polymers and polymer derivatives.
Any technique known to those skilled in the art may be used to produce a sustained release formulation comprising one or more of the agents described herein. See, for example, U.S. Pat. nos. 4,526,938; PCT publication WO 9I/05548; PCT publication WO 96/20698; ning et al, "Intratumoral Radioimmunotheraphy of a Human Colon Cancer Xenogran Using a Sustained-Release Gel," radius & Oncology,39:179189 1996; song et al, "Antibody Mediated Lung Targeting of Long-Circulating Emulsions," PDA Journal of Pharmaceutical Science & Technology,50:372397 1995; cleek et al, "Biodegradable Polymeric Carriers for a bFGF Antibody for Cardiovascular Application," pro.intl.symp.control.rel.bio.mate., 24:853854 1997; and Lam et al, "Microencapsulation of Recombinant Humanized Monoclonal Antibody for Local Delivery," proc.int' l. Symp.control rel.bioacl mate, 24:759 760,1997, each of which is incorporated by reference herein in its entirety. In one embodiment, the pump may be used in a controlled release system (see Langer, supra; sefton, CRC Crit. Ref. Biomed. Eng.,14:20, 1987; buchwald et al, surgery,88:507, 1980; and Saudek et al, N.Engl. J. Med.,321:574, 1989). In another embodiment, the polymeric material may be used to achieve controlled release of an agent comprising a dual antigen binding molecule or antigen binding fragment thereof (see, e.g., medical Applications of Controlled Release, langer and Wise (editions), CRC pres., boca Raton, fli. (1974), controlled Drug Bioavailability, drug Product Design and Performance, smolen and Ball (editions), wiley, n.y. (1984), range and Peppas, j., macromol. Sci. Rev. Macromol. Chem.,23:61, 1983; see also Levy et al, science,228:190, 1985; during et al, ann. Neurol.,25:351, 1989; howard et al, j. Neurosurg.,71:105, 1989); U.S. patent No. 5,679,377; U.S. patent No. 5,916,597; U.S. Pat. nos. 5,912,015; U.S. patent No. 5,989,463; U.S. patent No. 5,128,326; PCT publication number WO 99/15154; and PCT publication number WO 99/20253). In another embodiment, the controlled release system may be placed in proximity to the therapeutic target (e.g., affected joint) so that only a portion of the systemic dose is required (see, e.g., goodson, medical Applications of Controlled Release, simultaneously, volume 2, page 115138 (1984)). Other controlled release systems are available in Langer, science,249:15271533 A review of 1990 is discussed.
In addition, rAAV can be used for in vivo delivery of transgenes for scientific research, such as optogenetics, miRNA gene knockout, recombinase delivery of conditional gene deletions, CRISPR gene editing, and the like.
5.5. Pharmaceutical composition and kit
The invention further provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an agent of the invention comprising a rAAV molecule of the invention. In some embodiments, the pharmaceutical composition comprises a rAAV in combination with a pharmaceutically acceptable carrier for administration to a subject. In one embodiment, the term "pharmaceutically acceptable" refers to those approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant (e.g., freund's complete and incomplete adjuvant), excipient, or vehicle with which the agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is a common carrier. Saline solutions, as well as aqueous dextrose and glycerol solutions, can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Additional examples of pharmaceutically acceptable carriers, excipients, and stabilizers include, but are not limited to, buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid; a low molecular weight polypeptide; proteins such as serum albumin and gelatin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN as known in the art TM Polyethylene glycol (PEG) and PLURONICS TM . The pharmaceutical composition of the present invention eliminates the aboveThe ingredients may include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents and preservatives. These compositions may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations and the like.
In certain embodiments of the present invention, there is provided a pharmaceutical composition for use according to the methods of the present invention, comprising a therapeutically and/or prophylactically effective amount of an agent of the present invention and a pharmaceutically acceptable carrier.
In certain embodiments, the agents of the present invention are substantially purified (i.e., are substantially free of substances that limit their effects or produce undesirable side effects). In particular embodiments, the host or subject is an animal, e.g., a mammal such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) and a primate (e.g., a monkey such as a cynomolgus monkey and a human). In one embodiment, the host is a human.
The present invention provides additional kits that may be used in the above methods. In one embodiment, the kit comprises one or more agents of the invention, for example in one or more containers. In another embodiment, the kit further comprises one or more additional prophylactic or therapeutic agents suitable for treating a disorder in one or more containers.
The invention also provides an agent of the invention packaged in a hermetically sealed container, such as an ampoule or sachet of an amount of an indicator or active agent. In one embodiment, the agent is provided as a dry sterile lyophilized powder or anhydrous concentrate in a hermetically sealed container, and may be reconstituted to an appropriate concentration for administration to a subject, for example, with water or saline. Typically, the agent is provided as a dry sterile lyophilized powder in a hermetically sealed container in a unit dose of at least 5mg, more typically at least 10mg, at least 15mg, at least 25mg, at least 35mg, at least 45mg, at least 50mg or at least 75 mg. The lyophilized formulation should be stored in its original container between 2 and 8 ℃ and the agent should be administered within 12 hours, typically within 6 hours, within 5 hours, within 3 hours or within 1 hour after reconstitution. In an alternative embodiment, the agent of the present invention is provided in liquid form in a hermetically sealed container of the amount and concentration of the indicator or active agent. Typically, the liquid form of the agent is provided in a hermetically sealed container at least 1mg/ml, at least 2.5mg/ml, at least 5mg/ml, at least 8mg/ml, at least 10mg/ml, at least 15mg/kg, or at least 25 mg/ml.
The compositions of the present invention include both bulk pharmaceutical compositions (e.g., impure or non-sterile compositions) as well as pharmaceutical compositions (i.e., compositions suitable for administration to a subject or patient) that are useful in the manufacture of pharmaceutical compositions. The pharmaceutical compositions of the raw materials may be used to prepare unit dosage forms, e.g., comprising a prophylactically or therapeutically effective amount of the agents disclosed herein or combinations of those agents and a pharmaceutically acceptable carrier.
The invention also provides a pharmaceutical package or kit comprising one or more containers filled with one or more agents of the invention. In addition, one or more other prophylactic or therapeutic agents for treating a disease or disorder of interest may also be included in the pharmaceutical package or kit. The invention also provides a pharmaceutical package or kit comprising one or more containers filled with one or more ingredients of the pharmaceutical composition of the invention. Optionally, associated with such one or more containers may be an announcement in the form prescribed by a government agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which announcement reflects approval of the agency for human administration for manufacture, use or sale.
Generally, the ingredients of the compositions of the present invention, either alone or mixed together, are provided in unit dosage form (e.g., in dry lyophilized powder or anhydrous concentrate form) in a hermetically sealed container (e.g., ampoule or sachet) of the amount of the indicator or active agent. When the composition is to be administered by infusion, the composition may be dispensed using an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is to be administered by injection, an ampoule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.
6. Examples
The following examples report analysis of surface exposed loops on AAV9 capsids to identify candidates for capsid engineering by insertional mutagenesis. Other examples demonstrate the transduction and increased tissue tropism of the various AAV capsids described herein.
6.1.Example 1Analysis of AAV9 capsids
FIGS. 1 and 2 depict analysis of variable region four (AAV 9 VR-IV) of type 9 adeno-associated virus by amino acid sequence comparison with other AAVs VR-IV (FIG. 1) and protein models (FIG. 2). As shown, AAV9 VR-IV is exposed on the surface of the tip or outer surface of the 3-fold spike. Further analysis showed that there was little side chain interaction between VR-IV and VR-V, and that the sequence and structure of VR-IV was variable between AAV serotypes, and further likely to disrupt co-targeted neutralizing antibody epitopes and thus reduce immunogenicity of the modified capsid.
6.2.Example 2Construction of AAV9 mutants
Eight AAV9 mutants were constructed, each comprising a heterologous peptide, but located at different insertion points in the VR-IV loop. The heterologous peptide is a FLAG tag that follows the following residues in the vector identified as pRGNX1090-1097, as shown in Table 1.
TABLE 1
Carrier name FLAG tagged AAV9 VR-IV insertion site
pRGNX1090 I451
pRGNX1091 N452
pRGNX1092 G453
pRGNX1093 S454
pRGNX1094 G455
pRGNX1095 Q456
pRGNX1096 N457
pRGNX1097 Q458
6.3.Example 3Analysis of packaging efficiency
FIG. 3 depicts high packaging efficiency in terms of genome copy number per mL (GC/mL) for wild-type AAV9 and eight (8) candidate rAAV9 vectors (1090, 1091, 1092, 1093, 1094, 1095, 1096, and 1097), each containing FLAG inserts at different sites within the VR-IV of AAV 9. All vectors were packaged with luciferase transgene in 10mL cultures to facilitate determination of which insertion points did not disrupt capsid packaging; error bars represent standard error of the mean.
As shown, all candidates were packaged with high efficiency.
6.4.Example 4Analysis of surface FLAG exposure
FIG. 4 depicts surface exposure of FLAG inserts in each of eight (8) candidate rAAV9 vectors (1090, 1091, 1092, 1093, 1094, 1095, 1096, and 1097) as demonstrated by immunoprecipitation of the transduction vector through binding to anti-FLAG resin. Binding to anti-FLAG indicates an insertion point that allows formation of a capsid that displays peptide insertion on the surface.
The transduced cells were lysed and centrifuged. mu.L of the cell culture supernatant was loaded onto 20. Mu.L of agarose-FLAG beads and eluted with SDS-PAGE loading buffer which was also directly loaded onto the gel. For negative control, 293-ssc supernatant without FLAG insert was used.
As shown, 1090 had the lowest titer of the candidate vector, indicating minimal protein pull down. Very low titers were also observed with the positive control. It is likely that a sufficient amount of positive control was not loaded for visualization on SDS-PAGE.
6.5.Example 5Analysis of transduction efficiency
FIGS. 5A-5B depict transduction efficiency in Lec2 cells transduced with capsid vectors carrying a luciferase gene (as a transgene) packaged into each of wild-type AAV9 (9-luc) or eight (8) candidate rAAV9 vectors (1090, 1091, 1092, 1093, 1094, 1095, 1096, and 1097); the activity was expressed as percentage luciferase activity, 100% as activity of 9-luc (FIG. 5A), or as relative light units per microgram of protein (RLU) (FIG. 5B).
CHO-derived Lec2 cells were grown in αmem and 10% fbs. Lec2 cells were grown at approximately 2X10 8 MOI of GC vector (MOI of about 10,000) and treatment with Viraducin reagent (Lec 2 cells were transduced at MOI of about 10,000GC/cell but with 40. Mu.g/mL zinc chloride (ZnCl) 2 ) Similar results were observed at the time of treatment; the results are not shown). Lec2 cells are proline auxotrophs from CHO.
As shown, in vitro transduction efficiency was lower than that obtained using wild-type AAV9 (9-luc). Nevertheless, previous studies have shown that the introduction of homing peptides can reduce in vitro gene transfer in non-target cells (e.g., 293, lec2, or HeLa) while significantly increasing in vitro gene transfer in target cells (see, e.g., nicklin et al 2001; and Grifman et al 2001).
