CN1832755A - Uses of interferons for the treatment of severe acute respiratory syndrome and other viral infections - Google Patents

Abstract

This invention provides a method of treating a subject afflicted with severe acute respiratory syndrome (SARS), comprising administering to the subject an amount of an interferon polypeptide effective to reduce the concentration of SARS-associated coronavirus particles in the subject, thereby treating the subject. This invention also provides methods of treating a subject infected with certain viruses and methods of reducing a subject's risk of viral infection, comprising administering to the subject an interferon polypeptide. This invention further provides a method of treating a subject afflicted with influenza or reducing a subject's risk of influenza virus infection, comprising administering to the subject an interferon polypeptide.

Description

Use interferon therapy severe acute respiratory syndrome and other viral infection

The application requires the priority of the U.S. Provisional Application submitted on May 23rd, 2003 number 60/473,134, and its content is incorporated among the application as a reference at this.

Mentioned many lists of references in the application in full, these lists of references its separately content incorporate among the application as a reference at this.

Background of invention

Well-known interferon (IFN) be one by multiple eukaryotic cell (Zoon KC:Human Interferons:Structure and Function.p.1-12. is in Interferon 8.AcademicPress being exposed to the cytokine family that secretion obtains under the various stimulations, London, 1987; Walter etc., Cancer Biotherm Radiopharm1998 June; 13 (3): 143-54; Pestka, S., Biopolymers 2000; 55 (4): 254-287; Pestka, S., Methods in Enzymology, 78,1981; Pestka, S., Methods in Enzymology, 79,1981; Pestka, S., Methods in Enzymology, 119,1986).According to the chemistry and the biological nature of interferon it is classified.Interferon is divided into two classes, is called I type interferon and II type interferon (Pestka, S.; Langer; J.A.; Zoon, K.C.; Samuel, C.E.AnnRev Biochem 1987,56,727-777; Pestka, S., Biopolymers 2000; 55 (4): 254-287).Also known IFN-γ as immune interferon is unique II type interferon, and I type human interferon is then by five interferoids: IFN-α, IFN-β, IFN-ω, IFN-κ and IFN-τ form.A kind of people IFN-β and a kind of people IFN-ω are only arranged, but IFN-α family exists multiple.Only in ungulate, find IFN-τ; There is not people IFN-τ.IFN has antiviral, immunomodulating and antiproliferative activity.The clinical practice potentiality of interferon had been recognized already.

Isaacs and Lindenmann have found interferon (Proc.Royal Soc.London, Ser B 147,258,1957).Research to human leukocyte interferon purification and evaluation had obtained already from normal or leukemia (chronic lymphocytic leukemia or " CML ") the leukocytic homotype LeIF of donor prepared product (now being called IFN-α s) (Pestka, S., Biopolymers 2000; 55 (4): 254-287; Rubinstein, M.; Levy, W.P.; Moschera, J.A.; Lai, C.-Y.; Hershberg, R.D.; Bartlett, R.T.; Pestka, S.Arch Biochem Biophys 1981,210,307-318).Homotype fiblaferon (now being called IFN-β) is purification homogeneous (Friesen, H.-J. also; Stein, S.; Evinger, M.; Familletti, P.C.; Moschera, J.; Meienhofer, J.; Shively, J.; Pes tka, S.Arch Biochem Biophys1981,206,432-450).These interferon are to have the protein family that can effectively give its target cell antiviral state feature.In addition, interferon propagation capable of inhibiting cell, regulate immunne response and change protein expression.These characteristic prompting LeIFs can be used as therapeutic agent clinically and are used for the treatment of viral infection and malignant tumor.

In the past few decades, produce, evaluation, purification and clone obtain many humans and animals interferon.Some interferon prepared products have been used for clinical trial with the form of rough and purification.Cloned already and expressed and obtained several reorganization IFN-α.Then by the distinct methods purifying protein and be formulated as multiple dosage form and be used for clinical practice.The a plurality of administrative organizations in the whole world approval of the interferon of most of clinical practices, it is the mixture or the single kind of human alpha interferon (Hu-IFN-α).In some countries, Hu-IFN-β and γ also approved are used for clinical trial, and also ratify to be used for the treatment of application in some cases.The main argument of supporting these interferon clinical practices is that they are the natural molecule that normal individual produced.In fact, this concrete argument is, the prepared interferon of promising clinical practice be all its product natural or reorganization produces, represented the spontaneous interferon of normal person.This is correct for most of interferon and specific somatomedin, lymphokine, cytokine, hormone, thrombin and other albumen that has prepared.

Summary of the invention

The invention provides the nucleic acid of the polynucleotide that comprise the plain polypeptide at least a portion of coded interference, described interferon polypeptides comprises and is shown in SEQ ID NO:2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82,84,86 aminoacid sequence or its fragment one of at least.Therefore, an aspect of of the present present invention provides polynucleotide, described polynucleotide comprise be selected from by: (a) coding comprises the nucleotide sequence of the interferon polypeptides of the aminoacid sequence during these SEQ ID NOs are one of at least; (b) coding is shown in the nucleotide sequence of the biological active fragment of these SEQ ID NOs polypeptide one of at least; (c) with above-mentioned (a) or the nucleotide sequence of the group that one of at least complementary nucleotide sequence of any nucleotide sequence is formed (b).Other embodiments of the present invention comprise nucleic acid, described nucleic acid comprises and has with above-mentioned (a) and (b) or arbitrary nucleotide sequence at least 95% homogeneity (c), more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably polynucleotide of the nucleotide sequence of at least 99.25% homogeneity; Or under stringent hybridization condition the polynucleotide of multi-nucleotide hybrid with above-mentioned (a) and (b) or (c), and preferably with the polynucleotide that are shown in SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,61,63,65,67,69,71,73,75,77,79,81,83 or 85 multi-nucleotide hybrid one of at least.Described fragment comprises the biological active fragment of interferon polypeptides.SEQ ID NOs.1-26 is the feline interferon sequence.SEQ ID NOs.27-36 is a macaque interferon sequence.SEQ ID NOs.37-86 is the human interferon sequence.

" stringent hybridization condition " is defined as and comprises strict wash conditions, and those skilled in the art should be able to determine high like this condition, for example less salt and high temperature.The example of less salt is 0.1 X SSC.Pyritous example is 65-68 ℃.An embodiment is included under 42 ℃ and is comprising: be incubated overnight in the solution of shearing salmon sperm DNA of 50% Methanamide, 5 x SSC (150mM NaCl, 15mM trisodium citrate), 50mM sodium phosphate (pH7.6), 5 x DenhardtShi solution, 10% dextran sulfate and 20 μ g/ml degeneration, then washing filter paper under about 65 ℃ in 0.1 x SSC.When this uses, " high strict " also refers to following condition: (i) reach washing at high temperature with low ionic strength after hybridization, for example, washing in 0.1 x SSC and 0.1% (w/v) SDS under 50 ℃; (ii) in crossover process, use such condition so that hybridization temperature hangs down 25 ℃ for the double-stranded melting temperature than the polynucleotide of hybridizing, for example hybridizing among the smart DNA of Pacific herring in 1.5xSSPE, 10% (w/v) polyethylene glycol 6000,7% (w/v) SDS, 0.25mg/ml fracture under 65 ℃; Or (iii) for example, under 70 ℃,, hybridize in pH 7.2,5mM EDTA, 7% (w/v) SDS (28) and 0.5% (w/v) bovine lacto transfer technique optimizer at the 0.5M sodium phosphate; Or (iv) in crossover process, use denaturant such as Methanamide, for example, use 50% (v/v) Methanamide, 5 x SSC, 50mM sodium phosphate (pH 6.5) and 5 x DenhardtShi solution down at 42 ℃; Or (v) for example, at 42 ℃ of salmon sperm DNA (50 μ g/ml) and 10% dextran sulfates that use 50% (v/v) Methanamide, 5 x SSC, 50mM sodium phosphate (pH 6.8), 0.1% (w/v) tetrasodium pyrophosphate, 5 x DenhardtShi solution, supersound process down.

With regard to polypeptide, peptide and proteic fragment, they can be biological active fragments, and the length of any total length less than sequence described in the sequence identifier that provides at this can be provided.In one embodiment, described fragment length is at least 10 aminoacid.In another embodiment, described fragment length is at least 20 aminoacid.In other embodiments, described fragment length can be at least 30,40,50,60,70,80,90 or 100 aminoacid.In other embodiment, described fragment length can be at least 110,120,130,140,150,160 or 170 aminoacid.

With regard to nucleic acid fragment, they comprise and can be used as at those of the diagnostic probe of this discussion and primer.Such sequence can be to be used for those of specific recognition interferon nucleotide sequence described herein.And they can have any length.For example, they comprise that length is at least about 15 nucleotide and more preferably at least about 20 nucleotide, still more preferably at least about 30 nucleotide with also more preferably at least about those of 40 nucleotide.Certainly, be that the big fragment of 50-300 nucleotide also can be used such as those length, according to content of the present invention, be corresponding to the nucleotide sequence of the SEQ ID NOs that is provided at this shown in one of at least one of at least in as non-all then most fragment.With regard to length is the fragment of at least 20 nucleotide, for example, means from the fragment that comprise 20 or more a plurality of continuous bases of the nucleotide sequence of the SEQ ID NOs that is provided at this shown in one of at least in one of at least.Length is the fragment of 50-300 nucleotide, comprises that length for example is those of about 50,60,70,80,90 or 100 bases.They can comprise that also length is the fragment of about 110,120,130,140,150,160,170,180,190 or 200 bases.They also can comprise that length is the fragment of about 210,220,230,240,250,260,270,280,290 or 300 bases.

With the polynucleotide of " part " of polynucleotide hybridization comprise with mentioned polynucleotide at least about 15 nucleotide, and more preferably at least about 20 nucleotide, still more preferably at least about the polynucleotide (DNA or RNA) of 30 nucleotide and the hybridization of also more preferably about 30-70 nucleotide, be included in the polynucleotide of any length between the mentioned polynucleotide two ends (as 50 bases).As discussed above, they are used as diagnostic probe and primer, and more detailed description is as follows.

On the other hand, the invention provides the nucleic acid of the polynucleotide that comprise coding feline interferon polypeptide at least a portion, described polypeptide comprises aminoacid sequence or its fragment shown in SEQ ID NO:2,4,6,8,10,12,14,16,18,20,22,24,26 one of at least.Therefore, an aspect of of the present present invention provide comprise be selected from by: (a) coding comprises the nucleotide sequence of the feline interferon polypeptide of the aminoacid sequence during these SEQ ID NOs are one of at least; (b) coding is shown in the nucleotide sequence of the biological active fragment of these SEQ ID NOs polypeptide one of at least; (c) with above-mentioned (a) or the polynucleotide of the nucleotide sequence of the group that one of at least complementary nucleotide sequence of all nucleotide sequences is formed (b).Other embodiments of the present invention comprise nucleic acid, described nucleic acid comprises and has and arbitrary nucleotide sequence at least 95% homogeneity that is described in this, more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably polynucleotide of the nucleotide sequence of at least 99.25% homogeneity; Or under stringent hybridization condition be described in the polynucleotide of this multi-nucleotide hybrid, and preferably with the polynucleotide that are shown in SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23 or 25 multi-nucleotide hybrid one of at least.

The present invention further provides the nucleic acid of the polynucleotide that comprise coding macaque interferon polypeptides at least a portion, described polypeptide comprises aminoacid sequence or its fragment shown in SEQ ID NO:28,30,32,34,36 one of at least.Therefore, an aspect of of the present present invention provide comprise be selected from by: (a) coding comprises the nucleotide sequence of the macaque interferon polypeptides of the aminoacid sequence during these SEQ ID NOs are one of at least; (b) coding is shown in the nucleotide sequence of the biological active fragment of these SEQ ID NOs polypeptide one of at least; (c) with above-mentioned (a) or the polynucleotide of the nucleotide sequence of the group that one of at least complementary nucleotide sequence of all nucleotide sequences is formed (b).Other embodiments of the present invention comprise nucleic acid, described nucleic acid comprises and has and arbitrary nucleotide sequence at least 95% homogeneity that is described in this, more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably polynucleotide of the nucleotide sequence of at least 99.25% homogeneity; Or under stringent hybridization condition the polynucleotide of multi-nucleotide hybrid with above-mentioned (a) and (b) or (c), and preferably with the polynucleotide that are shown in SEQ ID NO:27,29,31,33 or 35 multi-nucleotide hybrid one of at least.

The present invention also provides the nucleic acid of the polynucleotide that comprise coding human interferon polypeptide at least a portion, and described polypeptide comprises aminoacid sequence or its fragment shown in SEQ ID NO:38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82,84,86 one of at least.Therefore, an aspect of of the present present invention provide comprise be selected from by: (a) coding comprises the nucleotide sequence of the human interferon polypeptide of the aminoacid sequence during these SEQ ID NOs are one of at least; (b) coding is shown in the nucleotide sequence of the biological active fragment of these SEQ ID NOs polypeptide one of at least; (c) with above-mentioned (a) or (b) all nucleotide sequences one of at least the group formed of complementary nucleotide sequence nucleotide sequence separate polynucleotide.Other embodiments of the present invention comprise isolating nucleic acid, described nucleic acid comprises and has and arbitrary nucleotide sequence at least 95% homogeneity that is described in this, more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably polynucleotide of the nucleotide sequence of at least 99.25% homogeneity; Or under stringent hybridization condition the polynucleotide of multi-nucleotide hybrid with above-mentioned (a) and (b) or (c), and preferably with the polynucleotide that are shown in SEQ ID NO:37,39,41,43,45,47,49,51,53,55,57,59,61,63,65,67,69,71,73,75,77,79,81,83 or 85 multi-nucleotide hybrid one of at least.

On the other hand, the nucleic acid of the present invention of the plain polypeptide of arbitrary coded interference those of complete amino acid sequence of polypeptide that can include, but not limited to encode in itself; And for the coded sequence of complete polypeptide and appended sequence, those of the additional secretion targeting sequencing of for example encoding, for example before albumen, proteinogen or preproprotein sequence.

The nucleic acid that is described in this that has following additional non-coding sequence simultaneously also is provided, described additional non-coding sequence comprises, for example, but be not limited to intron and noncoding 5 ' and 3 ' sequence, for example transcribe, mRNA processing, comprise montage and polyadenylation signal, for example work in the ribosome combination of mRNA and the stability transcribe, non-translated sequence; And additional coded sequence, its additional aminoacid of encoding for example provides those of additional function.

Therefore, the sequence of this polypeptide of encoding can merge labelled sequence, and for example coding is convenient to the sequence of the peptide of fused polypeptide purification.In the present invention's some embodiment preferred aspect this, marker amino acid sequence is six histidine peptides, for example pQE carrier (QIAGEN, Inc., 9259EtonAvenue, Chatsworth, Calif.91311) labelling that provides in, wherein many labellings can be bought acquisition.For instance, as described six histidine such as Gentz for the purification of fusion rotein provide convenience (Gentz etc. (1989) Proc.Natl.Acad.Sci.USA86:821-824)." HA " labelling is the peptide that another kind is used for purification, its corresponding to from the epi-position of influenza hemagglutinin protein (Wilson etc. (1984) Cell 37:767).Other examples that merge labellings comprise as follows: (1) MBP labelling is that (carrier is available from Roche for the part of maltose-binding protein ^TM(name of carrier example: pIVEX MBP), New EnglandBiological (carrier example name: pMAL-p2X); (2) HA labelling, be human influenza virus's hemagglutinin a part (carrier available from RocheJ (carrier example name: pIVEX HA-tag), BD Biosciences (pCMV-HA); (3) FLAG is that special eight amino acid epi-position (name from Sigma Chemical Co.J carrier example: gWiz/GFP) by carrier; (4) CBP labelling is that (carrier is available from StratageneJ: carrier example name: pDual) for the part of caldesmon; (5) GFP is that (carrier is available from StratageneJ: carrier example name: pDual) for the part of green fluorescent protein.Other are used to create the epitope tag commonly used of fusion rotein: c-myc, GST, AU1, AU5, DDDDK, E epi-position, E2 labelling, Glu-Glu, S1, KT-3, T7 epitope tag, V5 epitope tag, VSV-G, BFP, CFY, YFP.As discussed below, other such fusion rotein are included in N-or C-end and merge interferon to Fc.

The present invention also provides the recombinant vector that comprises nucleic acid of the present invention, and the host cell that comprises this recombinant vector, and prepares the method for above-mentioned carrier and host cell and use them to produce the method for interferon polypeptides or peptide by recombinant technique.

The present invention further provides a kind of interferon polypeptides, comprised and be selected from: the aminoacid sequence that (a) is shown in the interferon polypeptides of SEQ IDNO:2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82,84 or 86 acid sequence one of at least; (b) be shown in the aminoacid sequence of aminoacid sequence of the biological active fragment of these SEQ ID NOs polypeptide one of at least.The present invention also comprises those polypeptides at least 95% homogeneity that has and be described in this, more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably polypeptide of the aminoacid sequence of at least 99.25% homogeneity.Those at least 95% similaritys that have and be described in this are also provided, more preferably at least 96% similarity, more preferably 97% similarity also, even more preferably at least 98% similarity, and the more preferably polypeptide of the aminoacid sequence of at least 99.25% similarity.The polypeptide of aminoacid sequence that has with those at least 95%, 96%, 97%, 98% or 99.25% homologys that are described in this also is provided.The polynucleotide of coding aforementioned polypeptides also are provided.

These aspect other embodiments of the present invention relate to the peptide or the polypeptide of the aminoacid sequence of epi-position carrying (epitope-bearing) part that comprises the interferon polypeptides with the aminoacid sequence that is described in this.The peptide or the polypeptide of aminoacid sequence with epi-position bearing part of interferon polypeptides of the present invention comprises having at least 6 or 7, preferably at least 9, more preferably at least about the part of 30 aminoacid, also be included among the present invention although reach and comprise the epi-position carrying polypeptide of any length of the complete amino acid sequence of the invention described above polypeptide to about 50 amino acid whose such peptides.

In another embodiment, the invention provides a species specificity in conjunction with antibody with the interferon polypeptides that is described in this aminoacid sequence.Above-mentioned antibody can be monoclonal antibody.It also can be Fab, for example Fab or Fab ' fragment.Described antibody can be chimeric, humanization or total length people antibody.Described antibody can be feline antibody or macaque antibody.The present invention further provides and be used to separate specificity in conjunction with having the method for the antibody of the interferon polypeptides that is described in this aminoacid sequence.Above-mentioned antibody as described below is useful on therapeutics.

On the other hand, the present invention further provides a kind of feline interferon polypeptide, comprised and be selected from: the aminoacid sequence that (a) comprises the interferon polypeptides that is shown in SEQ ID NO:2,4,6,8,10,12,14,16,18,20,22,24 or 26 aminoacid sequence one of at least; (b) be shown in the aminoacid sequence of aminoacid sequence of the biological active fragment of these SEQ ID NOs polypeptide one of at least.The present invention also comprises those polypeptides at least 95% homogeneity that has and be described in this, more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably polypeptide of the aminoacid sequence of at least 99.25% homogeneity.Those at least 95% similaritys that have and be described in this are also provided, more preferably at least 96% similarity, more preferably 97% similarity also, even more preferably at least 98% similarity, and the more preferably polypeptide of the aminoacid sequence of at least 99.25% similarity.The polypeptide of aminoacid sequence that has with those at least 95%, 96%, 97%, 98% or 99.25% homologys that are described in this also is provided.The polynucleotide of coding aforementioned polypeptides also are provided.

On the other hand, the present invention further provides a kind of macaque interferon polypeptides, comprised and be selected from: the aminoacid sequence that (a) comprises the interferon polypeptides that is shown in SEQ ID NO:28,30,32,34 or 36 acid sequence one of at least; (b) be shown in the aminoacid sequence of aminoacid sequence of the biological active fragment of these SEQ ID NOs polypeptide one of at least.The present invention also comprises those polypeptides at least 95% homogeneity that has and be described in this, more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably polypeptide of the aminoacid sequence of at least 99.25% homogeneity.Those at least 95% similaritys that have and be described in this are also provided, more preferably at least 96% similarity, more preferably 97% similarity also, even more preferably at least 98% similarity, and the more preferably polypeptide of the aminoacid sequence of at least 99.25% similarity.The polypeptide of aminoacid sequence that has with those at least 95%, 96%, 97%, 98% or 99.25% homologys that are described in this also is provided.The polynucleotide of coding aforementioned polypeptides also are provided.

On the other hand, the present invention further provides a kind of human interferon polypeptide, comprised and be selected from: the aminoacid sequence that (a) comprises the interferon polypeptides that is shown in SEQ ID NO:38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82,84 or 86 acid sequence one of at least; (b) aminoacid sequence of the aminoacid sequence of the polypeptide that is shown in these SEQ ID NOs biological active fragment one of at least.The present invention also comprises those polypeptides at least 95% homogeneity that has and be described in this, more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably polypeptide of the aminoacid sequence of at least 99.25% homogeneity.Those at least 95% similaritys that have and be described in this are also provided, more preferably at least 96% similarity, more preferably 97% similarity also, even more preferably at least 98% similarity, and the more preferably polypeptide of the aminoacid sequence of at least 99.25% similarity.The polypeptide of aminoacid sequence that has with those at least 95%, 96%, 97%, 98% or 99.25% homologys that are described in this also is provided.The polynucleotide of coding aforementioned polypeptides also are provided.

On the other hand, the present invention further provides comprise arbitrary be described in this be used for external, exsomatize and body in give cell or give the interferon polynucleotide of multicellular organism or the compositions of interferon polypeptides.In the present invention aspect this in certain particularly preferred embodiment, described compositions comprises and is used for expressing interferon polynucleotide in order to the interferon polypeptides of disease treatment at host living beings.Particularly preferably be in this and in people patient, express to be used for the treatment of the malfunction relevant with endogenous interferon loss or shortage.

The present invention also provides pharmaceutical composition that comprises interferon polypeptides and the method for using it, for example, use is in order to the relevant disease of treatment or epidemic prevention system, for example viral infection, parasitic infection, bacterial infection, cancer, autoimmune disease, multiple sclerosis, lymphoma and allergy.Also provide treatment to need the method for interferon polypeptides individuality.In certain embodiment preferred, the pharmaceutical composition that is tried is a kind of non-human animal that is used to give, the veterinary composition of preferred non-human primate.The exemplary disease of available interference extract for treating includes but not limited to viral infection.Unrestricted, interferon therapy can be used for treating will benefit from the disease that suppresses the interferon-sensitive virus replication.The viral infection that can treat according to the present invention comprises severe acute respiratory syndrome (SARS), smallpox virus, vaccinia virus, monkey pox virus, west Nile virus, vaccinia virus, coronavirus, hepatitis A, hepatitis B, hepatitis C, other non-first type/non-hepatitis B, herpesvirus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex, human herpes virus type 6 (HHV-6), papillomavirus, poxvirus, pico+ribonucleic acid+virus, adenovirus, rhinovirus, people T has a liking for lymphocyte virus-1 type and 2 types (HTLV-1/-2), Human reoviruslike agent, rabies, retrovirus comprises HIV (human immunodeficiency virus) (HIV), encephalitis, arteritis virus, filamentous form virus, reovirus, papovavirus, Hepadnavirus, Astrovirus, Coxsackie virus, orthomyxoviridae family (influenza virus), Paramyxoviridae, echovirus, enterovirus and respiratory syncytial virus.Interested especially is the treatment of SARS, it is believed that to result from the novel coronavirus of the relevant coronavirus of SARS by name by SARS (April 19,2003 for Peiris etc., Lancet; 361 (9366): 1319-25; Ksiazek etc., New England Journal ofMedicine, April 30,2003, PubMed ID#12690092; Drosten etc., NewEngland Journal of Medicine, April 10,2003, PubMedID#12690091; Marra etc., Science, May 1,2003 publishes PubMedID#12730501.The PubMed paper can exist by ID# Http:// www.ncbi.nlm. Nih.gov/entrez/query.fcgi CMD=Search﹠amp; DB=PubMed) on conduct interviews.

Method of the present invention also is used to alleviate various immunoreation.The viral caused viral infection that the interferon polypeptides that is described in this can be used for treating SARS and is described in this.These interferon polypeptides also can be used for preventing purpose, for example prevention infection or make the patient avoid having the symptom relevant with this infection.Benefit from above-mentioned preventative therapy patient and comprise those of infection risk with rising, for example be exposed to virus or already by virus institute's infection or be exposed to the patient of viral individuality.

In one embodiment, interferon can be used as antiviral agent.Clinically, interferon has been used for the treatment of acquired immunity disease, viral hepatitis (comprising chronic hepatitis B, hepatitis C, hepatitis D), papillomavirus, herpes, viral encephalitis and prevention rhinitis and respiratory tract infection.

In another embodiment, interferon can be used as antiparasitic.Interferon can be used for for example treating Cryptosporidium parvum (Cryptosporidium parvum) to be infected.Also in another embodiment, interferon can be used as antibacterial agent.Clinically, interferon had been used for the antibacterium treatment already.For example, interferon can be used for the phthisical treatment of multidrug resistant.

In another embodiment, interferon can be used as the part of immunization therapy scheme.Interferon of the present invention can be used for immunization therapy clinically or more precisely, for example, prevention stops the rejection of graft to the host, or reduces for example progress of arthritis, multiple sclerosis or diabetes of autoimmune disease.

In another embodiment, interferon can be used as the part of treatment allergy scheme.Also in another embodiment, interferon can be used as vaccine adjuvant.Under preventative or therapeutic vaccine inoculation, interferon can be used as adjuvant or co-adjuvant is replied with enhancing or immune stimulatory.

Except that being used for common treatment of animals, this concrete invention is particularly related to the purposes that interferon is used for the treatment of primate, as the part of scheme for animals.In one embodiment, described interferon is the macaque interferon.This concrete invention also is particularly related to the purposes that interferon is used for the treatment of cat, as the part of scheme for animals.In one embodiment, described interferon is a feline interferon.

In certain embodiments, interferon is used for the treatment of the cat of viral infection.What for example, feline immunodeficiency virus (FIV) infected needs Supporting Therapy to keep the cat of normal health.Interferon can be used as the part of the cat treatment of FIV infection.Similarly, interferon also can be used as the part of the cat treatment of feline leukaemia virus (FeLV) infection.Feline leukaemia virus (FeLV) is the keep a cat pathogen of topmost mortality infectious disease of current U.S. man.

Interferon can be used for treating feline panleukopenia virus.Be also referred to as the cat infectious enteritis, cat " distemper " and cat ataxia or incoordination disease, feline panleukopenia virus is a kind of cat disease viral disease of highly infective, be characterised in that it breaks out, heating, inappetence (anorexia), dehydration, depression, vomiting, circulation quantity of leucocyte reduce (leukopenia), and common high mortality.Intrauterine (in uterus) infects can cause miscarriage, stillbirth, neonatal death and cerebellar hypoplasia (underdevelopment of cerebellum), has been shown as the kitten incoordination (ataxia) of 2-3 week size.All members of cat family (cat family) are all easily infected by agranulocytosis virus of cats (FPV), as racoon, coatimundi and circle tail cat in the Procyoniclae section.

Interferon can be used for treating the cat that infection has feline infectious peritonitis.Interferon can be used to the treatment infection rabic cat.Instruct in the embodiment of cat nursing at other, interferon can be used to treat inflammatory air flue disease (IAD).Also in another embodiment, interferon can be used to treat Canis familiaris L. or other domestic pets (de Mari K, Maynard L, Eun HM, Lebreux B.VetRec. (2003) 152:105-8).Still in other embodiments, interferon section is used for treating farming animals.In another embodiment, interferon can be used to treat the people.The invention provides a kind of method of suffering from the severe acute respiratory syndrome patient for the treatment of, comprise giving an amount of interferon that the patient can effectively reduce SARS associated coronavirus granule density in its body, thus the treatment patient.

The invention provides a kind of treatment for being selected from: coronavirus, smallpox virus, vaccinia virus (cowpox wirus), monkey pox virus, west Nile virus, vaccinia virus (vacciniavirus), respiratory syncytial virus, rhinovirus, arteritis virus, filamentous form virus, pico+ribonucleic acid+virus, reovirus, retrovirus, papovavirus, herpesvirus, poxvirus, Hepadnavirus, Astrovirus, Coxsackie virus, Paramyxoviridae, orthomyxoviridae family, echovirus, enterovirus, Cardioviruses, togavirus, rhabdovirus, Bunyavirus, arenavirus, borna virus, adenovirus, the patient's of the viral infection of parvovirus and yellow fever virus method, comprise giving an amount of interferon polypeptides that the patient can effectively reduce virion concentration in its body, thus the treatment patient.

The present invention relates to any Therapeutic Method that is described in this; also relate to and be used to prevent the ill or infected method of patient; or the reduction patient is ill or the method for infected risk, or protects the patient to exempt to suffer from the disease/situation relevant with specific virus, or prevents that the patient has the symptom relevant with viral infection.For example, the above-mentioned method that is used for the treatment of the viral infection patient also can be used to prevent the patient by viral infection, or is used for reducing patient's viral infection risk.

The invention provides a kind of method of the patient's of reduction viral infection risk, comprise giving the patient interferon polypeptides.In one embodiment, this method comprises and prevents that the patient is by viral infection.In one embodiment, this method comprises and prevents that the patient has the symptom relevant with viral infection.In one embodiment, this method comprises that the protection patient exempts to suffer from the disease/situation relevant with specific virus.Can give this protective effect by stoping or alleviating by the order of severity that infects caused disease/situation.In another embodiment, described protective effect also can give for other patients by reducing transmission of infection, can be realized by the order of severity that infects caused disease/situation by alleviating in its body.In another embodiment, by making patient's cell become that susceptible reaches prevention of risk or reduction to infecting more not.The method and the embodiment that are described in this may not be mutual exclusive.Described viral infection includes but not limited to by coronavirus, smallpox virus, vaccinia virus, monkey pox virus, west Nile virus, vaccinia virus, respiratory syncytial virus, rhinovirus, arteritis virus, filamentous form virus, pico+ribonucleic acid+virus, reovirus, retrovirus, papovavirus, herpesvirus, poxvirus, Hepadnavirus, Astrovirus, Coxsackie virus, Paramyxoviridae, orthomyxoviridae family, echovirus, enterovirus, Cardioviruses, togavirus, rhabdovirus, Bunyavirus, arenavirus, borna virus, adenovirus, caused those infection of parvovirus and yellow fever virus.

The invention provides a kind of treatment and suffer from influenza (orthomyxovirus) patient's method, comprise and give an amount of interferon polypeptides that the patient can effectively reduce influenza virus particles concentration in its body, wherein said interferon polypeptides comprises with the SEQ ID NOs that is described in this having one of at least at least 95% homogeneity, more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably aminoacid sequence of at least 99.25% homogeneity, thereby treatment patient.

Interferon polypeptides referred in this.When for example in relating to the context that treats and/or prevents, mentioning, (Zoon KC:Human Interferons:Structure and Function.p.1-12. is in Interferon 8.Academic Press to include but not limited to IFN-α polypeptide, IFN-beta polypeptides, IFN-γ polypeptide and IFN-ω polypeptide, London, 1987; Walter etc., Cancer Biotherm Radiopharm 1998 June; 13 (3): 143-54; Pestka, S., Biopolymers 2000; 55 (4): 254-287; Biopolymers2000; 55 (4): 254-287; Pestka, S., Methods in Enzymology, 78,1981; Pestka, S., Methods in Enzymology, 79,1981; Pestka, S., Methods in Enzymology, 119,1986; Pestka, S., Langer; J.A., Zoon, K.C., Samuel, C.E.Ann Rev Biochem 1987,56,727-777).They also include but not limited to people IFN, Mus IFN, cat IFN and macaque IFN.

In an embodiment of the interferon polypeptides that is described in this, described interferon polypeptides comprises the NO:2 with SEQ ID, 4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82, one of 84 or 86 have at least 95% homogeneity, more preferably at least 96% homogeneity, more preferably at least 97% homogeneity also, even more preferably at least 98% homogeneity, and the more preferably aminoacid sequence of at least 99.25% homogeneity.More preferably at least 96% similarity, more preferably 97% similarity also, even more preferably at least 98% similarity, and the more preferably polypeptide of the aminoacid sequence of at least 99.25% similarity are also provided to have and above-mentioned those at least 95% similaritys.The polypeptide of aminoacid sequence that has with those at least 95%, 96%, 97%, 98% or 99.25% homologys that are described in this also is provided.

In an embodiment of the interferon polypeptides that is described in this, described interferon polypeptides comprises and being selected from: SEQ ID NO:2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82,84 and 86 aminoacid sequence.In an embodiment of the interferon polypeptides that is described in this, described interferon polypeptides is that nucleic acid is coded, and this nucleic acid comprises and being selected from: SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,61,63,65,67,69,71,73,75,77,79,81,83 and 85 nucleotide sequence.In an embodiment of the interferon polypeptides that is described in this, described interferon polypeptides is that nucleic acid is coded, and this nucleic acid is selected from comprising under high stringent condition: the nucleic acid hybridization of SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,61,63,65,67,69,71,73,75,77,79,81,83 and 85 sequence.In an embodiment of the interferon polypeptides that is described in this, described interferon polypeptides is that nucleic acid is coded, and this nucleic acid is selected from being complementary under high stringent condition: the nucleic acid hybridization of SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,61,63,65,67,69,71,73,75,77,79,81,83 and 85 sequence.

