CN102101888B - 一种新型抗eb病毒所致肿瘤多肽及其应用与制备方法 - Google Patents
一种新型抗eb病毒所致肿瘤多肽及其应用与制备方法 Download PDFInfo
- Publication number
- CN102101888B CN102101888B CN2009102428380A CN200910242838A CN102101888B CN 102101888 B CN102101888 B CN 102101888B CN 2009102428380 A CN2009102428380 A CN 2009102428380A CN 200910242838 A CN200910242838 A CN 200910242838A CN 102101888 B CN102101888 B CN 102101888B
- Authority
- CN
- China
- Prior art keywords
- polypeptide
- ala
- leu
- glu
- lys
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 223
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 211
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 207
- 241000700605 Viruses Species 0.000 title claims abstract description 61
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 108010073254 Colicins Proteins 0.000 claims abstract description 88
- 230000003281 allosteric effect Effects 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 19
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 17
- 102000004310 Ion Channels Human genes 0.000 claims abstract description 16
- 102220471284 Guanine nucleotide exchange factor subunit RIC1_H40D_mutation Human genes 0.000 claims abstract description 10
- 102200051800 rs121434525 Human genes 0.000 claims abstract description 10
- 102220059797 rs786203763 Human genes 0.000 claims abstract description 10
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 9
- 102200142793 rs35418374 Human genes 0.000 claims abstract description 9
- 210000004408 hybridoma Anatomy 0.000 claims abstract description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 57
- 239000013612 plasmid Substances 0.000 claims description 55
- 230000008859 change Effects 0.000 claims description 32
- 241000701044 Human gammaherpesvirus 4 Species 0.000 claims description 27
- 108090000862 Ion Channels Proteins 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 10
- 239000002773 nucleotide Substances 0.000 claims description 8
- 125000003729 nucleotide group Chemical group 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 5
- 239000013604 expression vector Substances 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 230000028327 secretion Effects 0.000 claims description 3
- 230000001939 inductive effect Effects 0.000 claims description 2
- 206010070834 Sensitisation Diseases 0.000 abstract description 5
- 230000008313 sensitization Effects 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 3
- 230000003278 mimic effect Effects 0.000 abstract description 3
- 239000011148 porous material Substances 0.000 abstract description 3
- 230000000118 anti-neoplastic effect Effects 0.000 abstract description 2
- 231100000225 lethality Toxicity 0.000 abstract description 2
- 241000894006 Bacteria Species 0.000 description 45
- 210000004027 cell Anatomy 0.000 description 44
- 230000000259 anti-tumor effect Effects 0.000 description 40
- 241000699666 Mus <mouse, genus> Species 0.000 description 39
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 25
- 208000025036 lymphosarcoma Diseases 0.000 description 25
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 23
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 23
- 238000006384 oligomerization reaction Methods 0.000 description 20
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 19
- 238000002347 injection Methods 0.000 description 16
- 239000007924 injection Substances 0.000 description 16
- 230000003211 malignant effect Effects 0.000 description 16
- 210000004881 tumor cell Anatomy 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 14
- 108010005233 alanylglutamic acid Proteins 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 230000035772 mutation Effects 0.000 description 11
- 210000002966 serum Anatomy 0.000 description 11
- 230000004083 survival effect Effects 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 108010050848 glycylleucine Proteins 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 210000003462 vein Anatomy 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical group C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- DKJPOZOEBONHFS-ZLUOBGJFSA-N Ala-Ala-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O DKJPOZOEBONHFS-ZLUOBGJFSA-N 0.000 description 6
- LGQPPBQRUBVTIF-JBDRJPRFSA-N Ala-Ala-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LGQPPBQRUBVTIF-JBDRJPRFSA-N 0.000 description 6
- BLIMFWGRQKRCGT-YUMQZZPRSA-N Ala-Gly-Lys Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN BLIMFWGRQKRCGT-YUMQZZPRSA-N 0.000 description 6
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 6
- FHPXTPQBODWBIY-CIUDSAMLSA-N Glu-Ala-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FHPXTPQBODWBIY-CIUDSAMLSA-N 0.000 description 6