6.6.Example 6Analysis of packaging efficiency as a factor of composition and length of the inserted peptide
FIG. 6A depicts a bar graph showing that insertion following S454 of AAV9 capsids (SEQ ID NO: 67) of different peptide lengths and compositions may affect production efficiency of AAV particles in packaging cell lines. Ten peptides of different composition and length were inserted after S454 (between residues 454 and 455) within AAV9 VR-IV. Five days after transfection, qPCR was performed on the supernatant of the harvested transfected suspension HEK293 cells. The results depicted in the bar graph demonstrate that the nature and length of the insertion can affect the ability of AAV particles to be produced at high titers and packaged in 293 cells. (error bars represent standard error of average length of peptide, noted on Y-axis in brackets.)
AAV9 vectors with capsid proteins containing homing peptides with the following peptide sequences at the S454 insertion site were studied (table 2). Suspension-adapted HEK293 cells were incubated at 1x10 a day prior to transduction 6 Each cell/mL was inoculated in 10mL of medium. Using(Polypus transfection) triple plasmid DNA transfection was performed at a DNA: PEI ratio of 1:1.75. Cells were centrifuged 5 days after transfection and the supernatant was harvested and stored at-80 ℃.
Table 2.
Peptide # Tissue or target name Peptide sequences SEQ ID NO.
P1 Bone 1 (D8) DDDDDDDD 2
P2 Brain 1 LSSRLDA 3
P3 Brain 2 CLSSRLDAC 4
P4 Kidney 1 LPVAS 6
P5 Kidney 2 CLPVASC 5
P6 Muscle 1 ASSLNIA 7
P7 TfR1 HAIYPRH 10
P8 TfR2 THRPPMWSPVWP 11
P9 TfR3 RTIGPSV 12
P10 TfR4 CRTIGPSVC 13
Five days after transfection, qPCR was performed on the supernatant of the harvested transfected suspension HEK293 cells. The sample is subjected to dnase I treatment to remove residual plasmid or cellular DNA, followed by heat treatment to inactivate dnase I and denature the capsid. Samples were titrated by qPCR using TaqMan Universal PCR Master Mix, no ampraseung (thermo fisher scientific), and primers/probes for polyA sequences packaged in the transgenic constructs. Standard curves were established using the RGX-501 vector BDS.
Direct insertion of peptides of 5 to 10 amino acids in length after S454 resulted in AAV particles with sufficient titers, while the upper limit was possible, with significant packaging defects observed for peptide insertion of 12 amino acids in length.
6.7.Example 7Homing peptides alter the transduction properties of AAV9 in vitro upon insertion after S454.
FIGS. 6B-E depict fluorescence images of cell cultures of the Lec2 cell line (sialic acid deficient epithelial cell line) (FIG. 6B), the HT-22 cell line (neuronal cell line) (FIG. 6C), the hCMEC/D3 cell line (brain endothelial cell line) (FIG. 6D) and the C2C12 cell line (muscle cell line) (FIG. 6E). The cell lines were transduced with AAV9 wild type and the GFP transgene-containing S454 insertion homing peptide capsids of table 2.
Cell lines were grown at 5-20x10 24 hours prior to transduction 3 Individual cells/wells (depending on the cell line) were seeded in 96 wells. At 1x10 10 Individual particles/wells were transduced with AAV9-GFP vector (with or without insertion) and analyzed 48-96 hours post transduction by station 5 (BioTek), depending on the differences in expression rates for each cell line. Lec2 cells were cultured as in example 5, blood brain barrier hCMEC/D3 (EMD Millipore) cells were cultured according to the manufacturer's protocol, HT-22 and HUH7 cells were cultured in DMEM and 10% fbs, and C2C12 myoblasts were seeded in DMEM and 10% fbs and supplemented with 2% horse serum and 0.1% insulin 3 days prior to transfectionDifferentiation in DMEM. Aav9.s454.flag showed low transduction levels in each cell type tested.
The images show that homing peptides can alter the transduction properties of AAV9 in vitro when inserted after S454 in AAV9 capsid protein, compared to unmodified AAV9 capsid. P7 (TfR 1 peptide, HAIYPRH (SEQ ID NO: 10)) of all cell lines showed the highest transduction rate, followed by P9 (TfR 3 peptide, RTIGPSV (SEQ ID NO: 12)). P4 (kidney 1 peptide, LPVAS (SEQ ID NO: 6)) showed slightly higher transduction than AAV9 wild type for all cell types. Higher transduction rates of P6 (muscle 1 peptide, ASSINIA (SEQ ID NO: 7)) were observed in brain endothelial hCMEC/D3 cell line and C2C12 muscle cell line cultures compared to Lec2 and HT-22 cell line cultures. The P1 vector is not included in the image due to very low transduction efficiency, and the P8 vector is not included in the image due to low titer.
6.8.Example 8Analysis of peptide insertion points of AAV capsids
FIG. 7 depicts alignment of AAV 1-9e, 3B, rh, rh20, rh39, rh73, rh74 pattern 1 and pattern 2, hu12, hu21, hu26, hu37, hu51 and hu53 sequences having insertion sites for peptides enhancing ocular tissue tropism within or near the start codon of VP2, variable region 1 (VR-I), variable region 4 (VR-IV) and variable region 8 (VR-VIII), which insertion sites are highlighted in gray; the specific insertion site within the eighth variable region (VR-VIII) of each capsid protein is denoted by the symbol "#" (following amino acid residue 588 according to the amino acid numbering of AAV 9).
6.9.Example 9Comparison of AAV genome copy number/μg genomic DNA of various vectors
Fig. 8 depicts copies of GFP (green fluorescent protein) transgene expressed in mouse brain cells after administration of the following AAV vectors: AAV9; aav.php.eb; hDyn (AAV 9 with TLAAPFK (SEQ ID NO: 1) between 588-589 and without other amino acid modifications to the capsid sequence); aaav.php.s and aav.php.sh (see table 10).
AAV.PHP.B is a capsid with TLAVPFK (SEQ ID NO: 20) insertion in AAV9 capsid, without additional amino acid modifications to the capsid sequence. AAV.PHP.eB is a capsid with a TLAVPFK (SEQ ID NO: 20) insert in the AAV9 capsid, two amino acid modifications of the capsid sequence upstream of the PHP.B insert (see also Table 10). Table 3A summarizes the capsids used in the study.
TABLE 3A
Materials and methods
Constructs encoding GFP transgenic AAV9, aav.phpeb, aav.hdyn, aav.php.s and aav.php.sh were prepared and formulated in 1xpbs+0.001% pluronic. Female C57BL/6 mice were randomized into treatment groups based on body weight on day 1. Five groups of female C57BL/6 mice were each intravenously administered aav9.Gfp, aav.phpeb. Gfp, aav.hdyn. Gfp, aav.php.s. Gfp, or aav.php.sh.gfp according to table 3B below. The dosing volume was 10mL/kg (0.200 mL/20g mice). Mice were 8-12 weeks old at the start date. On day 15 post-administration, animals were euthanized and peripheral tissues including brain tissue, liver, anterior biceps, heart, kidney, lung, ovary and sciatic nerve were collected.
TABLE 3B
Group of Number of Agent Dosage of formulation Pathway Scheduling of
1 9 AAV9 2.5E12GC/kg iv Day 1
2 5 PHPeB 2.5E12GC/kg 1v Day 1
3 5 hDyn 2.5E12GC/kg iv Day 1
4 5 PHP.S 2.5E12GC/kg iv Day 1
5 5 PHP.SH 2.5E12GC/kg iv Day 1
Quantitative PCR (qPCR) was used to determine the number of vector genomes per μg of brain genomic DNA. Brain samples from injected mice were processed and genomic DNA isolated using blood and tissue genomic DNA kits from Qiagen. qPCR assays were performed on a quantsudio 5 instrument (Life Technologies Inc) following a standard curve method using primer-probe combinations specific for eGFP.
With all other AAV serotypes: AAV9, aav.phpeb, php.s and php.sh were at least one log higher in AAV vector genome copy number per μg of brain genomic DNA in mice administered aav.hdyn (see fig. 8). As shown in this study, GC/. Mu.g genomic DNA of AAV.hDyn, an AAV9 capsid containing a "TLAAPFK" (SEQ ID NO: 1) peptide insert (peptide from human ciliated axin) between residues 588-589 of the AAV9 capsid, was highest. The study demonstrated that in 5 mice with systemic administration of aav.hdyn carrying eGFP, transduction in the mouse brain was greater than 1E04GC/μg transgene on average. However, other modified AAV9 capsids, including vector AAV. PHPeB (which contains the "TLAVPFK" (SEQ ID NO: 20) sequence (peptide from mouse dynein)) showed less than 1E03 GC/. Mu.g transduction of transgenes in mouse brain after systemic treatment.
6.10.Example 9Construction of rAAV capsid containing LALGETTRPA (SEQ ID NO: 9)
FIG. 9A depicts the amino acid sequence of the capsid of the recombinant AAV3B vector, comprising a peptide insertion comprising amino acid sequence LALGETTRP (SEQ ID NO: 9) between N588 and T589 of VR-IIIV. The inserted peptide is shown in bold.
FIG. 9B depicts the amino acid sequence of the capsid of the recombinant AAV3B vector comprising a peptide insertion having amino acid sequence LALGETTRP (SEQ ID NO: 9) between S267 and S268 of VR-III. The inserted peptide is shown in bold.
FIG. 9C depicts the amino acid sequence of the capsid of the recombinant AAV3B vector comprising the peptide insertion of amino acid sequence LALGETTRP (SEQ ID NO: 9) between G454 and T455 of VR-IV. The inserted peptide is shown in bold.
6.11.Example 10Construction of rAAV capsid containing LALGETTRPA (SEQ ID NO: 9)
FIG. 10A depicts the amino acid sequence of the capsid of the recombinant AAVrh73 vector, which comprises the peptide insertion of amino acid sequence LALGETTRP (SEQ ID NO: 9) between N590 and T591 of VR-IIIV. The inserted peptide is shown in bold.
FIG. 10B depicts the amino acid sequence of a recombinant AAVrh73 vector capsid comprising peptide insertions of amino acid sequences between T270 and N271 of VR-III. The inserted peptide is shown in bold.
FIG. 10C depicts the amino acid sequence of the recombinant AAVrh73 vector capsid, comprising the peptide insertion of amino acid sequence LALGETTRPA (SEQ ID NO: 9) between G456 and G457 of VR-IV. The inserted peptide is shown in bold.
6.12.Example 11Construction of rAAV capsid containing LALGETTRPA (SEQ ID NO: 9)
FIG. 11A depicts the amino acid sequence of the capsid of the recombinant AAV8 vector comprising the peptide insertion of amino acid sequence LALGETTRP (SEQ ID NO: 9) between N590 and T591 of VR-VIII. The inserted peptide is shown in bold.
FIG. 11B depicts the amino acid sequence of the capsid of the recombinant AAV8 vector, which includes the peptide insertion of amino acid sequence LALGETTRP (SEQ ID NO: 9) between A269 and T270 of VR-III. The inserted peptide is shown in bold.
FIG. 11C depicts the amino acid sequence of the capsid of the recombinant AAV8 vector comprising the peptide insertion of amino acid sequence LALGETTRP (SEQ ID NO: 9) between T453 and T454 of VR-IV. The inserted peptide is shown in bold.