The invention provides the method that a kind of patient of prevention suffers from severe acute respiratory syndrome, comprise giving the patient interferon polypeptides.The invention provides the method that a kind of patient of reduction suffers from the severe acute respiratory syndrome risk, comprise giving the patient interferon polypeptides.

The present invention also provides a kind of prevention patient to suffer from and has been selected from: coronavirus, smallpox virus, vaccinia virus, monkey pox virus, west Nile virus, vaccinia virus, respiratory syncytial virus, rhinovirus, arteritis virus, filamentous form virus, pico+ribonucleic acid+virus, reovirus, retrovirus, papovavirus, herpesvirus, poxvirus, Hepadnavirus, Astrovirus, Coxsackie virus, Paramyxoviridae, orthomyxoviridae family, echovirus, enterovirus, Cardioviruses, togavirus, rhabdovirus, Bunyavirus, arenavirus, borna virus, adenovirus, syndromic method due to the virus of parvovirus and yellow fever virus comprises giving the patient an amount of interferon polypeptides.

The invention provides the method that a kind of patient of prevention suffers from influenza, comprise that giving the patient is described in this interferon polypeptides in right amount.The invention provides the method for a kind of patient of reduction, comprise that giving the patient is described in this interferon polypeptides in right amount for influenza institute infection risk.In being described in an embodiment of the method, described patient is human.Described patient includes but not limited to Canis familiaris L., cat, monkey and farming animals.

The invention provides the application that the interferon polypeptides that is described in this is used for any treatment that is described in this in preparation, prevents, prevents and reduce the medicine of risk method.

The invention provides a kind of drug packages, comprise Inteferon compositions and the instructions that is used for compositions is given the patient.This instructions can comprise writes and/or illustrated instructions.This instructions can be used for any treatment that is described in this, prevents, prevents and reduce the method for risk.

The present invention also relates to functional antagonist, be different from the wild type interferon as wherein one or more amino acid residues, it suppresses one or more biological activitys of wild type interferon.The unusual mistake that above-mentioned antagonist can be used to treat by endogenous interferon expressed or the caused disease of other activations.Described functional antagonist can be formulated as pharmaceutical preparation.

The present invention also provides a kind of screening technique that can strengthen or suppress the bioactive chemical compound of interferon polypeptides that is used to identify, it comprises and will contact under there is situation in interferon polypeptides with candidate compound by the enhanced receptor of interferon polypeptides, for example measure at candidate compound and interferon polypeptides and have antiviral activity under the situation, and should activity and the activity of standard level compare, described standard produces when contacting determined under not having the candidate compound situation between receptor and the interferon.In this was measured, overproof active increasing showed that this candidate compound is a kind of interferon activity agonist, reduced with respect to the activity of standard to show that then this chemical compound is a kind of interferon activity antagonist.

The present invention relates to a kind of method that is used for the treatment of the animal of the plain activity level of body internal interference that needs increase on the other hand, comprises giving above-mentioned animal a kind of of the present invention isolating interferon polypeptides for the treatment of effective dose or compositions of its agonist of comprising.

Another aspect of the invention is a kind of method that is used for the treatment of the animal of the plain activity level of body internal interference that needs reduce, and comprises giving above-mentioned animal a kind of compositions that comprises the interferon antagonist for the treatment of effective dose.Preferably supplying the antagonist of the present invention's usefulness is the interferon specific antibody.

Described dosage give to be the next day give but preferred Monday to twice.Dosage gave at least 24 weeks by injection usually.

Giving of dosage can be that intravenous, subcutaneous, intramuscular or any other acceptable general give method.Judgement according to the clinical nursing doctor, dosage and treatment usage should, certainly, depend on patient's age, sex and the medical history that to treat, neutrophil cell counting (as the order of severity of neutrophilic granulocyte minimizing), the order of severity of disease specific symptom and patient are to the toleration of treatment, and described toleration is confirmed by local toxicity and systemic side effects.During the initial screening of neutrophil cell, can determine dosage and frequency.

Also can use the Inteferon compositions that tried of the present invention to prepare the conventional medicine preparation.Said preparation comprises the interferon polypeptides and the pharmaceutically acceptable carrier for the treatment of effective dose.For example, adjuvant, diluent, antiseptic and/or solubilizing agent if desired, can be used in the present invention's practice.Comprise those the pharmaceutical composition of interferon of the present invention can comprise various buffer with certain limit pH and ionic strength (as, Tris-HCl, acetate, phosphate) diluent, carrier (as the human serum albumin), solubilizing agent (as, polyoxyethylene sorbitan or TWEEN ^TMPolysorbate) and antiseptic (as thimerosal, benzyl alcohol).Referring to, for example US 4,496, and 537.

The therapeutic dose for the treatment of the Inteferon compositions of above-mentioned disease depends on the interferon activity of compositions.It is the amount of the positive clinical response of a kind of appreciable impact effectively.With regard to treatment of viral infections, positive clinical response can by the minimizing of patient's body inner virus granule density or more commonly the alleviation by infection symptoms obtain indication.With regard to prophylactic treatment, positive clinical response can for example reduce by virus-free granule, patient's body inner virus granule density in patient's body or patient's body inner virus granule density maintains to be lower than and surpasses the concentration that above-mentioned patient then shows the threshold concentration of viral infection symptom.Prophylactic treatment used herein comprises makes the patient exempt to suffer from the disease that is caused by virus.

Though clinical dosage can cause side effect to a certain degree in some patient, for the mammal that comprises the people, maximal dose is to cause the maximum dose level of reluctant serious side effects clinically.For the object of the invention, above-mentioned serious side effects clinically is because serious influenza-like symptom, central nervous system depression, serious intestines and stomach disease, alopecia, serious pruritus or erythra and those side effect that need stop to treat.In fact white and/or erythrocyte and/or liver enzyme is unusual or also there is dose limit in anemia sample symptom.

Undoubtedly, interferon dosage can change slightly according to selected preparation.Generally speaking, however based on mammiferous disease, Inteferon compositions is to millions of approximately IU/m with about 100,000 ²The amount of every day gives.Above-mentioned listed scope is exemplary and those skilled in the art can determine the optimal dose of selected interferon based on clinical experience and therapeutic effect.

Pharmaceutical composition can solution, the form of suspension, tablet, capsule, lyophilized powder or the like prepares according to method well-known in the art.Also should be taken into account above-mentioned composition give should mainly pass through parenteral route, also can use per os or inhalation route although depend on technical staff's needs.

With regard to regard to the nucleic acid of DNA or RNA, term used herein " isolating " refers to divide the molecule of opening with other DNA or the RNA that are present in the macromole natural origin respectively.Isolating nucleic acid or peptide, polypeptide or the albumen that also refers to when preparing, to be substantially free of cellular material or culture medium or when chemically synthesizing, be substantially free of precursor or other chemicals of this term by recombinant DNA technology.In addition, " isolating nucleic acid " is intended to comprise not to be with the natural nucleic acid fragment that exists and can not find of pieces under native state.

A kind of method that preferably is used for measuring best global registration between enquirement sequence (query sequence) and the tested sequence (subject sequence), be also referred to as global sequence's comparison, can use and measure based on the FASTDB computer program of (Comp.App.Biosci., 6:237-245 (1990)) algorithms such as Brutlag.Term " sequence " comprises nucleotide and aminoacid sequence.In sequence alignment, enquirement and tested sequence all are nucleotide sequences or all are aminoacid sequences.The result of described global sequence comparison represents with homogeneity percent.The preferred parameter in order to calculate homogeneity percent that adopts in the FASTDB of DNA sequence retrieval is: matrix=Unitary, k-byte group (tuple)=4, mispairing point penalty=1, connect point penalty (JoiningPenalty)=30, randomization group length=0, threshold value=1, gap penalty=5, room size point penalty=0.05 and window size=500 or in the enquirement sequence length of nucleotide base, with littler being as the criterion.Being used to calculate the homogeneity of aminoacid comparison and the preferred parameter of similarity percent is: matrix=PAM 150, k-byte group=2, mispairing point penalty=1, connect point penalty=20, randomization group length=0, threshold value=1, gap penalty=5, room size point penalty=0.05 and window size=500 or in the enquirement sequence length of amino acid residue, with shorter being as the criterion.

Any albumen and/or nucleic acid sequence homology estimated in available multiple sequence comparison algorithm well known in the art and the program.Above-mentioned algorithm and program comprise, but never be limited to TBLASTN, BLASTP, FASTA, TFASTA and CLUSTALW (Pearson and Lipman, 1988, Proc.Natl.Acad.Sci.USA 85 (8): 2444-2448; Altschul etc., 1990, J.Mol.Biol.215 (3): 403-410; Thompson etc., 1994, Nucleic Acids Res.22 (2): 4673-4680; Higgins etc., 1996, MethodsEnzymol.266:383-402; Altschul etc., 1990, J.Mol.Biol.215 (3): 403-410; Altschul etc., 1993, Nature Genetics 3:266-272).

In an especially preferred embodiment, use the local comparison in basis well-known in the art research tool (" BLAST ") (referring to, as Karlin and Altschul, 1990, Proc.Natl.Acad Sci.USA 87:2267-2268; Altschul etc., 1990, J.Mol.Biol.215:403-410; Altschul etc., 1993, Nature Genetics3:266-272; Altschul etc., 1997, Nuc.Acids Res.25:3389-3402) assess proteins and nucleic acid sequence homology.Particularly, the blast program of five kinds of special uses is used to carry out following task: (1) BLASTP and BLAST3 put question to sequence to protein sequence data base comparing amino acid; (2) BLASTN compares nucleotide enquirement sequence to nucleotide sequence database; (3) the whole translation product of six frames of BLASTX nucleotide sequence (two chain) that the protein sequence data base is relatively putd question to; (4) TBLASTN is to being translated as the protein sequence that all six nucleotide sequence databases (two chain) of reading frame are relatively putd question to; And (5) TBLASTX compares six frame translation products of nucleotide enquirement sequence to six frame translation products of nucleotide sequence database.

Blast program is tested and appraised at the aminoacid of puing question to or nucleotide sequence and the section that tried between the sequence similarly that preferably obtains from albumen or nucleic acid sequence data storehouse determines homologous sequence, and this similar section is referred to herein as " high score section to ".High score section is to preferably determining (i.e. comparison) by the marking matrix, and many marking matrixes are well known in the art.Preferably, employed marking matrix is BLOSUM62 matrix (Gonnet etc., 1992, Science256:1443-1445; Henikoff and Henikoff, 1993, Proteins 17:49-61).Preferably less, PAM or PAM250 matrix also can use (referring to, for example Schwartz and Dayhoff compile, 1978, Matrices for Detecting DistanceRelationships:Atlas of Protein Sequence and Structure, Washington:National Biomedical Research Foundation).

The right statistical significance of all high score sections that the blast program evaluation is identified, and preferably select those sections that satisfies the specified significance threshold value of user, for example satisfy the section of the specified homology percent of user.Preferably, use the statistical significance formula of Karlin estimate the right statistical significance of high score section (referring to, for example Karlin and Altschul, 1990, Proc.Natl.Acad.Sci.USA 87:2267-2268).

The parameter that above-mentioned algorithm uses can be adjusted according to sequence length of being studied and homology degree.In some embodiments, parameter can be not have the employed default parameter of algorithm under the situation of instructions to the user.

In certain embodiments, used the Comp.App.Biosci.6:237-245 that is described in Brutlag etc., the FASTDB algorithm in 1990.In above-mentioned analysis, parameter is optional from as follows: matrix=Unitary, k-byte group=4, mispairing point penalty=1 connects point penalty=30, randomization group length=0, threshold value=1, gap penalty=5, room size point penalty=0.05, window size=500 or with the length of the sequence of probe hybridization, be as the criterion with shorter person.

Use said method and such as the algorithm of FASTA, and according to sequence length and the homology degree selection parameter of being studied, for example do not having the employed default parameter of algorithm under the situation of instructions to the user, can obtain to have proteic code nucleic acid with coded albumen at least 99.25%, at least 98%, at least 97%, at least 96%, at least 95%, at least 90%, at least 85%, at least 80% of a kind of nucleic acid or at least 75% homology.In certain embodiments, can use " default " opening point penalty (opening penalty) and " default " gap penalty and such as PAM 250 (a kind of marking matrix of standard: referring to Dayhoff etc., in: Atlas of ProteinSequence and Structure, Vol.5, Supp.3 (1978)) marking matrix is determined the homology level.

In addition, also can use .Comp.App.Biosci.6:237-245 such as Brutlag, 1990 described FASTDB algorithms are determined the level of peptides homologous.In above-mentioned analysis, parameter is optional from as follows: matrix=PAM 0, k-byte group=2, mispairing point penalty=1, connect point penalty=20, randomization group length=0, threshold value=1, window size=sequence length, gap penalty=5, room size point penalty=0.05, window size=500 or homologous sequence length are as the criterion with shorter person.

The present invention also comprises having the sequence that sequence more described herein is low homogeneity degree, can carry out one or more identical functions but it has enough similaritys.Similarity is determined by conservative aminoacid replacement.Above-mentioned replacement is those given amino acid whose replacements of aminoacid replacement with another kind of similar characteristic in polypeptide.Conservative replacement may be the phenotype silence.Generally be considered as conservative a kind ofly in aliphatic amino acid Ala, Val, Leu and Ile being replaced for another kind of replacing, the exchange of hydroxyl residue Ser and Thr, the exchange of acidic residues Asp and Glu, displacement between amide residues Asn and the Gln, the displacement between the exchange of alkaline residue Lys and Arg and aromatic residue Phy, the Tyr.Relating to may be that the guidance that the aminoacid of phenotype silence changes sees Bowie etc., Science 247:1306-1310 (1990).

For determining the homogeneity percent of two aminoacid sequences or two nucleotide sequences, sequence is compared with the best comparison purpose and (is used for best comparison as a side or two Fang Zhongke importing room at first and second aminoacid or nucleotide sequence, and for comparing purpose, nonhomologous sequence can be ignored).In a preferred embodiment, the comparison at least 30%, 40%, 50%, 60%, 70%, 80% 90% or more the control sequence of multiple-length be used for the comparison purpose.Then relatively be positioned at the amino acid residue or the nucleotide of corresponding amino acid position or nucleotide position.When a position in first sequence is the identical amino acid residue of the relevant position in second sequence or nucleotide when occupied, then molecule is same (aminoacid used herein or nucleic acid " homogeneity " are equivalent to aminoacid or nucleic acid " homology ") in this position.Homogeneity percent between the two sequences is the same positional number purpose function of sharing for sequence, will consider the number in the room that must import and the length in each room for the best comparison of two sequences.

(A.M. compiles Oxford University Press, New York, 1988 for Computational Molecular Biology, Lesk can to use arithmetic algorithm; Biocomputing:Informatics and Genome Projects, Smith, D.W. compiles AcademicPress, New York, 1993; Computer Analysis of Sequence Data, Part1, Griffin, A.M., and Griffin, H.G. compiles., Humana Press, NewJersey, 1994; Sequence Analysis in Molecular Biology, vonHeinje, G., Academic Press, 1987; And Sequence Analysis Primer, Gribskov, M. and Devereux, J. compiles, M Stockton Press, New York, 1991) finish between the two sequences sequence relatively and homogeneity and similarity percent definite.In a preferred embodiment, use Needleman and Wunsch (J Mol.Biol. (48): 444-453 (1970)) algorithm to determine two homogeneity percents between the aminoacid sequence, this algorithm incorporated in the GAP program of GCG software kit (obtain from Http:// www.gcg. Com), used Blossom 62 matrixes or PAM250 matrix, 16,14,12,10,8,6 or 4 room weight and 1,2,3,4,5 or 6 length weight.In still another preferred embodiment, the GAP program in the use GCG software kit (Devereux, J., etc., Nucleic Acids Res.12 (1): 387 (1984)) (obtain certainly Http:// www. Gcg.com) determine two homogeneity percents between the nucleotide sequence, used NWSgapdna.CMP matrix and 40,50,60,70 or 80 room weight and 1,2,3,4,5 or 6 length weight.In another embodiment, use E.Myers and W.Miller (CABIOS, 4:11-17 (1989)) algorithm is determined the homogeneity percent between two aminoacid or the nucleotide sequence, this algorithm has been incorporated in the ALIGN program (2.0 editions), has used PAM120 weight residue table, 12 room length point penalty and 4 gap penalty.

Nucleic acid of the present invention and protein sequence also can be used as " enquirement sequence " and carry out the search to sequence library, for example, and in order to identify other family members or correlated series.Can use Altschul, wait the NBLAST of (J.Mol.Biol.215:403-10 (1990)) and XBLAST program (2.0 editions) to carry out above-mentioned search.The NBLAST program of available score=100, word length=12 is carried out the BLAST nucleotide search, to obtain and the homologous nucleotide sequence of nucleic acid molecules of the present invention.The XBLAST program of available score=50, word length=3 is carried out the search of BLAST albumen with the aminoacid sequence of acquisition with albumen homology of the present invention.For purpose relatively, be to obtain the room comparison, can use the room BLAST (Gapped BLAST) described in the Altschul etc. (Nucleic Acids Res.25 (17): 3389-3402 (1997)).When using BLAST and room blast program, can use the default parameter of program (as XBLAST and NBLAST) separately.

Unless otherwise specified, practice of the present invention will be used cytobiology, cell culture, molecular biology, genetically modified organism, microbiology, recombinant DNA and immunologic routine techniques, and it is no more than the technical ability of this area.Above-mentioned technical description is in document.Referring to, for example, Molecular Cloning A Laboratory Manual, second edition, Sambrook, Fritsch and Maniatis compile (Cold Spring Harbor Laboratory Press:1989); DNA Cloning, Volumes I and II (D.N.Glover compiles, 1985); Oligonucleotide Synthesis (M.J.Gait compiles, 1984); .US such as Mullis 4,683,195; Nucleic Acid Hybridization (B.D.Hames and S.J.Higgins compile .1984); Transcription And Translation. (B.D.Hames and S.J.Higgins compile .1984); Culture Of Animal Cells (R.I.Freshney, Alan R.Liss, Inc., 1987); Immobilized Cells AndEnzymes (IRL Press, 1986); B.Perbal, A Practical Guide ToMolecular Cloning (1984); Monograph, and Methods In Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors ForMammalian Cells (J.H.Miller and M.P.Calos compile, and 1987, ColdSpring Harbor Laboratory); Methods In Enzymology, Vols.154 and 155 volumes such as () Wu, Immunochemical Methods In Cell And MolecularBiology (Mayer and Walker compiles Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D.M.Weir and C.C.Blackwell compile 1986); Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).

In described nucleotide of this paper sequence table and aminoacid sequence, with regard to nucleotide sequence, " n " or " x " can refer to any nucleotide, and with regard to protein sequence, " n " or " x " can refer to any aminoacid.

Other features and advantages of the present invention will be obviously in as detailed below with claim in.

The accompanying drawing summary

Fig. 1: the antiviral activity that has shown cat IFN α.

Fig. 2: the antiviral activity that has shown macaque IFN α.

Fig. 3: the PCR primer sequence that has shown the people IFN α that is used to increase.

Fig. 4: shown to be used for identifying that the primer of every kind of people IFN α is to (being specified in Fig. 3).

Fig. 5: interferon suppresses the sars coronavirus cytopathic effect.Interferon suppresses SARS CoV cytopathic effect in the dose dependent mode.This mensuration is by carrying out with SARS clinical isolates (GZ50) infected monkey kidney FRhk-4 cell.3 score is represented because virus causes that all cytopathy toxicity causes death (therefore, interferon does not have protection) and 0 score represents not have cell to be killed (interferon is protected fully) by virus.Referring to embodiment 8.

Fig. 6: interferon suppresses SARS CoV and duplicates.IFN α 2a and new forms of interferon be the effectiveness in SARS CoV (Urbani) cytopathic effect in suppressing cercopithecus aethiops cell (Vero 76).By direct visual assessment hepatocyte or measure the IC50 of viral inhibition by dimethyl diaminophenazine chloride dyeing hepatocyte.Referring to embodiment 9.

Fig. 7: interferon suppresses respiratory syncytial virus and duplicates.The inhibition ability of two kinds of clinical isolates of two kinds of clinical isolates of respiratory syncytial virus (RSV) B group and RSV A group being duplicated at testing in vitro IFN.Measure IC50 by serial dilution IFN, and virus protein is carried out immunoassay to measure the concentration of 50% inhibition virus replication.For those extended to the vertical sample of figure, the IC50 that is calculated was greater than 2500pg/ml, and was difficult for determined in this mensuration.Referring to embodiment 10.

Fig. 8: the effectiveness that interferon infects at protection people lung fibroblast resisiting influenza virus.The effectiveness that interferon vitro inhibition influenza virus grows in people's lung fibroblast.Measure every kind of interferon IC50, and the resulting IC50 value of IFN α 2a is made as 1.Measure Novel IFN α IC50/IFN α 2a IC50 ratio.Bigger in the figure numeral just represents that this interferon is more effective than IFN α 2a.Referring to embodiment 11.

Fig. 9: anti-yellow fever virus infects the protection hepatocyte: the effectiveness that the anti-YFV of interferon protection hepatocyte infects, and as the treating hepatitis c model, use the HepG2 hepatocyte to measure.Colorimetric determination IC50.Carry out independent mensuration twice.Referring to embodiment 12.

Figure 10: have in the cellular type that different virus attacks relatively IFN α 2a and a Novel IFN multiple.The effectiveness of test I FN α 2a and new forms of interferon on 5 kinds of different cellular types viral basis different with 3 kinds.In all cases, IFN α 2 activity are made as 1, and if IFN more effective then should value greater than 1, if render a service less then less than 1.Referring to embodiment 7 and 13.

Detailed Description Of The Invention

I. illustrative preparation

On the other hand, the invention provides the pharmaceutical preparation that comprises interferon, interferon activator or interferon antagonist. For the used interferon of the inventive method, interferon activator and/or interferon antagonist can be easily biologically acceptable medium prepare for administration described medium such as water, BS, polyalcohol (such as glycerine, propane diols, liquid macrogol etc.) or its suitable mixture. According to the known method of operating of pharmacists, can rule of thumb measure the optium concentration of active component in the selected medium. " biologically acceptable medium " used herein comprises arbitrary and all solvents that can be applicable to the desired method of administration of pharmaceutical preparation, decentralized medium etc. Above-mentioned medium known in this field is to the application of pharmaceutically active substance. Except any and the active inconsistent conventional media of the present composition or reagent, estimate that it can be used in the pharmaceutical preparation of the present invention. Suitable carrier and comprise that its formulation of other albumen is described in for example textbook RemingtonShi materia medica (Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985) in. These carriers comprise injectable " precipitate component " (deposit formulations).

Pharmaceutical preparation of the present invention also can comprise veterinary composition, as being fit to the pharmaceutical preparation of the present composition for animals, as being used for livestock, non-human primate or such as the treatment of the domestic animal of dog and cat.

Can load again or biodegradable device also can provide the method for importing. In recent years for the controlled delivery of the medicine that comprises the protein biological agent, already developed multiple release polymer device and tested in vivo. Multiple biocompatible polymer (comprising hydrogel) comprises biodegradable and nondegradable polymer, can be used to for the preparation of the implant at the specific target site sustained release.

But in the preparation per os of the present invention, parenteral, part, sheath/ventricles of the brain in (ICV), encephalic gives, directly gives central nervous system (in the chamber) or per rectum gives. Certainly, they are that the mode of method of administration gives by being suitable for separately. For example, they give with tablet or capsule form, by injection, suction, eyewash, ointment, suppository, control released membrane etc., give by injection, infusion or suction; Lotion or ointment give by the part; And suppository gives by rectum. In certain embodiments, preferred per os and part give. In one embodiment, interferon directly is delivered to mucous membrane of nasopharynx. In one embodiment, interferon directly is delivered to lung epithelial. This can make these cells that the resistance of virus is better than these setup action carriers of use in the whole body administration. Since it is so, the interferon of whole body can be minimal, so that side effect is minimum or elimination.

Phrase used herein " parenteral " and " parenteral gives " refer to be different from the administering mode through intestines or topical, usually by injection, and include but not limited in intravenous, intramuscular, the artery, in the sheath, in the capsule, in interior, intracardiac, the corium of eye socket, peritonaeum is interior, under tracheae, subcutaneous, epidermis in (subcuticular), the joint, under the tunicle, under the arachnoid, in the backbone and breastbone inner injection and infusion.

Phrase used herein " whole body administration ", " whole body gives ", " peripherally administered " and " periphery gives " refer to except the giving of compound, medicine or other materials that directly gives to central nervous system, bladder or other body compartments, so that it can enter patient system and therefore experience metabolism and other similar procedure, for example subcutaneous giving.

Can give people and other animals to be used for the treatment of by any these compounds of suitable method of administration, comprise per os, intranasal, for example spray as passing through, in the per rectum, vagina, in the parenteral, pond and local, as passing through pulvis, ointment or drops, comprise through cheek and sublingual administration.

Irrelevant with selected method of administration, the compound of the present invention that hydrated form that can be suitable uses, and/or pharmaceutical composition of the present invention is by well known to a person skilled in the art that such as the method that is described below or by other conventional method is formulated as pharmaceutically acceptable formulation.

The actual dose level of active component can change in pharmaceutical composition of the present invention, in order to can effectively reach desired treatment response for particular patient, composition and the amount that gives active component that mode obtains, the patient is answered avirulence.

Selected dosage level will depend on many factors, comprise discharge rate, the treatment of activity, method of administration, the administration time of specific compound that the present invention uses or its ester, salt or acid amides, employed specific compound duration, unite other drug, compound and/or the material of use, age, sex, body weight, state, general health and medical history before and well-known other factors of medical domain of the patient that will treat with employed particular composition.

Have the doctor of this area common skill or the required pharmaceutical composition that the animal doctor can easily determine or leave effective dose. For example, doctor or animal doctor can begin to be lower than the dosage of leaving employed compound of the present invention in pharmaceutical composition for the level that reaches the required amount of desired result for the treatment of, then little by little increase dosage until reach desired effect.

Generally speaking, the daily dose that the compounds of this invention is suitable can be a kind of like this amount of compound, can effectively produce the lowest dose level of result for the treatment of. Above-mentioned effective dose depends on factor described above usually.

If necessary, effective daily dose of reactive compound can two, three, four, five, six or more sub-doses in a whole day, give respectively with appropriate intervals, randomly, be unit dosage form.

Term " treatment " is intended to also comprise prevention, treatment, healing and the prevention of infection and propagates.

The patient who accepts this treatment can be any animal or animal vector (viral source) that needs that have, and comprises primate, particularly people, and other mammals, for example horse, ox, pig, rodent and sheep; And poultry generally speaking and pet.

Compound of the present invention can be like this or is given with the pharmaceutically acceptable and/or aseptic carrier form with mixture, also can unite with other reagent to give. The non-limitative example of mentioned reagent comprises the antimicrobial such as PCs, cephalosporins, aminoglycosides and glycopeptide class. Therefore conjoint therapy comprised continuously, simultaneously and in one way namely when follow-up medicine gives, the mode of its not complete obiteration of result for the treatment of of a kind of medicine that at first gives gives respectively reactive compound.

I1. pharmaceutical composition

Although compound of the present invention might give separately, preferably compound is given as pharmaceutical preparation (composition). Composition of the present invention can any people of being convenient to or the mode used of veterinary science prepare for administration. In certain embodiments, the described compound itself that is included in the pharmaceutical preparation is activated, or is prodrug, if change reactive compound under physiological environment.

Therefore, another aspect of the present invention provides pharmaceutically acceptable composition, comprises one or more above-claimed cpds for the treatment of effective dose, and it is prepared with one or more pharmaceutically acceptable carriers (additive) and/or diluent. The following detailed description in detail, pharmaceutical composition of the present invention can be formulated as specially solid or liquid form is used for administration, it is following to comprise that those are fit to: (1) is oral, for example, gavage agent (water or non-aqueous solution or suspension), tablet, bolus, pulvis, particle, be applied to the paste of tongue; (2) parenteral is for example through subcutaneous, intramuscular or intravenous injection, as for example sterile solution or suspension; (3) local dispenser for example is administered to emulsifiable paste, ointment or the spray of skin; Or (4) vagina is interior or drop rectum with drug, for example pessary, emulsifiable paste or foaming agent. Yet in certain embodiments, test-compound can be dissolved or suspended in the sterilized water simply. In certain embodiments, pharmaceutical preparation is nonthermal, and patient temperature namely can't raise.

As used herein phrase " treatment effective dose " refer at least one zooblast subgroup, effectively to produce some desired result for the treatment of and the cell of therefore treating in this approach of blocking-up biological results, with rational interests/risk than applicable to the compound in any Medical Treatment, material or comprise the amount of the composition of the compounds of this invention.

Phrase used herein " pharmaceutically acceptable " refers to those in the correct determination range of doctor, be suitable for the human and animal organize contact use and without excessive toxicity, stimulation, allergy or other problems or complication, have compound, material, composition and/or a formulation of the rational interests that matches with it/risk ratio.

Phrase used herein " pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, composition or carrier, for example liquid or solid filler, diluent, excipient, solvent or encapsulating material relate to from the part of an organ or health and transport or transport tested activator to another part of another organ or health. With formulation on the compatible meaning of other compositions, each carrier should be " acceptable " and harmless to the patient. Some examples that can be used as the material of pharmaceutically acceptable carrier comprise: (1) sugar, for example lactose, dextrose plus saccharose; (2) starch, for example cornstarch and farina; (3) cellulose and derivative thereof, for example sanlose, ethyl cellulose and cellulose acetate; (4) powdery tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum; (8) excipient, for example cocoa butter and suppository wax; (9) finish, for example peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil; (10) glycols, for example propane diols; (11) polyalcohols, for example glycerine, D-sorbite, sweet mellow wine and polyethylene glycol; (12) ester class, for example ethyl oleate and ethyl laurate; (13) agar; (14) buffer, for example magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) apirogen water; (17) isotonic saline solution; (18) woods Ge Shi (Ringer ' s) solution; (19) ethanol; (20) phosphate buffer; (21) other are used for the nontoxic compatible substances of pharmaceutical preparation.

III. illustrative formulation

Interferon of the present invention also can mix with the mixture of other molecules, molecular structure or compound, seals, coupling or otherwise be combined, as for example, liposome, polymer, receptor target molecule, per os, rectum, part or other formulations, be used for helping picked-up, distribute and/or absorb. Tested interferon can comprise in addition that also the formulation of penetration enhancer, carrier compound and/or transfection agents provides.

The present composition also comprises the salt of any pharmaceutically acceptable salt, ester or above-mentioned ester or any other can provide the compound of (directly or indirectly) BA metabolin or its residue when comprising people's animal. Therefore, for example the present invention openly also relates to pharmaceutically acceptable salt and other biological equivalent.

Pharmaceutically acceptable base addition salts forms with metal or amine, for example alkali and alkaline earth metal ions or organic amine. The example that is used as cationic metal is sodium, potassium, magnesium, calcium etc. The example of suitable amine is N, N,-dibenzyl-ethylenediamin, chloroprocanine, choline, diethanol amine, dicyclohexyl amine, ethylenediamine, N-METHYL-ALPHA-L-GLUCOSAMINE and procaine (referring to, such as Berge etc., " Pharmaceutical Salts; " J.of Pharma Sci., 1977,66,1-19). By conventional method free acid form is contacted the base addition salts that formation salt prepares described acid compound with the required alkali of q.s. Described free acid form can contact also with acid salt form by conventional method, and separated free acid obtains regeneration. Free acid form and they salt form separately is slightly different on some physical property, the solubility in polar solvent for example, but aspect other for the object of the invention salt be equal to their free acids separately. " medicinal addition salts " used herein comprises the formed pharmaceutically acceptable salt of sour form by a kind of composition of the present composition. These comprise the organic or inorganic acid salt of amine. Preferred acid salt is hydrochloride, acetate, salicylate, nitrate and phosphate. Other suitable pharmaceutically acceptable salts are well-known and comprise multiple inorganic and organic acid basic salt for those skilled in the art.

A. supramolecular complex

In certain embodiments, described formulation is as the part of " supramolecular complex ". For further illustrating, interferon can contact with at least a polymer and form compound, and then the polymer of this compound is processed under the condition that is enough to form the supramolecular complex that contains interferon and multidimensional polymer network. This polymer molecule can be line style or branching. Therefore, one group of mixture that two or more polymer molecules can be line style, branching or line style and branched polymer. Compound can be by any suitable method preparation well known in the art. For example, compound can form by contacting simply, mix with polymer or disperseing to disturb usually. Compound also can prepare by polymerization single polymerization monomer, and described monomer can be identical or different, can form the polymer of line style or branching in the presence of expression construct. Compound can be modified with at least a part again, so that the cellular uptake of guidance table expression constructs or realize in-vivo tissue or the cell distribution of expression construct for example. Compound can adopt any suitable form and preferably adopt particle form.