- MIWJDJAMMKHUAR-ZVZYQTTQSA-N Glu-Trp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N MIWJDJAMMKHUAR-ZVZYQTTQSA-N 0.000 description 6
- 206010020751 Hypersensitivity Diseases 0.000 description 6
- 238000012449 Kunming mouse Methods 0.000 description 6
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 6
- UCDHVOALNXENLC-KBPBESRZSA-N Leu-Gly-Tyr Chemical compound CC(C)C[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=C(O)C=C1 UCDHVOALNXENLC-KBPBESRZSA-N 0.000 description 6
- GAHJXEMYXKLZRQ-AJNGGQMLSA-N Lys-Lys-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GAHJXEMYXKLZRQ-AJNGGQMLSA-N 0.000 description 6
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 6
- 108091034117 Oligonucleotide Proteins 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 108010047495 alanylglycine Proteins 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 108010092854 aspartyllysine Proteins 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 5
- 108020004705 Codon Proteins 0.000 description 5
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 5
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical group C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 5
- 241000191967 Staphylococcus aureus Species 0.000 description 5
- 230000003187 abdominal effect Effects 0.000 description 5
- 208000026935 allergic disease Diseases 0.000 description 5
- 230000007815 allergy Effects 0.000 description 5
- 108010008355 arginyl-glutamine Proteins 0.000 description 5
- 238000013461 design Methods 0.000 description 5
- FDRNWTJTHBSPMW-GNXCPKRQSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical group [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C FDRNWTJTHBSPMW-GNXCPKRQSA-L 0.000 description 5
- 229960003376 levofloxacin Drugs 0.000 description 5
- 239000003016 pheromone Substances 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 4
- 241000282326 Felis catus Species 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 238000013467 fragmentation Methods 0.000 description 4
- 238000006062 fragmentation reaction Methods 0.000 description 4
- 230000002147 killing effect Effects 0.000 description 4
- 231100000636 lethal dose Toxicity 0.000 description 4
- 230000001665 lethal effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 3
- HHGYNJRJIINWAK-FXQIFTODSA-N Ala-Ala-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N HHGYNJRJIINWAK-FXQIFTODSA-N 0.000 description 3
- DVWVZSJAYIJZFI-FXQIFTODSA-N Ala-Arg-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O DVWVZSJAYIJZFI-FXQIFTODSA-N 0.000 description 3
- SVBXIUDNTRTKHE-CIUDSAMLSA-N Ala-Arg-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O SVBXIUDNTRTKHE-CIUDSAMLSA-N 0.000 description 3
- GFBLJMHGHAXGNY-ZLUOBGJFSA-N Ala-Asn-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O GFBLJMHGHAXGNY-ZLUOBGJFSA-N 0.000 description 3
- NFDVJAKFMXHJEQ-HERUPUMHSA-N Ala-Asp-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N NFDVJAKFMXHJEQ-HERUPUMHSA-N 0.000 description 3
- BGNLUHXLSAQYRQ-FXQIFTODSA-N Ala-Glu-Gln Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O BGNLUHXLSAQYRQ-FXQIFTODSA-N 0.000 description 3
- WKOBSJOZRJJVRZ-FXQIFTODSA-N Ala-Glu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WKOBSJOZRJJVRZ-FXQIFTODSA-N 0.000 description 3
- HXNNRBHASOSVPG-GUBZILKMSA-N Ala-Glu-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O HXNNRBHASOSVPG-GUBZILKMSA-N 0.000 description 3
- PUBLUECXJRHTBK-ACZMJKKPSA-N Ala-Glu-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O PUBLUECXJRHTBK-ACZMJKKPSA-N 0.000 description 3
- OBVSBEYOMDWLRJ-BFHQHQDPSA-N Ala-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N OBVSBEYOMDWLRJ-BFHQHQDPSA-N 0.000 description 3
- VNYMOTCMNHJGTG-JBDRJPRFSA-N Ala-Ile-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O VNYMOTCMNHJGTG-JBDRJPRFSA-N 0.000 description 3
- YHKANGMVQWRMAP-DCAQKATOSA-N Ala-Leu-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YHKANGMVQWRMAP-DCAQKATOSA-N 0.000 description 3
- HHRAXZAYZFFRAM-CIUDSAMLSA-N Ala-Leu-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O HHRAXZAYZFFRAM-CIUDSAMLSA-N 0.000 description 3
- CCDFBRZVTDDJNM-GUBZILKMSA-N Ala-Leu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CCDFBRZVTDDJNM-GUBZILKMSA-N 0.000 description 3
- WUHJHHGYVVJMQE-BJDJZHNGSA-N Ala-Leu-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WUHJHHGYVVJMQE-BJDJZHNGSA-N 0.000 description 3
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 3
- QUIGLPSHIFPEOV-CIUDSAMLSA-N Ala-Lys-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O QUIGLPSHIFPEOV-CIUDSAMLSA-N 0.000 description 3
- SDZRIBWEVVRDQI-CIUDSAMLSA-N Ala-Lys-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O SDZRIBWEVVRDQI-CIUDSAMLSA-N 0.000 description 3