6.13.Example 12In vitro test of transduction across the blood brain barrier
The ability of the modified capsids to cross the blood brain barrier was tested in an in vitro transwell assay using hCMEC/D3 BBB cells (SCC 066, millipore-Sigma) (see FIGS. 12A-12B). More specifically, the assay was adapted substantially from Sade, H.et al (2014 PLoS ONE 9 (4): e 96340) A human Blood-Brain Barrier transcytosis assay reveals Antibody Transcytosis influenced by pH-dependent Receptor Binding, month 4 2014, volume 9, phase 4; and Zhang, x., blood-brain barrier shuttle peptides enhance AAV transduction in the brain after systemic administration,2018Biomaterials 176:71-83. Briefly, 5×10 4 hCM (human immunodeficiency virus)EC/D3 cells/cm 2 Collagen-coated transwell inserts seeded in 12-well plates. Each insert contained 500. Mu.L of medium, and the lower chamber contained 1mL of medium. The medium was changed every other day. The supernatant was removed 10 days after inoculation (time zero (0)). At this 0 time point, by adding 1×10 9 The GC vectors were added to the upper insert chamber medium to transduce the cells. Samples of 10 μl lower chamber supernatant were removed at time intervals of 0.5, 3, 6 and 23 hours after transduction for testing. Each condition (vector) was tested in duplicate and titers against PolyA were measured by qPCR in triplicate.
Fig. 12A-12B depict in vitro transwell (fig. 12A) at aav.hdyn (AAV 9 with TLAAPFK (SEQ ID NO: 1) between amino acid residues 588-589) across the Blood Brain Barrier (BBB) cell layer, and the results show that aav.hdyn (represented by the inverted triangle in the figure) is faster than AAV9 (square) and passes through the BBB cell layer of the assay more rapidly and to a greater extent than AAV2 (circle) (fig. 12B). The in vitro assays developed predicted enhanced BBB cross-transport, and similar assays could also be used to predict targeting to other organs.
6.14.Example 13Transduction and biodistribution of modified capsids
6.14.1 materials and methods
A widely used AAV capsid (including AAV8, AAV9 and aavrh.10) was capsid modified by insertion of various peptide sequences after position S454 of VR-IV (table 4) or after position Q588 of the VR-VIII surface exposed loop, and insertion after the start codon of VP2, which starts at amino acid 137 (AAV 4, AAV4-4 and AAV 5) or amino acid 138 (AAV 1, AAV2, AAV3-3, AAV6, AAV7, AAV8, AAV9e, rh.10, rh.20, rh.39, rh.74 and hu.37) (fig. 7) (see also table 10 for certain capsid sequences) selected single to multiple amino acid mutations are also used to modify the capsid. See also Yost et al Structure-guided engineering of surface exposed loops on AAV caps.2019. Asgct Annual Meeting; and Wu et al 2000j virology (supra). It was demonstrated that packaging efficiency was not negatively affected after any of these capsid modifications were performed on a small scale.
rAAV with certain modified capsids were tested for in vitro transduction in Lec2 cells as described in example 5 above. In comparison to AAV9, transduction of the following modified AAV in Lec2 cells was tested: eB 588Ad, eB 588Hep, eB 588p79, eB 588Rab, AAV9588Ad, AAV9588Hep, AAV9588p79, AAV9588Rab, eB VP2 Ad, eB VP2 Hep, eB VP2 p79, eB VP2 Rab, AAV9 VP2 Ad, AAV9 VP2 Hep, AAV9 VP2 p79, AAV9 VP2 Rab. See table 4B below for the identity of AAV capsids.
To test biodistribution, the modified AAV was packaged with an eGFP transgene cassette containing a specific barcode corresponding to each individual capsid. New barcoded vectors were pooled and injected into mice to increase screening efficiency.
To analyze the biodistribution of genetically altered AAV vectors, various vectors encoding GFP were prepared and formulated in 1xpbs+0.0001% pluronic acid. All vectors were made with cis-plasmids containing ten (10) bp barcodes to enable Next Generation Sequencing (NGS) library (pool) preparation. Three (3) vector pools (study 1, study 2 and study 3 vectors) were intravenously injected into a cohort of 5 female C57B1/6 mice according to tables 4A-C. The dosing volume for each was 10mL/kg (0.2 mL/20g mice).
Mice were randomized into treatment groups according to body weight on day 1 and their age at the start date was 8-12 weeks. On day 15 post-administration, animals were euthanized and peripheral tissues including brain, kidney, liver, sciatic nerve, lung, heart and muscle tissue were collected. The same protocol was followed in studies with separate injections of capsids selected from the collection.
Genomic DNA (gDNA) was isolated from tissue samples using dnasy blood from Qiagen and tissue kit (69506). The barcode region of each vector was amplified using overlapping primers containing NGS as well as Unique Double Index (UDI) and multiple sequencing strategies as suggested by the manufacturer (Illumina). Illumina MiSeq using the reagents nano-and mini-kit v2 (MS-103-1001/1002) was used to determine the relative abundance of each barcoded AAV vector for each sample collected from mice. Thus, each of the carrier samples in tables 4A-C below were barcoded as described above to allow each read to be identified and sorted prior to final data analysis. The data were normalized to the composition of AAV in the initial injection pool and quantified using the total genomic copy number obtained from the qPCR analysis and primer-probe combinations specific for the barcoded samples.
TABLE 4A
TABLE 4B
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TABLE 4C
In studies with separate injections of capsids selected from the pool, qPCR was used to determine the number of vector genomes per μg of tissue genomic DNA. qPCR was performed on quantsudio 5 (Life Technologies, inc.) following the standard curve method using primer-probe combinations specific for eGFP (fig. 13).
From studies in which individual vectors were injected into mice for characterization, formalin-fixed mouse brains were sectioned at a thickness of 40 μm on a vibrating blade microtome (VT 1000S, leica) and floating sections were probed with antibodies against GFP to observe the cell distribution of the delivered vectors.
More specifically, fixed brains from AAV.hDyn-injected mice were sectioned using a Vibriome (Leica, VT-1000) and GFP expression was assessed using an anti-GFP antibody (AB 3080, millipore Sigma), a Vectastatin ABC kit (PK-6100, vector Labs) and a DAB peroxidase kit (SK-4100, vector Labs). In aav.hdyn-injected mice, GFP-expressing cells are widely distributed throughout the brain, including in the cortex, striatum, and hippocampus of the brain. Figures 15A-15C show images of these areas to a scale of 400um (discussed below).
6.14.2 results
The results are shown in FIGS. 13, 14A-14H and 15A-15C.
Data from Lec2 cell transduction assays are not shown. AAV9588Hep (AAV 9 with peptide TILSRSTQTG inserted after position 588 (SEQ ID NO: 15)) exhibited significantly higher transduction (4-fold) than wild-type AAV9, and AAV9 VP2 Ad (AAV 9 with peptide SITLVKSTQTV inserted after position 138 (SEQ ID NO: 14)), AAV9 VP2 Hep (AAV 9 with peptide TILSRSTQTG inserted after position 138 (SEQ ID NO: 15)) and AAV9 VP2 Rab (AAV 9 with peptide RSSEEDKSTQTT inserted after position 138 (SEQ ID NO: 19)) exhibited slightly higher Lec2 cell transduction relative to AAV 9. Other AAV tested exhibited lower levels of transduction than AAV 9.
Fig. 13 depicts the results of a Next Generation Sequencing (NGS) analysis of brain gDNA, revealing the relative abundance (percent composition) of the capsid assembly delivered to the mouse brain following intravenous injection. The data were normalized according to the composition of AAV in the initial injection pool and quantified using the total genome copy number obtained from qPCR analysis and primer-probe combinations specific for eGFP sequences. The data shown are from three different experiments. The dashed lines indicate which carriers are pooled together. Parental AAV9 was used as a standard and was included in each collection. The "BC" identifier is indicated in tables 4A, 4B, and 4C above.
FIGS. 14A-14H depict in vivo transduction profiles of AAV.hDyn in female C57B1/6 mice, showing increased copy number/μg gDNA in brain (FIG. 14A), liver (FIG. 14B), heart (FIG. 14C), lung (FIG. 14D), kidney (FIG. 14E), skeletal muscle (FIG. 14F), sciatic nerve (FIG. 14G) and ovary (FIG. 14H) of the mice that were initially subjected to the experiment or mice injected with AAV9 or AAV.hDyn, wherein AAV.hDyn shows increased brain biodistribution compared to AAV 9. The AAV vector genome copy number per μg of brain genomic DNA in mice administered aav.hdyn is at least one log higher compared to the parental AAV9 vector.
15A-15C show images from areas analyzed in the immunohistochemical analysis described above; the scale bar is 400 μm. Figures 15A-15C depict the distribution of GFP from aav.hdyn throughout the brain, with immunohistochemical staining images of brain sections from striatum (figure 15A), hippocampus (figure 15B) and cortex (figure 15C) revealing the overall transduction of the brain by the modified vector.
6.14.3 conclusion
AAV capsid modifications by insertion in the surface exposed loops of VR-IV and VR-VIII or by specific amino acid mutations do not affect their packaging efficiency and are capable of producing similar titers in the production systems described herein.
Intravenous administration of aav.hdyn to mice resulted in higher relative abundance of viral genomes and higher brain cell transduction compared to other modified AAV vectors and AAV9 tested.
6.15.Example 14Biological distribution of rAAV vector pool in cynomolgus monkeys after IVT injection
Following a single intravitreal Injection (IVT) in cynomolgus monkeys, administration, in vivo and post-mortem observations, and biodistribution of recombinant AAV pools with engineered capsid and GFP transgenes were assessed (table 5). The collection contains multiple capsids, each containing a unique barcode identifier, allowing identification using Next Generation Sequencing (NGS) analysis after administration to cynomolgus monkeys. All animals in this study did not receive prior treatment. The collection may comprise at least the following recombinant AAV having an engineered capsid listed in table 5.
TABLE 5 recombinant AAV for cynomolgus monkey study
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6.15.1 study design
Three female cynomolgus animals were used. Relevant tissues were collected to evaluate biodistribution associated with IVT injections (measured by NGS and PCR). Three animals received a single intravitreal injection.
A double sided bolus is administered at a dose volume of 50 μl for Intravitreal (IVT) injection.
6.15.2 observation and inspection
Clinical signs were recorded at least once daily starting approximately two weeks before dosing began and continuing throughout the study period. The animals were observed for clinical effects, signs of disease and/or death.
Animals were examined for ophthalmology prior to dose administration on days 2, 8, 15 and 22. In an ophthalmic examination performed after day 1, all animals were sedated with ketamine hydrochloride intramuscular Injection (IM). For the day 1 examination, animals were sedated with injection anesthesia (see section 15.3.3). The pupil was mydriated with 1% tolterodine before examination. The examination includes slit-lamp biopsy microscopy and indirect ophthalmoscopy. In addition, applanation tonometery was performed on animals prior to dosing, immediately after dose administration (about 10 to 15 minutes) and on days 2 and 22.
Blood samples (about 3 mL) were collected from peripheral veins about 2 to 3 weeks prior to dosing for neutralizing antibody analysis.