In certain preferred aspects, prepare tested interferon with cation type polymer. Illustrative cation type polymer comprises poly-(L) lysine (PLL) and polyaziridine (PEI). In certain preferred aspects, with the tested expression construct of polymer (β CD-polymer) preparation that contains beta-schardinger dextrin-. β CD-polymer can form clumping (polyplexes) with the cultured cell of nucleic acid and transfection. Can synthesize β CD-polymer, for example synthetic by diaminourea-cyclodextrin monomer A and imidodicarbonic diamide compound (diimidate) comonomer B condensation. Cyclodextrin is cyclic polysaccharide, comprises naturally occurring D (+) with α-(Isosorbide-5-Nitrae) bonding-glucopyranose unit. Modal cyclodextrin is alpha-cyclodextrin, beta-schardinger dextrin-and gamma-cyclodextrin, and they comprise respectively 6,7 or 8 glucopyranose unit. Illustrative cyclodextrin delivery system can easily be applicable to sending of tested interferon, is described in, such as the PCT application WO 00/01734 of Gonzalez etc. and the PCT application WO 00/33885 of Davis.

In certain embodiments, supramolecular complex is assembled for particulate, for example, has the microparticle formulation of 20-5000 nanometer (nm) average diameter. In another embodiment, particulate has the average diameter of 20-200nm. In another embodiment, particle has the average diameter of 2-10 micron. Granular size for example can be used for being delivered to lung at the 2-10 micron.

B. other cationic, non-lipid formulation

In certain embodiments, interferon is provided in cationic, the non-Lipid carriers and prepares the aerosol delivery that is used for by respiratory tract. Use poly-(aziridine) and such as the macromolecular preparation of dsRNA and dsRNA-coding plasmid can produce high-caliber lung transfection and in spray process stability increase. For lung, the PEI-nucleic acid preparation also can have high degree of specificity.

Except with the PEI preparation interferon, the present invention also relates to use the polymer of cyclodextrin-modification, for example poly-(aziridine) of cyclodextrin-modification. In certain embodiments, tested polymer has structural formula:

When wherein R occurs at every turn independently, represent H, low alkyl group, cyclodextrin part or

With

When occurring at every turn, m independently, represents from 2-10,000 integer, and preferably from 10-5,000, or from 100-1,000.

In certain embodiments, R represents the cyclodextrin part, its be nitrogen-atoms at least about 1%, more preferably at least about 2%, or at least about 3%, and at the most about 5% or and even 10%, if there is not the cyclodextrin part, then described nitrogen-atoms should be primary amine (R that namely has the representative H of twice appearance).

In certain embodiments, calculate by weight that polymer that cyclodextrin partly accounts for cyclodextrin-modification forms at least about 2%, 3% or 4%, at the most 5%, 7% or and even 10%.

In certain embodiments, in polymer, calculate by weight at least about 2%, 3% or 4%, at the most 5%, 7% or and even 10% aziridine subunit modified by the cyclodextrin part.

Have copolymer to the nucleophilic amino substituent poly-(aziridine) of the derivatization sensitivity of cyclodextrin part and also can be used for preparing the polymer of within the scope of the invention cyclodextrin-modification.

Illustrative cyclodextrin partly comprises the circulus that basically partly is comprised of 7-9 carbohydrate, and described carbohydrate part is the cyclodextrin of cyclodextrin and oxidation for example. The cyclodextrin part randomly is included in the coupling part that forms covalent bond between circulus and the main polymer chain, in this chain, preferably have 1-20 atom, alkyl chain for example, comprise dicarboxylic acid derivatives (such as glutaric acid derivatives, succinic acid derivative etc.), and assorted alkyl chain, for example few glycol chain.

C. Liposomal formulation

In certain embodiments, the invention provides the composition that comprises interferon, this interferon is encapsulated in the liposome or otherwise is combined with liposome. Liposome used herein refers to have the outer field lipid vesicle of lipid, generally forms one or more lipid bilayers, is wrapped in moisture kernel. In a preferred embodiment, liposome is the cationic liposome that is formed iipidomic one-tenth by the cation vesicle of about 20-80 mole percent, and remainder is that neutral vesicle forms lipid and/or other compositions. " vesicle forms lipid (vesicle-forming lipid) " used herein refers to have hydrophobic with the polar head-group part and from any amphipathic lipids that can spontaneously form separately double-deck vesicle in water, for example phospholipid. It is the diacyl chain lipid that a kind of preferred vesicle forms lipid, phosphatide for example, and its acyl chain length and has indefinite degree of unsaturation generally between about 14-22 carbon atom.

It is a kind of at spendable pH such as pH 4-9 place that the cation vesicle forms lipid, and its polar head-group (head proup) has the lipid of clean positive charge. Representative instance comprises phosphatide, phosphatidyl-ethanolamine for example, and the electropositivity part derivatization of its polar head-group such as lysine illustrates, the lipid DOPE (LYS-DOPE) that for example derives with 1B (Guo, etc., 1993). Being also included within such is the glycolipid class, for example has cerebroside and the gangliosides of cation polar head-group.

It is cholesterine amine and relevant cation sterols that other spendable cation vesicles form lipid. Illustrative cation lipid comprises 1,2-, two oleoyl oxygen-3-(trimethyl is amino) propane (DOTAP); N-[1-(2,3 ,-two tetradecane oxygen) propyl group]-N, N-dimethyl-N-ethoxy ammonium bromide (DMRIE); N-[1-(2,3 ,-two oleoyl oxygen) propyl group]-N, N-dimethyl-N-ethoxy ammonium bromide (DORIE); N-[1-(2,3-, two oleoyl oxygen) propyl group]-N, N, N-trimethyl ammonium chloride (DOTMA); 3 β [N-(N ', N '-dimethylamino ethane) carbamoyl] cholesterine (DC-Chol) and dimethyl dioctadecyl ammonium (DDAB).

Other liposomes form lipid by neutral vesicle and form, and described neutral vesicle forms that vesicle that lipid refers to not have net charge forms lipid or it can comprise the electronegative lipid in polar head-group of little percentage. Be included in this lipoids is phospholipid, for example phosphatid ylcholine (PC), phosphatidyl-ethanolamine (PE), phosphatidylinositols (PI) and sphingomyelins (SM), and cholesterine, cholesterin derivative, and other uncharged sterols.

Above-mentioned lipid can obtain from the commercial channel or prepare according to the method for announcing. Can comprise that other lipids in the present invention are glycolipid classes, for example cerebroside and gangliosides.

In one embodiment of the invention, interferon-liposome complex comprises the liposome with hydrophilic polymer chains face coat, and this coating can prolong the blood circulation time of plasmid/liposome complex effectively. Suitable hydrophilic polymer comprises cyclodextrin (CD), polyethylene glycol (PEG), PLA, polyglycolic acid, polyvinylpyrrolidone, Ju Jia oxazolin, PEOz, poly-hydroxypropyl (Methacrylamide), PMAm, polydimethylacrylamiin and the cellulose of deriving, for example CMC or hydroxyethylcellulose. Preferred hydrophilic polymer chains is polyethylene glycol (PEG), and the PEG chain preferably has at 500-10, and the molecular weight between 000 dalton is more preferably at 1,000-5, between 000 dalton. In hydrophilic polymer water soluble and the nonaqueous solvents such as chloroform.

Coating preferably forms in the lipid and prepares by being included in vesicle at phosphatide that its base is derived with polymer chain or other diacyl chain lipids. Prepare above-mentioned lipid and already be described in US 5,013 with this example methodology that forms the liposome of polymer coating, in 556 and 5,395,619, it is incorporated herein by reference at this.

Be to be understood that hydrophilic polymer can be stably and the lipid coupling, or by unsettled bonding coupling, allow the plasmid-lipidosome compound of polymer coating to deviate from or " release " hydrophilic polymer coating at this bonding during the blood circulation or behind target site location. Hydrophilic polymer particularly polyethylene glycol (PEG) and vesicle form lipid by in the response stimulating course effectively the contents industry that is connected of the key of release polymers chain for example have been described among WO 98/16202, the WO 98/16201, it is incorporated herein by reference at this, and Kirpotin, D. etc. (FEBS Letters is among the 388:115-118 (1996).

In one embodiment, releasable key is chemical releasable key, and it is cracking or cleaved under physiological condition optionally by giving suitable releasing agent, for example in the presence of enzyme or reducing agent. For example, ester and peptide bonding are by esterase or peptide enzymatic lysis. Disulfide bond is by giving the reducing agent cracking, for example glutathione or ascorbic acid, or the reducing agent cracking by existing in the body, and cysteine for example, it is present in blood plasma and the born of the same parents.

Other releasable bondings comprise the key of pH sensitivity and are exposed to the key of the lower cracking of glucose, light or heat. As an example, hydrophilic polymer chains can be connected on the liposome by the key of pH sensitivity, and the plasmid-lipidosome compound by target to having effective this key of cracking and can discharging the position of the pH of hydrophilic chain, tumor area for example. The key of illustrative pH sensitivity comprises acyloxy alkyl ether, acetal and ketal key. The example of the key of another cleavable is disulfide bond, at this general reference linkage containing sulfur. Linkage containing sulfur can synthesize to reach selected unstability degree, comprises the sulphur of disulfide bond, mixing-sulfone key and sulphur-sulfoxide key. With regard to these three kinds of keys, disulfide bond is to thiolysis sensitivity and sulphur-sulfoxide key is the most responsive least.

Above-mentioned releasable key can be used to control the release rate from the hydrophilic polymer segment of liposome complex. For example, a kind of very unsettled disulfide bond can be used for target to haemocyte or endothelial cell, because these cells are accessible and short liposome blood circulation life-span is just enough. In the other end, when target position is tumor tissues or other organs, can use long-lived or stable disulfide bond, normally need in this in liposome blood circulation life-span long for compound will arrive at desired target position.

The releasable key that connects hydrophilic polymer chains and liposome is in vivo generally as the result of environmental change and cracking, for example when liposome arrives at the ad-hoc location with slightly low pH, tumor tissues district for example, or when having the position of reducing condition, for example hypoxic tumour. Reducing condition also can be realized through the reducing agent that gives in the body, for example ascorbic acid, cysteine or glutathione. The key of this cleavable also can rupture in the outside stimulus process of response such as light and heat.

In another embodiment, described liposome complex comprise specific binding effectively to treatment institute for target cell affinity partly or the target part. Above-mentioned part can be connected to the end of surface of liposome or hydrophilic polymer chains. Illustrative part comprises antibody, be used for specific binding to part of target cell surface receptor etc., is described in, and PCT application WO US94/03103 for example is among WO 98/16202 and the WO 98/16201. This part also can be the fusion that hydrophobic segment is beneficial to compound and target cell.

The polycation condensing agent that is used for the condensation interferon can be the multi-charge cationic polymer, and biopolymer preferably, for example spermidine, spermine, polylysine, nucleoprotamine, total histone, such as the specificity group protein fragments of H1, H2, H3, H4 and other polycation polypeptide, but also can comprise biocompatible polymer, for example PB. Be to be understood that these polycation condensing agents can free alkali or salt form use, for example protamine sulfate and polylysine hydrobromate. In a preferred embodiment, the polycation condensing agent is histone, comprises total histone and particular group protein fragments with regard to this paper.

In certain embodiments, the hydrophobic segment in the polymer-lipid conjugate is the hydrophobic polypeptides sequence. Preferably, this peptide sequence is by about 5-80, and more preferably by 10-50, most preferably and/or aliphatic/aromatic amino acid residue nonpolar by 20-30 forms. These sequences are activated in the fusion process that triggers some enveloped virus and host cell, described virus comprises parainfluenza virus, for example sendai virus, simian virus-5 (SV5), measles virus, Newcastle disease virus (NDV) and respiratory syncytial virus (RSV) (RSV). Other examples comprise human reverse transcript virus, for example human immunodeficiency virus-1 (HIV-1), AIDS pathogen, and it is infection cell by plasma membrane fusion of peplos and host cell. Fusion occurs under physiology (namely neutral) pH, subsequently viral genetic (nucleocapsid) is injected in the cytoplasmic compartment of host cell.

D. the preparation of part guiding

In certain embodiments, the compound of polymerization, for example supramolecular complex and liposome of the present invention can effectively be attached to one or more ligand binding of specific cells surface protein on the target cell or matrix, therefore be beneficial to the chelating of compound and target cell, and in some example, strengthen cell to the picked-up of interferon. Only be used for illustrating, be suitable for supramolecular complex of the present invention and liposome target to the part example of specific cellular type and be listed in the table below in 1.

Table 1

Part	Acceptor	Cellular type
			Folate	Folate receptor	Epithelioma, stem cell
Water soluble vitamin	Vitamin receptor	Various cells
			Vitamin B6 phosphate (pyridoxyl phosphate)	CD4	The CD4+ lymphocyte
Apolipoprotein	LDL	Liver cell, vascular endothelial cell
			Insulin	Insulin receptor
Transferrins	TfR	Endothelial cell
			Galactolipin	Asialoglycoprotein receptor	Liver cell
Sialyl-Lewisx	E, P selects albumen	The endothelial cell of activation
			Mac-1	L selects albumen	Neutrophil, leucocyte
VEGF	Flk-1，2	Tumor endothelial cell
			Basic FGF	The FGF acceptor	Tumor endothelial cell
EGF	The EGF acceptor	Endothelial cell
			VCAM-1	a 4b 1Integrin	Vascular endothelial cell
ICAM-1	a Lb 2Integrin	Vascular endothelial cell
			PECAM-1/CD31	a vb 3Integrin	Vascular endothelial cell, Activated platelet
Osteopontin	a vb 1Integrin avb 5Integrin	Endothelial cell in the atherosclerotic plaque and smooth muscle cell
			The RGD sequence	a vb 3Integrin	Tumor endothelial cell, VSMC
HIV GP 120/41 or GP120	CD4	The CD4+ lymphocyte

The present invention also relates to the derivatization of the part of this compound transcytosis of tested polymer and liposome complex and promotion. For further illustrating, a kind of compound of polymerization for example supramolecular complex can be covalently bound to driving this compound transposition by the internalizing peptide of cell membrane with the thin inner cellular localization of convenient interferon. In this, internalizing peptide individually can be with relatively high speed by cell membrane, by carrying out such as transcytosis. This internalizing peptide is coupled on the polymer such as the side group by covalency.

In one embodiment, internalizing peptide is derived from fruit bat antepennepedia albumen or its homologue. 60 amino acid whose homeodomain transpositions that already confirmed homeoprotein antepennepedia also can be beneficial to its coupling heterologous polypeptide transposition by biomembrane. Referring to, such as Derossi etc. (1994) J Biol Chem 269:10444-10450; With Perez etc. (1992) J Cell Sci 102:717-722. Recently, confirmed that the little fragment to 16 amino acid longs of this albumen just is enough to drive the internalization effect. Referring to Derossi etc. (1996) J Biol Chem 271:18188-18193. The present invention relates to the interferon compound that a kind of at least a portion of using compound with respect to unmodified to be enough to increase the antepennepedia albumen (or its homologue) of the compound transmembrane transport of modifying is modified, reached the amount of statistically significant.

The example of another kind of internalizing peptide is HIV transactivator (TAT) albumen. This albumen see up can be divided into four domains (Kuppuswamy etc. (1989) Nucl.Acids Res. 17:3551-3561). In tissue is cultivated, the TAT albumen of purifying is absorbed (Frankel and Pabo by cell, (1989) Cell 55:1189-1193), peptide for example corresponding to the fragment of the residue 37-62 of TAT external be that cell institute absorbs (Green and Loewenstein, (1989) Cell 55:1179-1188) fast. The high alkalinity district has mediated internalization effect and target internalization part to nucleus (Ruben etc., (1989) J.Virol. 63:1-8). Comprise the peptide of sequence such as the CFITKALGISYGRKKRRQRRRPPQGS that is present in the high alkalinity district or analog be coupled to polymer to help internalization effect and those compounds of target to born of the same parents in environment.

Can prepare the another kind of illustrative cell polypeptide of striding, comprise the wasp toxin moiety (T.Higashijima etc., (1990) J.Biol.Chem. 265:14176) of the transmembrane transport that is enough to increase interferon compound.

Can prepare other suitable internalizing peptides, use all or part of such as histone, insulin, transferrins, alkaline albumin, prolactin and insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II) or other growth factors. For example, found that an insulin fragment has the affinity to insulin receptor on the capillary cell, and lower to the effectiveness that blood sugar reduces than insulin, can carry out transmembrane transport by receptor-mediated transcytosis, therefore can be used as internalizing peptide for tested striding for the cell polypeptide. The preferred growth factor internalizing peptide of deriving comprises EGF (EGF) derived peptide, for example CMHIESLDSYTC and CMYIEALDKYAC; TGF-β (β TGF) derived peptide; Peptide derived from PDGF (platelet derived growth factor) or PDGF-2; Peptide derived from IGF-I (IGF) or IGF-II; And FGF (fibroblast growth factor) peptide of deriving.

Another kind of transposition peptide/internalizing peptide has the membrane-binding that pH relies on. For a kind of internalizing peptide of taking helical conformation under acid pH, this internalizing peptide has obtained amphipathic, has hydrophobic and hydrophilic interface such as it. More precisely, in the pH of about 5.0-5.5 scope, internalizing peptide forms alpha-helix, and amphipathic structure is conducive to this partial insertion in the target film. Can find a kind of α-induce the acid pH environment of spiral, for example, existing low pH environment in intracellular. Above-mentioned internalizing peptide can be used for helping the transhipment of interferon compound, absorbs by cell endocytic mechanism, from the endosome compartment to cytoplasm.

Other preferred internalizing peptides comprise: aPoA-I and B; Peptide toxin, for example melittin, bombolittin, δ hemolysin and Moses's ichthyotoxin peptide (pardaxins); Antibacterial peptide, for example alamethicin; Peptide hormone, for example calcitonin, corticotropin-releasing factor, β endorphins, glucagon, parathyroid hormone, pancreatic polypeptide; And corresponding to the peptide of numerous secreted protein signal sequences.In addition, illustrative internalizing peptide can obtain modifying by connecting the substituent group that can strengthen internalizing peptide alpha-helix characteristic under acid pH.

The internalizing peptide that another class is suitable for the present invention's use is included in the hydrophobic domains of " hiding " under the physiology pH but exposing under the low pH environment of target cell endosome.The inductive exposure of separating folding and hydrophobic domains of firm generation pH-, this part just is attached on the lipid bilayer and causes the covalent linked complexes transposition to Cytoplasm.Above-mentioned internalizing peptide can be copied from identifying in as the sequence in Pseudomonas exotoxin A, clathrin or the diphtheria toxin, diphtherotoxin.

PFP or peptide also can be used as internalizing peptide herein.PFP or peptide can obtain from or derived from, for example C9 complement protein, cytolysis type T-cellular elements or NK-cellular elements.These parts can form ring-shaped structure in film, cell interior is transported and entered to the complex that allows thus to be connected by film.

Only internalizing peptide just is enough to cell membrane is passed through in the complex transposition to the insertion of film.Yet, can be by internalizing peptide be connected and improves transposition with the substrate (i.e. " auxiliary peptide ") of endocellular enzyme.Preferably will assist peptide to be connected to internalizing peptide reaches the Cytoplasm face by cell membrane a part.The end that auxiliary peptide is connected to transposition/internalization part or anchor peptide is favourable.Slave part of the present invention can contain one or more amino acid residues.In one embodiment, slave part can provide the substrate (for example, auxiliary peptide can contain tyrosine residue) of cells phosphorylation effect.

In this, illustrative slave part should be a kind of peptide substrates of N-myristoyl transferring enzyme, for example GNAAAARR (Eubanks etc.: Peptides.Chemistry and BiologyIn, Garland Marshall (volume), ESCOM, Leiden, 1988, pp566-69).In this construct, internalizing peptide should be connected to the C-end of auxiliary peptide, because the terminal glycine of N-is crucial for the activity of slave part.This T1249 that is connected to polymer complex be N-Semen Myristicae acidylate and further be anchored on the target cell membrane, be used for increasing the local concentration of complex on the cell membrane as it.

Suitable auxiliary peptide comprise be kinase substrate peptide, have the peptide of single positive charge and contain promising film in conjunction with glycosyl transferase the peptide of glycosylated sequence.By film can comprise sequence x-NLT-x in conjunction with the glycosylated auxiliary peptide of glycosyl transferase, for example wherein " x " can be another kind of peptide, a seed amino acid, coupling agent or hydrophobic molecule.When this hydrophobic tripeptides and microsome vesicle incubation, it passes tonoplast, in chamber side glycosylation, and owing to its hydrophilic is absorbed in (C.Hirschberg etc., (1987) in the vesicle Ann.Rev.Biochem.56:63-87).Therefore the auxiliary Toplink that contains sequence x-NLT-x strengthens the target cell reservation degree of corresponding complexes.

As mentioned above, internalizing peptide and auxiliary peptide can distinguish independently by chemical crosslinking or by noncovalent interaction (as, use Succ-PEG-DSPE-biotin conjugates, His ₆-Ni interaction etc.) add on interferon compound or the liposome.In some example, the peptide linker of non-structure (unstructured) can be included between peptide moiety and polymer composites or the liposome.

What also relate to is that above-mentioned internalizing peptide directly is connected with interferon with auxiliary Toplink, for example is connected to hydroxyl on the albumen main chain by covalent bond.In certain embodiments, this bonding is to the cracking sensitivity under the physiological condition, for example by being exposed to esterase or simple hydrolysis.Above-mentioned composition can use separately or prepare in polymeric complex or liposome.

E. respirable interferon

Another aspect of the present invention provides and has been used to send the aerosol of interferon to respiratory tract.Described respiratory tract comprises air flue, comprises oropharynx and larynx, downtake afterwards, it comprises trachea, afterwards extend bifurcated in bronchus and the bronchioles.Last air flue and downtake are called as the air flue that can conduct.Bronchiolus terminalis is divided into respiratory bronchioles afterwards, and it leads to last respiratory region, the deep of alveolar or lung afterwards.

At this, by suction give can per os and/or per nasal, trachea in (perforation or tracheostomy tube) or by respiratory assistance apparatus such as respirator.The example that is used for the medicinal transposition of aerosol delivery comprises metered dose inhaler (MDIs), powder inhaler (DPIs) and air-blast atomizer.Can be applicable to easily that the illustrative suction delivery system of sending that is tried interferon is described in, for example US 5,756, and 353; 5,858,784; With PCT application WO 98/31346; WO 98/10796; WO 00/27359; WO 01/54664; Among the WO 02/060412.Other aerosol preparations that can be used for sending interferon are described in US 6,294,153; 6,344,194; 6,071,497 and PCT application WO 02/066078; WO 02/053190; WO 01/60420; Among the WO 00/66206.

In a few minutes to a period of time of several hours, people's lungs can be removed or degrade fast and can pass through the cracked sedimentary aerosol of hydrolysis.In last air flue, ciliated epithelial cell helps " excalation of mucosa cilium (excalator) ", and granule is from the respiratory tract exhaust outlet thus.Pavia, D., " LungMucociliary Clearance ", in Aerosols and the Lung:Clinical and Experimental Aspects, Clarke, S.W. and Pavia, D. compiles., Butterworths, London, 1984.In the deep of lung, particle deposition in the near future pulmonary alveolar macrophage can engulf them..MicroscopyRes.Tech. such as Warheit, 26:412-422 (1993); And Brain, J.D., " Physiologyand Pathophysiology of Pulmonary Macrophages ", in The Reticuloendothelial System, S.M.Reichard and J.Filkins compile., Plenum, New.York, pp.315-327,1985.The deep of lung or alveolar are the aerocolloidal main target position of therapeutic that is used for the suction of interferon systemic delivery.

In preferred embodiments, particularly under the general administration situation of the interferon that hope is carried out, the interferon of atomizing is formulated as microgranule.Microgranule with 0.5-10 micron diameter can pass lung, sees through the most natural cover for defense.Less than 10 microns diameters is that to walk around larynx necessary; 0.5 the micron or bigger diameter be avoid being breathed out necessary.

In certain preferred aspects, tried interferon and prepare in supramolecular complex, as mentioned above, it has the diameter of 0.5-10 micron, can assemble for having the granule of 0.5-10 micron diameter.

What provide in liposome or the supramolecular complex in other embodiments, is tried interferon (as mentioned above) and can suitably prepare and be used for pulmonary and pass medicine.

(i). be used to form the polymer of microgranule

Except that above-mentioned supramolecular complex, many other polymer can be used for forming microgranule.Comprise microsphere (homogeneous spheroid), microcapsule (having nuclear and polymeric outer layer) and erose granule at this used term " microgranule ".

Polymer is preferably in expected interference in the plain time period that discharges or in the near future be biodegradable, usually in the scope in 1 year, and some months more commonly, modal several days to several weeks.Biodegradable can refer to the decomposition of microgranule, promptly forms the dissociating of polymer and/or the dissociating of polymer self of microgranule.It can be owing to following former thereby take place: change to the off-position pH of institute from the carrier pH at the granule place that is given, resemble in the presence of diketopiperazines; Hydrolysis resembles in the presence of poly-(hydroxy acid); By extracorpuscular ions diffusion such as calcium ion, resemble by form such as the polymer ions bonding of alginate microgranule in the presence of; By enzyme catalysis, resemble many polysaccharide and proteic in the presence of.Sometimes linear release may be the most useful, although pulse release or " discharge in batches " can provide more useful results in other cases.

Representational synthetic material is: diketopiperazines, poly-(hydroxy acid), such as poly-(lactic acid), poly-(hydroxyacetic acid) and copolymer thereof, polyanhydride, polyester, such as the poe class, polyamide, Merlon, TPO, such as polyethylene, polypropylene, poly-(ethylene glycol), poly-(oxirane), poly-(ethylene terephthalate), polyethylene-based chemical compound, such as polyvinyl alcohol, polyvinylether, polyvinyl ester, polyvinyl halides, polyvinylpyrrolidone, polyvinyl acetate and polrvinyl chloride, polystyrene, polysiloxanes, the polymer of acrylic acid and methacrylic acid, comprise poly-(methyl methacrylate), poly-(ethyl methacrylate), poly-(butyl methacrylate), poly-(isobutyl methacrylate), poly-(N-Hexyl methacrylate), poly-(isodecyl methacrylate), poly-(lauryl methacrylate), poly-(phenyl methacrylate), poly-(acrylic acid methyl ester .), poly-(isopropyl acrylate), poly-(Isobutyl 2-propenoate), poly-(acrylic acid stearyl), polyurethane and copolymer thereof, cellulose, comprise alkylcellulose, hydroxy alkyl cellulose, cellulose ether, cellulose esters, NC Nitroncellulose, methylcellulose, ethyl cellulose, hydroxy propyl cellulose, hydroxypropyl emthylcellulose, hydroxy butyl methyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate phthalate, carboxyethyl cellulose, Triafol T and sulfate cellulose sodium salt, poly-(butanoic acid), poly-(valeric acid) and poly-(lactide-copolymerization-caprolactone).

Natural polymer comprises that alginate and other polysaccharide comprise glucosan and cellulose, collagen, albumin and other hydrophilic albumen, zein and other prolamin and hydrophobin, their copolymer and mixture.Its chemical derivative used herein refers to displacement, the interpolation of chemical group, for example alkyl, alkylidene, hydroxylation, Oxidation and other modification used by those skilled in the art of routine.

Bioadhesive polymer comprises and is described in H.S.Sawhney, C.P.Pathak and J.A.Hubell Macromolecules, 1993,26, the biology among the 581-587 can lose the hydrogel of separating, poly-hyaluronic acid, casein, gelatin, glutin, polyanhydride, polyacrylic acid, alginate, chitosan and polyacrylate.

For further illustrating, substrate can well known to a person skilled in the art the method preparation by solvent evaporation, spray drying solvent extraction and other by polymer.Exploitation is used for preparing the method that is used for the microsphere that medicine sends and is described in document, for example Mathiowitz and Langer, J.Controlled Release 5,13-22 (1987); Mathiowitz etc., ReactivePolymers 6,275-283 (1987); With Mathiowitz etc., J.Appl.PolymerSci.35,755-774 (1988) is described.The selection of polymer is depended in the selection of this method, desired size, formalness and degree of crystallinity, and as Mathiowitz etc., ScanningMicroscopy 4,329-340 (1990); Mathiowitz etc., J.Appl.PolymerSci.45,125-134 (1992); With Benita etc., J.Pharm.Sci.73,1721-1724 (1984) is described.

In solvent evaporation, for example be described in Mathiowitz etc., (1990), among the US 4,272,398 of Benita and Jaffe, polymer dissolution is in volatile organic solvent.The interferon that exists with soluble form or be separated into fine particle is added in the polymer solution, and mixture is suspended from the aqueous phase that contains such as the surfactant of poly-(vinyl alcohol).The emulsion that stirring is produced stays microspheres with solid till most organic solvent evaporation.

Generally speaking, polymer is dissolvable in water dichloromethane.Can use several different polymer concentrations, for example, 0.05-0.20g/ml.After loading solution, intensively stirredly contain 1% (w/v) poly-(vinyl alcohol) (Sigma Chemical Co., St.Louis is in distilled water Mo.) what solution was suspended in 200ml with medicine.Stir after 4 hours, evaporate organic solvent from polymer, synthetic microsphere washes with water and dried overnight in freeze dryer.

Microsphere with different size (1-1000 micron, but be less than 10 microns for aerosol applications) and form can obtain such as the method for the relatively stable polymer of polyester and polystyrene by can be used for.Yet, may degrade owing to being exposed to water such as the labile polymer of polyanhydride.For these polymer, preferably hot melt encapsulates and removes solvent.

In the hot melt encapsulation, polymer at first melts, and then mixes with the interferon solid particle, preferably screens to appropriate size.The outstanding source of mixture in such as the immiscible solvent of silicone oil and continuous stirring, is heated above 5 ℃ of melting point polymers.In case emulsion is stable, and its cooling is solidified until polymer beads.The microsphere that generates with petroleum ether by decantation is to produce the free-flowing powder material.Can obtain to have the microsphere of 1-1000 micron diameter with this method.Outer surface with the prepared spheroid of this technology is normally smooth and fine and close.This method can be used the water unstable polymer, but is not limited to use the polymer with 1000-50000 molecular weight.

In spray drying, with polymer dissolution in organic solvent such as dichloromethane (0.04g/ml).The interferon of known quantity suspended (if insoluble) or altogether dissolving (if solvable) in polymer solution.This solution of spray drying or dispersion liquid can obtain the microsphere in 1-10 micron diameter scope then, and its form depends on selected polymer.

By the hydrogel microsphere of making such as alginate or poly-gel-type polymers phosphazine or other omega-dicarboxylic acids polymer can by with polymer dissolution in aqueous solution, suspension will be mixed the material of mixture, and polymeric blends extruded the microdroplet shaped device that is equipped with nitrogen jet current and prepares.The microsphere that generated is injected the ion hardening bath of slowly stirring, for example be described in Salib etc., Pharmazeutische Industrie 40-111A, 1230 (1978).The advantage of this system is and can wraps the surface of further being modified microsphere by them after manufacturing by using the polycationic polymer such as polylysine.For example, be described in Lim etc., J.Pharm.Sci.70,351-354 (1981).For example, with regard to alginate, hydrogel can obtain by the ionomer that carries out alginate with calcium ion, uses the outer surface such as polycation crosslinked this microgranule after manufacturing of polylysine then.Use varigrained extruder, the gentle body flow rate of polymer flow rate may command microsphere granularity.

Can by with polymer dissolution in acid solution and with the crosslinked chitosan microball for preparing of tripolyphosphate.For example, carboxymethyl cellulose (CMC) microsphere can be by preparing polymer dissolution in acid solution and with lead ion precipitation microsphere.Can prepare alginate/polyaziridine (PEI) to reduce the quantity of carboxyl on the alginate microcapsule.

(ii). pharmaceutical composition

Microgranule can be suspended in any suitable pharmaceutical carrier, and for example normal saline is used for patient's administration.In the most preferred embodiment, microgranule can drying or the lyophilized form storage before administration.They can then be suspended in the solution of capacity, for example are used for the aqueous solution of aerosol with administration, or with the dry powder administration.

(iii). target administration

Microgranule can be delivered to specific cells, particularly phagocyte and organ.Phagocyte in the Peyer patches can optionally be absorbed peroral administration microgranule.The phagocyte of reticuloendothelial system is also absorbed microgranule when by intravenous administration.The endocytosis of the microgranule that is undertaken by macrophage in the lung can be used for the targeting microgranule to spleen, bone marrow, liver and lymph node.