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 3
- IYKVSFNGSWTTNZ-GUBZILKMSA-N Ala-Val-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IYKVSFNGSWTTNZ-GUBZILKMSA-N 0.000 description 3
- OMSKGWFGWCQFBD-KZVJFYERSA-N Ala-Val-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OMSKGWFGWCQFBD-KZVJFYERSA-N 0.000 description 3
- MCYJBCKCAPERSE-FXQIFTODSA-N Arg-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N MCYJBCKCAPERSE-FXQIFTODSA-N 0.000 description 3
- KWKQGHSSNHPGOW-BQBZGAKWSA-N Arg-Ala-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)NCC(O)=O KWKQGHSSNHPGOW-BQBZGAKWSA-N 0.000 description 3
- USNSOPDIZILSJP-FXQIFTODSA-N Arg-Asn-Asn Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O USNSOPDIZILSJP-FXQIFTODSA-N 0.000 description 3
- WESHVRNMNFMVBE-FXQIFTODSA-N Arg-Asn-Asp Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)CN=C(N)N WESHVRNMNFMVBE-FXQIFTODSA-N 0.000 description 3
- ITVINTQUZMQWJR-QXEWZRGKSA-N Arg-Asn-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O ITVINTQUZMQWJR-QXEWZRGKSA-N 0.000 description 3
- JAYIQMNQDMOBFY-KKUMJFAQSA-N Arg-Glu-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JAYIQMNQDMOBFY-KKUMJFAQSA-N 0.000 description 3
- HJDNZFIYILEIKR-OSUNSFLBSA-N Arg-Ile-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O HJDNZFIYILEIKR-OSUNSFLBSA-N 0.000 description 3
- COXMUHNBYCVVRG-DCAQKATOSA-N Arg-Leu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O COXMUHNBYCVVRG-DCAQKATOSA-N 0.000 description 3
- NGTYEHIRESTSRX-UWVGGRQHSA-N Arg-Lys-Gly Chemical compound NCCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N NGTYEHIRESTSRX-UWVGGRQHSA-N 0.000 description 3
- NGYHSXDNNOFHNE-AVGNSLFASA-N Arg-Pro-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O NGYHSXDNNOFHNE-AVGNSLFASA-N 0.000 description 3
- FRBAHXABMQXSJQ-FXQIFTODSA-N Arg-Ser-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O FRBAHXABMQXSJQ-FXQIFTODSA-N 0.000 description 3
- RZVVKNIACROXRM-ZLUOBGJFSA-N Asn-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N RZVVKNIACROXRM-ZLUOBGJFSA-N 0.000 description 3
- VDCIPFYVCICPEC-FXQIFTODSA-N Asn-Arg-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O VDCIPFYVCICPEC-FXQIFTODSA-N 0.000 description 3
- HUZGPXBILPMCHM-IHRRRGAJSA-N Asn-Arg-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HUZGPXBILPMCHM-IHRRRGAJSA-N 0.000 description 3
- WPOLSNAQGVHROR-GUBZILKMSA-N Asn-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N WPOLSNAQGVHROR-GUBZILKMSA-N 0.000 description 3
- XVAPVJNJGLWGCS-ACZMJKKPSA-N Asn-Glu-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N XVAPVJNJGLWGCS-ACZMJKKPSA-N 0.000 description 3
- OLISTMZJGQUOGS-GMOBBJLQSA-N Asn-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N OLISTMZJGQUOGS-GMOBBJLQSA-N 0.000 description 3
- ZMUQQMGITUJQTI-CIUDSAMLSA-N Asn-Leu-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O ZMUQQMGITUJQTI-CIUDSAMLSA-N 0.000 description 3
- ORJQQZIXTOYGGH-SRVKXCTJSA-N Asn-Lys-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ORJQQZIXTOYGGH-SRVKXCTJSA-N 0.000 description 3
- PLTGTJAZQRGMPP-FXQIFTODSA-N Asn-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(N)=O PLTGTJAZQRGMPP-FXQIFTODSA-N 0.000 description 3
- XTMZYFMTYJNABC-ZLUOBGJFSA-N Asn-Ser-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N XTMZYFMTYJNABC-ZLUOBGJFSA-N 0.000 description 3
- WUQXMTITJLFXAU-JIOCBJNQSA-N Asn-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)N)N)O WUQXMTITJLFXAU-JIOCBJNQSA-N 0.000 description 3
- QHAJMRDEWNAIBQ-FXQIFTODSA-N Asp-Arg-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O QHAJMRDEWNAIBQ-FXQIFTODSA-N 0.000 description 3
- QXHVOUSPVAWEMX-ZLUOBGJFSA-N Asp-Asp-Ser Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O QXHVOUSPVAWEMX-ZLUOBGJFSA-N 0.000 description 3
- DGKCOYGQLNWNCJ-ACZMJKKPSA-N Asp-Glu-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O DGKCOYGQLNWNCJ-ACZMJKKPSA-N 0.000 description 3
- PZXPWHFYZXTFBI-YUMQZZPRSA-N Asp-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O PZXPWHFYZXTFBI-YUMQZZPRSA-N 0.000 description 3
- SVABRQFIHCSNCI-FOHZUACHSA-N Asp-Gly-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O SVABRQFIHCSNCI-FOHZUACHSA-N 0.000 description 3
- KQBVNNAPIURMPD-PEFMBERDSA-N Asp-Ile-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O KQBVNNAPIURMPD-PEFMBERDSA-N 0.000 description 3
- NVFSJIXJZCDICF-SRVKXCTJSA-N Asp-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N NVFSJIXJZCDICF-SRVKXCTJSA-N 0.000 description 3
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 3
- SFJUYBCDQBAYAJ-YDHLFZDLSA-N Asp-Val-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SFJUYBCDQBAYAJ-YDHLFZDLSA-N 0.000 description 3
- 101800003171 Casoparan Proteins 0.000 description 3