6.15.3 biological analysis sample collection
Blood samples (approximately 5 mL) were collected from peripheral veins of fasted animals for PBMC analysis prior to dose administration (day 1), 8 and 15, and prior to necropsy (day 22). Samples were obtained using heparin lithium tubes and time was recorded.
Blood samples were collected from peripheral veins for bioassays prior to dosing (day 1, 2 mL) and necropsy (day 22, 5 mL). Samples were collected in clot tubes and time recorded. The tube was kept at room temperature until complete solidification, and then centrifuged at about 2400rpm for 15 minutes at room temperature. Serum was collected, placed in labeled vials (autopsy samples divided into 1mL aliquots), frozen in liquid nitrogen, and stored at-60 ℃ or below.
6.15.4 necropsy
Any animals dying or moribund found to die after at least 21 days of treatment (day 22) were subjected to a general necropsy at a predetermined necropsy. All animals except those found to die were sedated with 8mg/kg ketamine hydrochloride (HCl) IM, maintained in an isoflurane/oxygen mixture, and provided a heparin sodium intravenous bolus at 200 IU/kg. Animals were perfused through the left ventricle with 0.001% sodium nitrite in saline.
The following tissues from all animals were preserved: bone marrow, brain, cecum, colon, dorsal root and ganglion, duodenum, esophagus, eye with optic nerve, macroscopic lesions, heart, ileum, jejunum, kidney, knee joint, liver, lung with bronchi, lymph node, ovary, pancreas, sciatic nerve, skeletal muscle, spinal cord, spleen, thyroid, trachea and vagus nerve.
6.15.5 biological analysis
The tissues were checked for vector copy number and transcript number by quantitative PCR and NGS methods.
6.15.6 results
Fig. 17A depicts the results of Next Generation Sequencing (NGS) analysis of different structures and cellular components of the eye (see fig. 16A and 16B for eye anatomy) revealing the relative abundance (percent composition) of the set of capsids after IVT. The data were normalized according to the composition of AAV in the initial injection pool and quantified using the total genome copy number obtained from qPCR analysis and primer-probe combinations specific for eGFP sequences. Aav2.7m8 was used as a standard and the data showed the best performing capsid relative to the aav2.7m8 capsid.
Fig. 17B depicts the number of transcripts (RNAs) in different tissues of the eye revealing the relative abundance (percentage composition) of capsid sets after IVT. The data were normalized according to the composition of AAV in the initial injection pool and quantified using the total genome copy number obtained from qPCR analysis and primer-probe combinations specific for eGFP sequences. Aav2.7m8 was used as a standard and the data showed the best performing capsid relative to the aav2.7m8 capsid.
6.16.Example 15 -biodistribution of the modified capsid in cynomolgus monkeys after IVT injection
Following a single intravitreal Injection (IVT) in cynomolgus monkeys, the highest hit recombinant AAV screened from the barcoded library in NHPs will be evaluated for administration, in vivo and post-mortem observations, and biodistribution (table 6). All animals in this study did not receive prior treatment.
TABLE 6 recombinant AAV for IVT cynomolgus monkey study
6.16.1 study design
For each capsid, two female cynomolgus animals will be used. Relevant tissues were collected and biodistribution associated with different AAV was assessed using IVT injection (see fig. 16A and B). A double sided bolus will be administered at a dose volume of 50 μl for IVT injection.
6.16.2 observation and inspection
Clinical signs were recorded at least once daily, starting approximately two weeks before the start of dosing and continuing throughout the study period. The animals were observed for clinical effects, disease and/or signs of mortality.
The animals will be examined for ophthalmology prior to dosing and on days 2, 8, 15 and 22. In an ophthalmic examination performed after day 1, all animals were sedated with ketamine hydrochloride IM. For the day 1 examination, animals were sedated with injection anesthesia.
The examination will be preceded by mydriasis with 1% topiramate. The examination will include slit-lamp biopsy microscopy, indirect ophthalmoscopy, fundus imaging, and OCT at selected time points.
Blood samples (about 3 mL) were collected from peripheral veins for neutralizing antibody analysis approximately 2 to 3 weeks prior to dose administration.
6.16.3 biological analysis sample collection
Blood samples were collected from peripheral veins for bioassays prior to dosing (day 1, 2 mL) and necropsy (day 28, 5 mL). Samples will be collected in a coagulation tube and time recorded. The tube was kept at room temperature until complete solidification, and then centrifuged at about 2400rpm for 15 minutes at room temperature. Serum was harvested, placed in labeled vials (autopsy samples divided into 1mL aliquots), frozen in liquid nitrogen, and stored at-60 ℃ or below.
6.16.4 necropsy
After at least 21 days of treatment (day 22), any moribund animals found to die or sacrificed will be subjected to a general necropsy at the scheduled necropsy. All animals except those found to die will be sedated with 8mg/kg ketamine hydrochloride IM, maintained in an isoflurane/oxygen mixture, and provided 200IU/kg heparin sodium intravenous bolus. The animal will be perfused through the left ventricle with 0.001% sodium nitrite in saline.
Eyes will be collected at the end of the study. One eye will be used for Immunohistochemistry (IHC) and the other eye for biodistribution studies. Peripheral tissue may be collected.
6.16.5 biological analysis
The vector copy number and the number of transcripts in the eye will be checked by quantitative PCR. GFP expression levels and localization will be checked using IHC.
6.17.Example 16Biological distribution of rAAV vector pool in cynomolgus monkeys after IVT injection
Pooled barcoded vectors were administered to NHPs by intravitreal injection and the biodistribution of vector DNA and RNA was assessed at 3 weeks post-administration, using the protocol described in examples 14 and 15 below. Specifically, vector collections were administered to both eyes (bilateral) of 2 groups of 2 adult cynomolgus monkeys (cynomolgus macaques) by IVT according to table 7 below:
TABLE 7
Ophthalmic examinations including slit lamp biopsy microscopy, indirect ophthalmoscopy and IOP measurements were performed prior to dose administration and on days 2, 8, 15 and 22. At week 3, the anatomy (see fig. 16A and B for ocular anatomy) was sacrificed and samples were collected in RNAlater-containing tubes and cryopreserved. The abundance of vector DNA and transcribed transgenic RNA in tissue samples relative to reference capsid AAV8 and AAV9 was assessed using common single factor ANOVA, along with post-hoc Dunnett multiple comparisons using Prism production.
The results show the relative abundance of vector DNA and transcribed transgenic RNA for the first 9 capsids relative to AAV9 abundance. Figures 18A-18C show the relative abundance of rAAV DNA and RNA (relative to AAV 9) of the nine most abundant capsids and control AAV8 and AAV9 in dissected cornea (figure 18A), iris (figure 18B) and lens (figure 18C) tissues. No RNA was detected in the cornea and lens tissue samples. Figures 19A-19C depict the relative abundance of the nine most abundant capsids in ciliary body (figure 19A), schlemm's canal (figure 19B) and trabecular meshwork (figure 19C) tissues and rAAV DNA and RNA expressed by the capsid plus barcode transgene (relative to AAV 9) in control AAV8 and AAV 9. Although not included in the bar graph, AAV3B RNA was detected in ciliary body tissue (abundance rank 47 in 118) and trabecular meshwork (abundance rank 26 in 118). Figures 20A-20C depict the relative abundance of rAAV DNA and RNA (relative to AAV 9) of the nine most abundant capsids and control AAV8 and AAV9 in the retina (figure 20A), RPE-choroid (figure 20B) and sclera (figure 20C). Although not on the bar graph, AAV3B DNA was detected in the sclera (abundance rank 37 among 118). Finally, figures 21A and 21B show the relative abundance of rAAV DNA and RNA (relative to AAV 9) of the nine most abundant capsids and control AAV8 and AAV9 in the optic nerve (orbital segment) (figure 21A) or optic nerve (cranial segment) (figure 20B). RNA transcribed from the transgene was not detected in optic nerve samples of the orbital or cranial segments.
The relative RNA abundance in tissues compared to AAV8 or AAV9 capsids is summarized in table 8 below.
TABLE 8
6.18.Example 17Comparison of the biodistribution of the vectors in the rAAV vector collection in cynomolgus monkeys and mice after IVT injection.
This example compares the biodistribution of intravitreally injected rAAV vector collections in cynomolgus monkeys as described in example 16 below, and in mice as described in example 13. In this example, as detailed in table 9 below, pooled vectors were administered bilaterally in each eye of 2 groups of 5C 57BL/6 mice, and then the mice were sacrificed 3 weeks after administration. Tissue from one eye was collected and stored in an RNAlater for RNA determination, while tissue from the other eye was frozen for DNA analysis.
TABLE 9
The biodistribution results show the relative abundance of DNA and RNA of rAAV relative to the different capsids of AAV9 in retinal tissue of mice (fig. 22A) and NHP (fig. 22B) and in RPE-choroids of mice (fig. 23A) and NHP (fig. 23B). Although not reflected in the bar graph, AAV3B DNA was detected in the mouse RPE-choroid (rank 73 in 118 capsids relative to abundance of AAV 9), and AAV3B RNA was detected in the mouse retina (rank 81 in 118 capsids relative to abundance of AAV 9) and the mouse RPE-choroid (rank 14 in 118 capsids relative to abundance of AAV 9).
This study showed enrichment of AAV2 and AAV4 in retina and RPE-choroidal tissues and rh.73 in mouse and NHP tissues when rAAV was administered via IVT administration. The relative abundance of rh.73 (DNA enrichment) in the pool of IVT injected female mice was also observed, as shown in fig. 24.
6.19 example 18: single rAAV vector formulation of AAV3B capsid biodistribution in cynomolgus monkeys after Intravitreal (IVT) injection
The rAAV vector formulation containing a single AAV vector AAV3B expressing GFP reporter gene from a universal CAG promoter (flanking AAV2 ITRs) was administered by IVT injection at a dose of 1.61E11GC per eye to a set of 2 NHPs (50 μl per eye injection volume). Control AAV2 variant (AAV 2 v) vectors expressing GFP were also administered by IVT injection at a dose of 1.61E11GC per eye to a group of 2 NHPs (50 μl per eye injection volume). This study followed a protocol similar to that described in the previous examples, e.g., examples 14, 15 and 16, however the biodistribution of AAV3B or control vector DNA and RNA in various ocular tissues as well as several peripheral tissues will be assessed after 3 weeks of sacrifice following vector administration.
Ophthalmic examinations are performed on intermittent days before and after dose administration, such as by slit lamp biopsy microscopy, indirect ophthalmoscopy and IOP measurements. At week 3 sacrifice, ocular tissues and optic nerves were dissected and extracted (see fig. 16A and B for ocular anatomy). Peripheral Blood Mononuclear Cells (PBMC), liver, brain and lacrimal glands were also extracted. Tissues were collected from the right eye and samples were collected in tubes with RNAlater (according to manufacturer's instructions) and snap frozen at-80 ℃ until qPCR could be performed. The biodistribution and transgene expression of AAV3B capsids in the left eye tissue of each subject will be analyzed by RT-qPCR methods. The right eye tissue of each subject was removed, collected in 4% paraformaldehyde and processed into paraffin blocks, and GFP expression was assessed by Immunohistochemistry (IHC), and hematoxylin and eosin (H & E) staining for histopathological analysis.