Microgranule also can carry out targeting by linking ligand, for example above-mentioned those, and its specificity or non-specific binding are to specific target site.The example of above-mentioned part comprises that also antibody and the fragment, lectin and the hormone that comprise the variable region or other have the organic molecule of receptor on the target cell surface.

(iv). the storage of microgranule

In preferred embodiments, microgranule passes through lyophilized for storage.Dosage depends on amount, the rate of release in the lung system and the pharmacokinetics of chemical compound of the interferon of being sealed.

(v). sending of microgranule

Microgranule can use several different methods to send, from directly giving to make some granules arrive lung system the nasal meatus, to using the powder drop instillator, to using conduit or intubate to arrive the lung road.Although the powder inhaler that those use the powder inhaler of hydrocarbon propellant not re-use and those depend on the patient respiratory suction can cause variable dosage, powder inhaler can be buied.The example of suitable propellant comprises hydrogen fluoroalkane (hydrofluoroalkane) propellant, for example 1,1,1, the 2-tetrafluoro for ethane (CF3CH2F) (HFA-134a) and 1,1,1,2,3,3,3-seven fluoro n-propanes (CF3CHFCF3) (HFA-227), hexafluoroethane, a chlorofluoromethane, 1,1-Difluoroethane and their combination.

F. be used for the medical apparatus coating that interferon discharges

Another aspect of the present invention relates to the medical apparatus of band coating.For example, in certain embodiments, the invention provides a kind of medical apparatus that is attached at least one surperficial coating that has, its floating coat comprises and is tried polymeric matrix and interferon.Above-mentioned coating can put on surgical implants, for example screw, plate, packing ring, stitching thread, prosthese anchor, hobnail, staple, electric lead, valve, thin film.Described device can be conduit, implantable vascular access mouth, blood storage bag, blood pipe fitting, maincenter venous duct, ductus arteriosus, blood vessel graft, intra-aortic balloon pump, cardiac valve, cardiovascular stitching thread, artificial heart, pacemaker, heart chamber auxiliary pump, device outside, blood filter, haemodialysis equipment, hemoperfusion apparatus, plasma removing device and the filter that is suitable for arranging in blood vessel.

In certain embodiments of the invention, the monomer that is used to form polymer merges and mixes the interferon dispersion that produces homogeneous with interferon in monomer solution.Then, utilize conventional painting method that dispersion is put on support or other devices, apply the back and use normal starter to cause cross-linking process such as uviol lamp.In other embodiments of the present invention, polymer composition and interferon merge the formation dispersion.Then this dispersion is applied on the surface of medical apparatus and to crosslinked polymer to form solid cladding.In other embodiments of the present invention, with suitable solvent polymer and interferon are merged to form dispersion, with conventional method it is applied on the support then.Then remove and desolvate by conventional method, heating evaporation for example, the result is that polymer and interferon (common formation continues the drug delivery system that discharges) are retained on the support as coating.Available a kind of similar method wherein is dissolved in interferon in the polymer composition.

In some embodiments of the present invention, this system comprises the polymer of relative stiffness.In other embodiments, this system comprises the polymer of softness and tool ductility.Also in other embodiments, this system comprises the polymer with viscosity.The hardness of this polymer, elasticity, viscosity and other characteristics are extensively variable, depend on the final physical form that this system is specific, and following institute goes through.

The embodiment of system of the present invention has adopted many different forms.In certain embodiments, this system is made up of the interferon that suspends or be dispersed in the polymer.In certain other embodiments, this system is made up of interferon and semisolid or gelatin polymer, and it is adapted to pass through injector to inject in body.In other embodiments of the present invention, this system is made up of interferon and softness and the flexible polymer of tool, and it is adapted to pass through suitable surgical method and inserts or implant.In the present invention further in the embodiment, this system is made up of hard, solid polymer, and it is adapted to pass through suitable surgical method and inserts or implant.In embodiment further, this system comprises having the polymer that suspends or be dispersed in interferon wherein, and wherein interferon and polymeric blends for example form coating on screw, support, the pacemaker etc. in the implant that surgical operation is used.In the specific embodiment of the present invention, this device is made up of hard, solid polymer, its implant of using with surgical operation for example surgical operation with screw, plate, support etc. or their certain a part of form shaping.In other embodiment of the present invention, this system comprises to have the polymer that the suture form of disperseing or being suspended in interferon wherein exists.

In certain embodiments of the invention, provide have for example medical apparatus of coating on the substrate of outer surface and this outer surface of surface a kind of comprising.This coating comprises polymer and is dispersed in interferon in this polymer, and wherein polymer can see through interferon or biodegradable with the release interferon.In certain embodiments of the invention, this device comprises and suspends or be dispersed in interferon in the suitable polymers, and wherein interferon and polymer are applied to whole substrate such as surgical operation with on the implant.Above-mentioned coating can obtain by spraying coating or immersion coating.

In other embodiments of the present invention, this device comprises interferon and polymer suspension or dispersion, and wherein polymer is inflexible, and forms the ingredient of the device that will be inserted into or implant.For example, particularly in embodiments of the invention, this device is a kind of surgical operation screw that is coated with suspension or is dispersed in the interferon in the polymer, support, pacemaker etc.In other particular of the present invention, wherein be suspended with tip or head or its part of the polymer formation surgical operation of interferon with screw.In other embodiments of the present invention, interferon suspend or disperse wherein polymer-coated surgical operation with implant on, for example surgical operation is with pipe fitting (for example colostomy pipe fitting, peritoneal lavage pipe fitting, conduit and intravenous pipe fitting).Also in another embodiment of the invention, this device is a kind of the have polymer that applies on it and intravenous injection needle of interferon.

As discussed above, coating of the present invention comprises biology can lose the polymer of separating that loses that separate or abiotic.Biology can lose the polymer phase of separating is based on contemplated system or device to abiotic selection of losing the polymer of separating final use.In some embodiments of the present invention, advantageously biological can the erosion of polymer separated.For example, be surgical operation with implantable device for example during the coating on screw, support, the pacemaker etc. in system, polymer is advantageously biological can be lost and separates.Wherein polymer is advantageously biological can lose suspended substance or the dispersion that other embodiments of the present invention of separating comprise implantable, inhalant or injectable interferon in polymer, does not wherein use other element (for example screw or anchor).

In some embodiments of the present invention, it is poor that wherein polymer penetration and biology can lose separating property, advantageously, the speed that this polymer biological erosion is separated is sufficiently slow than the speed that interferon discharges, thereby this polymer still is retained in original position in the long period of time after interferon discharges already, but it is finally separated and absorbed in the surrounding tissue by the biology erosion.For example, at device is to comprise to suspend or be dispersed in biology that biology can lose the interferon in the depolymerization compound can lose when separating stitching thread, advantageously, the speed that the polymer biological erosion is separated is enough slow, thereby interferon discharged with linear mode in about 3 to about 14 days a period of time, but this stitching thread retained for about 3 thoughtful about 6 months a period of times.The similar device of the present invention comprises and comprises suspension or be dispersed in the surgical operation staple that biology can lose the interferon in the depolymerization compound.

In other embodiments of the present invention, the speed that discharges of polymer biological erosion speed of separating and interferon also is favourable at the identical order of magnitude.For example, suspend or be dispersed in interferon in the polymer when system comprises, wherein said polymer is applied to surgical operation with instrument for example orthopedic surgery screw, support, pacemaker or abiotic when losing on the stitching thread of separating, it is favourable that this polymer is separated with the biological erosion of a kind of like this speed, makes that promptly directly being exposed on every side the interferon surface area of soma passes by to remain unchanged basically in time.

In other embodiments of the present invention, polymer support is porous to the water in surrounding tissue such as the blood plasma.Under these circumstances, the aqueous solution permeable polymer, thus touch interferon.Dissolution velocity can be depending on a complex set of variable, for example the polymer penetration of physiological fluid, interferon dissolubility, pH, ionic strength and albumen composition etc.

In some embodiments of the present invention, polymer is that abiotic the erosion separated.The abiotic polymer of separating that loses can be used for such system especially, and this system comprises and a kind ofly is intended to be coated in the surgical operation that is suitable for inserting permanent or semipermanently or implants with on the implant or constitute the polymer of its component.Wherein polymer advantageously comprises orthopedic surgery screw, support, prosthetic joint, artificial valve, permanent stitching thread, pacemaker etc. in the devices illustrated that surgical operation forms permanent coating on implant.

Exist multiple at percutaneous spendable different support behind the pipe coronary angioplasty.Though many supports can use in the present invention, for the sake of simplicity, the minority support will be described in the illustrative embodiment of the present invention.Those skilled in the art will appreciate that many supports can use in the present invention.In addition, as mentioned above, other medical apparatus also can use.

Support as a kind of tubular structure, is stayed in the duct chamber to alleviate obstruction usually.In general, support is inserted in the chamber in the mode of on-expansible, expands automatically then, or expands by means of the another kind of device of original position.A kind of typical expansion method is that it expands in blood vessel that narrows down or body passage so that the cavity of shearing and disintegrating the obstruction relevant with the blood vessel wall component and obtain to enlarge owing to utilized the angioplasty air bag of conduit embedding.

Can make support of the present invention in many ways.For example, support can be made the stainless steel tube hollow or molding that carries out machining from available laser, discharging milling, chemical attack or additive method.Support is inserted in the body and places desired position with the form of on-expansible.In an illustrative embodiment, can in blood vessel, produce expansion effectively by balloon catheter, the final diameter of its medium-height trestle is the function of employed balloon catheter diameter.

Be to be understood that support of the present invention can be equipped with shape-memory material, comprises for example suitable Nitinol or rustless steel.

The structure that is formed by rustless steel can be shaped and self expandable by make rustless steel in predetermined mode, for example by it being twisted into the twisted shape structure.In this embodiment, enough little in its space compressible so that occupy behind support molding already is so that it can insert in blood vessel or its hetero-organization by the insertion instrument, and wherein the insertion instrument comprises suitable conduit or easily bent bar.

In case expose from conduit, support can be shaped with expansion for desired structure, in this expansion starting or trigger for the change or the electricity irritation of pressure, temperature automatically.

Irrelevant with the design of support, the preferred interferon that applies has enough specificitys and competent concentration so that effective dose to be provided in damage zone.In this, " container dimensional " in the coating preferably is decided to be and can makes interferon be applied to desired position fully with desired amount.

In an alternate exemplary embodiment, the total inner surface of support and outer surface can be coated with the interferon of therapeutic dose.But should emphatically point out paint-on technique can change with the difference of interferon.Equally, coating technology also can change with the difference of the material of forming support or other intracavity medical apparatus.

The intracavity medical apparatus comprises the medicine coating of passing that continues release.This interferon coating can be applied to by the painting method of routine on the support, and for example immersion coating, injection apply and dip-coating applies.

In one embodiment, the intracavity medical apparatus comprises the microscler tubular bracket that can radial expansion that has along inner chamber surface that the support longitudinal axis extends and opposing outer face.Support can comprise permanent implantable stent, implantable stent graft or falsework, wherein falsework be defined as a kind of in blood vessel expansible and support that after this can regain from blood vessel.Supporting structure can comprise screwed pipe support, memory screwed pipe support, Nitinol support, network, scaffold type support, casing support, permeable support, the support with temperature sensor, porous support or the like.Can be according to the conventional method stent, for example by expandable balloon catheter, by self-deploying machinery (discharging the back) or by other proper implements from conduit.Microscler tubular bracket that can radial expansion can be a kind of stent graft, and wherein this stent graft is the set composite that has support in intra-graft or outside.This graft can be a kind of blood vessel graft for example ePTFE graft, biology graft or woven fabric graft.

Interferon can be added into or in many ways attached on the support.In an illustrative embodiment, interferon directly adds in the polymeric substrate and is ejected on the rack outer surface.Along with the past of time, interferon flows out in the surrounding tissue from polymeric substrate.Preferred interferon kept 3 days on support at least, and about at the most 6 months, more preferably between 7-30 days.

In certain embodiments, polymer of the present invention comprises the porous polymer of tolerance biologically of any interferon, and when having permeability, it is not the main speed determiner of interferon rate of release from polymer.

In certain embodiments of the invention, polymer is that abiotic the erosion separated.The abiotic example that loses the polymer of separating that uses among the present invention comprises poly-(ethylene-copolymerization-vinylacetate) (EVA), and polyvinyl alcohol and polyurethane are for example based on the polyurethane of Merlon.In other embodiments of the present invention, polymer can biological can lose and separate.That can use in the present invention can biological can lose the examples of polymer of separating and comprise polyanhydride, polylactic acid, polyglycolic acid, poe, polyalkyl alpha-cyanacrylate or their derivant and copolymer.One of ordinary skill in the art would recognize that and select biological can the erosion to separate or abioticly lose the physical form that the polymer of separating depends on that this system is final, the following detailed description in detail.Other illustrative polymer comprise polysiloxanes and derived from hyaluronic polymer.Those skilled in the art should understand that polymer of the present invention is to be suitable for giving permeability so that it does not prepare interferon does not become the condition of main speed determiner from the polymer dispose procedure under.

In addition, suitable polymers comprises naturally occurring (collagen, hyaluronic acid etc.) or with body fluid and mammalian tissues is biocompatible and be insoluble to the synthetic material of the body fluid that this polymer will contact substantially.In addition, suitable polymers stoped basically dispersion/be suspended in this polymer interferon and body fluid in interaction between the protein component.Should avoid using rapidly-soluble polymer or dissolubility is high in body fluid polymer maybe can allow interactional polymer between interferon and the protein component in some cases, this is because the dissolving of polymer or can influence the stability of drug release with the interaction of protein component.

Other suitable polymers comprise polypropylene, polyester, polyethylene-vinyl acetate (PVA or EVA), poly(ethylene oxide) (PEO), poly(propylene oxide), the polycarboxylic acid, polyalkyl acrylate, cellulose ether, silicone, poly-(dl-lactide-copolymerization-Acetic acid, hydroxy-, bimol. cyclic ester), various Eudragrits (NE30D for example, RS PO and RL PO), poly-alkyl alkylacrylate copolymer, the polyester-polyurethane ester block copolymer, polyethers-block polymers of polyurethane Ju diethyleno dioxide ketone, poly--(beta-hydroxy-butanoic acid ester), polylactic acid (PLA), polycaprolactone, polyglycolic acid and PEO-PLA copolymer.

Coating of the present invention can be by mixing one or more suitable monomers and suitable interferon, and polymerization single polymerization monomer formation polymer system forms then.Like this, interferon dissolves or is dispersed in the polymer.In other embodiments, interferon is mixed in liquid polymers or polymeric dispersions, then polymer is further handled to form coating of the present invention.Suitable further processing method can comprise carries out crosslinkedly with suitable crosslinked interferon, further this liquid polymers of polymerization or polymeric dispersions carry out copolymerization with suitable monomers, carry out block copolymerization etc. with the suitable polymers block.Should further handle interferon is absorbed in the polymer so that interferon suspends or is dispersed in this polymer support.

Many non-erosion depolymerization compounds can be used for being connected with interferon.The film forming polymer that can be used as coating in this application can absorbablely maybe can not absorb, and should be biocompatible, to minimize the stimulation to blood vessel wall.This polymer can be a Biostatic or biological absorbable, depend on desired release rate or desired polymer stabilizing degree, but can preferred biological absorbable polymer, this is because do not resemble the polymer of Biostatic, it can not exist for a long time after implantation, just can not cause any disadvantageous, long-term local response.In addition, biological absorbable polymer does not exist in longer a period of time owing to can remove the caused risk of adhering to that loses of biotic environment stress of coating between support and coating, and the problem that is encapsulated into the further introducing of tissue back institute at support.

Spendable suitable film forming biologically absorbable polymer comprises and is selected from following polymer: aliphatic polyester, poly-(aminoacid), copolymerization (ether-ester), poly-oxalic acid alkylene ester, polyamide, poly-(iminocarbonic ester), poe, Ju Evil ester (polyoxaesters), polyamide ester, contain acylamino-De Ju Evil ester, poly-(acid anhydride), polyphosphazene, biomolecule and composition thereof.For the object of the invention, aliphatic polyester comprises that (it comprises d-lactic acid to lactide, 1-lactic acid and Study of Meso-Lactide), 6-caprolactone, Acetic acid, hydroxy-, bimol. cyclic ester (comprising glycolic), butyric ester, hydroxyl valerate, to-diethyleno dioxide ketones, propylene carbonate (and alkyl derivative), 1,4-Dioxepane-2-ketone, 1,5-Dioxepane-2-ketone, 6,6-dimethyl-1, the homopolymer of 4-diox-2-ketone and copolymer and polymer blend thereof.Poly-(iminocarbonic ester) that be used for the object of the invention comprises the Handbook ofBiodegradable Polymers that is described in Kemnitzer and Kohn, Domb, and Kost and Wisemen compile, and HardwoodAcademic Press is among 1997, the 251-272.The copolymerization (ether-ester) that is used for the object of the invention comprises that those are described in the Journal of BiomaterialsResearch of Cohn and Younes, Vol.22, the 993-1009 page or leaf, 1988 and Cohn, Polymer Preprints (ACS Division of Polymer Chemistry) Vol.30 (1), 498 pages, the copolyesters-ether (as PEO/PLA) in 1989.The poly-oxalic acid alkylene ester that is used for the object of the invention comprises US 4,208,511; 4,141,087; 4,130,639; 4,140,678; In 4,105,034 and 4,205,399 (being incorporated herein by reference at this).Polyphosphazene, by L-lactide, D, the binary that L-lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, Dui diethyleno dioxide ketone, propylene carbonate and 6-caprolactone are made-, ternary-and the more blended monomer based polyalcohol of high-order for example by Allcock at The Encyclopedia of Polymer Science, Vol.13, the 31-41 page or leaf, WileyIntersciences, John Wiley﹠amp; Sons, in 1988 and by Vandorpe, Schacht, Dejardin and Lemmouchi be at Handbook of Biodegradable Polymers, Domb, and Kost and Wisemen compile, Hardwood Academic Press, 1997, describe in the 161-182 page or leaf (it is incorporated herein by reference at this).Polyanhydride is HOOC-C from form ₆H ₄-O-(CH ₂) _m-O-C ₆H ₄The diacid of-COOH, wherein m is the integer of 2-8, and the copolymer that forms with the aliphatic alpha-ω of 12 carbon atoms at the most-diacid.Ju Evil ester, Ju Evil amide (polyoxaamides) and contain amine and/or acylamino-De Ju Evil ester is described in following in one or more: US 5,464, and 929; 5,595,751; 5,597,579; 5,607,687; 5,618,552; 5,620,698; 5,645,850; 5,648,088; 5,698,213 and 5,700,583 (it is incorporated herein by reference at this).Poe, for example those are described in Heller, Handbook of Biodegradable Polymers, Domb, Kost and Wisemen compile, Hardwood Academic Press, 1997, in the 99-118 page or leaf (being incorporated herein by reference at this).But the film-forming polymer biomolecule that is used for the object of the invention comprise naturally occurring in human body enzymatic degradation or in human body the material of hydrolytically unstable, fibrin for example, Fibrinogen, collagen, elastin laminin and absorbable biocompatible polysaccharide, for example chitosan, starch, fatty acid (and ester), glucose-glucosan (glucoso-glycans) and hyaluronic acid.

Suitable film forming Biostatic polymer with low relatively long-term tissue response, for example polyurethane, silicone, poly-(methyl) acrylate, polyester, poly-trialkylphosphine oxide (poly(ethylene oxide)), polyvinyl alcohol, Polyethylene Glycol and polyvinylpyrrolidone, and hydrogel, for example those also can be used by crosslinked polyvidon and the formed hydrogel of polyester.Other polymer also can use, if they can dissolve, solidify or be aggregated on the support.These polymer comprise polyolefin, polyisobutylene and ethene-alpha-olefin copolymer; Acrylic polymer (comprising methacrylate) and copolymer, vinyl halide polymer and copolymer, for example polrvinyl chloride; Polyvinylether, for example polyvinyl methyl ether; Polyvinylidene halogenide, for example polyvinylidene fluoride and polyvinylidene chloride; Polyacrylonitrile, polyethylene ketone; The polyvinyl aromatic compounds is polystyrene for example; Polyvinyl ester and for example polyvinyl acetate; Vinyl monomer to each other and and the copolymer of alkene, for example ethylene-methyl methacrylate methyl terpolymer, acrylonitritrile-styrene resin, ABS resin and vinyl-vinyl acetate copolymer; Polyamide, for example nylon 66 and polycaprolactam; Alkyd resins; Merlon; Polyformaldehyde; Polyimides; Polyethers; Epoxy resin, polyurethane; Rayon; Rayon-triacetate, cellulose, cellulose acetate, acetylbutyrylcellulose; Cellophane; Celluloid; Cellulose propionate; Cellulose ether (being carboxymethyl cellulose and hydroxy alkyl cellulose); And their combination.The polyamide that is used for the application's purpose should comprise that also form is-NH-(CH ₂) _n-CO-and NH-(CH ₂) _x-NH-CO-(CH ₂) _yThe polyamide of-CO, wherein the n integer of 6-13 preferably; X is the integer of 6-12; And y is the integer of 4-16.Above-mentioned listed be illustrative and unrestricted.

The polymer that is used for coating can be that molecular weight is enough high so that unlike wax shape and the film forming polymer that is not clamminess.This polymer also should be attached on the support, and should not be easy deformation so after deposition on the support, and such deformation energy makes it be substituted by hemodynamic stress.Polymer molecular weight should be enough high so that enough toughness to be provided, and makes this polymer do not wiped in support operation or process of expansion, and should not can in the support process of expansion break.In certain embodiments, this polymer melting temperature surpasses 40 ℃, preferably surpasses about 45 ℃, more preferably above 50 ℃ and most preferably above 55 ℃.

In coating mix, can prepare coating by one or more therapeutic interferon are mixed with coated polymeric.This interferon can liquid, grain solid in small, broken bits or any other suitable profile exist.Randomly, this chemical compound can comprise one or more additives, as non-toxic auxiliary substances, and for example diluent, carrier, excipient, stabilizing agent etc.Other suitable additives can be prepared with this polymer and interferon.For example, the hydrophilic polymer of describing listed biocompatible film forming polymer before being selected from can add in the biocompatible hydrophobic coating to change its release profile figure (or hydrophobic polymer can add to change its release profile figure in the hydrophilic coating).Example is to add to be selected from: the hydrophilic polymer of poly(ethylene oxide), polyvinylpyrrolidone, Polyethylene Glycol, carboxymethyl cellulose, hydroxy methocel and their combination to the aliphatic polyester coating to change its release profile figure.Suitable relative amount can be determined by monitoring release profile figure external and/or the interior therapeutic interferon.

Coating layer thickness can determine interferon effusive speed from substrate.In fact, interferon flows out from substrate by the diffusion through polymeric matrix.Polymer is permeable, therefore allows solid, liquids and gases therefrom to leave.The total thickness of polymeric matrices about 1 micron to about 20 microns or bigger scope.Should point out before polymeric substrate is attached on the medical apparatus, can use prime coat emphatically and carry out Treatment of Metal Surface.For example, pickling, alkali cleaning, salinization and parylene deposition can be used as the part of described overall treatment.

For further illustrating, poly-(ethylene-copolymerization-vinyl acetate), polybutyl methacrylate and interferon solution can several different methods add in the support or on the support.For example, solution can be ejected on the support or support can immerse in the solution.Additive method comprises that rotation applies and the RF plasma polymerization.In an illustrative embodiment, solution is ejected on the support, and is dry then.In another illustrative embodiment, solution can be with the electric charge of a kind of polar electric charge and supporting band opposite polarity.In the method, solution and support are attracted each other.In using such spraying method, can cut the waste and also can control the coating layer thickness that will obtain more accurately.

In another illustrative embodiment, interferon can be incorporated in the poly-fluoro copolymers of film forming, this copolymer comprises an amount of first that is selected from polymeric vinylidene fluoride and polymeric tetrafluoroethene, with an amount of second portion that is different from this first, it obtains with first's copolymerization, therefore produce poly-fluoro copolymers, this second portion can provide the toughness or the elasticity of poly-fluoro copolymers, and wherein the relative amount of first and second portion can both provide thus effectively and produce coating and the film that can be effectively used to handle implantable medical apparatus.

In one embodiment of the invention, the outer surface of the distensible tubular bracket of medical apparatus comprises coating of the present invention in the tube chamber of the present invention.Rack outer surface with coating is tissue contacting surface and is biocompatible." surface that the interferon delivery system that continues to discharge applies " and " surface of coating " synonym, this surface is applied, is covered or be full of by the interferon delivery system of lasting release of the present invention.The example of delivery system (sustained release, lasting release, slow release) had been described in applicant's US series application 10/193 already, 654, be disclosed as US2003/0017169, and PCT/US01/50355, disclosed as WO 02/053174, its content is incorporated herein by reference in this application.

In an optional embodiment, the surface of internal cavity of the microscler radial expansible tubulose support of medical apparatus or the surface that whole surface (being surfaces externally and internally) has coating in the tube chamber of the present invention.Surface of internal cavity with interferon delivery system coating of lasting release of the present invention also is the surface of fluid contact, and is bio-compatible and blood compatibility.

IV. interferon polypeptides variant

Some mutant forms (or variant) that should expect interferon polypeptides of the present invention can be used as agonist or antagonist.Though do not wish limited by any particular theory, the mutant forms of the well-known protein signal factor can be in conjunction with suitable receptor and still can not be activated this receptor.The said mutation body protein is by replacing wild-type protein and blocking normal receptor activation and as antagonist.In addition, as everyone knows compared to wild-type protein,, can carry out one or more amino acid whose replacements to many albumen in order to increase their activity.Above-mentioned agonist for example can have compared to wild-type protein, the half-life of increase, and binding affinity, stable or active.Exist many well-known methods of desired active mutant (or variant) that are used for obtaining to have.

The method of generation mass mutation body/misfolded proteins well known in the art.In one embodiment, the present invention is intended to use the interferon polypeptides that produces by combinatorial mutagenesis.Said method is well known in the art, is convenient to produce point mutation body and truncated mutant, and is particularly useful for identifying the potential variant sequence (as homologue) that has function in specified analysis.The purpose in screening combinations thereof library is to produce interferon variant or the homologue that for example can be used as agonist or antagonist.Therefore, can produce with respect to the natural deutero-variant of combined method that has type and have increase effectiveness of this albumen.Similarly, can produce interferon variant as antagonist by combined method of the present invention, they can be simulated at this, for example, be bonded on other extracellular matrix components (for example receptor), also can not induce any biological effect, therefore suppressed the effect of interferon polypeptides or interferon agonist.In addition, some domain of handling interferon by the inventive method can provide the domain that more is applicable in fusion or the chimeric protein, for example, confirms to have the domain of specific useful properties.

For further illustrating the level of development of combinatorial mutagenesis technology, note Gallop etc. the comment of (1994) J Med Chem 37:1233 has been described the aggregate level of the early stage combinatorial library technology nineties in 20th century.Particularly, Gallop etc. is stated at the 1239th page " [s] creening the analog libraries aids in determining the minimumsize of the active sequence and in identifying those residuescritical for binding and intolerant of substitution ".In addition, .US5 such as .PCT such as Ladner application WO 90/02809, Goeddel, 223,408 and the open WO92/15679 of .PCT such as Markland illustrated those skilled in the art and can be used for producing and can carry out rapid screening has the variant/segmental variant library of given activity with evaluation concrete technology.These technology can produce the big library of related variants/truncate as illustration and proof in the art, and need not to attempt over-drastic experiment with regard to separable specific variant.Gustin etc. (1993) Virology 193:653, with Bass etc. (1990) Proteins:Structure, Function and Genetics 8:309-314 has also described other illustrative technology in this area, is applicable to produce interferon polypeptides mutation variant of the present invention.

In fact, very clear in the combinatorial mutagenesis field, the large scale mutagenesis of interferon protein, for which residue biological function being played a crucial role does not have any predictability, and it can produce has the bioactive a large amount of variants of equivalence.In other words, said method can be used to produce the variant array with enhanced activity or antagonist activities.In fact, combination technique can be screened billions of different variants by high throughput analysis, need not to understand in advance or know Key residues.

V. antibody antagonist

Can expect some antibody and can be used as interferon antagonist.Antibody can have special affinity and specificity to defined epitope.Antibody can suppress this albumen and other by competitiveness or noncompetitive and resists this proteic function for the required proteic interaction of himself function with its combining of epi-position on albumen.

Antibody with interferon antagonist activity can obtain identifying with the roughly the same mode of other interferon antagonists.For example, candidate's antibody can be expressed the cell of reporter gene, the antibody that can cause the reporter gene expression decreased is exactly antagonist.

In a kind of variation, antibody of the present invention can be single-chain antibody (scFv), comprises the variable antigen binding domain that connects by peptide linker.Single-chain antibody is expressed as single polypeptide chain and can expresses in antibacterial, also can be used as the part of phage display library.Like this, the phage of expressing suitable scFv can have interferon antagonist activity.Then, can from phage, reclaim the coding single-chain antibody nucleic acid and be used to produce a large amount of scFv.The structure in scFv library and screening at large be described in many documents (US 5,258,498; 5,482,858; 5,091,513; 4,946,778; 5,969,108; 5,871,907; 5,223,409; 5,225,539).

G. humanIFN-'s allele and protein product

Following table 2 is for example understood common human interferon-alpha family gene/proteic allele and according to Pestka, S. (1983) Arch Biochem Biophys 221:1-37; Diaz, M.O., Pomykala, H.M., Bohlander, S.K., Maltepe, E., Malik, K., Brownstein, B., and Olopade, O.I. (1994) Genomics 22:540-52; And Pestka, S. (1986) Meth.Enzymol 119:3-14 and Krause, C.D., Lunn, C.A., Izotova, L.S., Mirochnitchenko, O., Kotenko, S.V., Lundell, D.J., Narula, S.K., and Pestka, the commentary of S. (2000) J Biol Chem.275:22995-3004 makes up.

Table 2

Gene	Albumen (allelic variant title)
		IFNA1	IFN-α1，IFN-αD
IFNA2	IFN-α2，IFN-α2b，IFN-αA，IFN-α2a，IFN-α2c
		IFNA4	IFN-α4a，FN-α76，IFN-α4b，IFN-α74，IFN- αM
IFNA5	IFN-α5，IFN-αG，IFN-α61
		IFNA6	IFN-α6，IFN-αK，IFN-α54
IFNA7	IFN-α7，IFN-αJ，IFN-αJ1
		IFNA8	IFN-α8，IFN-αB2，IFN-αB
IFNA10	IFN-αC，ψIFN-α10，ψIFN-αL，IFN-α6L
		IFNA13	IFN-α 13 (sequence is identical with IFN-α 1)
IFNA14	IFN-α14，IFN-αH，IFN-αH1
		IFNA16	IFN-α16，IFN-αWA，IFN-αO
IFNA17	IFN-α17，IFN-αI，IFN-α88
		IFNA21	IFN-α21，IFN-αF
IFNA22	IFN-α22，IFN-αGX-1
		IFNAP22	ψIFN-αE

Note: ψ refers to pseudogene

The allelic variant of human interferon-alpha gene and interferon-' alpha ' mutant had been reported in the following application already: WO 2002/095067; WO 02/079249; WO 02/101048; WO 02/095067; WO 02/083733; WO 02/086156; WO 2002/083733; WO 03/000896; WO 02/101048; WO 02/079249; WO 03/000896; WO 2004/022593; WO 2004/022747; WO 03/023032; WO 2004/022593.Also referring to following publication: (1) Kim etc., Cancer Lett.2003 Jan 28; 189 (2): 183-8; (2) Hussain etc., J Interferon Cytokine Res.2000 Sep; 20 (9): 763-8; (3) Hussain etc., J Interferon Cytokine Res.1998Jul; 18 (7): 469-77; (4) Nyman etc., Biochem is Jan 15 J.1998; 329 (Pt2): 295-302; (5) Golovleva etc., J Interferon Cytokine Res.1997Oct; 17 (10): 637-45; (6) Hussain etc., J Interferon CytokineRes.1997 Sep; 17 (9): 559-66; (7) Golovleva, I., Saha, N., Beckman, L.Hum Hered.1997Jul-Aug; 47 (4): 185-8; (8) Golovleva etc., 1997Apr; 18 (4): 645-7; (9) Kita etc., J InterferonCytokine Res.1997Mar; 17 (3): 135-40; (10) Golovleva etc., AmJ Hum Genet.1996Sep; 59 (3): 570-8; (11) Hussain etc., JInterferon Cytokine Res.1996Jul; 16 (7): 523-9; (12) Linge etc., Biochim Biophys Acta.1995Dec 27; 1264 (3): 363-8; (13) Gewert etc., J Interferon Cytokine Res.1995May; 15 (5): 403-6; (14) Lee etc., J Interferon Cytokine Res.1995Apr; 15 (4): 341-9; (15) Kaluz etc., Acta Virol.1994Apr; 38 (2): 101-4; (16) Emanuel etc., J Interferon Res.1993Jun; 13 (3): 227-31; (17) Kaluz etc., Acta Virol.1993Feb; 37 (1): 97-100; (18) Shekhter etc., Dokl Akad Nauk SSSR.1990; 314:998-1001; (19) Li etc., Sci China is B.1992Feb; 35 (2): 200-6.