- INFBPLSHYFALDE-ACZMJKKPSA-N Gln-Asn-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O INFBPLSHYFALDE-ACZMJKKPSA-N 0.000 description 3
- IKDOHQHEFPPGJG-FXQIFTODSA-N Gln-Asp-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O IKDOHQHEFPPGJG-FXQIFTODSA-N 0.000 description 3
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 3
- NPTGGVQJYRSMCM-GLLZPBPUSA-N Gln-Gln-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NPTGGVQJYRSMCM-GLLZPBPUSA-N 0.000 description 3
- MLSKFHLRFVGNLL-WDCWCFNPSA-N Gln-Leu-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MLSKFHLRFVGNLL-WDCWCFNPSA-N 0.000 description 3
- TWIAMTNJOMRDAK-GUBZILKMSA-N Gln-Lys-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O TWIAMTNJOMRDAK-GUBZILKMSA-N 0.000 description 3
- HPCOBEHVEHWREJ-DCAQKATOSA-N Gln-Lys-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HPCOBEHVEHWREJ-DCAQKATOSA-N 0.000 description 3
- KSKFIECUYMYWNS-AVGNSLFASA-N Gln-Lys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N KSKFIECUYMYWNS-AVGNSLFASA-N 0.000 description 3
- LURQDGKYBFWWJA-MNXVOIDGSA-N Gln-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N LURQDGKYBFWWJA-MNXVOIDGSA-N 0.000 description 3
- BUVMZWZNWMKASN-QEJZJMRPSA-N Glu-Asn-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)N)C(O)=O)=CNC2=C1 BUVMZWZNWMKASN-QEJZJMRPSA-N 0.000 description 3
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 3
- OXEMJGCAJFFREE-FXQIFTODSA-N Glu-Gln-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O OXEMJGCAJFFREE-FXQIFTODSA-N 0.000 description 3
- PVBBEKPHARMPHX-DCAQKATOSA-N Glu-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCC(O)=O PVBBEKPHARMPHX-DCAQKATOSA-N 0.000 description 3
- CGOHAEBMDSEKFB-FXQIFTODSA-N Glu-Glu-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O CGOHAEBMDSEKFB-FXQIFTODSA-N 0.000 description 3
- MTAOBYXRYJZRGQ-WDSKDSINSA-N Glu-Gly-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MTAOBYXRYJZRGQ-WDSKDSINSA-N 0.000 description 3
- ZWABFSSWTSAMQN-KBIXCLLPSA-N Glu-Ile-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O ZWABFSSWTSAMQN-KBIXCLLPSA-N 0.000 description 3
- SJJHXJDSNQJMMW-SRVKXCTJSA-N Glu-Lys-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O SJJHXJDSNQJMMW-SRVKXCTJSA-N 0.000 description 3
- SWRVAQHFBRZVNX-GUBZILKMSA-N Glu-Lys-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O SWRVAQHFBRZVNX-GUBZILKMSA-N 0.000 description 3
- CUPSDFQZTVVTSK-GUBZILKMSA-N Glu-Lys-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O CUPSDFQZTVVTSK-GUBZILKMSA-N 0.000 description 3
- BCYGDJXHAGZNPQ-DCAQKATOSA-N Glu-Lys-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O BCYGDJXHAGZNPQ-DCAQKATOSA-N 0.000 description 3
- AQNYKMCFCCZEEL-JYJNAYRXSA-N Glu-Lys-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AQNYKMCFCCZEEL-JYJNAYRXSA-N 0.000 description 3
- KJBGAZSLZAQDPV-KKUMJFAQSA-N Glu-Phe-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N KJBGAZSLZAQDPV-KKUMJFAQSA-N 0.000 description 3
- RXJFSLQVMGYQEL-IHRRRGAJSA-N Glu-Tyr-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(O)=O)CC1=CC=C(O)C=C1 RXJFSLQVMGYQEL-IHRRRGAJSA-N 0.000 description 3
- OCDLPQDYTJPWNG-YUMQZZPRSA-N Gly-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN OCDLPQDYTJPWNG-YUMQZZPRSA-N 0.000 description 3
- KMSGYZQRXPUKGI-BYPYZUCNSA-N Gly-Gly-Asn Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC(N)=O KMSGYZQRXPUKGI-BYPYZUCNSA-N 0.000 description 3
- GDOZQTNZPCUARW-YFKPBYRVSA-N Gly-Gly-Glu Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O GDOZQTNZPCUARW-YFKPBYRVSA-N 0.000 description 3
- AAHSHTLISQUZJL-QSFUFRPTSA-N Gly-Ile-Ile Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AAHSHTLISQUZJL-QSFUFRPTSA-N 0.000 description 3
- GNNJKUYDWFIBTK-QWRGUYRKSA-N Gly-Tyr-Asp Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O GNNJKUYDWFIBTK-QWRGUYRKSA-N 0.000 description 3
- HQSKKSLNLSTONK-JTQLQIEISA-N Gly-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 HQSKKSLNLSTONK-JTQLQIEISA-N 0.000 description 3
- ZHHLTWUOWXHVQJ-YUMQZZPRSA-N His-Ser-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZHHLTWUOWXHVQJ-YUMQZZPRSA-N 0.000 description 3
- ZZHGKECPZXPXJF-PCBIJLKTSA-N Ile-Asn-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZZHGKECPZXPXJF-PCBIJLKTSA-N 0.000 description 3
- WIZPFZKOFZXDQG-HTFCKZLJSA-N Ile-Ile-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O WIZPFZKOFZXDQG-HTFCKZLJSA-N 0.000 description 3
- TWYOYAKMLHWMOJ-ZPFDUUQYSA-N Ile-Leu-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O TWYOYAKMLHWMOJ-ZPFDUUQYSA-N 0.000 description 3
- OUUCIIJSBIBCHB-ZPFDUUQYSA-N Ile-Leu-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O OUUCIIJSBIBCHB-ZPFDUUQYSA-N 0.000 description 3
- FFAUOCITXBMRBT-YTFOTSKYSA-N Ile-Lys-Ile Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FFAUOCITXBMRBT-YTFOTSKYSA-N 0.000 description 3