6.20 example 19: capsid biodistribution of rAAV vector pool in cynomolgus monkeys after suprachoroidal (SCS) injection
Pooled barcode vector was administered to NHP by suprachoroidal injection. The pooled mixture consisted of 118 different AAV capsids, including the native isolates and engineered AAV as described herein, with GFP reporter expressed from the universal CAG promoter. Suprachoroidal studies followed a protocol similar to that described in examples 14, 15 and 16 below, except that the vector pool was administered to both eyes (bilateral) of 2 adult cynomolgus monkeys via SCS at a dose of 7.2E11GC per eye. Prior to suprachoroidal injection, animals were anesthetized with ketamine and dexmedetomidine. AAV libraries (pools) were delivered to the suprachoroidal space (SCS) of each eye via a single SCS injection of 100 μl.
Ophthalmic examinations such as slit lamp biopsy microscopy, indirect ophthalmoscopy and IOP measurements are performed prior to dose administration and on intermittent days. At week 3 sacrifice, tissues were harvested and samples were collected in tubes with RNAlater (following manufacturer's instructions) and snap frozen at-80 ℃ until DNA and RNA analysis in ocular tissues including aqueous humor, vitreous humor, choroidal-Retinal Pigment Epithelium (RPE), cornea, iris-ciliary body, lens, optic nerve, retina and sclera (biodistribution of each vector in the collection) could be performed by NGS.
6.21. Capsid amino acid sequence
Table 10 provides the amino acid sequences of certain engineered and non-engineered capsid proteins described and/or used in the studies described herein. Heterologous peptides and amino acid substitutions are indicated in grey shading.
TABLE 10 capsid amino acid sequence
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7. Equivalent cases
Although the invention has been described in detail with reference to particular embodiments, it should be understood that functionally equivalent variations are within the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
The discussion herein provides a better understanding of the nature of the problems faced in the art, and should not be construed in any way as an admission that any reference herein is prior art, nor should it be construed as an admission that such reference constitutes "prior art" to the present application.
All references, including patent applications and publications, cited herein are hereby incorporated by reference in their entirety and for all purposes to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.
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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> 23
<211> 743
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 23
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> 24
<211> 743
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 24
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> 25
<211> 743
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 25
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> 26
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 26
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> 27
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 27
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> 28
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 28
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> 29
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 29
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> 30
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 30
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> 31
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 31
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> 32
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 32
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> 33
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 33
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> 34
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 34
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> 35
<211> 744
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 35
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> 36
<211> 743
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 36
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> 37
<211> 745
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 37
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> 38
<211> 741
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 38
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> 39
<211> 743
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 39
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> 40
<211> 743
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 40
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> 41
<211> 743
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 41
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> 42
<211> 743
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 42
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> 43
<211> 745
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 43
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> 44
<211> 747
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 44
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> 45
<211> 746
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 45
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> 46
<211> 753
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 46
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> 47
<211> 754
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 47
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> 48
<211> 35
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<220>
<221> misc_feature
<222> (14)..(15)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (23)..(23)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (30)..(30)
<223> Xaa can be any naturally occurring amino acid
<400> 48
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> 49
<211> 35
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 49
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> 50
<211> 35
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 50
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> 51
<211> 35
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 51
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> 52
<211> 36
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 52
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> 53
<211> 36
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 53
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> 54
<211> 29
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 54
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> 55
<211> 36
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 55
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> 56
<211> 35
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 56
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> 57
<211> 34
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 57
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> 58
<211> 35
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 58
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> 59
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 59
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> 60
<211> 735
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 60
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> 61
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 62
<211> 734
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 62
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> 63
<211> 724
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 63
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> 64
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 65
<211> 737
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 66
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 67
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 68
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 69
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 70
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 71
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 72
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 73
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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> 74
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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 Arg
130 135 140
Pro 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
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 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 Arg Thr Val Asn Asp 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> 75
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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 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 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 Ser 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 Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Ser Asn Met Ser Ala Gln Ala Arg 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
Asn Lys Asp Asp Glu Asp Arg Phe Phe Pro Ser Ser Gly Ile Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Asn 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 Arg Gln Asn Thr 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 Ala Phe Asn Gln Ala 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 Asn 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> 76
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 76
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 Gly 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 Gly 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 Thr 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
Asn 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 His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Ser Thr Thr Phe Ser Ala 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> 77
<211> 735
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 77
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 Ile 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 Ala 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 Arg Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Ser 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 Ser 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 Met 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 Ala Ala Asp Asn Asn
485 490 495
Asn Ser Asp 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 Tyr Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Asp Ser Gly 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 Ser Gly Asn Thr Gln Ala Ala Thr
580 585 590
Ser 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> 78
<211> 735
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 78
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 Gln 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 His 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 Thr Ser Leu Gly Ser Thr 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 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 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 Pro 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 Asn Arg Thr
435 440 445
Gln Ser Asn Ser Gly Thr Leu Gln Gln Ser Arg Leu Leu Phe Ser Gln
450 455 460
Ala Gly Pro Thr Ser Met Ser Leu Gln Ala Lys Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Leu Ser Lys Gln Ala Asn Asp Asn Asn
485 490 495
Asn Ser Asn Phe Pro Trp Thr Ala 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 Met His Gly Thr Leu Ile Phe Gly Lys
530 535 540
Gln Gly Thr Asn Ala Asn Asp Ala Asp Leu Glu His 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 Asn Val Ser Asn Asn Leu Gln Asn Ser Asn Thr Gly Pro Thr Thr
580 585 590
Glu Asn Val Asn His Gln Gly Ala 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 Met Ile Lys Asn Thr Pro Val Pro Ala Asn
645 650 655
Pro Pro Thr Asn Phe Ser Ser 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> 79
<211> 735
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 79
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 Ile 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 Ala 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 Ser 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 Ser 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 Met 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 Ala Ala Asp Asn Asn
485 490 495
Asn Ser Asp 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 Tyr Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Asp Ser Gly 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 Ser Gly Asn Thr Gln Ala Ala Thr
580 585 590
Ser 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> 80
<211> 734
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 80
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 Ala 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 Arg Gln Pro Pro
180 185 190
Ala Ala Pro Thr Ser Leu Gly Ser Thr 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 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 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 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 Thr Ala Ser Gly Thr Gln Gln Ser Arg Leu Leu Phe Ser Gln Ala
450 455 460
Gly Pro Thr Ser Met Ser Leu Gln Ala Lys Asn Trp Leu Pro Gly Pro
465 470 475 480
Cys Tyr Arg Gln Gln Arg Leu Ser Lys Gln Ala Asn Asp Asn Asn Asn
485 490 495
Ser Asn Phe Pro Trp Thr Gly Ala Thr Lys Tyr Tyr Leu Asn Gly Arg
500 505 510
Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp Asp
515 520 525
Glu Glu Lys Phe Phe Pro Met His Gly Thr Leu Ile Phe Gly Lys Glu
530 535 540
Gly Thr Asn Ala Thr Asn Ala Glu Leu Glu Asn Val Met Ile Thr Asp
545 550 555 560
Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr Gly
565 570 575
Tyr Val Ser Asn Asn Leu Gln Asn Ser Asn Thr Ala Ala Ser Thr Glu
580 585 590
Thr Val Asn His Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asp Arg
595 600 605
Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp
610 615 620
Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His
625 630 635 640
Pro Pro Pro Gln Ile Met Ile Lys Asn Thr Pro Val Pro Ala Asn Pro
645 650 655
Pro Thr Asn Phe Ser Ser Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr
660 665 670
Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu
675 680 685
Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn
690 695 700
Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser
705 710 715 720
Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730
<210> 81
<211> 733
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<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 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 Glu 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 Leu Glu Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly Lys
145 150 155 160
Lys Gly Lys Gln Pro Ala Lys Lys Arg Leu Asn Phe Glu Glu Asp Thr
165 170 175
Gly Ala Gly Asp Gly Pro Pro Glu Gly Ser Asp Thr Ser Ala Met Ser
180 185 190
Ser Asp Ile Glu Met Arg Ala Ala Pro Gly Gly Asn Ala Val Asp Ala
195 200 205
Gly Gln Gly Ser Asp Gly Val Gly Asn Ala Ser Gly Asp Trp His Cys
210 215 220
Asp Ser Thr Trp Ser Glu Gly Lys Val Thr Thr Thr Ser Thr Arg Thr
225 230 235 240
Trp Val Leu Pro Thr Tyr Asn Asn His Leu Tyr Leu Arg Leu Gly Thr
245 250 255
Thr Ser Asn 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 Leu 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 Ile Val Thr Gly Glu Asn Gln Asn Gln Thr Asp Arg Asn Ala
370 375 380
Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn
385 390 395 400
Asn Phe Glu Thr Ala Tyr Asn Phe Glu Lys Val Pro Phe His Ser Met
405 410 415
Tyr Ala His Ser Gln Ser Leu Asp Gly Leu Met Asn Pro Leu Leu Asp
420 425 430
Gln Tyr Leu Trp His Leu Gln Ser Thr Thr Ser Gly Glu Thr Leu Asn
435 440 445
Gln Gly Asn Ala Ala Thr Thr Phe Gly Lys Ile Arg Ser Gly Asp Phe
450 455 460
Ala Phe Tyr Arg Lys Asn Trp Leu Pro Gly Pro Cys Val Lys Gln Gln
465 470 475 480
Arg Phe Ser Lys Thr Ala Ser Gln Asn Tyr Lys Ile Pro Ala Ser Gly
485 490 495
Gly Asn Ala Leu Leu Lys Tyr Asp Thr His Tyr Thr Leu Asn Asn Arg
500 505 510
Trp Ser Asn Ile Ala Pro Gly Pro Pro Met Ala Thr Ala Gly Pro Ser
515 520 525
Asp Gly Asp Phe Ser Asn Ala Gln Leu Ile Phe Pro Gly Pro Ser Val
530 535 540
Thr Gly Asn Thr Thr Thr Ser Ala Asn Asn Leu Leu Phe Thr Ser Glu
545 550 555 560
Glu Glu Ile Ala Ala Thr Asn Pro Arg Asp Thr Asp Met Phe Gly Gln
565 570 575
Ile Ala Asp Asn Asn Gln Asn Ala Thr Thr Ala Pro Ile Thr Gly Asn
580 585 590
Val Thr Ala Met Gly Val Leu Pro Gly Met Val Trp Gln Asn Arg Asp
595 600 605
Ile Tyr Tyr Gln Gly Pro Ile Trp Ala Lys Ile Pro His Ala Asp Gly
610 615 620
His Phe His Pro Ser Pro Leu Ile Gly Gly Phe Gly Leu Lys His Pro
625 630 635 640