Example

The present invention now summarizes, should be easier to understand with reference to the following example, and described embodiment is included in some aspect of the present invention and the embodiment that only is used to illustrate purpose, and and is not intended to the restriction invention.

Embodiment 1: cat IFNa clone's separation

By using standard method to carry out the genomic DNA of pcr amplification from cat pneumonocyte system (AKD), separation has obtained cat IFN α clone.Separate and obtain 9 different sequences and called after Fe-IFN-α A (SEQ ID NO:9), Fe-IFN-α B (SEQ ID NO:11), Fe-IFN-α C (SEQ ID NO:13), Fe-IFN-α D (SEQ ID NO:15), Fe-IFN-α E (SEQ IDNO:17), Fe-IFN-α F (SEQ ID NO:19), Fe-IFN-α G (SEQ ID NO:21), Fe-IFN-α H (SEQ ID NO:23) and Fe-IFN-α I (SEQ ID NO:25).Also provide as follows corresponding to the aminoacid sequence of each in the middle of these: Fe-IFN-α A (SEQ ID NO:10), Fe-IFN-α B (SEQ ID NO:12), Fe-IFN-α C (SEQ ID NO:14), Fe-IFN-α D (SEQ ID NO:16), Fe-IFN-α E (SEQ ID NO:18), Fe-IFN-α F (SEQ ID NO:20), Fe-IFN-α G (SEQ ID NO:22), Fe-IFN-α H (SEQ IDNO:24) and Fe-IFN-α I (SEQ ID NO:26).

Use standard method to carry out PCR.Genomic DNA is carried out the two-wheeled amplification.The flank primer of cat sequence of being used to increase is:

5 ' primer: 5 '-CTCTTCCTTCTTGGTGGCCCTG-3 '

3 ' primer: 5 '-GTGATGAGTCAGTGAGAATCATTTC-3 '

Embodiment 2: the antiviral activity of cat IFN α

Use cytopathic effect algoscopy (CPE) to measure the antiviral activity that is tried interferon.In brief, with the interferon of serial dilution and test cell at 37 ℃ of following incubation 1-4 hours.Then add virus to cell and 37 ℃ of following incubations 16 hours.Survivaling cell is estimated by the picked-up of violet staining, the dilution factor of the interferon under about 50% survival of the cell of mensuration viral infection.

Fig. 1 has summarized these result of experiment, and it has described the antiviral activity that passes through CPE mensuration that cat IFN-α A, IFN-α B, IFN-α C, IFN-α D, IFN-α E, IFN-α F, IFN-α G and IFN-α I have separately.The activity of cat IFN-α H is not measured in this experiment.In this concrete experiment, test cell is that AKD cat pneumonocyte and virus are vesicular stomatitis virus (VSV).

Embodiment 3: macaque IFN α clone's separation

By using standard method to carry out the genomic DNA of pcr amplification from RhMK cell line (LLCMK-2), separation has obtained macaque IFN α clone.Two independent primers are to being used for extension increasing sequence.Use first primer right, separate obtaining a sequence and called after Rh-IFN-α 4b (SEQID 29).Aminoacid sequence corresponding to Rh-IFN-α 4b nucleotide sequence is designated in SEQ ID NO:30.

Use standard method to carry out PCR.Genomic DNA is carried out the two-wheeled amplification.The flank primer of this macaque sequence of being used to increase is:

5 ' primer: 5 '-CTTCAGAGAACCTGGAGCC-3 '

3 ' primer: 5 '-AATCATTTCCATGTTGAACCAG-3 '

By use the standard method and second primer to carry out to pcr amplification from the genomic DNA of RhMK cell line (LLCMK-2), separate obtaining three kinds of other monkey IFN α clones: Rh-IFN-α D1 (SEQ ID NO:31), Rh-IFN-α D2 (SEQ ID NO:33) and Rh-IFN-α D3 (SEQ ID NO:35).Also provide as follows corresponding to the aminoacid sequence of each in the middle of these: Rh-IFN-α D1 (SEQ ID NO:32), Rh-IFN-α D2 (SEQ IDNO:34) and Rh-IFN-α D3 (SEQ ID NO:36).

Use standard method to carry out PCR.Genomic DNA is carried out the two-wheeled amplification.The flank primer of these macaque sequences of being used to increase is:

5 ' primer: 5 '-AGAAGCATCTGCCTGCAATATC-3 '

3 ' primer: 5 '-GCTATGACCATGATTACGAATTC-3 '

Embodiment 4: the antiviral activity of macaque IFN α

Use cytopathic effect algoscopy (CPE) to measure the antiviral activity that is tried interferon.In brief, with the interferon of serial dilution and test cell at 37 ℃ of following incubation 1-4 hours.Then add virus to cell and 37 ℃ of following incubations 16 hours.Survivaling cell is estimated by the picked-up of violet staining, the dilution factor of the interferon under about 50% survival of the cell of mensuration viral infection.

Fig. 2 has summarized result of experiment, and it has been described macaque IFN-α 4b and has had the antiviral activity of measuring by CPE.The activity of macaque IFN-α D1, IFN-α D2 and IFN-α D3 is not measured in this experiment.Ma-Da Shi Ren Bovis seu Bubali the endotheliocyte (MDBK) or the African green monkey kidney cell (Vero) that use VSV to infect carry out this experiment as test cell.

Embodiment 5: humanIFN-clone's separation

According to being described in US 5,789,551,5,869,293 and 6,001,589 method separation obtains 18 kinds of human interferon-alphas.In brief, by using the pcr analysis human gene group DNA of standard method.Used primer is described in Fig. 3 and 4 in this analysis.

18 kinds of human interferon-alphas that use this method to identify are: hu-IFN-α 001 (SEQ ID No:37), hu-IFN-α 002 (SEQ ID No:39), hu-IFN-α 003 (SEQ ID No:41), hu-IFN-α 004 (SEQ ID No:43), hu-IFN-α 005 (SEQ ID No:45), hu-IFN-α 006 (SEQ ID No:47), hu-IFN-α 007 (SEQ ID No:49), hu-IFN-α 008 (SEQ ID No:51), hu-IFN-α 009 (SEQ ID No:53), hu-IFN-α 010 (SEQ ID No:55), hu-IFN-α 011 (SEQ ID No:57), hu-IFN-α 012 (SEQ ID No:59), hu-IFN-α 013 (SEQ ID No:61), hu-IFN-α 014 (SEQ ID No:63), hu-IFN-α 015 (SEQ ID No:65), hu-IFN-α 016 (SEQ ID No:67), hu-IFN-α 017 (SEQ ID No:69), hu-IFN-α 018 (SEQ ID No:71).Also provide as follows corresponding to the aminoacid sequence of each in the middle of these: hu-IFN-α 001 (SEQ ID No:38), hu-IFN-α 002 (SEQ IDNo:40), hu-IFN-α 003 (SEQ ID No:42), hu-IFN-α 004 (SEQ ID No:44), hu-IFN-α 005 (SEQ ID No:46), hu-IFN-α 006 (SEQ ID No:48), hu-IFN-α 007 (SEQ ID No:50), hu-IFN-α 008 (SEQ ID No:52), hu-IFN-α 009 (SEQ ID No:54), hu-IFN-α 010 (SEQ ID No:56), hu-IFN-α 011 (SEQ ID No:58), hu-IFN-α 012 (SEQ ID No:60), hu-IFN-α 013 (SEQ ID No:62), hu-IFN-α 014 (SEQ ID No:64), hu-IFN-α 015 (SEQ ID No:66), hu-IFN-α 016 (SEQ ID No:68), hu-IFN-α 017 (SEQ ID No:70), hu-IFN-α 018 (SEQ ID No:72).

In addition, use the e. coli codon of optimization to hu-IFN-α 001 and hu-IFN-α 012 reverse translation (back translated) and called after hu-IFN-α 001-BT (SEQID No:73) and hu-IFN-α 012-BT (SEQ ID No:75).Also provide as follows corresponding to the aminoacid sequence of each in the middle of these: hu-IFN-α 001-BT (SEQ ID No:74) and hu-IFN-α 012-BT (SEQ ID No:76).

Embodiment 6: the separation of people IFN α variant

Contain in the process of expression vector of people IFN α of above detailed description at structure, produced the following clone who contains sudden change.Can test these IFN α variant activity.IFN α variant can contain reticent the replacement, therefore has the identical activity with wild type IFN α.In other words, variant can contain the replacement of this polypeptide active that changes.This replacement may increase, improves or enlarge active, is a kind of IFN alfa agonists therefore.In addition, this replacement may reduce or interferon activity, is a kind of IFN alpha-2 antagonists therefore.

The nucleotide sequence of variant provides as follows: hu-IFN-α 019 (SEQ ID No:77), hu-IFN-α 020 (SEQ ID No:79), hu-IFN-α 021 (SEQ ID No:81), hu-IFN-α 022 (SEQ ID No:83) and hu-IFN-α 023 (SEQ ID No:85).Also provide as follows corresponding to the aminoacid sequence of each in the middle of these: hu-IFN-α 019 (SEQID No:78), hu-IFN-α 020 (SEQ ID No:80), hu-IFN-α 021 (SEQ IDNo:82), hu-IFN-α 022 (SEQ ID No:84) and hu-IFN-α 023 (SEQ ID No:86).

Embodiment 7: the antiviral activity of people IFN α

Also use the CPE algoscopy to measure the antiviral activity of people IFN α, details is summarized as above.This algoscopy is used following test cell and virus combination: MDBK test cell and VSV; People's epithelium squamous cell (HEP-2) and VSV; Mice connective tissue fibroblast (L929) and EMC; People's lung squamous cell (H226) and VSV; And people's lung fibroblast and influenza virus.

Those skilled in the art will appreciate that maybe and can determine, only use routine test, can obtain many equivalents that are described in this particular of the present invention.Following claim is intended to comprise these equivalents.Multiple publication is incorporated in the application's the full text.The content of these publications is incorporated among the application as a reference at this.Referring to Figure 10 and the more detailed embodiment that illustrates 13.

Embodiment 8: interferon is to the inhibition of sars coronavirus cytopathic effect

Material and method:, will be added with 10% hyclone (FBS, the FRhk-4 cell (5 * 10 in MEM culture medium Invitrogen) for estimating the anti--SARS-CoV activity of interferon ³/ hole) be seeded in the 96 porocyte culture plates and overnight incubation.Then with the various forms of interferon incubations 1 hour of cell with the variable concentrations that is dissolved in 100 1MEM culture medium.Then infecting them with SARS-CoV (GZ50 strain) also cultivates.After infecting 24 hours with SARS-CoV, the degree of protection of the anti-SARS-CoV virocyte of the cell that is provided pathological changes effect obtains measuring by observe and write down cellular morphology under phase contrast microscope.Each test is parallel carries out three parts and repeat at least three times.The cell of Gan Raning not is flat, and the cell that SARS-CoV infects becomes refractive and arches upward.The grading that SARS-CoV brings out cytopathic effect is 0 (no CPE); ± 1 (weak CPE); ± 2 (moderate CP E); Not ± 3 (strong CPE does not add protective agent).

Preceding 16 hours of infection with cell inoculation in 96 hole wares.The conditioned medium of self-infection cell 10 times of serial dilutions and be used for infection cell in containing the MEM of 1%FBS in the future.Each dilution factor uses 10 holes, and 2 holes do not have viral infection in contrast.Under phase contrast microscope, write down CPE in back 24 hours in infection, and calculate the infectious titer (50% tissue culture infective dose) of virus according to standard method.

Result: referring to Fig. 5.External measuring SAR CoV, GZ50 separator to the test of the inhibition of the cytopathic effect of FRhk-4 monkey-kidney cells in the effectiveness of test I FN α 2a and new forms of interferon.As scheming the X finding, the IFN α 2b of 20ng/ml concentration can not suppress sars coronavirus fully and kill these cell activity in the culture medium.IFN α 012 is being more effective aspect these cells of protection, and the concentration of 20ng/ml just can be protected fully, and IC50 is between 0.8-0.16ng/ml.The IFN α 023 of 4ng/ml can more effectively give to protect fully, and IC50 is between 0.8-0.16ng/ml.

Embodiment 9: the inhibitory action that interferon duplicates SARS CoV

Material and method: cell and virus: African green monkey kidney cell (Vero 76) obtains from American type culture collection (ATCC; Manassas, VA, USA).This cell uses conventional method at additional 5% heat-inactivated fetal bovine serum (FBS; Hyclone Laboratories; Cultivate among the Logan UT, minimum essential medium USA) (MEM).For antiviral is measured, serum is reduced to 2% and to add final concentration be that the gentamycin of 50 μ g/ml is in culture medium.

Severe acute respiratory syndrome coronavirus (SARS CoV), Urbani strain (200300592) obtain from CDC and go down to posterity in Vero 76 cells with conventional method.

Cytopathic effect (CPE) suppresses to measure.Use .2001 (Barnard, D.L., Stowell, V.D., Seley, K.L., Hegde, V.R., Das, S.R., Rajappan, V.P., Schneller, S.W., Smee, D.F. ， ﹠amp such as Barnard; Sidwell, R.W.2001, Antiviral Chemistry﹠amp; Chemotherapy 12:221-230) experimental program.In this test, (four single log 10 or seven 1/2log10 dilution factors) test compounds one to twice under variable concentrations is utilized spectrophotometer check cell survival (as follows) by dimethyl diaminophenazine chloride (NR) picked-up test then on same culture plate.Isopyknic virus (infection multiplicity [MOI]=0.001) and chemical compound are added in the cell monolayer that the 80-90% in the 96 hole tissue culturing plates converges.In the hole of assessment interferon, before being exposed to virus, use interferon pretreatment hole 24 hours then.The MOI that uses makes the 100% cell showed cell pathological changes effect (CPE) in 3-5 days in the virus control.This culture plate shows viral completely CPE at the cell of 37 ℃ of following incubations in virus control, as observed by optical microscope.Measure the inhibitory action of every kind of drug level to viral CPE, three parts of parallel repetitions, for cytotoxic assay, two parts of parallel repetitions.6 holes on every microtest plate are reserved as cell contrast that infect, untreated, on every microtest plate 6 holes only add in the culture medium virus and as the contrast of virus replication.For every group of chemical compound being tested, Alferon is included as the positive control medicine.Based on for the algoscopy of CPE, for each concentration, the linear regression analysis of the CPE grading meansigma methods of the percent that 50% valid density (IC50) of interferon can contrast untreated by being expressed as, that do not infect is calculated for all.

The Cytotoxic dimethyl diaminophenazine chloride of CPE inhibitory action and chemical compound (NR) picked-up algoscopy.This is determined at above-mentioned identical CPE and suppresses to carry out on the test board to suppress active also by the visual observations cytotoxicity with check.By we grasped between range estimation and NR measure usually dependency greater than 95% (Barnard, D.L., Stowell, V.D., Seley, K.L., Hegde, V.R., Das, S.R., Rajappan, V.P., Schneller, S.W., Smee, D.F and Sidwell, R.W.2001, Antiviral Chemistry﹠amp; Chemotherapy12:221-230).This NR measures and uses as (Baniard, D.L., Sidwell, R.W. such as Barnard, Xiao, W., Player, M.R., Adah, S and Torrence, P.F. (1999) Antiviral Research 41:119-134) modification method (Cavenaugh, the P.R.Jr. of described Cavenaugh etc., Moskwa, P.S., Donish, W.H., Pera, P.J., Richardson, D and Andrese, A.P. (1990) Investigational New Drugs 8:347-354) carry out.

In brief, from each hole of culture plate, remove culture medium, 0.034%NR is added in each hole of culture plate and with this culture plate in the dark in 37 ℃ of incubations 2 hours.Remove NR solution from the hole, rinsing is also used the residual dyestuff of the S buffered alcohol extraction of rensonShi citrate buffer.With microplate reader (microplate reader) (Bio-Tek EL 1309; Bio-Tek Instruments, Inc., Winooski VT) reads 540nm/450nm place absorbance.The absorbance numeric representation is the percent of untreated control, and calculates the IC50 value as mentioned above.

Result: referring to Fig. 6.In the inhibiting algoscopy of external another kind of SARS CoV, tested the effectiveness of IFN α 2a and new forms of interferon inhibition SARS CoV.In these experiments, different Strain-Urbani and cell line-African green monkey kidney cell (Vero 76) have been used.When measuring, aspect the protection cell, only there is IFN α 012 more effective than IFN α 2a by the dimethyl diaminophenazine chloride picked-up.It is more effective than IFN α 2a that range estimation has confirmed that all three kinds of new forms of interferon (IFN α 003, α 023 and α 012) have all shown, IFN α 012 is proved to have the highest antiviral activity once more.

Embodiment 10: the inhibitory action that interferon duplicates respiratory syncytial virus

Material and method: in flat 96 well culture plates, in the Eagles MEM that mixes 5% hyclone (FBS), cultivate people embryo diploid fibroblast to converging.Infect cell monolayer with different RSV clinical isolates down at low MOI (about 0.01) then, virus treated absorption at room temperature 1 hour.Remove virus removal, also use MEM and the contrast of no medicine of the interpolation 2%FBS of the various interferon that contain serial dilution to replace PBS with PBS washing cell monolayer.At 36 ℃ of following incubations after 3 days, that cell is fixing and with 5%BSA/PBS sealing 1 hour in 0.05% glutaraldehyde/PBS.After the washing, the mouse monoclonal antibody (with A and the cross reaction of B hypotype) that adds dilution is to cell monolayer and 36 ℃ of following incubations 1 hour.After the washing, with albumen-A-HRP conjugate under recommended density in 36 ℃ with cell monolayer incubation 1 hour.After the washing, add substrate and pass through to add the dilute sulfuric acid stopped reaction.Measure 450nm place absorbance.Data are drawn and are measured 50% terminal point.

Result: referring to Fig. 7.In external respiratory syncytial virus (RSV) infection model, tested the effectiveness of IFN α 2a and new forms of interferon.For most of separators, IFN α 012 is more effective than IFN α 2a except that VS1511, and IFN α 023 is the most effective in the Strain of all tests.IFN α 003 and α 001 render a service not high in this test macro.

Embodiment 11: the effectiveness that interferon protection people lung fibroblast resisiting influenza virus infects

Material and method:, carry out viral sensitivity determination for determining available suitable virus titer in this algoscopy.Two rows' (duplicate rows) 100 μ l cells are cultivated on 96 hole microtitration plates with the concentration of 2.0E+5 people's lung fibroblast (HLF)/milliliter.Microtitration plate is placed 37 ℃ and 5.0%CO ₂Under spend the night.At second day, respectively microtitration plate is carried out the influenza virus titer determination.Titer plate is carried out serial dilution in 1: 2, obtain 24 parts of diluents altogether.Then these viral dilution liquid of 50 μ l are added on the cell of microtitration plate and place incubator to spend the night.At the 3rd day, with violet staining titer plate and dry.For obtaining to be used for the virus work diluent of this mensuration, used wherein to occur 3 holes of terminal point on last the right, hole that 100% cell kills.In this case, from the determined diluent of thinking the best of 1: 20 influenza virus diluent of our viral work mother solution.

Tire for obtaining interferon, at first interferon is diluted to about 8000U/ml in 90%DMEM, 10%FBS.This solution with 10 μ l adds in the culture medium of 190 μ l on the 96 hole microtitration plates then.Carry out 2 times of dilutions on this titer plate, preparation is 12 parts of interferon diluents altogether.A kind of people IFN α A laboratory standard thing of concentration known also is diluted to 1: 20 and serial dilution on this plate in first hole.To the HLF cell counting and be diluted to the concentration of 2.0E+5 cells/ml.These cells with 100 μ l add in each hole then.Then microtitration plate is placed on the platform agitator and vibrated 10 minutes.Then this titer plate is placed incubator (37 ℃, 5.0%CO ₂) in spend the night.At second day, influenza virus is diluted to predetermined concentration, promptly 1: 20, and add 50 μ l in each hole.Place incubator to spend the night titer plate again.Then also dry to titer plate dyeing with crystal violet.Tire for measuring interferon, measured and 50% terminal point that kills wherein occurs.Then, the terminal point with this terminal point and people IFN α A laboratory standard thing compares.

Result: referring to Fig. 8.In external influenza virus model, test the effectiveness of new forms of interferon, used WSN/A Strain (H1N1) and normal people's lung fibroblast (HLF).Having measured virocyte pathological changes effect 50% suppresses required IFN concentration and is expressed as relative potency.In this was measured, IFN α 003 was equivalent to IFN α 2a, and IFN α 001 effectiveness is lower.IFN α 012 is more than 20 times of IFN α 2a effectiveness.

Embodiment 12: the effectiveness that the anti-yellow fever virus of interferon protection hepatocyte infects

Material and method: with the flat 96 hole microtitration plates of HepG2 cell inoculation 0.1%I Collagen Type VI bag quilt of dilution in 1: 40 in PBS.Before the antiviral agent that interpolation is inferred, cultured cell converges (sub-confluent) monolayer to dividing.Flat part of chemical compound that repeats six parts added in B2 to the G2 hole, and on this titer plate, prepare 3 times of diluents (B2-B10, C2-C10 etc.).There is not chemical compound to add the 11st row to.

There was under the cell situation incubation chemical compound 27 hours.Add yellow fever virus strain 17D (original seed 6) in B, C and D are capable in cell, every hole 50 μ l are to provide 500pfu/ the hole.When occurring fully killing the cell of viral infection, measure the cell of survival by XTT and the PMS that in every hole, adds 25 μ l/ holes, and with titer plate 37 ℃ of following incubations 1 hour.Before the sealing titer plate, titer plate is cooled to room temperature continues 10 minutes, analyze the titer plate absorbance at the 450nm place with spectrophotometer.

Result: referring to Fig. 9.New forms of interferon protection HepG2 hepatocyte is not compared by effectiveness and the IFN α 2a that yellow fever virus kills.IFN α 012 is effective slightly than IFN α 2a, and IFN α 003 and α 023 are obviously more effective than IFN α 2a.Because YFV is relevant especially with hepatitis C virus, it can be used as the model of hepatitis C test.

Embodiment 13: the comparison of IFN α 2a and Novel IFN s in the various kinds of cell type of attacking with different virus

Material and method: antiviral determination experiment scheme:

HEp-2 cell/VSV

For being identified for the suitable virus titer of this mensuration, at first carry out viral sensitivity determination.Two rows' 100 μ l cells are cultivated on 96 hole microtitration plates with the concentration of 3.0E+5 HEp-2 cells/ml.Microtitration plate is placed 37 ℃, 5.0%CO ₂Under spend the night.At second day, respectively microtitration plate is carried out the VSV titer determination.Titer plate is carried out serial dilution in 1: 2, obtain 24 parts of diluents altogether.Then these viral dilution liquid of 50 μ l are added on the cell of microtitration plate and place incubator to spend the night.At the 3rd day, with violet staining titer plate and dry.For obtaining to be used for the virus work diluent of this mensuration, used wherein to occur 3 holes of terminal point on last the right, hole that 100% cell kills.In this case, from our viral 1 of the mother solution of working: the 150VSV diluent is determined thinks best diluent.

For measuring interferon IC50, at first interferon is diluted to about 8000U/ml in 90%DMEM, 10%FBS.This solution with 10 μ l adds in the culture medium of 190 μ l on the 96 hole microtitration plates then.In this titer plate preparation, carry out 2 times of dilutions, to obtain 12 parts of interferon diluents altogether.A kind of people IFN α A laboratory standard thing of concentration known also is diluted to 1: 20 and serial dilution on this plate in first hole.To the HEP-2 cell counting and be diluted to the concentration of 3.0E+5 cells/ml.These cells with 100 μ l add in each hole then.Then microtitration plate is placed on the platform agitator and vibrated 10 minutes.Then this titer plate is placed incubator (37 ℃, 5.0%CO ₂) in spend the night.At second day, VSV is diluted to predetermined concentration, promptly 1: 150, and add 50 μ l in each hole.Once more, place incubator to spend the night titer plate.Then also dry to titer plate dyeing with crystal violet.Tire for measuring interferon, measured and 50% terminal point that kills wherein occurs.Then, the terminal point with this terminal point and people IFN α A laboratory standard thing compares.

H226 cell/VSV

For being identified for the suitable virus titer of this mensuration, at first carry out viral sensitivity determination.Two rows' 100 μ l cells are cultivated on 96 hole microtitration plates with the concentration of 2.5E+5H226 cells/ml.Microtitration plate is placed 37 ℃, 5.0%CO ₂Under spend the night.At second day, respectively microtitration plate is carried out the VSV titration.Titer plate is carried out serial dilution in 1: 2, obtain 24 parts of diluents altogether.Then these viral dilution liquid of 50 μ l are added on the cell of microtitration plate and place incubator to spend the night.At the 3rd day, with violet staining titer plate and dry.For obtaining to be used for the virus work diluent of this mensuration, used wherein to occur 3 holes of terminal point on last the right, hole that 100% cell kills.In this case, from our viral 1 of the mother solution of working: the 1000VSV diluent is determined thinks best diluent.

For measuring interferon IC50, at first interferon is diluted to about 8000U/ml in 90%RPMI, 10%FBS.This solution with 10 μ l adds in the culture medium of 190 μ l on the 96 hole microtitration plates then.On this titer plate, carry out 2 times of dilutions, to obtain 12 parts of interferon diluents altogether.A kind of people IFN α A laboratory standard thing of concentration known also is diluted to 1: 20 and serial dilution on this plate in first hole.To the H226 cell counting and be diluted to the concentration of 2.5E+5 cells/ml.These cells with 100 μ l add in each hole then.Then microtitration plate is placed on the platform agitator and vibrated 10 minutes.Then this titer plate is placed incubator (37 ℃, 5.0%CO ₂) in spend the night.At second day, VSV is diluted to predetermined concentration, promptly 1: 1000, and add 50 μ l in each hole.Once more, place incubator to spend the night titer plate.Then also dry to titer plate dyeing with crystal violet.Tire for measuring interferon, measured and 50% terminal point that kills wherein occurs.Then, the terminal point with this terminal point and people IFN α A laboratory standard thing compares.

HLF cell/influenza virus

For mensuration is used for the suitable virus titer of this mensuration, at first carry out viral sensitivity determination.Two rows' 100 μ l cells are cultivated on 96 hole microtitration plates with the concentration of 2.0E+5HLF cells/ml.Microtitration plate is placed 37 ℃, 5.0%CO ₂Under spend the night.At second day, respectively microtitration plate is carried out the influenza virus titer determination.Titer plate is carried out serial dilution in 1: 2, obtain 24 parts of diluents altogether.Then these viral dilution liquid of 50 μ l are added on the cell of microtitration plate and place incubator to spend the night.At the 3rd day, with violet staining titer plate and dry.For obtaining to be used for the virus work diluent of this mensuration, used wherein to occur 3 holes of terminal point on last the right, hole that 100% cell kills.In this case, be determined the diluent of thinking the best from our 1: 20 influenza virus diluent of virus work mother solution.

For measuring interferon IC50, at first interferon is diluted to about 8000U/ml in 90%DMEM, 10%FBS.This solution with 10 μ l adds in the culture medium of 190 μ l on the 96 hole microtitration plates then.On this titer plate, carry out 2 times of dilutions, to obtain 12 parts of interferon diluents altogether.A kind of people IFN α A laboratory standard thing of concentration known also is diluted to 1: 20 and serial dilution on this plate in first hole.To the HLF cell counting and be diluted to the concentration of 2.0E+5 cells/ml.These cells with 100 μ l add in each hole then.Then microtitration plate is placed on the platform agitator and vibrated 10 minutes.Then this titer plate is placed incubator (37 ℃, 5.0%CO ₂) in spend the night.At second day, influenza virus is diluted to predetermined concentration, promptly 1: 20, and add 50 μ l in each hole.Once more, place incubator to spend the night titer plate.Then also dry to titer plate dyeing with crystal violet.Tire for measuring interferon, measured and 50% terminal point that kills wherein occurs.Then, the terminal point with this terminal point and people IFN α A laboratory standard thing compares.

L cell/EMCV

For being identified for the suitable virus titer of this mensuration, at first carry out viral sensitivity determination.Double 100 μ l cells are cultivated on 96 hole microtitration plates with the concentration of 3.0E+5L cells/ml.Microtitration plate is placed 37 ℃, 5.0%CO ₂Under spend the night.At second day, respectively microtitration plate is carried out the EMCV titer determination.Titer plate is carried out serial dilution in 1: 2, obtain 24 parts of diluents altogether.Then these viral dilution liquid of 50 μ l are added on the cell of microtitration plate and place incubator to spend the night.At the 3rd day, with violet staining titer plate and dry.For obtaining to be used for the virus work diluent of this mensuration, used wherein to occur 3 holes of terminal point on last the right, hole that 100% cell kills.In this case, from our viral 1 of the mother solution of working: the 2000EMCV diluent is determined thinks best diluent.

For measuring interferon IC50, at first interferon is diluted to about 8000U/ml in 90%MEM, 10%FBS.This solution with 10 μ l adds in the culture medium of 190 μ l on the 96 hole microtitration plates then.On this titer plate, carry out 2 times of dilutions, to obtain 12 parts of interferon diluents altogether.A kind of people IFN α A laboratory standard thing of concentration known also is diluted to 1: 20 and serial dilution on this plate in first hole.To the HEP-2 cell counting and be diluted to the concentration of 3.0E+5 cells/ml.These cells with 100 μ l add in each hole then.Then microtitration plate is placed on the platform agitator and vibrated 10 minutes.Then this titer plate is placed incubator (37 ℃, 5.0%CO ₂) in spend the night.At second day, EMCV is diluted to predetermined concentration, promptly 1: 2000, and add 50 μ l in each hole.Once more, place incubator to spend the night titer plate.Then also dry to titer plate dyeing with crystal violet.Tire for measuring interferon, measured and 50% terminal point that kills wherein occurs.Then, the terminal point with this terminal point and people IFN α A laboratory standard thing compares.

Result: referring to Figure 10.Having measured new forms of interferon protection various kinds of cell is the effectiveness that antiviral is attacked.Described cell line is cattle cell line, MDBK, mouse cell line, L cell and 3 kinds of human cell line HEP-2, H226 and HLF.IFN α 012 and α 023 are better than IFN α 2a (not test of IFN α 023 in HLF/Flu measures) in everyone cell line test.Confirmed the remarkable activity (being about 70 times that IFN α 2a renders a service) of 012 pair of Mus cell of IFN α in addition, and IFN α 2a effectiveness is very low.Just might more be willing in the mouse model that infects, use this IFN than other.

Difference at different virus/these IFN relative effectivenes of cell centering shows that selected IFN or selected IFN combination may be the first-selections that the treatment specific virus infects.For example, IFN α 003 infects obviously more effective at the anti-VSV of protection HEP-2 cell than IFN α 2a, and IFN α 003 effectiveness is similar to IFN α 2a in the test of HLF/Flu virus.

Though also should be understood that not confirm IFN α 021 and IFN α 018 tool antiviral activity efficiently in the listed algoscopy of this paper, clear other virus/cell combination may be high response to these IFN.In other words, should expect these IFN allows to can be used as the IFN antagonist under the active condition of adjusting endogenous IFN at some.

Sequence table

＜110〉Pestka Biomedical Lab Inc.