- FJWALBCCVIHZBS-QXEWZRGKSA-N Ile-Met-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)O)N FJWALBCCVIHZBS-QXEWZRGKSA-N 0.000 description 3
- COWHUQXTSYTKQC-RWRJDSDZSA-N Ile-Thr-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N COWHUQXTSYTKQC-RWRJDSDZSA-N 0.000 description 3
- JZBVBOKASHNXAD-NAKRPEOUSA-N Ile-Val-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N JZBVBOKASHNXAD-NAKRPEOUSA-N 0.000 description 3
- YHFPHRUWZMEOIX-CYDGBPFRSA-N Ile-Val-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)O)N YHFPHRUWZMEOIX-CYDGBPFRSA-N 0.000 description 3
- WGNOPSQMIQERPK-UHFFFAOYSA-N Leu-Asn-Pro Natural products CC(C)CC(N)C(=O)NC(CC(=O)N)C(=O)N1CCCC1C(=O)O WGNOPSQMIQERPK-UHFFFAOYSA-N 0.000 description 3
- FIJMQLGQLBLBOL-HJGDQZAQSA-N Leu-Asn-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FIJMQLGQLBLBOL-HJGDQZAQSA-N 0.000 description 3
- QLQHWWCSCLZUMA-KKUMJFAQSA-N Leu-Asp-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QLQHWWCSCLZUMA-KKUMJFAQSA-N 0.000 description 3
- OHZIZVWQXJPBJS-IXOXFDKPSA-N Leu-His-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OHZIZVWQXJPBJS-IXOXFDKPSA-N 0.000 description 3
- JNDYEOUZBLOVOF-AVGNSLFASA-N Leu-Leu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JNDYEOUZBLOVOF-AVGNSLFASA-N 0.000 description 3
- LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 description 3
- PPQRKXHCLYCBSP-IHRRRGAJSA-N Leu-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)O)N PPQRKXHCLYCBSP-IHRRRGAJSA-N 0.000 description 3
- ZRHDPZAAWLXXIR-SRVKXCTJSA-N Leu-Lys-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O ZRHDPZAAWLXXIR-SRVKXCTJSA-N 0.000 description 3
- OVZLLFONXILPDZ-VOAKCMCISA-N Leu-Lys-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OVZLLFONXILPDZ-VOAKCMCISA-N 0.000 description 3
- IZPVWNSAVUQBGP-CIUDSAMLSA-N Leu-Ser-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IZPVWNSAVUQBGP-CIUDSAMLSA-N 0.000 description 3
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 3
- MPOHDJKRBLVGCT-CIUDSAMLSA-N Lys-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N MPOHDJKRBLVGCT-CIUDSAMLSA-N 0.000 description 3
- ALSRJRIWBNENFY-DCAQKATOSA-N Lys-Arg-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O ALSRJRIWBNENFY-DCAQKATOSA-N 0.000 description 3
- GQUDMNDPQTXZRV-DCAQKATOSA-N Lys-Arg-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O GQUDMNDPQTXZRV-DCAQKATOSA-N 0.000 description 3
- SJNZALDHDUYDBU-IHRRRGAJSA-N Lys-Arg-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(O)=O SJNZALDHDUYDBU-IHRRRGAJSA-N 0.000 description 3
- SWWCDAGDQHTKIE-RHYQMDGZSA-N Lys-Arg-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWWCDAGDQHTKIE-RHYQMDGZSA-N 0.000 description 3
- HKCCVDWHHTVVPN-CIUDSAMLSA-N Lys-Asp-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O HKCCVDWHHTVVPN-CIUDSAMLSA-N 0.000 description 3
- LPAJOCKCPRZEAG-MNXVOIDGSA-N Lys-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCCCN LPAJOCKCPRZEAG-MNXVOIDGSA-N 0.000 description 3
- KYNNSEJZFVCDIV-ZPFDUUQYSA-N Lys-Ile-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O KYNNSEJZFVCDIV-ZPFDUUQYSA-N 0.000 description 3
- NCZIQZYZPUPMKY-PPCPHDFISA-N Lys-Ile-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NCZIQZYZPUPMKY-PPCPHDFISA-N 0.000 description 3
- NQSFIPWBPXNJII-PMVMPFDFSA-N Lys-Phe-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 NQSFIPWBPXNJII-PMVMPFDFSA-N 0.000 description 3
- RPWTZTBIFGENIA-VOAKCMCISA-N Lys-Thr-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O RPWTZTBIFGENIA-VOAKCMCISA-N 0.000 description 3
- RQILLQOQXLZTCK-KBPBESRZSA-N Lys-Tyr-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O RQILLQOQXLZTCK-KBPBESRZSA-N 0.000 description 3
- GAELMDJMQDUDLJ-BQBZGAKWSA-N Met-Ala-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O GAELMDJMQDUDLJ-BQBZGAKWSA-N 0.000 description 3
- AFFKUNVPPLQUGA-DCAQKATOSA-N Met-Leu-Ala Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O AFFKUNVPPLQUGA-DCAQKATOSA-N 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 3
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 3
- 108010079364 N-glycylalanine Proteins 0.000 description 3
- ZWJKVFAYPLPCQB-UNQGMJICSA-N Phe-Arg-Thr Chemical compound C[C@@H](O)[C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)Cc1ccccc1)C(O)=O ZWJKVFAYPLPCQB-UNQGMJICSA-N 0.000 description 3
- HBGFEEQFVBWYJQ-KBPBESRZSA-N Phe-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 HBGFEEQFVBWYJQ-KBPBESRZSA-N 0.000 description 3
- LRBSWBVUCLLRLU-BZSNNMDCSA-N Phe-Leu-Lys Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(O)=O LRBSWBVUCLLRLU-BZSNNMDCSA-N 0.000 description 3
- MMJJFXWMCMJMQA-STQMWFEESA-N Phe-Pro-Gly Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)C1=CC=CC=C1 MMJJFXWMCMJMQA-STQMWFEESA-N 0.000 description 3