Pro Pro Gln Ile Phe Ile Lys Asn Thr Pro Val Pro Ala Tyr Pro Ala
645 650 655
Thr Thr Phe Thr Ala Ala Arg Val Asp Ser Phe Ile Thr Gln Tyr Ser
660 665 670
Thr Gly Gln Val Ala Val Gln Ile Glu Trp Glu Ile Glu Lys Glu Arg
675 680 685
Ser Lys Arg Trp Asn Pro Glu Val Gln Phe Thr Ser Asn Cys Gly Asn
690 695 700
Gln Ser Ser Met Leu Trp Ala Pro Asp Thr Thr Gly Lys Tyr Thr Glu
705 710 715 720
Pro Arg Val Ile Gly Ser Arg Tyr Leu Thr Asn His Leu
725 730
<210> 82
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 82
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 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 Ser Gln Pro Ala Lys Lys Lys 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 Gly 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 Ser 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> 83
<211> 644
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<220>
<221> misc_feature
<222> (434)..(434)
<223> Xaa can be any naturally occurring amino acid
<400> 83
Lys Ala Tyr Asp Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg
1 5 10 15
Tyr Asn His Ala Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr
20 25 30
Ser Phe Gly Gly Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg
35 40 45
Val Leu Glu Pro Leu Gly Leu Val Glu Thr Pro Ala Lys Thr Ala Pro
50 55 60
Gly Lys Lys Arg Pro Val Asp Ser Pro Asp Ser Thr Ser Gly Ile Gly
65 70 75 80
Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
85 90 95
Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
100 105 110
Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly Gly
115 120 125
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ala
130 135 140
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile
145 150 155 160
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
165 170 175
Tyr Lys Gln Ile Ser Ser Gln Ser Ala Gly Ser Thr Asn Asp Asn Val
180 185 190
Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe
195 200 205
His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn
210 215 220
Trp Gly Phe Arg Pro Lys Lys Leu Asn Phe Lys Leu Phe Asn Ile Gln
225 230 235 240
Val Lys Glu Val Thr Thr Asn Asp Gly Val Thr Thr Ile Ala Asn Asn
245 250 255
Leu Thr Ser Thr Val Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu Pro
260 265 270
Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala
275 280 285
Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly
290 295 300
Ser Gln Ser Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro
305 310 315 320
Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe
325 330 335
Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp
340 345 350
Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ala Arg
355 360 365
Thr Gln Ser Asn Ala Gly Gly Thr Ala Gly Asn Arg Glu Leu Gln Phe
370 375 380
Tyr Gln Gly Gly Pro Thr Thr Met Ala Glu Gln Ala Lys Asn Trp Leu
385 390 395 400
Pro Gly Pro Cys Phe Arg Gln Gln Arg Val Ser Lys Thr Leu Asp Gln
405 410 415
Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His Leu
420 425 430
Asn Xaa Arg Asn Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr His
435 440 445
Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Ile Phe
450 455 460
Gly Lys Thr Gly Ala Ala Asn Lys Thr Thr Leu Glu Asn Val Leu Met
465 470 475 480
Thr Asn Glu Glu Glu Ile Arg Pro Thr Asn Pro Val Ala Thr Glu Glu
485 490 495
Tyr Gly Ile Val Ser Ser Asn Leu Gln Ala Ala Ser Thr Ala Ala Gln
500 505 510
Thr Gln Val Val Asn Asn Gln Gly Ala Leu Pro Gly Met Val Trp Gln
515 520 525
Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
530 535 540
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
545 550 555 560
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
565 570 575
Asn Pro Pro Glu Val Phe Thr Pro Ala Lys Phe Ala Ser Phe Ile Thr
580 585 590
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
595 600 605
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
610 615 620
Phe Asp Lys Gln Thr Gly Val Asp Phe Ala Val Asp Ser Gln Gly Val
625 630 635 640
Tyr Ser Glu Pro
<210> 84
<211> 735
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 84
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 Gln 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 His 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 Thr Ser Leu Gly Ser Thr 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 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 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 Pro 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 Asn Arg Thr
435 440 445
Gln Ser Asn Ser Gly Thr Leu Gln Gln Ser Arg Leu Leu Phe Ser Gln
450 455 460
Ala Gly Pro Thr Ser Met Ser Leu Gln Ala Lys Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Leu Ser Lys Gln Ala Asn Asp Asn Asn
485 490 495
Asn Ser Asn Phe Pro Trp Thr Ala 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 Met His Gly Thr Leu Ile Phe Gly Lys
530 535 540
Gln Gly Thr Asn Ala Asn Asp Ala Asp Leu Glu His 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 Asn Val Ser Asn Asn Leu Gln Asn Ser Asn Thr Gly Pro Thr Thr
580 585 590
Glu Asn Val Asn His Gln Gly Ala 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 Met Ile Lys Asn Thr Pro Val Pro Ala Asn
645 650 655
Pro Pro Thr Asn Phe Ser Ser 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> 85
<211> 735
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 85
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 Ala 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 Ser 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 Gly Gly Asn Thr 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> 86
<211> 735
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 86
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 Asn 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 Ser 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 Val
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 Leu 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 Ala 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 Ser Gly Asn Thr Gln Ala Ala Thr
580 585 590
Ser 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> 87
<211> 733
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 87
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 Ile Glu Ser Pro Asp Ser Ser Thr Gly Ile Gly Lys Lys Gly Gln
145 150 155 160
Gln Pro Ala Lys Lys Lys Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu
165 170 175
Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro Ala Gly Pro Ser
180 185 190
Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly Gly Ala Pro Met Ala
195 200 205
Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser Ser Gly Asn Trp
210 215 220
His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile Thr Thr Ser Thr
225 230 235 240
Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu Tyr Lys Gln Ile
245 250 255
Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp Asn Thr Tyr Phe Gly
260 265 270
Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His
275 280 285
Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe
290 295 300
Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu
305 310 315 320
Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala Asn Asn Leu Thr Ser
325 330 335
Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr Val Leu
340 345 350
Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe
355 360 365
Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser Gln Ala
370 375 380
Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met
385 390 395 400
Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr Gln Phe Glu Asp Val
405 410 415
Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met
420 425 430
Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Gln Ser
435 440 445
Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu Phe Ser Gln Ala Gly
450 455 460
Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys
465 470 475 480
Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Ser Gln Asn Asn Asn Ser
485 490 495
Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly Arg Asp
500 505 510
Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr His Lys Gly Asp Glu
515 520 525
Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met Phe Gly Lys Gln Gly
530 535 540
Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val Met Leu Thr Ser Glu
545 550 555 560
Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr Gly Val
565 570 575
Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala Pro Ile Val Gly Ala
580 585 590
Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp
595 600 605
Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly
610 615 620
Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro
625 630 635 640
Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro
645 650 655
Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe Ile Thr Gln Tyr Ser
660 665 670
Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn
675 680 685
Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys
690 695 700
Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu Gly Thr Tyr Ser Glu
705 710 715 720
Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Ser Leu
725 730
<210> 88
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 88
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 Cys 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> 89
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 89
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> 90
<211> 728
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 90
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Gly 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 Arg 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
Lys Gln Leu Glu Gln 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 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 Ile Glu Ser Pro Asp Ser Ser Thr Gly Ile Gly Lys Asn Gly Gln
145 150 155 160
Pro Pro Ala Lys Lys Lys Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu
165 170 175
Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Ser
180 185 190
Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly Gly Ala Pro Met Ala
195 200 205
Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ala Ser Gly Asn Trp
210 215 220
His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile Thr Thr Ser Thr
225 230 235 240
Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu Tyr Lys Gln Ile
245 250 255
Ser Ser Gln Ser Gly Ala Thr Asn Asp Asn His Phe Phe Gly Tyr Ser
260 265 270
Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser
275 280 285
Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro
290 295 300
Arg Lys Leu Arg Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr
305 310 315 320
Thr Asn Asp Gly Val Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Ile
325 330 335
Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu Pro Tyr Val Leu Gly Ser
340 345 350
Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile
355 360 365
Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser Gln Ser Val Gly
370 375 380
Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg
385 390 395 400
Thr Gly Asp Asn Phe Glu Phe Ser Tyr Thr Phe Glu Glu Val Pro Phe
405 410 415
His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro
420 425 430
Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ala Arg Thr Gln Ser Thr Thr
435 440 445
Gly Ser Thr Arg Glu Leu Gln Phe His Gln Ala Gly Pro Asn Thr Met
450 455 460
Ala Glu Gln Ser Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln
465 470 475 480
Arg Leu Ser Lys Asn Ile Asp Ser Asn Asn Asn Ser Asn Phe Ala Trp
485 490 495
Thr Gly Ala Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Thr Asn
500 505 510
Pro Gly Val Ala Met Ala Thr Asn Lys Asp Asp Glu Asp Gln Phe Phe
515 520 525
Pro Ile Asn Gly Val Leu Val Phe Gly Lys Thr Gly Ala Ala Asn Lys
530 535 540
Thr Thr Leu Glu Asn Val Leu Met Thr Ser Glu Glu Glu Ile Lys Thr
545 550 555 560
Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Val Val Ser Ser Asn Leu
565 570 575
Gln Ser Ser Thr Ala Gly Pro Gln Thr Gln Thr Val Asn Ser Gln Gly
580 585 590
Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly
595 600 605
Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser
610 615 620
Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu
625 630 635 640
Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Pro Glu Val Phe Thr Pro
645 650 655
Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser
660 665 670
Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn
675 680 685
Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Ala Lys Ser Asn Asn Val Glu
690 695 700
Phe Ala Val Asn Asn Glu Gly Val Tyr Thr Glu Pro Arg Pro Ile Gly
705 710 715 720
Thr Arg Tyr Leu Thr Arg Asn Leu
725
<210> 91
<211> 728
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 91
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 Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Lys Gln Leu Glu Gln 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 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 Ile Glu Ser Pro Asp Ser Ser Thr Gly Ile Gly Lys Lys Gly Gln
145 150 155 160
Gln Pro Ala Lys Lys Lys Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu
165 170 175
Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Ser
180 185 190
Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly Gly Ala Pro Met Ala
195 200 205
Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ala Ser Gly Asn Trp
210 215 220
His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile Thr Thr Ser Thr
225 230 235 240
Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu Tyr Lys Gln Ile
245 250 255
Ser Ser Gln Ser Gly Ala Thr Asn Asp Asn His Phe Phe Gly Tyr Ser
260 265 270
Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser
275 280 285
Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro
290 295 300
Arg Lys Leu Arg Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr
305 310 315 320
Thr Asn Asp Gly Val Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Ile
325 330 335
Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu Pro Tyr Val Leu Gly Ser
340 345 350
Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile
355 360 365
Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser Gln Ser Met Gly
370 375 380
Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg
385 390 395 400
Thr Gly Asn Asn Phe Glu Phe Ser Tyr Thr Phe Glu Glu Val Pro Phe
405 410 415
His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro
420 425 430
Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ala Arg Thr Gln Ser Thr Thr
435 440 445
Gly Ser Thr Arg Glu Leu Gln Phe His Gln Ala Gly Pro Asn Thr Met
450 455 460
Ala Glu Gln Ser Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln
465 470 475 480
Arg Leu Ser Lys Asn Ile Asp Ser Asn Asn Asn Ser Asn Phe Ala Trp
485 490 495
Thr Gly Ala Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Thr Asn
500 505 510
Pro Gly Val Ala Met Ala Thr Asn Lys Asp Asp Glu Gly Gln Phe Phe
515 520 525
Pro Ile Asn Gly Val Leu Val Phe Gly Lys Thr Gly Ala Ala Asn Lys
530 535 540
Thr Thr Leu Glu Asn Val Leu Met Thr Ser Glu Glu Glu Ile Lys Thr
545 550 555 560
Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Val Val Ser Ser Asn Leu
565 570 575
Gln Ser Ser Thr Ala Gly Pro Gln Thr Gln Thr Val Asn Ser Gln Gly
580 585 590
Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly
595 600 605
Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser
610 615 620
Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu
625 630 635 640
Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Pro Gly Val Phe Thr Pro
645 650 655
Ala Leu Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser
660 665 670
Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn
675 680 685
Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Ala Lys Ser Asn Asn Val Glu
690 695 700
Phe Ala Val Asn Asn Glu Gly Val Tyr Thr Glu Pro Arg Pro Ile Gly
705 710 715 720
Thr Arg Tyr Leu Thr Arg Asn Leu
725
<210> 92
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 92
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 Arg 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 Ala Pro Ser Ser Val 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 Ser 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 Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Ser Asn Met Ser Ala Gln Ala Arg 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
Asn Lys Asp Asp Glu Asp Arg Phe Phe Pro Ser Ser Gly Ile Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Asn Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Ala Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Thr 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 Ala Phe Asn Gln Ala 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 Asn 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> 93
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 93
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 His 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 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 Pro 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 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 Thr Asn Gly Ala