＜120〉use interferon therapy severe acute respiratory syndrome and other viral infection

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85 90 95

Leu?Glu?Ala?Cys?Val?Val?Gln?Glu?Val?Gly?Glu?Gly?Glu?Ala?Pro?Leu

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Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Ile?Val?Arg

130 135 140

Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser?Thr?Ala?Leu?Gln?Lys

145 150 155 160

Arg?Leu?Arg?Ser?Glu?Lys

165

<210>5

<211>516

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(513)

<223>

<400>5

tgt?gac?ctg?cct?cag?acc?cac?ggc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?ggc?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Gly?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcc?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttt?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ctg?cag?gag?gtg?gag?gag?gga?gag?gct?ccc?ctg 336

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?att?cat?ccc?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc 384

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

caa?aga?ctc?tcc?ctc?tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc 432

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

tgg?gag?atc?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca 480

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

aca?gcc?ttg?cag?aaa?aga?tta?agg?agc?gag?aaa?tga 516

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>6

<211>171

<212>PRT

＜213〉cat

<400>6

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Gly?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>7

<211>516

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(513)

<223>

<400>7

tgt?gac?ctg?cct?cag?acc?cac?gtc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?gac?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcg?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttt?tgc?scg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ccg?cag?gag?gtg?gag?gag?gga?gag?gct?ccc?ctg 336

Leu?Glu?Ala?Cys?Val?Pro?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?att?cat?ccc?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc 384

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

caa?aga?ctc?tcc?ctc?tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc 432

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

tgg?gag?atc?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca 480

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

aca?gcc?ttg?cag?aaa?aga?tta?agg?agc?gag?aaa?tga 516

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>8

<211>171

<212>PRT

＜213〉cat

<400>8

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Pro?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>9

<211>516

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(513)

<223>

<400>9

tgt?gac?ctg?cct?cag?acc?cac?ggc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?gac?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcg?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttt?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ctg?cag?gag?gtg?gag?gag?gga?gag?gct?ccc?ctg 336

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?att?car?ccc?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc 384

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

caa?aga?ctc?tcc?ctc?tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc 432

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

tgg?gag?atc?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca 480

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

aca?gcc?ttg?cag?aaa?aga?tta?agg?agc?gag?aaa?tga 516

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>10

<211>171

<212>PRT

＜213〉cat

<400>10

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>11

<211>516

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(513)

<223>

<400>11

tgt?gac?ctg?cct?cag?acc?cac?ggc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?gac?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcg?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttc?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ctg?cag?gag?gtg?gag?gag?gga?gag?gct?ccc?ctg 336

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?att?cat?ccc?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc 384

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

caa?aga?ctc?tcc?ctc?tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc 432

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

tgg?gag?atc?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca 480

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

aca?gcc?ttg?cag?aaa?aga?tta?agg?agc?gag?aaa?tga 516

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>12

<211>171

<212>PRT

＜213〉cat

<400>12

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>13

<211>516

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(513)

<223>

<400>13

tgt?gac?ctg?cct?cag?acc?cac?ggc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?gac?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcg?tct?gct?gct?tgg?aat?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttt?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ctg?cag?gag?gtg?gag?gag?gga?gag?gct?ccc?ctg 336

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?att?cat?ccc?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc 384

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

caa?aga?ctc?tcc?ctc?tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc 432

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

tgg?gag?atc?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca 480

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

aca?gcc?ttg?cag?aaa?aga?tta?agg?agc?gag?aaa?tga 516

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>14

<211>171

<212>PRT

＜213〉cat

<400>14

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>15

<211>516

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(513)

<223>

<400>15

tgt?gac?ctg?cct?cag?acc?cac?gtc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?gac?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcg?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttt?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ctg?cag?gag?gtg?gag?gag?gga?gag?gct?ccc?ctg 336

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?att?cat?ccc?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc 384

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

caa?aga?ctc?tcc?ctc?tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc 432

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

tgg?gag?atc?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca 480

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

aca?gcc?ttg?cag?aaa?aga?tta?agg?agc?gag?aaa?tga 516

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>16

<211>171

<212>PRT

＜213〉cat

<400>16

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>17

<211>501

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(498)

<223>

<400>17

tgt?gac?ctg?cct?cag?acc?cac?gtc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?gac?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcg?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttc?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?gtg?cag?gag?gtg?ggg?gag?gga?gag?gct?ccc?ctc 336

Leu?Glu?Ala?Cys?Val?Val?Gln?Glu?Val?Gly?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc?caa?aga?ctc?tcc?ctc 384

Thr?Asn?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe?Gln?Arg?Leu?Ser?Leu

115 120 125

tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?atc?gtc?aga 432

Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Ile?Val?Arg

130 135 140

gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca?aca?gcc?ttg?cag?aaa 480

Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser?Thr?Ala?Leu?Gln?Lys

145 150 155 160

aga?tta?agg?agc?gag?aaa?tga 501

Arg?Leu?Arg?Ser?Glu?Lys

165

<210>18

<211>166

<212>PRT

＜213〉cat

<400>18

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Val?Gln?Glu?Val?Gly?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe?Gln?Arg?Leu?Ser?Leu

115 120 125

Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Ile?Val?Arg

130 135 140

Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser?Thr?Ala?Leu?Gln?Lys

145 150 155 160

Arg?Leu?Arg?Ser?Glu?Lys

165

<210>19

<211>516

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(513)

<223>

<400>19

tgt?gac?ctg?cct?cag?acc?cac?ggc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?ggc?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Gly?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcc?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttt?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ctg?cag?gag?gtg?gag?gag?gga?gag?gct?ccc?ctg 336

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?att?cat?ccc?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc 384

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

caa?aga?ctc?tcc?ctc?tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc 432

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

tgg?gag?atc?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca 480

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

aca?gcc?ttg?cag?aaa?aga?tta?agg?agc?gag?aaa?tga 516

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>20

<211>171

<212>PRT

＜213〉cat

<400>20

Cys?Asp?Leu?Pro?Gln?Thr?His?Gly?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Gly?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>21

<211>516

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(513)

<223>

<400>21

tgt?gac?ctg?cct?cag?acc?cac?gtc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?gac?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcg?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttc?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ctg?cag?gag?gtg?gag?gag?gga?gag?gct?ccc?ctg 336

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?att?cat?ccc?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc 384

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

caa?aga?ctc?tcc?ctc?tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc 432

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

tgg?gag?atc?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca 480

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

aca?gcc?ttg?cag?aaa?aga?tta?agg?agc?gag?aaa?tga 516

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>22

<211>171

<212>PRT

＜213〉cat

<400>22

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>23

<211>501

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(498)

<223>

<400>23

tgt?gac?ctg?cct?cag?acc?cac?gtc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?tcc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?gac?cag?tcc 144

Arg?Asn?Asp?Ser?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcg?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttc?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ctg?cag?gag?gtg?ggg?gag?gga?gag?gct?ccc?ctc 336

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Gly?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc?caa?aga?ctc?tcc?ctc 384

Thr?Asn?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe?Gln?Arg?Leu?ser?Leu

115 120 125

tac?ctg?caa?gag?aag?aaa?tcc?agc?cct?tgt?gcc?tgg?gag?atc?gtc?aga 432

Tyr?Leu?Gln?Glu?Lys?Lys?Ser?Ser?Pro?Cys?Ala?Trp?Glu?Ile?Val?Arg

130 135 140

gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca?aca?gcc?ttg?cag?aaa 480

Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser?Thr?Ala?Leu?Gln?Lys

145 150 155 160

aga?tta?agg?agc?gag?aaa?tga 501

Arg?Leu?Arg?Ser?Glu?Lys

165

<210>24

<211>166

<212>PRT

＜213〉cat

<400>24

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Ser?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Leu?Gln?Glu?Val?Gly?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe?Gln?Arg?Leu?Ser?Leu

115 120 125

Tyr?Leu?Gln?Glu?Lys?Lys?Ser?Ser?Pro?Cys?Ala?Trp?Glu?Ile?Val?Arg

130 135 140

Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser?Thr?Ala?Leu?Gln?Lys

145 150 155 160

Arg?Leu?Arg?Ser?Glu?Lys

165

<210>25

<211>516

<212>DNA

＜213〉cat

<220>

<221>CDS

<222>(1)..(513)

<223>

<400>25

tgt?gac?ctg?cct?cag?acc?cac?gtc?ctg?ctg?aac?agg?agg?gcc?ttg?acg 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

ctc?ctg?gga?caa?atg?agg?aga?ctc?cct?gcc?agc?tcc?tgt?cag?aag?gac 96

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

aga?aat?gac?ttc?gcc?ttc?ccc?cag?gac?gtg?ttc?ggt?gga?gac?cag?tcc 144

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

cac?aag?gcc?caa?gcc?ctc?tcg?gtg?gtg?cac?gtg?acg?aac?cag?aag?atc 192

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

ttc?cac?ttc?ttc?tgc?aca?gag?gcg?tcc?tcg?tct?gct?gct?tgg?aac?acc 240

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

acc?ctc?ctg?gag?gaa?ttt?tgc?acg?gga?ctt?gat?cgg?cag?ctg?acc?cgc 288

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

ctg?gaa?gcc?tgt?gtc?ccg?cag?gag?gtg?gag?gag?gga?gag?gct?ccc?ctg 336

Leu?Glu?Ala?Cys?Val?Pro?Gln?Glu?Val?Glu?Glu?Gly?GLu?Ala?Pro?Leu

100 105 110

acg?aac?gag?gac?att?cat?ccc?gag?gac?tcc?atc?ctg?agg?aac?tac?ttc 384

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

caa?aga?ctc?tcc?ctc?tac?ctg?caa?gag?aag?aaa?tac?agc?cct?tgt?gcc 432

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

tgg?gag?atc?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttg?tat?tat?tca?tca 480

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

aca?gcc?ttg?cag?aaa?aga?tta?agg?agc?gag?aaa?tga 516

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?Lys

165 170

<210>26

<211>171

<212>PRT

＜213〉cat

<400>26

Cys?Asp?Leu?Pro?Gln?Thr?His?Val?Leu?Leu?Asn?Arg?Arg?Ala?Leu?Thr

1 5 10 15

Leu?Leu?Gly?Gln?Met?Arg?Arg?Leu?Pro?Ala?Ser?Ser?Cys?Gln?Lys?Asp

20 25 30

Arg?Asn?Asp?Phe?Ala?Phe?Pro?Gln?Asp?Val?Phe?Gly?Gly?Asp?Gln?Ser

35 40 45

His?Lys?Ala?Gln?Ala?Leu?Ser?Val?Val?His?Val?Thr?Asn?Gln?Lys?Ile

50 55 60

Phe?His?Phe?Phe?Cys?Thr?Glu?Ala?Ser?Ser?Ser?Ala?Ala?Trp?Asn?Thr

65 70 75 80

Thr?Leu?Leu?Glu?Glu?Phe?Cys?Thr?Gly?Leu?Asp?Arg?Gln?Leu?Thr?Arg

85 90 95

Leu?Glu?Ala?Cys?Val?Pro?Gln?Glu?Val?Glu?Glu?Gly?Glu?Ala?Pro?Leu

100 105 110

Thr?Asn?Glu?Asp?Ile?His?Pro?Glu?Asp?Ser?Ile?Leu?Arg?Asn?Tyr?Phe

115 120 125

Gln?Arg?Leu?Ser?Leu?Tyr?Leu?Gln?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

130 135 140

Trp?Glu?Ile?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Tyr?Tyr?Ser?Ser

145 150 155 160

Thr?Ala?Leu?Gln?Lys?Arg?Leu?Arg?Ser?Glu?tys

165 170

<210>27

<211>501

<212>DNA

＜213〉macaque

<220>

<221>CDS

<222>(1)..(498)

<223>

<400>27

tgt?gat?ctg?cct?gag?acc?cac?agc?ctg?gat?aac?agg?aag?acc?atg?atg 48

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Asp?Asn?Arg?Lys?Thr?Met?Met

1 5 10 15

ctc?ctg?gca?cag?atg?agc?aga?atc?tct?cct?tcc?tcc?tgt?ctg?atg?gac 96

Leu?Leu?Ala?Gln?Met?Ser?Arg?Ile?Ser?Pro?Ser?Ser?Cys?Leu?Met?Asp

20 25 30

aga?cat?gac?ttt?gga?ttt?ccc?cag?cag?gag?ttt?gat?ggc?aac?cag?ttc 144

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Gln?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

cag?aag?gct?cca?gcc?atc?tct?gtc?ctc?cat?gag?ctg?atc?cag?cag?acc 192

Gln?Lys?Ala?Pro?Ala?Ile?Ser?Val?Leu?His?Glu?Leu?Ile?Gln?Gln?Thr

50 55 60

ttc?aac?ctc?ttt?acc?aca?aaa?gac?tca?tct?gct?gct?tgg?gat?gag?gac 240

Phe?Asn?Leu?Phe?Thr?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Asp

65 70 75 80

ctc?cta?gac?aaa?ttc?tgc?act?gaa?ctc?tac?cag?cag?ctg?aat?gac?ttg 288

Leu?Leu?Asp?Lys?Phe?Cys?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

gaa?gcc?tgt?gtc?atg?cag?cag?gag?agg?gtg?gga?gaa?act?ccc?Gtg?atg 336

Glu?Ala?Cys?Val?Met?Gln?Gln?Glu?Arg?Val?Gly?Glu?Thr?Pro?Leu?Met

100 105 110

aat?gcg?gac?tcc?acc?ttg?gct?gtg?aag?aaa?tac?ttc?cga?aga?atc?act 384

Asn?Ala?Asp?Ser?Thr?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Arg?Arg?Ile?Thr

115 120 125

ctc?tat?ctg?aca?gag?aag?aas?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tct?ttc?tct?tta?tca?aca?aac?ttg?caa?gaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Thr?Asn?Leu?Gln?Glu

145 150 155 160

aga?tta?agg?agg?aag?gaa?taa 501

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>28

<211>166

<212>PRT

＜213〉macaque

<400>28

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Asp?Asn?Arg?Lys?Thr?Met?Met

1 5 10 15

Leu?Leu?Ala?Gln?Met?Ser?Arg?Ile?Ser?Pro?Ser?Ser?Cys?Leu?Met?Asp

20 25 30

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Gln?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

Gln?Lys?Ala?Pro?Ala?Ile?Ser?Val?Leu?His?Glu?Leu?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Thr?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Asp

65 70 75 80

Leu?Leu?Asp?Lys?Phe?Cys?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

Glu?Ala?Cys?Val?Met?Gln?Gln?Glu?Arg?Val?Gly?Glu?Thr?Pro?Leu?Met

100 105 110

Asn?Ala?Asp?Ser?Thr?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Arg?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Thr?Asn?Leu?Gln?Glu

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>29

<211>501

<212>DNA

＜213〉macaque

<220>

<221>CDS

<222>(1)..(498)

<223>

<400>29

tgt?gat?ctg?cct?gag?acc?cac?agc?ctg?ggt?aat?agg?agg?gcc?ttg?ata 48

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

ctc?ctg?gca?caa?atg?gga?aga?atc?tct?cat?ttc?tcc?tgc?ctg?aag?gac 96

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?His?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

aga?cat?gat?ttc?gga?ttc?ccc?gag?gag?gag?ttt?gat?ggc?cac?cag?ttc 144

Arg?His?Asp?Phe?Gly?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly?His?Gln?Phe

35 40 45

cag?aag?act?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag?cag?acc 192

Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr

50 55 60

ttc?aat?ctc?ttc?agc?aca?gag?gac?tca?tct?gct?gct?tgg?gaa?cag?agc 240

Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser

65 70 75 80

ctc?cta?gaa?aaa?ttt?tcc?act?gaa?ctt?tac?cag?caa?ctg?aat?gac?ctg 288

Leu?Leu?Glu?Lys?Phe?ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

gaa?gca?tgt?gtg?ata?cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg 336

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 110

aat?gtg?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa?aga?atc?act 384

Asn?Val?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

ctt?tat?cta?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tcc?ctc?tcg?ttt?tca?aca?aac?ttg?caa?aaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

aga?tta?agg?agg?aag?gaa?taa 501

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>30

<211>166

<212>PRT

＜213〉macaque

<400>30

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?His?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

Arg?His?Asp?Phe?Gly?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly?His?Gln?Phe

35 40 45

Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser

65 70 75 80

Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 1l0

Asn?Val?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>31

<211>501

<212>DNA

＜213〉macaque

<220>

<221>CDS

<222>(1)..(498)

<223>

<400>31

tgt?gat?ctg?cct?gag?acc?cac?agc?ctg?gat?aac?agg?aag?acc?atg?atg 48

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Asp?Asn?Arg?Lys?Thr?Met?Met

1 5 10 15

ctc?ctg?gca?cag?atg?agc?aga?atc?tct?cct?tcc?tcc?tgt?ctg?atg?gac 96

Leu?Leu?Ala?Gln?Met?Ser?Arg?Ile?Ser?Pro?Ser?Ser?Cys?Leu?Met?Asp

20 25 30

aga?cat?gac?ttt?gga?ttt?ccc?cag?cag?gag?ttt?gat?ggc?aac?cag?ttc 144

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Gln?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

cag?aag?gct?cca?gcc?atc?tct?gtc?ctc?cat?gag?ctg?atc?cag?cag?acc 192

Gln?Lys?Ala?Pro?Ala?Ile?Ser?Val?Leu?His?Glu?Leu?Ile?Gln?Gln?Thr

50 55 60

ttc?aac?ctc?ttt?acc?aca?aaa?gac?tca?tct?gct?gct?tgg?gat?gag?gac 240

Phe?Asn?Leu?Phe?Thr?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Asp

65 70 75 80

ctc?cta?gac?aaa?ttc?tgc?act?gaa?ctc?tac?cag?cag?ctg?aat?gac?ttg 288

Leu?Leu?Asp?Lys?Phe?Cys?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

gaa?gcc?tgt?gtc?atg?cag?cag?gag?agg?gtg?gga?gaa?act?ccc?ctg?atg 336

Glu?Ala?Cys?Val?Met?Gln?Gln?Glu?Arg?Val?Gly?Glu?Thr?Pro?Leu?Met

100 105 110

aat?gcg?gac?tcc?acc?ttg?gct?gtg?aag?aaa?tac?ttc?cga?aga?atc?act 384

Asn?Ala?Asp?Ser?Thr?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Arg?Arg?Ile?Thr

115 120 125

ctc?tat?ctg?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tcc?ttc?tct?tta?tca?aca?aac?ttg?caa?gaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Thr?Asn?Leu?Gln?Glu

145 150 155 160

aga?tta?agg?agg?aag?gaa?taa 501

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>32

<211>166

<212>PRT

＜213〉macaque

<400>32

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Asp?Asn?Arg?Lys?Thr?Met?Met

1 5 10 15

Leu?Leu?Ala?Gln?Met?Ser?Arg?Ile?Ser?Pro?Ser?Ser?Cys?Leu?Met?Asp

20 25 30

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Gln?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

Gln?Lys?Ala?Pro?Ala?Ile?Ser?Val?Leu?His?Glu?Leu?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Thr?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Asp

65 70 75 80

Leu?Leu?Asp?Lys?Phe?Cys?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

Glu?Ala?Cys?Val?Met?Gln?Gln?Glu?Arg?Val?Gly?Glu?Thr?Pro?Leu?Met

100 105 110

Asn?Ala?Asp?Ser?Thr?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Arg?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Thr?Asn?Leu?Gln?Glu

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>33

<211>501

<212>DNA

＜213〉macaque

<220>

<221>CDS

<222>(1)..(498)

<223>

<400>33

tgt?gat?ctg?cct?gag?acc?cac?agc?ctg?gat?aac?agg?aag?acc?atg?atg 48

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Asp?Asn?Arg?Lys?Thr?Met?Met

1 5 10 15

ctc?ctg?gca?cag?atg?agc?aga?atc?tct?cct?tcc?tcc?tgt?ctg?atg?gac 96

Leu?Leu?Ala?Gln?Met?Ser?Arg?Ile?Ser?Pro?Ser?Ser?Cys?Leu?Met?Asp

20 25 30

aga?cat?gac?ttt?gga?ttt?ccc?cag?cag?gag?ttt?gat?ggc?aac?cag?ttc 144

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Gln?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

cag?aag?gct?cca?gcc?atc?tct?gtc?ctc?cat?gag?ctg?atc?cag?cag?acc 192

Gln?Lys?Ala?Pro?Ala?Ile?Ser?Val?Leu?His?Glu?Leu?Ile?Gln?Gln?Thr

50 55 60

ttc?aac?ctc?ttt?acc?aca?aaa?gac?tca?tct?gct?gct?tgg?gat?gag?gac 240

Phe?Asn?Leu?Phe?Thr?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Asp

65 70 75 80

ctc?cta?gac?aaa?ttc?tgc?act?gaa?ctc?tac?cag?cag?ctg?aat?gac?ttg 288

Leu?Leu?Asp?Lys?Phe?Cys?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

gaa?gcc?tgt?gtc?atg?cag?cag?gag?agg?gtg?gga?gaa?act?ccc?ctg?atg 336

Glu?Ala?Cys?Val?Met?Gln?Gln?Glu?Arg?Val?Gly?Glu?Thr?Pro?Leu?Met

100 105 110

aat?gcg?gac?tcc?acc?ttg?gct?gtg?aag?aaa?tac?ttc?cga?aga?atc?act 384

Asn?Ala?Asp?Ser?Thr?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Arg?Arg?Ile?Thr

115 120 125

ctc?tat?ctg?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tct?ttc?tct?tta?tca?aca?aac?ttg?caa?gaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Thr?Asn?Leu?Gln?Glu

145 150 155 160

aga?tta?agg?agg?aag?gaa?taa 501

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>34

<211>166

<212>PRT

＜213〉macaque

<400>34

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Asp?Asn?Arg?Lys?Thr?Met?Met

1 5 10 15

Leu?Leu?Ala?Gln?Met?Ser?Arg?Ile?Ser?Pro?Ser?Ser?Cys?Leu?Met?Asp

20 25 30

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Gln?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

Gln?Lys?Ala?Pro?Ala?Ile?Ser?Val?Leu?His?Glu?Leu?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Thr?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Asp

65 70 75 80

Leu?Leu?Asp?Lys?Phe?Cys?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

Glu?Ala?Cys?Val?Met?Gln?Gln?Glu?Arg?Val?Gly?Glu?Thr?Pro?Leu?Met

100 105 110

Asn?Ala?Asp?Ser?Thr?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Arg?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Thr?Asn?Leu?Gln?Glu

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>35

<211>501

<212>DNA

＜213〉macaque

<220>

<221>CDS

<222>(1)..(498)

<223>

<400>35

tgt?gat?ctg?cct?gag?acc?cac?agc?ctg?gat?aac?aga?agg?acc?atg?atg 48

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Asp?Asn?Arg?Arg?Thr?Met?Met

1 5 10 15

ctc?ctg?aaa?caa?atg?agc?aga?atc?tct?cct?tcc?tcc?tgt?ctg?atg?gac 96

Leu?Leu?Lys?Gln?Met?Ser?Arg?Ile?Ser?Pro?Ser?Ser?Cys?Leu?Met?Asp

20 25 30

aga?cat?gac?ttt?gga?ttt?ccc?cag?cag?gag?ttt?gat?ggc?aac?cag?ttc 144

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Gln?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

cag?aag?gct?cca?gcc?atc?tct?gtc?ctc?cat?gag?ctg?atc?cag?cag?acc 192

Gln?Lys?Ala?Pro?Ala?Ile?Ser?Val?Leu?His?Glu?Leu?Ile?Gln?Gln?Thr

50 55 60

ttc?aac?ctc?ttt?acc?aca?aaa?gac?tca?tct?gct?gct?tgg?gat?gag?gac 240

Phe?Asn?Leu?Phe?Thr?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Asp

65 70 75 80

ctc?cta?gac?aaa?ttc?tgc?act?gaa?ctc?tac?cag?cag?ctg?aat?gac?ttg 288

Leu?Leu?Asp?Lys?Phe?Cys?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

gaa?gcc?tgt?gtc?atg?cag?cag?gag?agg?gtg?gga?gaa?act?ctc?ctg?atg 336

Glu?Ala?Cys?Val?Met?Gln?Gln?Glu?Arg?Val?Gly?Glu?Thr?Leu?Leu?Met

100 105 110

aat?gcg?gac?tcc?acc?ttg?gct?gtg?aag?aaa?tac?ttc?cga?aga?atc?act 384

Asn?Ala?Asp?Ser?Thr?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Arg?Arg?Ile?Thr

115 120 125

ctc?tat?ctg?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tcc?ttc?tct?tta?tca?aca?aac?ttg?caa?gaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Thr?Asn?Leu?Gln?Glu

145 150 155 160

aga?tta?agg?agg?aag?gaa?taa 501

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>36

<211>166

<212>PRT

＜213〉macaque

<400>36

Cys?Asp?Leu?Pro?Glu?Thr?His?Ser?Leu?Asp?Asn?Arg?Arg?Thr?Met?Met

1 5 10 15

Leu?Leu?Lys?Gln?Met?Ser?Arg?Ile?Ser?Pro?Ser?Ser?Cys?Leu?Met?Asp

20 25 30

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Gln?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

Gln?Lys?Ala?Pro?Ala?Ile?Ser?Val?Leu?His?Glu?Leu?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Thr?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Asp

65 70 75 80

Leu?Leu?Asp?Lys?Phe?Cys?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

Glu?Ala?Cys?Val?Met?Gln?Gln?Glu?Arg?Val?Gly?Glu?Thr?Leu?Leu?Met

100 105 110

Asn?Ala?Asp?Ser?Thr?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Arg?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Thr?Asn?Leu?Gln?Glu

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>37

<211>570

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(1)..(567)

<223>

<400>37

atg?gcc?ttg?tcc?ttt?tct?tta?ctg?atg?gtc?gtg?ctg?gta?ctc?agc?tac 48

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Val?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

aaa?tcc?atc?tgc?tct?ctg?ggc?tgt?gat?ctg?cct?cag?acc?cac?agc?ctg 96

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

cgt?aat?agg?agg?gcc?ttg?ata?ctc?ctg?gca?caa?atg?gga?aga?atc?tct 144

Arg?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

cct?ttc?tcc?tgc?ttg?aag?gac?aga?cat?gaa?ttc?aga?ttc?cca?gag?gag 192

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu

50 55 60

gag?ttt?gat?ggc?cac?cag?ttc?cag?aag?act?caa?gcc?atc?tct?gtc?ctc 240

Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

cat?gag?atg?atc?cag?cag?acc?ttc?aat?ctc?ttc?agc?aca?gag?gac?tca 288

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

tct?gct?gct?tgg?gaa?cag?agc?ctc?cta?gaa?aaa?ttt?tcc?act?gaa?ctt 336

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

tac?cag?caa?ctg?aat?gac?ctg?gaa?gca?tgt?gtg?ata?cag?gag?gtt?ggg 384

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

gtg?gaa?gag?act?ccc?ctg?atg?aat?gag?gac?tcc?atc?ctg?gct?gtg?agg 432

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

aaa?tac?ttc?caa?aga?atc?act?ctt?tat?cta?aca?gag?aag?aaa?tac?agc 480

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tcc?ctc?tcg 528

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

ttt?tca?aca?aac?ttg?caa?aaa?aga?tta?agg?agg?aag?gat?tga 570

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>38

<211>189

<212>PRT

＜213〉homo sapiens

<400>38

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Val?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Arg?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu

50 55 60

Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?GIu?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>39

<211>753

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(102)..(572)

<223>

<400>39

atagctagca?tgcgcaaatt?taaagcgctg?attcagaaaa?cctagaggcc?gcggttcaag 60

ttacccacct?caggtagcct?agtgatattt?gcaaaatccc?a?atg?gcc?cgg?tcc?ttt 116

Met?Ala?Arg?Ser?Phe

1 5

tct?tta?ctg?atg?gtc?gtg?ctg?gta?ctc?agc?tac?aaa?tcc?atc?tgc?tct 164

Ser?Leu?Leu?Met?Val?Val?Leu?Val?Leu?Ser?Tyr?Lys?Ser?Ile?Cys?Ser

10 15 20

ctg?ggc?tgt?gat?ctg?cct?cag?acc?cac?agc?ctg?cgt?aat?agg?agg?gcc 212

Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Arg?Asn?Arg?Arg?Ala

25 30 35

ttg?ata?ctc?ctg?gca?caa?atg?gga?aga?atc?tct?cct?ttc?tcc?tgc?ttg 260

Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu

40 45 50

aag?gac?aga?cat?gaa?ttc?aga?ttc?cca?gag?gag?gag?ttt?gat?ggc?aac 308

Lys?Asp?Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly?Asn

55 60 65

cag?ttc?cag?aag?act?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag 356

Gln?Phe?Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln

70 75 80 85

cag?acc?ttc?aat?ctc?ttc?agc?aca?gag?gac?tca?tct?gct?gct?tgg?gaa 404

Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu

90 95 100

cag?agc?ttc?cta?gaa?aaa?ttt?tcc?act?gaa?ctt?tac?cag?caa?ctg?aat 452

Gln?Ser?Phe?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn

105 110 115

aac?ttg?gaa?gca?tgt?gtg?ata?cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc 500

Asn?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro

120 125 130

ctg?atg?aat?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa?aga 548

Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg

135 140 145

atc?act?ctt?tat?cta?aca?gag?aag?aaatacagcc?cttgtgcctg?ggaggttgtc 602

Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys

150 155

agagcagaaa?tcatgagatc?cctctcgttt?tcaacaaact?tgcaaaaaag?attaaggagg 662

aaggattgaa?acctggttca?acatggaaat?gatcctgatt?gactaataca?ttatctcaca 722

ctttcatgat?tcttccaatc?gatcgcgcgc?a 753

<210>40

<211>157

<212>PRT

＜213〉homo sapiens

<400>40

Met?Ala?Arg?Ser?Phe?Ser?Leu?Leu?Met?Val?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Arg?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Phe?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

Tyr?Gln?Gln?Leu?Asn?Asn?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys

145 150 155

<210>41

<211>755

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(103)..(672)

<223>

<220>

＜221〉multiple character

<222>(733)..(733)

＜223〉n=a, c,, g, or t

<400>41

tatagctagc?atgcgcaaat?ttaaagcgct?gatcagaaaa?cctagaggcc?gaagttcaag 60

gttatccatc?tcaagtagcc?tagcaatatt?tgcaacatcc?ca?atg?gcc?ctg?tcc 114

Met?Ala?Leu?Ser

1

ttt?tct?tta?ctg?atg?gtc?gtg?ctg?gtg?ctc?agc?tac?aaa?tcc?atc?tgt 162

Phe?Ser?Leu?Leu?Met?Val?Val?Leu?Val?Leu?Ser?Tyr?Lys?Ser?Ile?Cys

5 10 15 20

tct?ctg?ggc?tgt?gat?ctg?cct?cag?acc?cac?agc?ctg?ggt?aat?agg?agg 210

Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg

25 30 35

gcc?ttg?ata?ctc?ctg?gga?caa?atg?gga?aga?atc?tct?cct?ttt?tcc?tgc 258

Ala?Leu?Ile?Leu?Leu?Gly?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys

40 45 50

ctg?aag?gac?aga?cat?gat?ttc?cga?atc?ccc?cag?gag?gag?ttt?gat?ggc 306

Leu?Lys?Asp?Arg?His?Asp?Phe?Arg?Ile?Pro?Gln?Glu?Glu?Phe?Asp?Gly

55 60 65

aac?cag?ttc?cag?aag?gct?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?ttc 354

Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Phe

70 75 80

cag?cag?acc?ttc?aat?ctc?ttc?agc?aca?gag?gac?tca?tct?gct?gct?tgg 402

Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp

85 90 95 100

gaa?cag?agc?ctc?cta?gaa?aaa?ttt?tcc?act?gaa?ctt?tac?cag?caa?ctg 450

Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu

105 110 115

aat?gac?ctg?gaa?gca?tgt?gtg?ata?cag?gag?gtt?ggg?atg?gaa?gag?act 498

Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Met?Glu?Glu?Thr

120 125 130

ccc?ctg?atg?aat?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa 546

Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln

135 140 145

aga?atc?act?ctt?tat?cta?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg 594

Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp

150 155 160

gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tct?ctc?tct?ttt?tca?aca?aac 642

Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn

165 170 175 180

ttg?caa?aaa?ata?tta?agg?agg?aag?gat?tga?aaactggttc?aacatggcaa 692

Leu?Gln?Lys?Ile?Leu?Arg?Arg?Lys?Asp

185

tgatcctgat?tgactaatac?attatctcac?actttcatga?ntcttccaat?cgatcgcgcg 752

cac 755

<210>42

<211>189

<212>PRT

＜213〉homo sapiens

<400>42

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Val?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Gly?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Arg?Ile?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Phe?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Met?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Ile?Leu?Arg?Arg?Lys?Asp

180 185

<210>43

<211>759

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(758)..(758)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(86)..(655)

<223>

<400>43

gtgcgcgcga?tcgattcaga?aaacctagag?gccgaagttc?aaggttatcc?atctcaagta 60

gcctagcaat?atttgcaaca?tccca?atg?gcc?ctg?tcc?ttt?tct?tta?ctt?atg 112

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met

1 5

gcc?gtg?ctg?gtg?ctc?agc?tac?aaa?tcc?atc?tgt?tct?cta?ggc?tgt?gat 160

Ala?Val?Leu?Val?Leu?Ser?Tyr?Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp

10 15 20 25

ctg?cct?cag?acc?cac?agc?ctg?ggt?aat?agg?agg?gcc?ttg?ata?ctc?ctg 208

Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu

30 35 40

gca?caa?atg?gga?aga?atc?tct?cct?ttc?tcc?tgc?ctg?aag?gac?aga?cat 256

Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His

45 50 55

gat?ttc?cga?atc?ccc?cag?gag?gag?ttt?gat?ggc?aac?cag?ttc?cag?aag 304

Asp?Phe?Arg?Ile?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys

60 65 70

gct?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag?cag?acc?ttc?aat 352

Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn

75 80 85

ctc?ttc?agc?aca?gag?gac?tca?tct?gct?gct?tgg?gaa?cag?agc?ctc?cta 400

Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu

90 95 100 105

gaa?aaa?ttt?tcc?act?gaa?ctt?tac?cag?caa?ctg?aat?gac?ctg?gaa?gca 448

Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala

110 115 120

tgt?gtg?ata?cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg?aat?gag 496

Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu

125 130 135

gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa?aga?atc?act?ctt?tat 544

Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?phe?Gln?Arg?Ile?Thr?Leu?Tyr