- RGMLUHANLDVMPB-ULQDDVLXSA-N Phe-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N RGMLUHANLDVMPB-ULQDDVLXSA-N 0.000 description 3
- KDIIENQUNVNWHR-JYJNAYRXSA-N Pro-Arg-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KDIIENQUNVNWHR-JYJNAYRXSA-N 0.000 description 3
- ORPZXBQTEHINPB-SRVKXCTJSA-N Pro-Arg-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1)C(O)=O ORPZXBQTEHINPB-SRVKXCTJSA-N 0.000 description 3
- VOZIBWWZSBIXQN-SRVKXCTJSA-N Pro-Glu-Lys Chemical compound NCCCC[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1)C(O)=O VOZIBWWZSBIXQN-SRVKXCTJSA-N 0.000 description 3
- KDBHVPXBQADZKY-GUBZILKMSA-N Pro-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KDBHVPXBQADZKY-GUBZILKMSA-N 0.000 description 3
- FIXILCYTSAUERA-FXQIFTODSA-N Ser-Ala-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FIXILCYTSAUERA-FXQIFTODSA-N 0.000 description 3
- MMGJPDWSIOAGTH-ACZMJKKPSA-N Ser-Ala-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MMGJPDWSIOAGTH-ACZMJKKPSA-N 0.000 description 3
- SRTCFKGBYBZRHA-ACZMJKKPSA-N Ser-Ala-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SRTCFKGBYBZRHA-ACZMJKKPSA-N 0.000 description 3
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 3
- HBZBPFLJNDXRAY-FXQIFTODSA-N Ser-Ala-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O HBZBPFLJNDXRAY-FXQIFTODSA-N 0.000 description 3
- HQTKVSCNCDLXSX-BQBZGAKWSA-N Ser-Arg-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O HQTKVSCNCDLXSX-BQBZGAKWSA-N 0.000 description 3
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 3
- GHPQVUYZQQGEDA-BIIVOSGPSA-N Ser-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)N)C(=O)O GHPQVUYZQQGEDA-BIIVOSGPSA-N 0.000 description 3
- MUARUIBTKQJKFY-WHFBIAKZSA-N Ser-Gly-Asp Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MUARUIBTKQJKFY-WHFBIAKZSA-N 0.000 description 3
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 3
- HEUVHBXOVZONPU-BJDJZHNGSA-N Ser-Leu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HEUVHBXOVZONPU-BJDJZHNGSA-N 0.000 description 3
- ILZAUMFXKSIUEF-SRVKXCTJSA-N Ser-Ser-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ILZAUMFXKSIUEF-SRVKXCTJSA-N 0.000 description 3
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 3
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 3
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 3
- DGDCHPCRMWEOJR-FQPOAREZSA-N Thr-Ala-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DGDCHPCRMWEOJR-FQPOAREZSA-N 0.000 description 3
- LHUBVKCLOVALIA-HJGDQZAQSA-N Thr-Arg-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O LHUBVKCLOVALIA-HJGDQZAQSA-N 0.000 description 3
- VFEHSAJCWWHDBH-RHYQMDGZSA-N Thr-Arg-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O VFEHSAJCWWHDBH-RHYQMDGZSA-N 0.000 description 3
- CEXFELBFVHLYDZ-XGEHTFHBSA-N Thr-Arg-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O CEXFELBFVHLYDZ-XGEHTFHBSA-N 0.000 description 3
- QGXCWPNQVCYJEL-NUMRIWBASA-N Thr-Asn-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QGXCWPNQVCYJEL-NUMRIWBASA-N 0.000 description 3
- PAOYNIKMYOGBMR-PBCZWWQYSA-N Thr-Asn-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O PAOYNIKMYOGBMR-PBCZWWQYSA-N 0.000 description 3
- ONNSECRQFSTMCC-XKBZYTNZSA-N Thr-Glu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ONNSECRQFSTMCC-XKBZYTNZSA-N 0.000 description 3
- XOTBWOCSLMBGMF-SUSMZKCASA-N Thr-Glu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XOTBWOCSLMBGMF-SUSMZKCASA-N 0.000 description 3
- XUGYQLFEJYZOKQ-NGTWOADLSA-N Thr-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N XUGYQLFEJYZOKQ-NGTWOADLSA-N 0.000 description 3
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-N 0.000 description 3
- AHERARIZBPOMNU-KATARQTJSA-N Thr-Ser-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O AHERARIZBPOMNU-KATARQTJSA-N 0.000 description 3
- VBMOVTMNHWPZJR-SUSMZKCASA-N Thr-Thr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VBMOVTMNHWPZJR-SUSMZKCASA-N 0.000 description 3
- DKKHULUSOSWGHS-UWJYBYFXSA-N Tyr-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N DKKHULUSOSWGHS-UWJYBYFXSA-N 0.000 description 3
- MVFQLSPDMMFCMW-KKUMJFAQSA-N Tyr-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O MVFQLSPDMMFCMW-KKUMJFAQSA-N 0.000 description 3
- KHCSOLAHNLOXJR-BZSNNMDCSA-N Tyr-Leu-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHCSOLAHNLOXJR-BZSNNMDCSA-N 0.000 description 3
- XLDYBRXERHITNH-QSFUFRPTSA-N Val-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)C(C)C XLDYBRXERHITNH-QSFUFRPTSA-N 0.000 description 3
- LKUDRJSNRWVGMS-QSFUFRPTSA-N Val-Ile-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N LKUDRJSNRWVGMS-QSFUFRPTSA-N 0.000 description 3
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-N 0.000 description 3