580 585 590
Pro Ile Val 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 Val 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> 94
<211> 736
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 94
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> 95
<211> 734
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 95
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> 96
<211> 738
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 96
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
<210> 97
<211> 746
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 97
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 Arg
130 135 140
Pro 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
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 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 Leu Ala Leu Gly
580 585 590
Glu Thr Thr Arg Pro Ala Thr Ala Pro Thr Thr Arg Thr Val Asn Asp
595 600 605
Gln Gly Ala 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 His Phe His
625 630 635 640
Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln
645 650 655
Ile Met Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Pro Thr Thr Phe
660 665 670
Ser Pro Ala Lys Phe Ala 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 Asn Lys Ser Val Asn
705 710 715 720
Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro
725 730 735
Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 98
<211> 746
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 98
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 Arg
130 135 140
Pro 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 Leu Ala Leu Gly Glu Thr
260 265 270
Thr Arg Pro Ala Ser Asn Asp Asn His 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 Lys
305 310 315 320
Leu Ser Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Gln Asn
325 330 335
Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Val 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 Val 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 Ser 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 Asn Arg Thr Gln Gly Thr Thr Ser Gly
450 455 460
Thr Thr Asn Gln Ser Arg Leu Leu Phe Ser Gln Ala Gly Pro Gln Ser
465 470 475 480
Met Ser Leu Gln Ala Arg Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln
485 490 495
Gln Arg Leu Ser Lys Thr Ala Asn Asp Asn Asn Asn Ser Asn Phe Pro
500 505 510
Trp Thr Ala Ala Ser Lys Tyr His Leu Asn Gly Arg Asp Ser Leu Val
515 520 525
Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp Asp Glu Glu Lys Phe
530 535 540
Phe Pro Met His Gly Asn Leu Ile Phe Gly Lys Glu Gly Thr Thr Ala
545 550 555 560
Ser Asn Ala Glu Leu Asp Asn Val Met Ile Thr Asp Glu Glu Glu Ile
565 570 575
Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr Gly Thr Val Ala Asn
580 585 590
Asn Leu Gln Ser Ser Asn Thr Ala Pro Thr Thr Arg Thr Val Asn Asp
595 600 605
Gln Gly Ala 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 His Phe His
625 630 635 640
Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln
645 650 655
Ile Met Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Pro Thr Thr Phe
660 665 670
Ser Pro Ala Lys Phe Ala 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 Asn Lys Ser Val Asn
705 710 715 720
Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro
725 730 735
Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 99
<211> 746
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 99
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 Arg
130 135 140
Pro 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
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 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 Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala
450 455 460
Thr Thr Asn Gln Ser Arg Leu Leu Phe Ser Gln Ala Gly Pro Gln Ser
465 470 475 480
Met Ser Leu Gln Ala Arg Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln
485 490 495
Gln Arg Leu Ser Lys Thr Ala Asn Asp Asn Asn Asn Ser Asn Phe Pro
500 505 510
Trp Thr Ala Ala Ser Lys Tyr His Leu Asn Gly Arg Asp Ser Leu Val
515 520 525
Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp Asp Glu Glu Lys Phe
530 535 540
Phe Pro Met His Gly Asn Leu Ile Phe Gly Lys Glu Gly Thr Thr Ala
545 550 555 560
Ser Asn Ala Glu Leu Asp Asn Val Met Ile Thr Asp Glu Glu Glu Ile
565 570 575
Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr Gly Thr Val Ala Asn
580 585 590
Asn Leu Gln Ser Ser Asn Thr Ala Pro Thr Thr Arg Thr Val Asn Asp
595 600 605
Gln Gly Ala 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 His Phe His
625 630 635 640
Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln
645 650 655
Ile Met Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Pro Thr Thr Phe
660 665 670
Ser Pro Ala Lys Phe Ala 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 Asn Lys Ser Val Asn
705 710 715 720
Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro
725 730 735
Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 100
<211> 748
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 100
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 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 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 Ser 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 Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Ser Asn Met Ser Ala Gln Ala Arg 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
Asn Lys Asp Asp Glu Asp Arg Phe Phe Pro Ser Ser Gly Ile Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Asn 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 Arg Gln Asn Leu Ala
580 585 590
Leu Gly Glu Thr Thr Arg Pro Ala Thr Ala Pro Ile Val Gly Ala Val
595 600 605
Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val
610 615 620
Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn
625 630 635 640
Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro
645 650 655
Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr
660 665 670
Ala Phe Asn Gln Ala Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr
675 680 685
Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser
690 695 700
Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser
705 710 715 720
Thr Asn Val Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro
725 730 735
Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 101
<211> 748
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 101
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 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 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 Leu Ala
260 265 270
Leu Gly Glu Thr Thr Arg Pro Ala Asn Asp Asn Thr 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 Ser Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val
325 330 335
Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr
340 345 350
Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr Val Leu Gly
355 360 365
Ser Ala His Gln 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 Asn 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 Ser Phe Ser Tyr Thr Phe Glu Asp 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 Gln Ser Thr
450 455 460
Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu Phe Ser Gln Ala Gly Pro
465 470 475 480
Ser Asn Met Ser Ala Gln Ala Arg Asn Trp Leu Pro Gly Pro Cys Tyr
485 490 495
Arg Gln Gln Arg Val Ser Thr Thr Leu Ser Gln Asn Asn Asn Ser Asn
500 505 510
Phe Ala Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly Arg Asp Ser
515 520 525
Leu Val Asn Pro Gly Val Ala Met Ala Thr Asn Lys Asp Asp Glu Asp
530 535 540
Arg Phe Phe Pro Ser Ser Gly Ile Leu Met Phe Gly Lys Gln Gly Ala
545 550 555 560
Gly Lys Asp Asn Val Asp Tyr Ser Asn Val Met Leu Thr Ser Glu Glu
565 570 575
Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr Gly Val Val
580 585 590
Ala Asp Asn Leu Gln Arg Gln Asn Thr Ala Pro Ile Val Gly Ala Val
595 600 605
Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val
610 615 620
Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn
625 630 635 640
Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro
645 650 655
Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr
660 665 670
Ala Phe Asn Gln Ala Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr
675 680 685
Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser
690 695 700
Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser
705 710 715 720
Thr Asn Val Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro
725 730 735
Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 102
<211> 748
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 102
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 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 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 Ser 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 Leu Ala Leu Gly Glu Thr Thr Arg Pro
450 455 460
Ala Gly Thr Ala Gly Thr Gln Gln Leu Leu Phe Ser Gln Ala Gly Pro
465 470 475 480
Ser Asn Met Ser Ala Gln Ala Arg Asn Trp Leu Pro Gly Pro Cys Tyr
485 490 495
Arg Gln Gln Arg Val Ser Thr Thr Leu Ser Gln Asn Asn Asn Ser Asn
500 505 510
Phe Ala Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly Arg Asp Ser
515 520 525
Leu Val Asn Pro Gly Val Ala Met Ala Thr Asn Lys Asp Asp Glu Asp
530 535 540
Arg Phe Phe Pro Ser Ser Gly Ile Leu Met Phe Gly Lys Gln Gly Ala
545 550 555 560
Gly Lys Asp Asn Val Asp Tyr Ser Asn Val Met Leu Thr Ser Glu Glu
565 570 575
Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr Gly Val Val
580 585 590
Ala Asp Asn Leu Gln Arg Gln Asn Thr Ala Pro Ile Val Gly Ala Val
595 600 605
Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val
610 615 620
Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn
625 630 635 640
Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro
645 650 655
Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr
660 665 670
Ala Phe Asn Gln Ala Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr
675 680 685
Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser
690 695 700
Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser
705 710 715 720
Thr Asn Val Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro
725 730 735
Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 103
<211> 748
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 103
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 Ala Thr Ala Pro Gln Ile Gly Thr Val
595 600 605
Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val
610 615 620
Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn
625 630 635 640
Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro
645 650 655
Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr
660 665 670
Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr
675 680 685
Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser
690 695 700
Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser
705 710 715 720
Thr Ser Val Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro
725 730 735
Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 104
<211> 748
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 104
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 Ala Thr Asn Asp Asn Thr 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 Ser Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val
325 330 335
Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr
340 345 350
Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr Val Leu Gly
355 360 365
Ser Ala His Gln 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 Asn 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 Thr Tyr Thr Phe Glu Asp 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 Gln Thr Thr
450 455 460
Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro
465 470 475 480
Asn Thr Met Ala Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr
485 490 495
Arg Gln Gln Arg Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn
500 505 510
Phe Ala Trp Thr Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser
515 520 525
Leu Ala Asn Pro Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu
530 535 540
Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala
545 550 555 560
Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu
565 570 575
Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val
580 585 590
Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala Pro Gln Ile Gly Thr Val
595 600 605
Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val
610 615 620
Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn
625 630 635 640
Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro
645 650 655
Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr
660 665 670
Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr
675 680 685
Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser
690 695 700
Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser
705 710 715 720
Thr Ser Val Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro
725 730 735
Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 105
<211> 748
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 105
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 Ala Thr
450 455 460
Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro
465 470 475 480
Asn Thr Met Ala Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr
485 490 495
Arg Gln Gln Arg Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn
500 505 510
Phe Ala Trp Thr Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser
515 520 525
Leu Ala Asn Pro Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu
530 535 540
Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala
545 550 555 560
Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu
565 570 575
Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val
580 585 590
Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala Pro Gln Ile Gly Thr Val
595 600 605
Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val
610 615 620
Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn
625 630 635 640
Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro
645 650 655
Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr
660 665 670
Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr
675 680 685
Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser
690 695 700
Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser
705 710 715 720
Thr Ser Val Asp Phe Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro
725 730 735
Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 106
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 106
His Ala Ile Tyr Pro Arg
1 5
<210> 107
<211> 700
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct; capsid sequences
<400> 107
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 Arg 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 Ala Pro Ser Ser Val 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 Ser 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 Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Ser Asn Met Ser Ala Gln Ala Arg 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
Asn Lys Asp Asp Glu Asp Arg Phe Phe Pro Ser Ser Gly Ile Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Asn 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 Thr 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 Ala Phe Asn Gln Ala Lys Leu Asn Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Val Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu
690 695 700

Claims (31)

1. A method of delivering a transgene to an ocular tissue cell, the method comprising contacting the cell with a rAAV vector comprising a transgene encoding an ocular disease therapeutic operably linked to one or more regulatory elements that promote expression of the ocular disease therapeutic in the ocular tissue cell, wherein the rAAV has the following capsids: AAV1 (SEQ ID NO: 59); AAV2 (SEQ D NO: 60); AAV3 SEQ ID NO:61 A) is provided; AAV3B (SEQ ID NO: 74); AAV4 (SEQ ID NO: 62); AAV5 (SEQ ID NO: 63); AAV6 (SEQ ID NO: 64); AAV7 (SEQ ID NO: 65); AAV8 (SEQ ID NO: 66); AAV9 (SEQ ID NO: 67); AAV9e (SEQ ID NO: 68); AAVrh.10 (SEQ ID NO: 69); AAVrh.20 (SEQ ID NO: 70); AAVhu.37 (SEQ ID NO: 71); AAVrh39 (SEQ ID NO: 73); AAV rh73 (SEQ ID NO: 75); AAVrh.74 (SEQ ID NO:72 or SEQ ID NO: 96); AAVhu.51 (SEQ ID NO: 76); AAVhu.21 (SEQ ID NO: 77); AAVhu.12 (SEQ ID NO: 78); AAVhu.26 (SEQ ID NO: 79); AAVrh.24 (SEQ ID NO: 87); AAVhu.38 (SEQ ID NO: 88); AAVrh.72 (SEQ ID NO: 89); AAVhu.56 (SEQ ID NO: 86); AAVcy.5 (SEQ ID NO: 90); AAVcy.6 (SEQ ID NO: 91); AAVrh.46 (SEQ ID NO: 92); AAVrh.13 (SEQ ID NO: 85); AAVrh.64.R1 (SEQ ID NO: 107); AAV9.S454-TFR3 (SEQ D NO: 42); AAV8.BBB (SEQ ID NO: 26); AAV8.BBB. LD (SEQ D NO: 27); AAV8.Y703F (Y703F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering); AAV9.Y443F (Y443F substitution in amino acid sequence SEQ ID NO:67, see FIG. 7 for numbering); or AAV9.Y6F (Y6F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering).