140 145 150

cta?ata?gag?agg?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca 592

Leu?Ile?Glu?Arg?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala

155 160 165

gaa?atc?atg?aga?tcc?ctc?tcg?ttt?tca?aca?aac?ttg?caa?aaa?aga?tta 640

Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu

170 175 180 185

agg?agg?aag?gat?tga?aaactggttc?aacatggcaa?tgatcctgat?tgactaatac 695

Arg?Arg?Lys?Asp

attatctcac?actttcatga?gttcttccaa?tcagcgcttt?aaatttgcgc?atgctagcta 755

tant 759

<210>44

<211>189

<212>PRT

＜213〉homo sapiens

<400>44

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Arg?Ile?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Ile?Glu?Arg?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>45

<211>756

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(105)..(674)

<223>

<400>45

atatagctag?catgcgcaaa?tttaaagcgc?tgattcagaa?aacctagagg?ccgaagttca 60

aggttaccca?tctcaagtag?cctagcaaca?tttgcaacat?ccca?atg?gcc?ctg?tcc 116

Met?Ala?Leu?Ser

1

ttt?tct?tta?ctg?atg?gcc?gtg?ctg?gtg?ctc?agc?tac?aaa?tcc?atc?tgt 164

Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr?Lys?Ser?Ile?Cys

5 10 15 20

tct?cta?ggc?tgt?gat?ctg?cct?cag?acc?cac?agc?ctg?ggt?aat?agg?agg 212

Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg

25 30 35

gcc?ttg?ata?ctc?ctg?gca?caa?atg?gga?aga?atc?tct?cct?ttc?tcc?tgc 260

Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys

40 45 50

ctg?aag?gac?aga?cat?gac?ttt?gga?ctt?ccc?cag?gag?gag?ttt?gat?ggc 308

Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Leu?Pro?Gln?Glu?Glu?Phe?Asp?Gly

55 60 65

aac?cag?ttc?cag?aag?act?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc 356

Asn?Gln?Phe?Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile

70 75 80

cag?cag?aec?ttc?aat?ctc?ttc?agc?aca?aag?gat?tca?tct?gct?gct?tgg 404

Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp

85 90 95 100

gat?gag?agc?ctc?cta?gac?aaa?ttc?tac?att?gaa?ctt?ttc?cag?caa?ctg 452

Asp?Glu?Ser?Leu?Leu?Asp?Lys?Phe?Tyr?Ile?Glu?Leu?Phe?Gln?Gln?Leu

105 110 115

aat?gtc?cta?gaa?gcc?tgt?gtg?aca?cag?gag?gtt?ggg?gtg?gaa?gag?att 500

Asn?Val?Leu?Glu?Ala?Cys?Val?Thr?Gln?Glu?Val?Gly?Val?Glu?Glu?Ile

120 125 130

gcc?ctg?atg?aat?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttt?caa 548

Ala?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln

135 140 145

aga?atc?act?ctt?tat?ctg?atg?ggg?aag?aaa?tac?agc?cct?tgt?gcc?tgg 596

Arg?Ile?Thr?Leu?Tyr?Leu?Met?Gly?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp

150 155 160

gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttc?tct?ttt?tca?aca?aac 644

Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Phe?Ser?Thr?Asn

165 170 175 180

ttg?caa?aaa?gga?tta?aga?agg?aag?gat?tga?aaactcattc?aacatggaaa 694

Leu?Gln?Lys?Gly?Leu?Arg?Arg?Lys?Agp

185

tgatcctcat?tgattaatac?atcatctcac?actttcatga?ttcttccaat?cgatcgcgcg 754

ca 756

<210>46

<211>189

<212>PRT

＜213〉homo sapiens

<400>46

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Leu?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Asp?Glu?Ser?Leu?Leu?Asp?Lys?Phe?Tyr?Ile?Glu?Leu

100 105 110

Phe?Gln?Gln?Leu?Asn?Val?Leu?Glu?Ala?Cys?Val?Thr?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Ile?Ala?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Met?Gly?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Gly?Leu?Arg?Arg?Lys?Asp

180 185

<210>47

<211>756

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(1)..(755)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(86)..(655)

<223>

<400>47

tggcgcgcga?tcgattcaga?aaacctagag?gccgaagttc?aaggttatcc?atctcaagta 60

gcctagcaat?atttgcaaca?tccca?atg?gcc?ctg?tcc?ttt?tct?tta?ctt?atg 112

Met?Ala?LeL?Ser?Phe?Ser?Leu?Leu?Met

1 5

gcc?gtg?ctg?gtg?ctc?agc?tac?aaa?tcc?atc?tgt?tct?cta?ggc?tgt?gat 160

Ala?Val?Leu?Val?Leu?Ser?Tyr?Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp

10 15 20 25

ctg?cct?cag?acc?cac?agc?ctg?ggt?aat?agg?agg?gcc?tcg?ata?ctc?ctg 208

Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Ser?Ile?Leu?Leu

30 35 40

gga?caa?atg?gga?aga?atc?tct?cct?ttc?tcc?tgc?ctg?aag?gac?aga?cat 256

Gly?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His

45 50 55

gat?ttc?cga?atc?ccc?cag?gag?gag?ttt?gat?ggc?aac?cag?ttc?cag?aag 304

Asp?Phe?Arg?Ile?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys

60 65 70

gct?caa?gcc?atc?tct?gcc?ttc?cat?gag?atg?atc?cag?cag?acc?ttc?aat 352

Ala?Gln?Ala?Ile?Ser?Ala?Phe?His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn

75 80 85

ctc?ttc?agc?aca?aag?gat?tca?tct?gct?gct?tgg?gat?gag?acc?ctc?cta 400

Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Thr?Leu?Leu

90 95 100 105

gac?aaa?ttc?tac?att?gaa?ctt?ttc?cag?caa?ctg?aat?gac?cta?gaa?gcc 448

Asp?Lys?Phe?Tyr?Ile?Glu?Leu?Phe?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala

110 115 120

tgt?gtg?aca?cag?gag?gtt?ggg?gtg?gaa?gag?att?gcc?ctg?atg?aat?gag 496

Cys?Val?Thr?Gln?Glu?Val?Gly?Val?Glu?Glu?Ile?Ala?Leu?Met?Asn?Glu

125 130 135

gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttt?caa?aga?atc?act?ctt?tat 544

Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr

140 145 150

ctg?atg?ggg?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca 592

Leu?Met?Gly?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala

155 160 165

gaa?atc?atg?aga?tcc?ttc?tct?ttt?tca?aca?aac?ttg?caa?aaa?gga?tta 640

Glu?Ile?Met?Arg?Ser?Phe?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys?Gly?Leu

170 175 180 185

aga?agg?aag?gat?tga?aaactcattc?aacatggaaa?tgatcctcat?tgattaatac 695

Arg?Arg?Lys?Asp

atcatctcac?actttcatga?gttcttccaa?tcagcgcttt?aaatttgcgc?atgctaggtn 755

t 756

<210>48

<211>189

<212>PRT

＜213〉homo sapiens

<400>48

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Ser?Ile?Leu?Leu?Gly?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Arg?Ile?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Ala?Phe

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Asp?Glu?Thr?Leu?Leu?Asp?Lys?Phe?Tyr?Ile?Glu?Leu

100 105 110

Phe?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Thr?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Ile?Ala?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Met?Gly?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Gly?Leu?Arg?Arg?Lys?Asp

180 185

<210>49

<211>758

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(757)..(757)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(85)..(654)

<223>

<400>49

tgcgcgcgat?cgattcagaa?aacctagagg?ccgaagttca?aggttatcca?tctcaagtag 60

cctagcaata?tttgcaacat?ccca?atg?gcc?ctg?tcc?ttt?tct?tta?ctg?atg 111

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met

1 5

gcc?gtg?ctg?gtg?ctc?agc?tac?aaa?tcc?atc?tgt?tct?ctg?ggc?tgt?gat 159

Ala?Val?Leu?Val?Leu?Ser?Tyr?Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp

10 15 20 25

ctg?cct?cag?acc?cac?agc?ctg?ggt?aat?agg?agg?gcc?ttg?ata?ctc?ctg 207

Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu

30 35 40

gca?caa?atg?gga?aga?atc?tct?cat?ttc?tcc?tgc?ctg?aag?gac?aga?cat 255

Ala?Gln?Met?Gly?Arg?Ile?Ser?His?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His

45 50 55

gat?ttc?gga?ttc?ccc?gag?gag?gag?ttt?gat?ggc?cac?cag?ttc?cag?aag 303

Asp?Phe?Gly?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys

60 65 70

gct?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag?cag?acc?ttc?aat 351

Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn

75 80 85

ctc?ttc?agc?aca?gag?gac?tca?tct?gct?gct?tgg?gaa?cag?agc?ctc?cta 399

Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu

90 95 100 105

gaa?aaa?ttt?tcc?act?gaa?ctt?tac?cag?caa?ctg?aat?gac?ctg?gaa?gca 447

Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala

110 115 120

tgt?gtg?ata?cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg?aat?gag 495

Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu

125 130 135

gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa?aga?atc?act?ctt?tat 543

Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr

140 145 150

cta?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca 591

Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala

155 160 165

gaa?atc?atg?aga?tcc?ctc?tcg?ttt?tca?aca?aac?ttg?caa?aaa?aga?tta 639

Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu

170 175 180 185

agg?agg?aag?gat?tga?aacctggttc?aacatggaaa?tgatcctgat?tgactaatac 694

Arg?Arg?Lys?Asp

attatctcac?actttcatga?gttcttccaa?tcagcgcttt?aaatttgcgc?atgctagcta 754

ccnc 758

<210>50

<211>189

<212>PRT

＜213〉homo sapiens

<400>50

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

His?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Glu?Glu

50 55 60

Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Ays?Phe?Ser?Thr?Glu?Leu

100 105 110

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 l55 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>51

<211>896

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(1)..(896)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(63)..(632)

<223>

<400>51

atgctcgctg?cgcaaattaa?agcgctgatc?tcaagtagcc?tagcaatatt?ggcaacatcc 60

ca?atg?gcc?ctg?tcc?ttt?tct?tta?ctg?atg?gcc?gtg?ctg?gtg?ctc?agc 107

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser

1 5 10 15

tac?aaa?tcc?atc?tgt?tct?ctg?ggc?tgt?gat?ctg?cct?cag?acc?cac?agc 155

Tyr?Lys?Ser?Ile?Cys?ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser

20 25 30

ctg?ggt?aat?agg?agg?gcc?ttg?ata?ctc?ctg?gca?caa?gtg?gga?aga?atc 203

Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Val?Gly?Arg?Ile

35 40 45

tct?cat?ttc?tcc?tgc?ctg?aag?gac?aga?cat?gat?ttc?gga?ttc?ccc?gag 251

Ser?His?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Glu

50 55 60

gag?gag?ttt?gat?ggc?cac?cag?ttc?cag?aag?gct?caa?gcc?atc?tct?gtc 299

Glu?Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val

65 70 75

ctc?cat?gag?atg?atc?cag?cag?acc?ttc?aat?ctc?ttc?agc?aca?gag?gac 347

Leu?His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp

80 85 90 95

tca?tct?gct?gct?tgg?gaa?cag?agc?ctc?cta?gaa?aaa?ttt?tcc?act?gaa 395

Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu

100 105 110

ctt?tac?cag?caa?ctg?aat?gac?ctg?gaa?gca?tgt?gtg?ata?cag?gag?gtt 443

Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val

115 120 125

ggg?gtg?gaa?gag?act?ccc?ctg?atg?aat?gag?gac?tcc?atc?ctg?gct?gtg 491

Gly?Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val

130 135 140

agg?aaa?tac?ttc?caa?aga?atc?act?ctt?tat?cta?aca?gag?aag?aaa?tac 539

Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr

145 150 155

agc?cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tcc?ctc 587

Ser?Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu

160 165 170 175

tcg?ttt?tca?aca?aac?ttg?caa?aaa?aga?tta?agg?agg?aag?gat?tga 632

Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

aacctggttc?aacatggaaa?tgatctgtat?tgactaatac?atcgatcgcg?cgcagatctn 692

ctgttcgaat?tccngatgag?ctgcataatc?ttttanggta?atgcgttggt?ccatacaacc 752

ttcttagtac?atgcaaccat?ttnaccggca?gangtaaaat?agtcaacacg?cacngngtta 812

gatattatcc?ttgcggngat?agattaacgt?ntgagcccaa?aaaagaaacc?cttacccaag 872

aaccacttga?ggaccncgtn?gcct 896

<210>52

<211>189

<212>PRT

＜213〉homo sapiens

<400>52

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Val?Gly?Arg?Ile?Ser

35 40 45

His?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Glu?Glu

50 55 60

Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>53

<211>741

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(1)..(741)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(66)..(635)

<223>

<400>53

gnnnnnnnna?gngtgtgttn?nttnnnngat?ctntttgaaa?tcccagcaat?attggcaaca 60

tccca?atg?gcc?ctg?tcc?ttt?tct?tta?ctg?atg?gcc?gtg?ctg?gtg?ctc?agc 110

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser

1 5 10 15

tac?aaa?tcc?atc?tgt?tct?ctg?ggc?tgt?gat?ctg?cct?cag?acc?cac?agc 158

Tyr?Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser

20 25 30

ctg?ggt?aat?agg?agg?gcc?ttg?ata?ctc?ctg?gca?caa?atg?gga?aga?atc 206

Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile

35 40 45

tct?cat?ttc?tcc?tgc?ctg?aag?gac?aga?cat?gat?ttc?gga?ttc?ccc?gag 254

Ser?His?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Glu

50 55 60

gag?gag?ttt?gat?ggc?cac?cag?ttc?cag?aag?gct?caa?gcc?atc?tct?gtc 302

Glu?Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val

65 70 75

ctc?cat?gag?atg?atc?cag?cag?acc?ttc?aat?ctc?ttc?agc?aca?gag?gac 350

Leu?His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp

80 85 90 95

tca?tct?gct?gct?tgg?gaa?cag?agc?ctc?cta?gaa?aaa?ttt?tcc?act?gaa 398

Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu

100 105 110

ctt?tac?cag?caa?ctg?aat?gac?ctg?gaa?gca?tgt?gtg?ata?cag?gag?gtt 446

Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val

115 120 125

ggg?gtg?gaa?gag?act?ccc?ctg?atg?aat?gag?gac?tcc?atc?ctg?gct?gtg 494

Gly?Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val

130 135 140

agg?aaa?tac?ttc?caa?aga?atc?act?ctt?tat?cta?ata?gag?agg?aaa?tac 542

Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Ile?Glu?Arg?Lys?Tyr

145 150 155

agc?cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tcc?ctc 590

Ser?Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu

160 165 170 175

tcg?ttt?tca?aca?aac?ttg?caa?aaa?aga?tta?agg?agg?aag?gat?tga 635

Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

aaactggttc?aacatggaaa?tgatctgtat?tgactaatat?cagcgctttg?natttgcgca 695

acggncatca?aanttcaann?nnaacncann?nnnncnnnnn?nnnnnc 741

<210>54

<211>189

<212>PRT

＜213〉homo sapiens

<400>54

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

His?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Glu?Glu

50 55 60

Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Ile?Glu?Arg?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>55

<211>756

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(104)..(673)

<223>

<400>55

tatagctagc?atgcgcaaat?ttaaagcgct?gattcagaaa?acctagaggc?cgaagttcaa 60

ggttatccat?ctcaagtagc?ctagcaatat?ttgcaacatc?cca?atg?gcc?ctg?tcc 115

Met?Ala?Leu?Ser

1

ttt?tct?tta?ctg?acg?gcc?gtg?ctg?gtg?ctc?agc?tac?aaa?tcc?atc?tgt 163

Phe?Ser?Leu?Leu?Thr?Ala?Val?Leu?Val?Leu?Ser?Tyr?Lys?Ser?Ile?Cys

5 10 15 20

tct?ctg?ggc?tgt?gat?ctg?cct?cag?acc?cac?agc?ctg?ggt?aat?agg?agg 211

Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg

25 30 35

gcc?ttg?ata?ctc?ctg?gca?caa?atg?gga?aga?atc?tct?cat?ttc?tcc?tgc 259

Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?His?Phe?Ser?Cys

40 45 50

ctg?aag?gac?aga?cat?gat?ttc?gga?ttc?ccc?gag?gag?gag?ttt?gat?ggc 307

Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly

55 60 65

cac?cag?ttc?cag?aag?gct?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc 355

His?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile

70 75 80

cag?cag?acc?ttc?aat?ctc?ttc?agc?aca?gag?gac?tca?tct?gct?gct?tgg 403

Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp

85 90 95 100

gaa?cag?agc?ctc?cta?gaa?aaa?ttt?tcc?act?gaa?ctt?tac?cag?caa?ctg 451

Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu

105 110 115

aat?gac?ctg?gaa?gca?tgt?gtg?ata?cag?gag?gtt?ggg?gtg?gaa?gag?act 499

Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr

120 125 130

ccc?ctg?atg?aat?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa 547

Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln

135 140 145

aga?atc?act?ctt?tat?cta?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg 595

Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?ser?Pro?Cys?Ala?Trp

150 155 160

gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tcc?ctc?tcg?ttt?tca?aca?aac 643

Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn

165 170 175 180

ttg?caa?aaa?aga?tta?agg?agg?aag?gat?tga?aacctggttc?aacatggaaa 693

Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

185

tgatcctgat?tgactaatac?attatctcac?actttcatga?ttcttccaat?cgatcgcgcg 753

cac 756

<210>56

<211>189

<212>PRT

＜213〉homo sapiens

<400>56

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Thr?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

His?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Glu?Glu

50 55 60

Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>57

<211>878

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(1)..(878)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(58)..(627)

<223>

<400>57

ttgacgcccc?cttgttaccc?ctcatcaacc?agcccagcag?catcttcggg?attccca 57

atg?gca?ttg?ccc?ttt?gct?tta?atg?atg?gcc?ctg?gtg?gtg?ctc?agc?tgc 105

Met?Ala?Leu?Pro?Phe?Ala?Leu?Met?Met?Ala?Leu?Val?Val?Leu?Ser?Cys

1 5 10 15

aag?tca?agc?tgc?tct?ctg?ggc?tgt?aat?ctg?tct?caa?acc?cac?agc?ctg 153

Lys?Ser?Ser?Cys?Ser?Leu?Gly?Cys?Asn?Leu?Ser?Gln?Thr?His?Ser?Leu

20 25 30

aat?aac?agg?agg?act?ttg?atg?ctc?atg?gca?caa?atg?agg?aga?atc?tct 201

Asn?Asn?Arg?Arg?Thr?Leu?Met?Leu?Met?Ala?Gln?Met?Arg?Arg?Ile?Ser

35 40 45

cct?ttc?tcc?tgc?ctg?aag?gac?aga?cat?gac?ttt?gaa?ttt?ccc?cag?gag 249

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu

50 55 60

gaa?ttt?gat?ggc?aac?cag?ttc?cag?aaa?gct?caa?gcc?atc?tct?gtc?ctc 297

Glu?Phe?Asp?Gly?ASn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

cat?gag?atg?atg?cag?cag?acc?ttc?aat?ctc?ttc?agc?aca?aag?aac?tca 345

His?Glu?Met?Met?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asn?Ser

85 90 95

tct?gct?gct?tgg?gat?gag?gcc?ctc?cta?gaa?aaa?ttc?tac?att?gaa?ctt 393

Ser?Ala?Ala?Trp?Asp?Glu?Ala?Leu?Leu?Glu?Lys?Phe?Tyr?Ile?Glu?Leu

100 105 110

ttc?cag?caa?atg?aat?gac?ctg?gaa?gcc?tgt?gtg?ata?cag?gag?gtt?ggg 441

Phe?Gln?Gln?Met?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

gtg?gaa?gag?act?ccc?ctg?atg?aat?gag?gac?tcc?atc?ctg?gct?gtg?aag 489

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Lys

130 135 140

aaa?tac?ttc?caa?aga?atc?act?ctt?tat?ctg?atg?gag?aag?aaa?tac?agc 537

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Met?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tcc?ctc?tct 585

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

ttt?tca?aca?aac?ttg?caa?aaa?aga?tta?agg?agg?aag?gat?tga 627

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

aaactggttc?atcatggaaa?tgattcatca?gcgctttaaa?tttgcgcatg?ctagctatag 687

ttctagaggt?cgaaattcac?ctcgaaaagc?aagctgatna?accgatncaa?ttnaaggctc 747

cnttttggag?cctttttttt?ttggagattt?tcaaccgtga?aaaaantatt?attcgcaatt 807

ccagctaant?cacctcgaaa?gcaagcttga?tnaanccgtt?ccaattaaan?gcttcctttg 867

gaggcctttt?t 878

<210>58

<211>189

<212>PRT

＜213〉homo sapiens

<400>58

Met?Ala?Leu?Pro?Phe?Ala?Leu?Met?Met?Ala?Leu?Val?Val?Leu?Ser?Cys

1 5 10 15

Lys?Ser?Ser?Cys?Ser?Leu?Gly?Cys?Asn?Leu?Ser?Gln?Thr?His?Ser?Leu

20 25 30

Asn?Asn?Arg?Arg?Thr?Leu?Met?Leu?Met?Ala?Gln?Met?Arg?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Met?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asn?Ser

85 90 95

Ser?Ala?Ala?Trp?Asp?Glu?Ala?Leu?Leu?Glu?Lys?Phe?Tyr?Ile?Glu?Leu

100 105 110

Phe?Gln?Gln?Met?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Lys

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Met?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>59

<211>869

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(1)..(869)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(77)..(646)

<223>

<400>59

tttgaagtcc?gttgcgcana?ttcaaagcgc?tgattacccc?tcatcaacca?gcccagcagc 60

atcttcggga?ttccca?atg?gca?ttg?ccc?ttt?gct?tta?atg?atg?gcc?ctg?gtg 112

Met?Ala?Leu?Pro?Phe?Ala?Leu?Met?Met?Ala?Leu?Val

1 5 10

gtg?ctc?agc?tgc?aag?tca?agc?tgc?tct?ctg?ggc?tgt?aat?ctg?tct?caa 160

Val?Leu?Ser?Cys?Lys?Ser?Ser?Cys?Ser?Leu?Gly?Cys?Asn?Leu?Ser?Gln

15 20 25

acc?tac?agc?ctg?aat?aac?agg?agg?act?ttg?atg?ctc?atg?gca?caa?atg 208

Thr?Tyr?Ser?Leu?Asn?Asn?Arg?Arg?Thr?Leu?Met?Leu?Met?Ala?Gln?Met

30 35 40

agg?aga?atc?tct?cct?ttc?tcc?tgc?ctg?aag?gac?aga?cat?gac?ttt?gaa 256

Arg?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Glu

45 50 55 60

ttt?ccc?cag?gag?gaa?ttt?gat?ggc?aac?cag?ttc?cag?aaa?gct?caa?gcc 304

Phe?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala

65 70 75

atc?tct?gtc?ctc?cat?gag?atg?atg?cag?cag?acc?ttc?aat?ctc?ttc?agc 352

Ile?Ser?Val?Leu?His?Glu?Met?Met?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser

80 85 90

aca?aag?aac?tca?tct?gct?gct?tgg?gat?gag?acc?ctc?cta?gaa?aaa?ttc 400

Thr?Lys?Asn?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Thr?Leu?Leu?Glu?Lys?Phe

95 100 105

tac?att?gaa?ctt?ttc?cag?caa?atg?aat?gac?ctg?gaa?gcc?tgt?gtg?ata 448

Tyr?Ile?Glu?Leu?Phe?Gln?Gln?Met?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile

110 115 120

cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg?aat?gag?gac?tcc?atc 496

Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile

125 130 135 140

ctg?gct?gtg?aag?aaa?tac?ttc?caa?aga?atc?act?ctt?tat?ctg?atg?gag 544

Leu?Ala?Val?Lys?Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Met?Glu

145 150 155

aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc?atg 592

Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met

160 165 170

aga?tcc?ctc?tct?ttt?tca?aca?aac?ttg?caa?aaa?aga?tta?agg?agg?aag 640

Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys

175 180 185

gat?tga?aaactggttc?atcatggaaa?tgattcatcg?atcgcgcgca?gatctcctgt 696

Asp

tcgaattccg?gatgagctgc?ataatctttc?anggtaatgc?gttggtncat?acaaccttct 756

tagtacatgc?aaccattata?ccgncagagg?taaaatagtc?aacacgcacn?gnggtagata 816

ttatcccttg?cggggataga?ttaacgtntg?acncaaaaag?aaccattacn?can 869

<210>60

<211>189

<212>PRT

＜213〉homo sapiens

<400>60

Met?Ala?Leu?Pro?Phe?Ala?Leu?Met?Met?Ala?Leu?Val?Val?Leu?Ser?Cys

1 5 10 15

Lys?Ser?Ser?Cys?Ser?Leu?Gly?Cys?Asn?Leu?Ser?Gln?Thr?Tyr?Ser?Leu

20 25 30

Agn?Asn?Arg?Arg?Thr?Leu?Met?Leu?Met?Ala?Gln?Met?Arg?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Met?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asn?Ser

85 90 95

Ser?Ala?Ala?Trp?Asp?Glu?Thr?Leu?Leu?Glu?Lys?Phe?Tyr?Ile?Glu?Leu

100 105 110

Phe?Gln?Gln?Met?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Lys

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Met?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>61

<211>679

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(1)..(679)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(81)..(650)

<223>

<400>61

nttgttttnt?nnnnagngaa?nctttttgcn?caaatccaag?cgctgatctc?aagtagccta 60

gcaatattgg?caacatccca?atg?gcc?ctg?tcc?ttt?tct?tta?ctg?atg?gcc?gtg 113

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val

1 5 10

ctg?gtg?ctc?agc?tac?aaa?tcc?atc?tgt?tct?ctg?ggc?tgt?gat?ctg?cct 161

Leu?Val?Leu?Ser?Tyr?Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro

15 20 25

cag?acc?cac?agc?ctg?ggt?aat?agg?agg?gcc?ttg?ata?ctc?ctg?gca?caa 209

Gln?Thr?His?ger?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln

30 35 40

atg?gga?aga?atc?tct?cct?ttc?tcc?tgc?ctg?aag?gac?aga?cat?gac?ttt 257

Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe

45 50 55

gga?ttc?ccc?caa?gag?gag?ttt?gat?ggc?aac?cag?ttc?cag?aag?gct?caa 305

Gly?Phe?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln

60 65 70 75

gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag?cag?acc?ttc?aat?ctc?ttc 353

Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe

80 85 90

agc?aca?aag?gac?tca?tct?gct?act?tgg?gaa?cag?agc?ctc?cta?gaa?aaa 401

Ser?Thr?Lys?Asp?Ser?Ser?Ala?Thr?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys

95 100 105

ttt?ccc?act?gaa?ctt?aac?cag?cag?ctg?aat?gac?ctg?gaa?gcc?tgc?gtg 449

Phe?Pro?Thr?Glu?Leu?Asn?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val

110 115 120

ata?cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg?aat?gtg?gac?tcc 497

Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Val?Asp?Ser

125 130 135

atc?ctg?gct?gtg?aag?aaa?tac?ttc?caa?aga?atc?act?ctt?tat?ctg?aca 545

Ile?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr

140 145 150 155

gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc 593

Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile

160 165 170

atg?aga?tcc?ttc?tct?tta?tca?aaa?att?ttt?caa?gaa?aga?tta?agg?agg 641

Met?Arg?Ser?Phe?Ser?Leu?Ser?Lys?Ile?Phe?Gln?Glu?Arg?Leu?Arg?Arg

175 180 185

aag?gaa?tga?aacctgtttc?aacatggaaa?tgatctgta 679

Lys?Glu

<210>62

<211>189

<212>PRT

＜213〉homo sapiens

<400>62

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser

85 90 95

Ser?Ala?Thr?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Pro?Thr?Glu?Leu

100 105 110

Asn?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Val?Asp?Ser?Ile?Leu?Ala?Val?Lys

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser

165 170 175

Leu?Ser?Lys?Ile?Phe?Gln?Glu?Arg?Leu?Arg?Arg?Lys?Glu

180 185

<210>63

<211>735

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(67)..(636)

<223>

<400>63

tatagctagc?atgcgcaaat?ttaaagcgct?gatctcaagt?agcctagcaa?tattggcaac 60

atccca?atg?gcc?ctg?tcc?ttt?tct?tta?ctg?atg?gcc?gtg?ctg?gtg?ctc 108

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu

1 5 10

agc?tac?aaa?tcc?atc?tgt?tct?ctg?ggc?tgt?gat?ctg?cct?cag?acc?cac 156

Ser?Tyr?Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His

15 20 25 30

agc?ctg?ggt?aat?agg?agg?gcc?ttg?ata?ctc?ctg?gca?caa?atg?gga?aga 204

Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg

35 40 45

atc?tct?cct?ttc?tcc?tgc?ctg?aag?gac?aga?cat?gac?ttt?gga?ttc?ccc 252

Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro

50 55 60

cag?gag?gag?ttt?gat?ggc?aac?cag?ttc?cag?aag?gct?caa?gcc?atc?tct 300

Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser

65 70 75

gtc?ctc?cat?gag?atg?atc?cag?cag?acc?ttc?aat?ctc?ttc?agc?aca?aag 348

Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys

80 85 90

gac?tca?tct?gct?act?tgg?gaa?cag?agc?ctc?cta?gaa?aaa?ttt?tcc?act 396

Asp?Ser?Ser?Ala?Thr?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr

95 100 105 110

gaa?ctt?aac?cag?cag?ctg?aat?gac?ctg?gaa?gcc?tgc?gtg?ata?cag?gag 444

Glu?Leu?Asn?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu

115 120 125

gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg?aat?gtg?gac?tcc?atc?ctg?gct 492

Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Val?Asp?Ser?Ile?Leu?Ala

130 135 140

gtg?aag?aaa?tac?ttc?caa?aga?atc?act?ctt?tat?ctg?aca?gag?aag?aaa 540

Val?Lys?Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys

145 150 155

tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tcc 588

Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser

160 165 170

tcc?tct?tta?tca?aaa?att?ttt?caa?gaa?aga?tta?agg?agg?aag?gaa?tga 636

Ser?Ser?Leu?Ser?Lys?Ile?Phe?Gln?Glu?Arg?Leu?Arg?Arg?Lys?Glu

175 180 185

aacctgtttc?aacatggaaa?tgatctgtat?tgcgtattag?tcaatacaga?tcatttccct 696

cgccaatatt?gctaggctac?ttgagatcga?tcgcgcgca 735

<210>64

<211>189

<212>PRT

＜213〉homo sapiens

<400>64

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser

85 90 95

Ser?Ala?Thr?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

Asn?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Val?Asp?Ser?Ile?Leu?Ala?Val?Lys

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Ser?Ser

165 170 175

Leu?Ser?Lys?Ile?Phe?Gln?Glu?Arg?Leu?Arg?Arg?Lys?Glu

180 185

<210>65

<211>661

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(1)..(661)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(56)..(625)

<223>

<400>65

ntanctagca?tgcgcaaatt?taaagcgctg?atcagcagca?tccacaacat?ctaca?atg 58

Met

1

gcc?ttg?act?ttt?tat?tta?ctg?gtg?gcc?cta?gtg?gtg?ctc?agc?tac?aag 106

Ala?Leu?Thr?Phe?Tyr?Leu?Leu?Val?Ala?Leu?Val?Val?Leu?Ser?Tyr?Lys

5 10 15

tca?ttc?agc?tct?ctg?ggc?tgt?gat?ctg?cct?cag?act?cac?agc?ctg?ggt 154

Ser?Phe?Ser?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly

20 25 30

aac?agg?agg?gcc?ttg?ata?ctc?ctg?gca?caa?atg?cga?aga?atc?tct?cct 202

Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Arg?Arg?Ile?Ser?Pro

35 40 45

ttc?tcc?tgc?ctg?aag?gac?aga?cat?gac?ttt?gaa?ttc?ccc?cag?gag?gag 250

Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu?Glu

50 55 60 65

ttt?gat?gat?aaa?cag?ttc?cag?aag?gct?caa?gcc?atc?tct?gtc?ctc?cat 298

Phe?Asp?Asp?Lys?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His

70 75 80

gag?atg?atc?cag?cgg?acc?ttc?aac?ctc?ttc?agc?aca?aag?gac?tca?tct 346

Glu?Met?Ile?Gln?Arg?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser

85 90 95

gct?gct?ttg?gat?gag?acc?ctt?cta?gat?gaa?ttc?tac?atc?gaa?ctt?gac 394

Ala?Ala?Leu?Asp?Glu?Thr?Leu?Leu?Asp?Glu?Phe?Tyr?Ile?Glu?Leu?Asp

100 105 110

cag?cag?ctg?aat?gac?ctg?gag?tcc?tgt?gtg?gtg?cag?gaa?gtg?ggg?gtg 442

Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ser?Cys?Val?Val?Gln?Glu?Val?Gly?Val