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 108010013835 arginine glutamate Proteins 0.000 description 3
- 108010010430 asparagine-proline-alanine Proteins 0.000 description 3
- 108010077245 asparaginyl-proline Proteins 0.000 description 3
- 108010093581 aspartyl-proline Proteins 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 3
- 108010048994 glycyl-tyrosyl-alanine Proteins 0.000 description 3
- 108010045126 glycyl-tyrosyl-glycine Proteins 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 108010040030 histidinoalanine Proteins 0.000 description 3
- 108010018006 histidylserine Proteins 0.000 description 3
- 108010034529 leucyl-lysine Proteins 0.000 description 3
- 108010030617 leucyl-phenylalanyl-valine Proteins 0.000 description 3
- 108010087810 leucyl-seryl-glutamyl-leucine Proteins 0.000 description 3
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 3
- 108010038320 lysylphenylalanine Proteins 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229960003085 meticillin Drugs 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 108010051242 phenylalanylserine Proteins 0.000 description 3
- 108010093296 prolyl-prolyl-alanine Proteins 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 108010026333 seryl-proline Proteins 0.000 description 3
- 238000004088 simulation Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 108010061238 threonyl-glycine Proteins 0.000 description 3
- 238000012549 training Methods 0.000 description 3
- 108010058119 tryptophyl-glycyl-glycine Proteins 0.000 description 3
- 108010038745 tryptophylglycine Proteins 0.000 description 3
- 108010051110 tyrosyl-lysine Proteins 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- BYXHQQCXAJARLQ-ZLUOBGJFSA-N Ala-Ala-Ala Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O BYXHQQCXAJARLQ-ZLUOBGJFSA-N 0.000 description 2
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 2
- OCJRHJZKGGSPRW-IUCAKERBSA-N Glu-Lys-Gly Chemical compound NCCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O OCJRHJZKGGSPRW-IUCAKERBSA-N 0.000 description 2
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 2
- RVGMVLVBDRQVKB-UWVGGRQHSA-N Gly-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN RVGMVLVBDRQVKB-UWVGGRQHSA-N 0.000 description 2
- ZDNNDIJTUHQCAM-MXAVVETBSA-N Ile-Ser-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N ZDNNDIJTUHQCAM-MXAVVETBSA-N 0.000 description 2
- 101710116034 Immunity protein Proteins 0.000 description 2
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 2
- ABHVWYPPHDYFNY-WDSOQIARSA-N Met-His-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CN=CN1 ABHVWYPPHDYFNY-WDSOQIARSA-N 0.000 description 2
- XKFJENWJGHMDLI-QWRGUYRKSA-N Ser-Phe-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O XKFJENWJGHMDLI-QWRGUYRKSA-N 0.000 description 2
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 2
- MDXLPNRXCFOBTL-BZSNNMDCSA-N Tyr-Ser-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MDXLPNRXCFOBTL-BZSNNMDCSA-N 0.000 description 2
- JIODCDXKCJRMEH-NHCYSSNCSA-N Val-Arg-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N JIODCDXKCJRMEH-NHCYSSNCSA-N 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 108010020532 tyrosyl-proline Proteins 0.000 description 2
- 101150029857 23 gene Proteins 0.000 description 1
- WMYJZJRILUVVRG-WDSKDSINSA-N Ala-Gly-Gln Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O WMYJZJRILUVVRG-WDSKDSINSA-N 0.000 description 1
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 1
- 241001146209 Curio rowleyanus Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LLEUXCDZPQOJMY-AAEUAGOBSA-N Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(O)=O)=CNC2=C1 LLEUXCDZPQOJMY-AAEUAGOBSA-N 0.000 description 1
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 206010062049 Lymphocytic infiltration Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 108010071384 Peptide T Proteins 0.000 description 1
- VEUACYMXJKXALX-IHRRRGAJSA-N Pro-Tyr-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VEUACYMXJKXALX-IHRRRGAJSA-N 0.000 description 1
- QKWYXRPICJEQAJ-KJEVXHAQSA-N Pro-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@@H]2CCCN2)O QKWYXRPICJEQAJ-KJEVXHAQSA-N 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- DIHPMRTXPYMDJZ-KAOXEZKKSA-N Thr-Tyr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N)O DIHPMRTXPYMDJZ-KAOXEZKKSA-N 0.000 description 1
- JWGXUKHIKXZWNG-RYUDHWBXSA-N Tyr-Gly-Gln Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O JWGXUKHIKXZWNG-RYUDHWBXSA-N 0.000 description 1