2. A method of delivering a transgene to ocular tissue or ocular tissue target cells or cellular matrix thereof in a subject in need thereof, the method comprising administering to the subject a rAAV vector comprising a transgene encoding an ocular disease therapeutic operably linked to one or more regulatory elements that promote expression of the ocular disease therapeutic in the ocular tissue, wherein the rAAV has capsid AAV1 (SEQ ID NO: 59); AAV2 (SEQ ID NO: 60); AAV3 SEQ ID NO:61 A) is provided; AAV3B (SEQ ID NO: 74); AAV4 (SEQ ID NO: 62); AAV5 (SEQ ID NO: 63); AAV6 (SEQ ID NO: 64); AAV7 (SEQ ID NO: 65); AAV8 (SEQ ID NO: 66); AAV9 (SEQ ID NO: 67); AAV9e (SEQ ID NO: 68); AAVrh.10 (SEQ ID NO: 69); AAVrh.20 (SEQ ID NO: 70); AAVhu.37 (SEQ ID NO: 71); AAVrh39 (SEQ ID NO: 73); AAVrh73 (SEQ ID NO: 75); AAVrh.74 (SEQ ID NO:72 or SEQ ID NO: 96); AAVhu.51 (SEQ ID NO: 76); AAVhu.21 (SEQ ID NO: 77); AAVhu.12 (SEQ ID NO: 78); AAVhu.26 (SEQ ID NO: 79); AAVrh.24 (SEQ ID NO: 87); AAVhu.38 (SEQ ID NO: 88); AAVrh.72 (SEQ ID NO: 89); AAVhu.56 (SEQ ID NO: 86); AAVcy.5 (SEQ ID NO: 90); AAVcy.6 (SEQ ID NO: 91); AAVrh.46 (SEQ ID NO: 92); AAVrh.13 (SEQ ID NO: 85); AAVrh.64.R1 (SEQ ID NO: 107); AAV9.S454-TFR3 (SEQ ID NO: 42); AAV8.BBB (SEQ ID NO: 26); AAV8.BBB. LD (SEQ ID NO: 27); AAV8.Y703F (Y703F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering); AAV9.Y443F (Y443F substitution in amino acid sequence SEQ ID NO:67, see FIG. 7 for numbering); or AAV9.Y6F (Y6F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering).
3. The method of claim 1 or 2, wherein the capsid is an AAV3B serotype, an aavrh.73 serotype, an aav.hu.26 serotype, an aavhu.51, an AAVrh64R1 serotype, or an aav9.s454.tfr3 capsid.
4. The method of any one of claims 1 to 3, wherein the ocular tissue or ocular tissue target cell is a corneal tissue or cell, an iris tissue or cell, a ciliary body tissue or cell, a schlemm's canal tissue or cell, a trabecular meshwork tissue or cell, a retinal tissue or cell, an RPE-choroidal tissue or cell, or an optic nerve cell.
5. The method of claim 4, wherein the ocular tissue or ocular tissue target cell is a retinal tissue or cell or an RPE-choroidal tissue or cell.
6. The method of claim 5, wherein the capsid is an AAV3B or aavrh.73 capsid.
7. The method of claims 1-6, wherein the ocular disease is non-infectious uveitis.
8. The method of claims 1-4, wherein the ocular disease is glaucoma.
9. The method of claim 8, wherein the rAAV targets the trabecular meshwork and/or the schlemm's canal.
10. The method of claim 8 or 9, wherein the capsid is an AAV1 capsid, AAV2, AAV7 capsid, AAV3B capsid, aav.hu.26 capsid, or AAV9.s454-TFR3 capsid.
11. The method of any one of claims 1-10, wherein the rAAV vector is administered intravitreally, suprachoroidal or intracamerally.
12. The method of any one of claims 1-10, wherein the rAAV vector is administered systemically.
13. The method of any one of claims 1-12, wherein the rAAV vector provided is administered in the absence of hyaluronic acid.
14. A pharmaceutical composition for delivering a transgene to an ocular tissue cell, the composition comprising a rAAV vector comprising a transgene encoding an ocular disease therapeutic operably linked to one or more regulatory elements that promote expression of the ocular disease therapeutic in the ocular tissue cell, wherein the rAAV has the following capsids: AAV1 (SEQ ID NO: 59); AAV2 (SEQ ID NO: 60); AAV3 SEQ ID NO:61 A) is provided; AAV3B (SEQ ID NO: 74); AAV4 (SEQ ID NO: 62); AAV5 (SEQ ID NO: 63); AAV6 (SEQ ID NO: 64); AAV7 (SEQ ID NO: 65); AAV8 (SEQ ID NO: 66); AAV9 (SEQ ID NO: 67); AAV9e (SEQ ID NO: 68); AAVrh.10 (SEQ ID NO: 69); AAVrh.20 (SEQ ID NO: 70); AAVhu.37 (SEQ ID NO: 71); AAVrh39 (SEQ ID NO: 73); AAVrh73 (SEQ ID NO: 75); AAVrh.74 (SEQ ID NO:72 or SEQ ID NO: 96); AAVhu.51 (SEQ ID NO: 76); AAVhu.21 (SEQ ID NO: 77); AAVhu.12 (SEQ ID NO: 78); AAVhu.26 (SEQ ID NO: 79); AAVrh.24 (SEQ ID NO: 87); AAVhu.38 (SEQ ID NO: 88); AAVrh.72 (SEQ ID NO: 89); AAVhu.56 (SEQ ID NO: 86); AAVcy.5 (SEQ ID NO: 90); AAVcy.6 (SEQ ID NO: 91); AAVrh.46 (SEQ ID NO: 92); AAVrh.13 (SEQ ID NO: 85); AAVrh.64.R1 (SEQ ID NO: 107); AAV9.S454-TFR3 (SEQ ID NO: 42); AAV8.BBB (SEQ ID NO: 26); AAV8.BBB. LD (SEQ ID NO: 27); AAV8.Y703F (Y703F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering); AAV9.Y443F (Y443F substitution in amino acid sequence SEQ ID NO:67, see FIG. 7 for numbering); or AAV9.Y6F (Y6F substitution in amino acid sequence SEQ ID NO:66, see FIG. 7 for numbering).
15. The pharmaceutical composition of claim 14, wherein the capsid is an AAV3B serotype, an aavrh.73 serotype, an aav.hu.26 serotype, an aavhu.51, an AAVrh64R1 serotype, or an aav9.s454.tfr3 capsid.
16. The pharmaceutical composition of claim 14 or 15, wherein the ocular tissue or ocular tissue target cell is a corneal tissue or cell, an iris tissue or cell, a ciliary body tissue or cell, schlemm's canal tissue or cell, a trabecular meshwork tissue or cell, a retinal tissue or cell, an RPE-choroidal tissue or cell, or an optic nerve cell.
17. The pharmaceutical composition of claim 16, wherein the ocular tissue or ocular tissue target cell is a retinal tissue or cell or RPE-choroidal tissue or cell.
18. The pharmaceutical composition of claim 17, wherein the capsid is an AAV3B or aavrh.73 capsid.
19. The pharmaceutical composition of claims 14-18, wherein the ocular disease is non-infectious uveitis.
20. The pharmaceutical composition of claims 14-18, wherein the ocular disease is glaucoma.
21. The pharmaceutical composition of claim 20, wherein the rAAV targets the trabecular meshwork and/or the schlemm's canal.
22. The pharmaceutical composition of claim 20 or 21, wherein the capsid is an AAV3B serotype, an aavrh.73 serotype, an aav.hu.26 serotype, an aavhu.51, an AAVrh64R1 serotype, or an aav9.s454.tfr3 capsid.
23. The pharmaceutical composition of any one of claims 14-22, wherein the rAAV vector is administered intravitreally, suprachoroidal space, or intracamerally.
24. The method of any one of claims 14-22, wherein the rAAV vector is administered systemically.
25. The method of claims 14-24, wherein the rAAV vector provided is administered in the absence of hyaluronic acid.
26. The method or pharmaceutical composition of any one of claims 1-25, wherein the rAAV exhibits at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater transduction in a target tissue as compared to a reference AAV capsid.
27. The method or pharmaceutical composition of any one of claims 1 to 26, wherein the abundance of a transgenic RNA in the target tissue is 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the abundance of a transgenic RNA from the reference AAV capsid.
28. The method or pharmaceutical composition of claim 26 or 27, wherein the reference AAV capsid is AAV2, AAV8, or AAV9.
29. A method of treating an ocular disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 14-22 or 25.
30. A nucleic acid comprising a nucleotide sequence encoding the rAAV capsid protein of any one of the preceding claims, or encoding an amino acid sequence sharing at least 80% identity therewith.
31. A packaging cell capable of expressing the nucleic acid of claim 30 to produce an AAV vector comprising a capsid protein encoded by the nucleotide sequence.
CN202180067084.9A 2020-10-07 2021-10-07 Adeno-associated virus for ocular delivery of gene therapy Pending CN116568815A (en)

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US63/088,982 2020-10-07
US202163187197P 2021-05-11 2021-05-11
US63/187,197 2021-05-11
PCT/US2021/054008 WO2022076711A2 (en) 2020-10-07 2021-10-07 Adeno-associated viruses for ocular delivery of gene therapy

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