115 120 125

ata?gag?tct?ccc?ctg?atg?tac?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa 490

Ile?Glu?Ser?Pro?Leu?Met?Tyr?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys

130 135 140 145

tac?ttc?caa?aga?atc?act?cta?tat?ctg?aca?gag?aag?aaa?tac?agc?tct 538

Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Ser

150 155 160

tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tcc?ttc?tct?tta 586

Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu

165 170 175

tca?atc?aac?ttg?caa?aaa?aga?ttg?aag?agt?aag?gaa?tga?gacctggtac 635

Ser?Ile?Asn?Leu?Gln?Lys?Arg?Leu?Lys?Ser?Lys?Glu

180 185

aacacggaaa?tgatcgatcg?cgcgca 661

<210>66

<211>189

<212>PRT

＜213〉homo sapiens

<400>66

Met?Ala?Leu?Thr?Phe?Tyr?Leu?Leu?Val?Ala?Leu?Val?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Phe?Ser?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Arg?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Asp?Lys?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Arg?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser

85 90 95

Ser?Ala?Ala?Leu?Asp?Glu?Thr?Leu?Leu?Asp?Glu?Phe?Tyr?Ile?Glu?Leu

100 105 110

Asp?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ser?Cys?Val?Val?Gln?Glu?Val?Gly

115 120 125

Val?Ile?Glu?Ser?Pro?Leu?Met?Tyr?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

LyS?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

1451 50 155 160

Ser?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser

165 170 175

Leu?Ser?Ile?Asn?Leu?Gln?Lys?Arg?Leu?Lys?Ser?Lys?Glu

180 185

<210>67

<211>661

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(38)..(607)

<223>

<400>67

tgcgcgcgat?cgatcagcag?catccacaac?atctaca?atg?gcc?ttg?act?ttt?tat 55

Met?Ala?Leu?Thr?Phe?Tyr

1 5

tta?ctg?gtg?gcc?cta?gtg?gtg?ctc?agc?tac?aag?tca?ttc?agc?tct?ctg 103

Leu?Leu?Val?Ala?Leu?Val?Val?Leu?Ser?Tyr?Lys?Ser?Phe?Ser?Ser?Leu

10 15 20

ggc?tgt?gat?ctg?cct?cag?act?cac?agc?ctg?ggt?aac?agg?agg?gcc?ttg 151

Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu

25 30 35

ata?ctc?ctg?gca?caa?atg?cga?aga?atc?tct?cct?ttc?tcc?tgc?ctg?aag 199

Ile?Leu?Leu?Ala?Gln?Met?Arg?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys

40 45 50

gac?agc?cat?gac?ttt?gaa?ttc?ccc?cag?gag?gag?ttt?gat?gat?aaa?cag 247

Asp?Ser?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu?Glu?Phe?Asp?Asp?Lys?Gln

55 60 65 70

ttc?cag?aag?gct?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag?cag 295

Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln

75 80 85

acc?ttc?aac?ctc?ttc?agc?aca?aag?gac?tca?tct?gct?gct?ttg?gat?gag 343

Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Leu?Asp?Glu

90 95 100

acc?ctt?cta?gat?gaa?ttc?tac?atc?gaa?ctt?gac?cag?cag?ctg?aat?gac 391

Thr?Leu?Leu?Asp?Glu?Phe?Tyr?Ile?Glu?Leu?Asp?Gln?Gln?Leu?Asn?Asp

105 110 115

ctg?gag?tcc?tgt?gtg?atg?cag?gaa?gtg?ggg?gtg?ata?gag?tct?ccc?ctg 439

Leu?Glu?Ser?Cys?Val?Met?Gln?Glu?Val?Gly?Val?Ile?Glu?Ser?Pro?Leu

120 125 130

atg?tac?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa?aga?atc 487

Met?Tyr?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile

135 140 145 150

act?cta?tat?ctg?aca?gag?aag?aaa?tac?agc?tct?tgt?gcc?tgg?gag?gtt 535

Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Ser?Cys?Ala?Trp?Glu?Val

155 160 165

gtc?aga?gca?gaa?atc?atg?aga?tcc?ttc?tct?tta?tca?atc?aac?ttg?caa 583

Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Ile?Asn?Leu?Gln

170 175 180

aaa?aga?ttg?aag?agt?aag?gaa?tga?gacctggtac?aacacggaaa?tgatcagcgc 637

Lys?Arg?Leu?Lys?Ser?Lys?Glu

185

tttaaatttg?cgcatgctag?ctat 661

<210>68

<211>189

<212>PRT

＜213〉homo sapiens

<400>68

Met?Ala?Leu?Thr?Phe?Tyr?Leu?Leu?Val?Ala?Leu?Val?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Phe?Ser?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Arg?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Ser?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Asp?Lys?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser

85 90 95

Ser?Ala?Ala?Leu?Asp?Glu?Thr?Leu?Leu?Asp?Glu?Phe?Tyr?Ile?Glu?Leu

100 105 110

Asp?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ser?Cys?Val?Met?Gln?Glu?Val?Gly

115 120 125

Val?Ile?Glu?Ser?Pro?Leu?Met?Tyr?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Ser?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser

165 170 175

Leu?Ser?Ile?Asn?Leu?Gln?Lys?Arg?Leu?Lys?Ser?Lys?Glu

180 185

<210>69

<211>570

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(1)..(570)

<223>

<400>69

atg?gcc?ttg?tcc?ttt?tct?tta?ctg?atg?gtc?gtg?ctg?gta?ctc?agc?tac 48

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Val?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

aaa?tcc?atc?tgc?tct?ctg?ggc?tgt?gat?ctg?cct?cag?acc?cac?agc?ctg 96

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

cgt?aat?agg?agg?gcc?ttg?ata?ctc?ctg?gca?caa?atg?gga?aga?atc?tct 144

Arg?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

cct?ttc?tcc?tgc?ttg?aag?gac?aga?cat?gaa?ttc?aga?ttc?cca?gag?gag 192

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu

50 55 60

gag?ttt?gat?ggc?cac?cag?ttc?cag?aag?act?caa?gcc?atc?tct?gtc?ctc 240

Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

cat?gag?atg?atc?cag?cag?acc?ttc?aat?ctc?ttc?agc?aca?gag?gac?tca 288

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

tct?gct?gct?tgg?gaa?cag?agc?ctc?cta?gaa?aaa?ttt?tcc?act?gaa?ctt 336

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

tac?cag?caa?ctg?aat?gac?ctg?gaa?gca?tgt?gtg?ata?cag?gag?gtt?ggg 384

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

gtg?gaa?gag?act?ccc?ctg?atg?aat?gag?gac?tcc?atc?ctg?gct?gtg?agg 432

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

aaa?tac?ttc?caa?aga?atc?act?ctt?tat?cta?aca?gag?aag?aaa?tac?agc 480

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc?atg?aga?tcc?ctc?tcg 528

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

ttt?tca?aca?aac?ttg?caa?aaa?aga?tta?agg?agg?aag?gat?tga 570

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>70

<211>189

<212>PRT

＜213〉homo sapiens

<400>70

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Val?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Arg?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu

50 55 60

Glu?Phe?Asp?Gly?His?Gln?Phe?Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser

85 90 95

Ser?Ala?Ala?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu

100 105 110

Tyr?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser

165 170 175

Phe?Ser?Thr?Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

180 185

<210>71

<211>679

<212>DNA

＜213〉homo sapiens

<220>

＜221〉multiple character

<222>(1)..(679)

＜223〉n=a, c, g, or t

<220>

<221>CDS

<222>(81)..(650)

<223>

<400>71

nttgttttnt?nnnnagngaa?nctttttgcn?caaatccaag?cgctgatctc?aagtagccta 60

gcaatattgg?caacatccca?atg?gcc?ctg?tcc?ttt?tct?tta?ctg?atg?gcc?gtg 113

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val

1 5 10

ctg?gtg?ctc?agc?tac?aaa?tcc?atc?tgt?tct?ctg?ggc?tgt?gat?ctg?cct 161

Leu?Val?Leu?Ser?Tyr?Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro

15 20 25

cag?acc?cac?agc?ctg?ggt?aat?agg?agg?gcc?ttg?ata?ctc?ctg?gca?caa 209

Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln

30 35 40

atg?gga?aga?atc?tct?cct?ttc?tcc?tgc?ctg?aag?gac?aga?cat?gac?ttt 257

Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe

45 50 55

gga?ttc?ccc?caa?gag?gag?ttt?gat?ggc?aac?cag?ttc?cag?aag?gct?caa 305

Gly?Phe?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln

60 65 70 75

gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag?cag?acc?ttc?aat?ctc?ttc 353

Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe

80 85 90

agc?aca?aag?gac?tca?tct?gct?act?tgg?gaa?cag?agc?ctc?cta?gaa?aaa 401

Ser?Thr?Lys?Asp?Ser?Ser?Ala?Thr?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys

95 100 105

ttt?ccc?act?gaa?ctt?aac?cag?cag?ctg?aat?gac?ctg?gaa?gcc?tgc?gtg 449

Phe?Pro?Thr?Glu?Leu?Asn?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val

110 115 120

ata?cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg?aat?gtg?gac?tcc 497

Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Val?Asp?Ser

125 130 135

atc?ctg?gct?gtg?aag?aaa?tac?ttc?caa?aga?atc?act?ctt?tat?ctg?aca 545

Ile?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr

140 145 150 155

gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc?aga?gca?gaa?atc 593

Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile

160 165 170

atg?aga?tcc?ttc?tct?tta?tca?aaa?att?ttt?caa?gaa?aga?tta?agg?agg 641

Met?Arg?Ser?Phe?Ser?Leu?Ser?Lys?Ile?Phe?Gln?Glu?Arg?Leu?Arg?Arg

175 180 185

aag?gaa?tga?aacctgttte?aacatggaaa?tgatctgta 679

Lys?Glu

<210>72

<211>189

<212>PRT

＜213〉homo sapiens

<400>72

Met?Ala?Leu?Ser?Phe?Ser?Leu?Leu?Met?Ala?Val?Leu?Val?Leu?Ser?Tyr

1 5 10 15

Lys?Ser?Ile?Cys?Ser?Leu?Gly?Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu

20 25 30

Gly?Asn?Arg?Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser

35 40 45

Pro?Phe?Ser?Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Glu

50 55 60

Glu?Phe?Asp?Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu

65 70 75 80

His?Glu?Met?Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser

85 90 95

ser?Ala?Thr?Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Pro?Thr?Glu?Leu

100 105 110

Asn?Gln?Gln?Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly

115 120 125

Val?Glu?Glu?Thr?Pro?Leu?Met?Asn?Val?Asp?Ser?Ile?Leu?Ala?Val?Lys

130 135 140

Lys?Tyr?Phe?Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser

145 150 155 160

Pro?Cys?Ala?Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser

165 170 175

Leu?Ser?Lys?Ile?Phe?Gln?Glu?Arg?Leu?Arg?Arg?Lys?Glu

180 185

<210>73

<211>523

<212>DMA

＜213〉homo sapiens

<220>

<221>CDS

<222>(14)..(514)

<223>

<400>73

agatcttctg?atg?tgc?gac?ctg?ccg?cag?acc?cac?tcc?ctg?cgt?aac?cgt 49

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Arg?Asn?Arg

1 5 10

cgt?gct?ctg?atc?ctg?ctg?gct?cag?atg?ggt?cgt?atc?tcc?ccg?ttc?tcc 97

Arg?Ala?Leu?Ile?Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser

15 20 25

tgc?ctg?aaa?gac?cgt?cac?gaa?ttc?cgt?ttc?ccg?gaa?gaa?gaa?ttc?gat 145

Cys?Leu?Lys?Asp?Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu?Glu?Phe?Asp

30 35 40

ggc?cac?cag?ttc?cag?aaa?acc?cag?gct?atc?tcc?gtt?ctg?cac?gaa?atg 193

Gly?His?Gln?Phe?Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met

45 50 55 60

atc?cag?cag?acc?ttc?aac?ctg?ttc?tcc?acc?gaa?gac?tcc?tcc?gcg?gct 241

Ile?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala

65 70 75

tgg?gaa?cag?tcc?ctg?ctg?gaa?aaa?ttc?tcc?acc?gaa?ctg?tac?cag?cag 289

Trp?Glu?Gln?Ser?Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln

80 85 90

ctg?aac?gac?ctg?gaa?gct?tgc?gtt?atc?cag?gaa?gtt?ggt?gtt?gaa?gaa 337

Leu?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu

95 100 105

acc?ccg?ctg?atg?aac?gaa?gac?tcc?atc?ctg?gct?gtt?cgt?aaa?tac?ttc 385

Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe

110 115 120

cag?cgt?atc?acc?ctg?tac?ctg?acc?gaa?aaa?aaa?tac?tcc?ccg?tgc?gca 433

Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

125 130 135 140

tgg?gaa?gtt?gtt?cgt?gct?gaa?atc?atg?cgt?tcc?ctg?tcc?ttc?tcc?acc 481

Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr

145 150 155

aac?ctg?cag?aaa?cgt?ctg?cgt?cgt?aaa?gac?tga?tgatctaga 523

Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

160 165

<210>74

<211>166

<212>PRT

＜213〉homo sapiens

<400>74

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Arg?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly?His?Gln?Phe

35 40 45

Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser

65 70 75 80

Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 110

Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Asp

165

<210>75

<211>523

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(14)..(514)

<223>

<400>75

agatcttctg?atg?tgc?aac?ctg?tcc?cag?acc?tac?tcc?ctg?aac?aac?cgt 49

Cys?Asn?Leu?Ser?Gln?Thr?Tyr?Ser?Leu?Asn?Asn?Arg

1 5 10

cgt?acc?ctg?atg?ctg?atg?gct?cag?atg?cgt?cgt?atc?tcc?ccg?ttc?tcc 97

Arg?Thr?Leu?Met?Leu?Met?Ala?Gln?Met?Arg?Arg?Ile?Ser?Pro?Phe?Ser

15 20 25

tgc?ctg?aaa?gac?cgt?cac?gac?ttc?gaa?ttc?ccg?cag?gaa?gaa?ttc?gac 145

Cys?Leu?Lys?Asp?Arg?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu?Glu?Phe?Asp

30 35 40

ggt?aac?cag?ttc?cag?aaa?gct?cag?gct?atc?tcc?gtt?ctg?cac?gaa?atg 193

Gly?Asn?Gln?Phe?Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met

45 50 55 60

atg?cag?cag?acc?ttc?aac?ctg?ttc?tcc?acc?aaa?aac?tcc?tct?gca?gct 241

Met?Gln?Gln?Thr?Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asn?Ser?Ser?Ala?Ala

65 70 75

tgg?gac?gaa?acc?ctg?ctg?gaa?aaa?ttc?tac?atc?gaa?ctg?ttc?cag?cag 289

Trp?Asp?Glu?Thr?Leu?Leu?Glu?Lys?Phe?Tyr?Ile?Glu?Leu?Phe?Gln?Gln

80 85 90

atg?aac?gac?ctg?gaa?gct?tgc?gtt?atc?cag?gaa?gtt?ggt?gtt?gaa?gaa 337

Met?Asn?Asp?Leu?Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu

95 100 105

acc?ccg?ctg?atg?aac?gaa?gac?tcc?atc?ctg?gct?gtt?aaa?aaa?tac?ttc 385

Thr?Pro?Leu?Met?Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Lys?Lys?Tyr?Phe

110 115 120

cag?cgt?atc?acc?ctg?tac?ctg?atg?gaa?aaa?aaa?tac?tcc?ccg?tgc?gca 433

Gln?Arg?Ile?Thr?Leu?Tyr?Leu?Met?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala

125 130 135 140

tgg?gaa?gtt?gtt?cgt?gct?gaa?atc?atg?cgt?tcc?ctg?tcc?ttc?tcc?acc 48l

Trp?Glu?Val?Val?Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr

145 150 155

aac?ctg?cag?aaa?cgt?ctg?cgt?cgt?aaa?gac?tga?tgatctaga 523

Asn?Leu?Gln?Lys?Arg?Leu?Arg?Arg?Lys?Asp

160 165

<210>76

<211>166

<212>PRT

＜213〉homo sapiens

<400>76

Cys?Asn?Leu?Ser?Gln?Thr?Tyr?Ser?Leu?Asn?Asn?Arg?Arg?Thr?Leu?Met

1 5 10 15

Leu?Met?Ala?Gln?Met?Arg?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

Arg?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Met?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asn?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Thr

65 70 75 80

Leu?Leu?Glu?Lys?Phe?Tyr?Ile?Glu?Leu?Phe?Gln?Gln?Met?Asn?Asp?Leu

85 90 95

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 110

Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Met?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Asp

165

<210>77

<211>501

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(1)..(501)

<223>

<400>77

tgt?gat?ctg?cct?cag?acc?cac?agc?ctg?cgt?aat?agg?agg?gcc?ttg?ata 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Arg?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

ctc?ctg?gca?caa?atg?gga?aga?atc?tct?cct?ttc?tcc?tgc?ttg?aag?gac 96

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

aga?cat?gaa?ttc?aga?ttc?cca?gag?gag?gag?ttt?gat?ggc?aac?cag?ttc 144

Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

cag?aag?act?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag?cag?acc 192

Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr

50 55 60

ttc?aat?ctc?ttc?agc?aca?gag?gac?tca?tct?gct?gct?tgg?gaa?cag?agc 240

Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser

65 70 75 80

ctc?cta?gaa?aaa?ttt?tcc?act?gaa?ctt?tac?cag?caa?ctg?aat?aac?ttg 288

Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asn?Leu

85 90 95

gaa?gca?tgt?gtg?ata?cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg 336

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 110

aat?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa?aga?atc?act 384

Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

ctt?tat?cta?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tcc?ctc?tcg?ttt?tca?aca?aac?ttg?caa?aaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

aga?tta?agg?agg?aag?gat?tga 501

Arg?Leu?Arg?Arg?Lys?Asp

165

<210>78

<211>166

<212>PRT

＜213〉homo sapiens

<400>78

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Arg?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

Arg?His?Glu?Phe?Arg?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser

65 70 75 80

Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asn?Leu

85 90 95

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 110

Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Asp

165

<210>79

<211>501

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(1)..(501)

<223>

<400>79

tgt?gat?ctg?cct?cag?acc?cac?agc?ctg?ggt?aat?agg?agg?gcc?ttg?ata 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

ctc?ctg?gca?caa?atg?gga?aga?atc?tct?cct?ttc?tcc?tgc?ctg?aag?gac 96

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

aga?cat?gac?ttt?gga?ctt?ccc?cag?gag?gag?ttt?gat?ggc?aac?cag?ttc 144

Arg?His?Asp?Phe?Gly?Leu?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

cag?aag?act?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag?cag?acc 192

Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr

50 55 60

ttc?aat?ctc?ttc?agc?aca?aag?gat?tca?tct?gct?gct?tgg?gat?gag?acc 240

Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Thr

65 70 75 80

ctc?cta?gac?aaa?ttc?tac?att?gaa?ctt?ttc?cag?caa?ctg?aat?gtc?cta 288

Leu?Leu?Asp?Lys?Phe?Tyr?Ile?Glu?Leu?Phe?Gln?Gln?Leu?Asn?Val?Leu

85 90 95

gaa?gcc?tgt?gtg?aca?cag?gag?gtt?ggg?gtg?gaa?gag?att?gcc?ctg?atg 336

Glu?Ala?Cys?Val?Thr?Gln?Glu?Val?Gly?Val?Glu?Glu?Ile?Ala?Leu?Met

100 105 110

aat?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttt?caa?aga?atc?act 384

Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

ctt?tat?ctg?atg?ggg?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Met?Gly?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tcc?ttc?tct?ttt?tca?aca?aac?ttg?caa?aaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

gga?tta?aga?agg?aag?gat?tga 501

Gly?Leu?Arg?Arg?Lys?Asp

165

<210>80

<211>166

<212>PRT

＜213〉homo sapiens

<400>80

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

Arg?His?Asp?Phe?Gly?Leu?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

Gln?Lys?Thr?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Trp?Asp?Glu?Thr

65 70 75 80

Leu?Leu?Asp?Lys?Phe?Tyr?Ile?Glu?Leu?Phe?Gln?Gln?Leu?Asn?Val?Leu

85 90 95

Glu?Ala?Cys?Val?Thr?Gln?Glu?Val?Gly?Val?Glu?Glu?Ile?Ala?Leu?Met

100 105 110

Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Met?Gly?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

Gly?Leu?Arg?Arg?Lys?Asp

165

<210>81

<211>501

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(1)..(501)

<223>

<400>81

tgt?gat?ctg?cct?cag?acc?cac?agc?ctg?ggt?aat?agg?agg?gcc?ttg?ata 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

ctc?ctg?gca?caa?atg?gga?aga?atc?tct?cat?ttc?tcc?tgc?ctg?aag?gac 96

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?His?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

aga?cat?gat?ttc?gga?ttc?ccc?gag?gag?gag?ttt?gat?ggc?cac?cag?ttc 144

Arg?His?Asp?Phe?Gly?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly?His?Gln?Phe

35 40 45

cag?aag?gct?caa?gcc?atc?tcc?gtc?ctc?cat?gag?atg?atc?cag?cag?acc 192

Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr

50 55 60

ttc?aat?ctc?ttc?agc?aca?gag?gac?tca?tct?gct?gct?tgg?gaa?cag?agc 240

Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser

65 70 75 80

ctc?cta?gaa?aaa?ttt?tcc?act?gaa?ctt?tac?cag?caa?ctg?aat?gac?ctg 288

Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

gaa?gca?tgt?gtg?ata?cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg 336

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 110

aat?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa?aga?atc?act 384

Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

ctt?tat?cta?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tcc?ctc?tcg?ttt?tca?aca?aac?ttg?caa?aaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

aga?tta?agg?agg?aag?gat?tga 501

Arg?Leu?Arg?Arg?Lys?Asp

165

<210>82

<211>166

<212>PRT

＜213〉homo sapiens

<400>82

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?His?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

Arg?His?Asp?Phe?Gly?Phe?Pro?Glu?Glu?Glu?Phe?Asp?Gly?His?Gln?Phe

35 40 45

Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Ser?Thr?Glu?Asp?Ser?Ser?Ala?Ala?Trp?Glu?Gln?Ser

65 70 75 80

Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Tyr?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 110

Asn?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Leu?Ser?Phe?Ser?Thr?Asn?Leu?Gln?Lys

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Asp

165

<210>83

<211>501

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(1)..(501)

<223>

<400>83

tgt?gat?ctg?cct?cag?acc?cac?agc?ctg?ggt?aat?agg?agg?gcc?ttg?ata 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

ctc?ctg?gca?caa?atg?gga?aga?atc?tct?cct?ttc?tcc?tgc?ctg?aag?gac 96

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

aga?cat?gac?ttt?gga?ttc?ccc?cag?gag?gag?ttt?gat?ggc?aac?cag?ttc 144

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

cag?aag?gct?caa?gcc?atc?tct?gtc?ctc?cat?gag?acg?atc?cag?cag?acc 192

Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Thr?Ile?Gln?Gln?Thr

50 55 60

ttc?aat?ctc?ttc?agc?aca?aag?gac?tct?tct?gct?act?tgg?gaa?cag?agc 240

Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser?Ala?Thr?Trp?Glu?Gln?Ser

65 70 75 80

ctc?cta?gaa?aaa?ttt?tcc?act?gaa?ctt?aac?cag?cag?ctg?aat?gac?ctg 288

Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Asn?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

gaa?gcc?tgc?gtg?ata?cag?gag?gtt?ggg?gtg?gaa?gag?act?ccc?ctg?atg 336

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 110

aat?gtg?gac?tcc?atc?ctg?gct?gtg?aag?aaa?tac?ttc?caa?aga?atc?act 384

Asn?Val?Asp?Ser?Ile?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

ctt?tat?ctg?aca?gag?aag?aaa?tac?agc?cct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tcc?ttc?tct?tta?tca?aaa?att?ttt?caa?gaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Lys?Ile?Phe?Gln?Glu

145 150 155 160

aga?tta?agg?agg?aag?gaa?tga 501

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>84

<211>166

<212>PRT

＜213〉homo sapiens

<400>84

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

Leu?Leu?Ala?Gln?Met?Gly?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

Arg?His?Asp?Phe?Gly?Phe?Pro?Gln?Glu?Glu?Phe?Asp?Gly?Asn?Gln?Phe

35 40 45

Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Thr?Ile?Gln?Gln?Thr

50 55 60

Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser?Ala?Thr?Trp?Glu?Gln?Ser

65 70 75 80

Leu?Leu?Glu?Lys?Phe?Ser?Thr?Glu?Leu?Asn?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

Glu?Ala?Cys?Val?Ile?Gln?Glu?Val?Gly?Val?Glu?Glu?Thr?Pro?Leu?Met

100 105 110

Asn?Val?Asp?Ser?Ile?Leu?Ala?Val?Lys?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Pro?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Lys?Ile?Phe?Gln?Glu

145 150 155 160

Arg?Leu?Arg?Arg?Lys?Glu

165

<210>85

<211>501

<212>DNA

＜213〉homo sapiens

<220>

<221>CDS

<222>(1)..(501)

<223>

<400>85

tgt?gat?ctg?cct?cag?act?cac?agc?ctg?ggt?aac?agg?agg?gcc?ttg?ata 48

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

ctc?ctg?gca?caa?atg?cga?aga?atc?tct?cct?ttc?tcc?tgc?ctg?aag?gac 96

Leu?Leu?Ala?Gln?Met?Arg?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

aga?cat?gac?ttt?gaa?ttc?ccc?cag?gag?gag?ttt?gat?gat?aaa?cag?ttc 144

Arg?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu?Glu?Phe?Asp?Asp?Lys?Gln?Phe

35 40 45

cag?aag?gct?caa?gcc?atc?tct?gtc?ctc?cat?gag?atg?atc?cag?cgg?acc 192

Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Arg?Thr

50 55 60

ttc?aac?ctc?ttc?agc?aca?aag?gac?tca?tct?gct?gct?ttg?gat?gag?acc 240

Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Leu?Asp?Glu?Thr

65 70 75 80

ctt?cta?gat?gaa?ttc?tac?atc?gaa?ctt?gac?cag?cag?ctg?aat?gac?ctg 288

Leu?Leu?Asp?Glu?Phe?Tyr?Ile?Glu?Leu?Asp?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

gag?tcc?tgt?gtg?atg?cag?gaa?gtg?ggg?gtg?aaa?gag?tct?ccc?ctg?atg 336

Glu?Ser?Cys?Val?Met?Gln?Glu?Val?Gly?Val?Lys?Glu?Ser?Pro?Leu?Met

100 105 110

tac?gag?gac?tcc?atc?ctg?gct?gtg?agg?aaa?tac?ttc?caa?aga?atc?act 384

Tyr?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

cta?tat?ctg?aca?gag?aag?aaa?tac?agc?tct?tgt?gcc?tgg?gag?gtt?gtc 432

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Ser?Cys?Ala?Trp?Glu?Val?Val

130 135 140

aga?gca?gaa?atc?atg?aga?tcc?ttc?tct?tta?tca?atc?aac?ttg?caa?aaa 480

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Ile?Asn?Leu?Gln?Lys

145 150 155 160

aga?ttg?aag?agt?aag?gaa?tga 501

Arg?Leu?Lys?Ser?Lys?Glu

165

<210>86

<211>166

<212>PRT

＜213〉homo sapiens

<400>86

Cys?Asp?Leu?Pro?Gln?Thr?His?Ser?Leu?Gly?Asn?Arg?Arg?Ala?Leu?Ile

1 5 10 15

Leu?Leu?Ala?Gln?Met?Arg?Arg?Ile?Ser?Pro?Phe?Ser?Cys?Leu?Lys?Asp

20 25 30

Arg?His?Asp?Phe?Glu?Phe?Pro?Gln?Glu?Glu?Phe?Asp?Asp?Lys?Gln?Phe

35 40 45

Gln?Lys?Ala?Gln?Ala?Ile?Ser?Val?Leu?His?Glu?Met?Ile?Gln?Arg?Thr

50 55 60

Phe?Asn?Leu?Phe?Ser?Thr?Lys?Asp?Ser?Ser?Ala?Ala?Leu?Asp?Glu?Thr

65 70 75 80

Leu?Leu?Asp?Glu?Phe?Tyr?Ile?Glu?Leu?Asp?Gln?Gln?Leu?Asn?Asp?Leu

85 90 95

Glu?Ser?Cys?Val?Met?Gln?Glu?Val?Gly?Val?Lys?Glu?Ser?Pro?Leu?Met

100 105 110

Tyr?Glu?Asp?Ser?Ile?Leu?Ala?Val?Arg?Lys?Tyr?Phe?Gln?Arg?Ile?Thr

115 120 125

Leu?Tyr?Leu?Thr?Glu?Lys?Lys?Tyr?Ser?Ser?Cys?Ala?Trp?Glu?Val?Val

130 135 140

Arg?Ala?Glu?Ile?Met?Arg?Ser?Phe?Ser?Leu?Ser?Ile?Asn?Leu?Gln?Lys

145 150 155 160

Arg?Leu?Lys?Ser?Lys?Glu

165

Claims (12)

1. method for the treatment of the experimenter of viral infection or reducing this experimenter's viral infection risk, thereby comprise and give the risk that experimenter's interferon polypeptides has been treated the experimenter of viral infection or reduced experimenter's viral infection, described polypeptide comprises the NO:2 with SEQ ID, 4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82, one of 84 or 86 have the aminoacid sequence of at least 95% homogeneity, and be not naturally occurring interferon allele, wherein virus is selected from: the coronavirus that severe acute respiratory syndrome is relevant, influenza virus, coronavirus, smallpox virus, vaccinia virus, west Nile virus, vaccinia virus, respiratory syncytial virus, rhinovirus, arteritis virus, filamentous form virus, pico+ribonucleic acid+virus, reovirus, retrovirus, papovavirus, herpesvirus, poxvirus, Hepadnavirus, Astrovirus, Coxsackie virus, paramyxovirus, influenza virus, echovirus, enterovirus, Cardioviruses, togavirus, rhabdovirus, Bunyavirus, arenavirus, borna virus, adenovirus, parvovirus and yellow fever virus.

2. the process of claim 1 wherein that interferon polypeptides comprises is selected from SEQ ID NO:2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82,84 and 86 aminoacid sequence.

3. the method for claim 1, wherein interferon polypeptides is that nucleic acid is coded, and this nucleic acid comprises and is selected from SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,61,63,65,67,69,71,73,75,77,79,81,83 and 85 nucleotide sequence.

4. the method for claim 1, wherein interferon polypeptides is that nucleic acid is coded, this nucleic acid under high stringent condition with comprise the nucleic acid hybridization that is selected from SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,61,63,65,67,69,71,73,75,77,79,81,83 and 85 sequence.

5. the method for claim 1, wherein interferon polypeptides is that nucleic acid is coded, this nucleic acid under high stringent condition with and be selected from SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,61,63,65,67,69,71,73,75,77,79,81,83 and 85 the complementary nucleic acid hybridization of sequence.

6. claim 1 or 2 method, wherein the experimenter is the mankind, non-human primate, felid, Canis animals or farming animals.

7. claim 1 or 2 method, interferon per nasal wherein, per os, parenteral, the part, per rectum by injection, sucks, collyrium, ointment, suppository, sustained release diaphragm, infusion or suction give.

8. claim 1 or 2 method, wherein interferon is given mucous membrane of nasopharynx or the lung epithelial to the experimenter.

9. claim 1 or 2 method, thus the amount of the interferon polypeptides that wherein gives is effectively to reduce the amount of virion concentration treatment experimenter among the experimenter.

10. claim 1 or 2 method, thus the amount of the interferon polypeptides that wherein gives is to stop effectively or to reduce that virion concentration increases the amount of prophylactically treating the experimenter among the experimenter.

11. drug packages, comprise Inteferon compositions and the instructions that is used for compositions is given the experimenter, wherein (i) this instructions is used for the treatment of the viral infection experimenter or reduces experimenter's viral infection risk, wherein said virus is selected from: the coronavirus that severe acute respiratory syndrome is relevant, influenza virus, coronavirus, smallpox virus, vaccinia virus, west Nile virus, vaccinia virus, respiratory syncytial virus, rhinovirus, arteritis virus, filamentous form virus, pico+ribonucleic acid+virus, reovirus, retrovirus, papovavirus, herpesvirus, poxvirus, Hepadnavirus, Astrovirus, Coxsackie virus, paramyxovirus, influenza virus, echovirus, enterovirus, Cardioviruses, togavirus, rhabdovirus, Bunyavirus, arenavirus, borna virus, adenovirus, parvovirus and yellow fever virus and (ii) described interferon polypeptides comprise the NO:2 with SEQ ID, 4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82, one of 84 or 86 have the aminoacid sequence of at least 95% homogeneity.

12. the drug packages of claim 11, wherein Inteferon compositions comprises and is selected from SEQ IDNO:2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,52,54,56,58,60,62,64,66,68,70,72,74,76,78,80,82,84 or 86 interferon.

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