- VPEFOFYNHBWFNQ-UFYCRDLUSA-N Tyr-Pro-Tyr Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 VPEFOFYNHBWFNQ-UFYCRDLUSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 229960000479 ceftriaxone sodium Drugs 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 108010056602 colicin immunity proteins Proteins 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000003147 molecular marker Substances 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000011049 pearl Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000013615 primer Substances 0.000 description 1
- 239000002987 primer (paints) Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- -1 propidium iodides Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
- C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
- C07K14/245—Escherichia (G)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16211—Lymphocryptovirus, e.g. human herpesvirus 4, Epstein-Barr Virus
- C12N2710/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Immunology (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Plant Pathology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本发明“一种新型抗EB病毒所致肿瘤多肽及其应用与制备方法”，属于抗肿瘤药物领域，由可形成离子通道的大肠菌素变构多肽与抗EB病毒抗体多肽或者抗EB病毒抗体的模拟抗体多肽构成，所述可形成离子通道的大肠菌素变构多肽由野生型大肠菌素E1、Ia、Ib、A、B、N或其水性孔道结构域的肽链突变了氨基酸残基G11A、H22G、A26G、V31L和H40D而获得，所述抗EB病毒抗体的氨基酸序列与ATCC HB-168杂交瘤分泌的单克隆抗体相同。为治疗EB病毒所致肿瘤提供一种改进的杀伤力强、安全性高，高特异性且致敏可能性较低的药物及其制备方法。
Description
技术领域
本发明涉及抗肿瘤药物领域，特别涉及一种新型抗EB病毒所致肿瘤多肽及其应用与制备方法。
背景技术
在抗生素研究领域，人们一直在致力于开发模仿同种异株细菌之间互相杀伤的工作方式来开发新型抗生素，自然界中有不少细菌毒素直接在细菌胞膜上形成离子通道来杀死细菌，其模式标本就是大肠杆菌分泌的一种细菌毒素-大肠菌素。其中大肠菌素Ia自1952年被Jacob发现之后，经过数代人的努力，1996年Qiu et al(Major transmemebrane movementsoociated with colicin Ia channel gating.J.Gen.Physiology，107：313-328(1996))终于揭示了大肠菌素Ia在人工脂质双分子膜上所形成离子通道开放和关闭时的跨膜立体结构，为在分子水平上设计和制备新型的抗菌素奠定了理论基础。并相继有大肠菌素多肽与白色连珠球菌信息素、葡萄球菌信息素等信号肽分子连接而成的多肽分子能够通过信息素识别靶细菌细胞，将大肠菌素引导到靶细菌细胞膜上形成跨膜离子通道导致胞容物外泄致死细胞。
恶性肿瘤是对人类健康的巨大威胁。全世界每年死于恶性肿瘤的患者约有七百万人，其中中国就占有六分之一，恶性肿瘤已是我国第二位的死亡原因。由于其病因、发病机制、临床表现尚未阐明，故防治效果不理想。现有抗肿瘤药物在肿瘤治疗中占重要地位，虽然对一些肿瘤已取得一定的疗效，但仍存在着对肿瘤细胞的选择性差，免疫抑制及不良反应多而严重，产生耐药性等缺陷。
EB病毒所致的非洲儿童恶性淋巴肉瘤，Hodgkin’s淋巴肉瘤和鼻咽癌细胞表面均带有特异的EB病毒表面抗原，因此，EB病毒表面抗原可以认为是该类肿瘤细胞的一种特异性标志物。在EB病毒所致的肿瘤药物上，专利号为ZL200410081446.8的发明，公开了大肠菌素与识别EB病毒表面抗原的模拟抗体结合形成的抗肿瘤多肽，能够特异性杀死机体中的EB病毒所致癌细胞，而对正常细胞没有伤害，杀伤力是其他抗癌药物的若干倍，克服了近年来使用的抗肿瘤药物中存在的药物选择性差、产生耐药性、杀死癌细胞的同时正常组织也受到严重损伤等问题，Xiao-Qing Qiu等，2007的文章中对比了一系列结构的模拟抗体与大肠菌素构成的抗肿瘤多肽的杀肿瘤的能力，发现VHCDR1-VHFR2-VLCDR3及VLCDR1-VHFR2-VHCDR3两种结构的模拟抗体与大肠菌素构成的抗肿瘤多肽具有较好的杀伤能力(Xiao-Qing Qiu et al.，2007，Small antibody mimetics comprising two complementarity-determining regions and aframework region for tumor targeting，Nature Biotechnology 25，921-929，1 August 2007)，这为进一步制备抗EB病毒所致肿瘤多肽提供了更多的候选模拟抗体。
但是在上述抗肿瘤多肽中，由于大肠菌素多肽的熟睡端存在较易引起超敏反应的氨基酸残基，有可能导致含有大肠杆菌多肽的药物较易引起机体异常的免疫应答；有研究报道，很多癌症患者由于其代谢机制受到癌细胞干扰而不正常，对多肽类药物容易产生过敏反应，而导致不能用药，因此有必要对大肠菌素多肽进行改进，以获得更安全适合更多患者的抗癌药物。
发明内容
本发明根据上述领域存在的不足，提供一种新型抗EB病毒所致肿瘤多肽及其应用与制备方法。为治疗EB病毒所致肿瘤提供高杀伤力、高特异性，且致敏可能性较低的药物。
一种新型抗EB病毒所致肿瘤多肽，由可形成离子通道的大肠菌素变构多肽与抗EB病毒抗体多肽或者抗EB病毒抗体的模拟抗体多肽可操作地连接构成，所述可形成离子通道的大肠菌素变构多肽由野生型大肠菌素El、Ia、Ib、A、B、N或其水性孔道结构域的肽链突变了氨基酸残基G11A、H22G、A26G、V31L和H40D而获得，所述抗EB病毒抗体多肽的氨基酸序列与ATCC HB-168杂交瘤分泌的抗体多肽相同。
所述模拟抗体多肽指所述抗EB病毒抗体的重链CDR1区、重链CDR1-CDR2连接肽段和轻链CDR3的连接肽。
所述可形成离子通道的大肠菌素变构多肽由野生型大肠菌素Ia突变而来。
所述新型抗EB病毒所致肿瘤多肽，具有如SEQ ID NO.29所示的氨基酸序列。
编码所述新型抗EB病毒所致肿瘤多肽的基因。
所述基因，具有如SEQ ID NO.30所示的核苷酸序列。
含有上述基因的重组质粒。
上述新型抗EB病毒所致肿瘤多肽的制备方法，步骤如下：将上述重组质粒转化到表达系统中进行表达，分离纯化表达的多肽。
上述新型抗EB病毒所致肿瘤多肽在制备治疗和预防EB病毒所致肿瘤的药物中的应用。
一种大肠菌素Ia的变构多肽，其氨基酸序列如SEQ ID NO.24所示。
编码大肠菌素Ia的变构多肽的基因。
所述基因在制备多肽药物中的应用，指将所述基因与诱导多肽的基因可操作地连接并克隆到表达载体中，然后将表达载体转化到表达系统中，分离纯化表达的多肽
本发明提供的新型抗EB病毒所致肿瘤多肽，由可形成离子通道的大肠菌素变构多肽与抗EB病毒的抗体多肽或者抗EB病毒的抗体的模拟抗体多肽构成。由于野生大肠菌素多肽分子中存在容易引起超敏反应的氨基酸残基，本发明在可形成离子通道结构的大肠菌素的多肽分子中，选择性地突变了疏水区段部分容易引起机体超敏反应的氨基酸残基，如本发明的一个优选实施例中，大肠菌素Ia的多肽突变位置为：G11A、H22G、A26G、V31L和H40D，实验数据表明，采用大肠菌素Ia多肽和变构的Ia多肽分别注射免疫小鼠，注射变构的Ia的小鼠产生的血清效价要比前者低1～2个数量级，即免疫应答水平较低，证明变构的多肽降低了引起机体过敏的可能性；同时变构多肽仍然保留了在细胞膜上形成跨膜离子通道的功能，实验证明，本发明的重组多肽对肿瘤细胞的杀伤能力未受影响，说明突变的氨基酸残基没有影响大肠菌素形成离子通道的功能。本发明提供的新型抗EB病毒所致肿瘤多肽中，抗EB病毒的抗体多肽或者抗EB病毒的抗体的模拟多肽通过与EB病毒所致的肿瘤细胞的表面特异性抗原识别，大肠菌素变构多肽引导至靶细胞膜上，大肠菌素变构多肽的跨膜离子通道结构域疏水区段插入肿瘤细胞膜中，进而形成离子通道，靶肿瘤细胞因内容物泄漏而被致死；抗EB病毒的抗体多肽的氨基酸序列完全参照ATCC HB-168杂交瘤细胞分泌单克隆抗体的多肽的氨基酸序列。
本发明的实施例中优选采用上述抗EB病毒抗体的模拟抗体多肽可操作地连接在大肠菌素变构多肽的羧基端而获得分子量较小的本发明的抗肿瘤多肽，即这些小分子模拟多肽仅包括该抗EB病毒的抗体多肽的VHCDR1区、VLCDR3区，VHCDR1-VHCDR2连接肽段和轻链VLCDR3区连接的肽链VHCDR1-VHFR2-VLCDR3，得到氨基酸序列如SEQ ID NO.25所示的新型抗肿瘤多肽1的模拟抗体，模拟抗体仅包含不到30个氨基酸，在分子量上远远小于天然抗体150个氨基酸，既达到了对抗原识别能力的要求又大幅度消减了抗肿瘤多肽的分子量，有利于提高本发明抗肿瘤多肽在组织中的穿透能力。
本发明的另一目的是提供编码本发明所述抗肿瘤多肽的基因序列。本发明抗肿瘤多肽的基因由编码大肠菌素变构多肽的基因与编码抗EB病毒的抗体多肽的基因或者其模拟抗体多肽的基因可操作地连接构成，其中大肠菌素多肽和抗EB病毒抗体的基因序列是已知的，大肠菌素变构多肽的基因是在大肠菌素多肽基因的相应密码子上进行如下点突变而得：G11A、H22G、A26G、V31L和H40D。由于密码子的兼并性，本领域技术人员可在不改变氨基酸序列的前提下对编码本发明所述的抗肿瘤多肽的核苷酸序列进行调整。
本发明所述的重组质粒，是指将装载了野生大肠菌素基因的原始载体进行双链核苷酸点突变，在目标突变位置上插入突变密码子，获得含有大肠菌素变构多肽的基因的突变载体，相同的点突变技术将编码抗EB病毒的抗体的模拟抗体基因经插入到大肠菌素变构多肽基因的羧基端，得到本发明的重组质粒。原始载体pSELECTTM-1购于Promega公司，其中装载了大肠菌素Ia和Immunity蛋白基因，点突变操作按照Strategene公司试剂盒说明书；本发明针对点突变制备大肠菌素变构多肽，其中突变了5个密码子，因此设计了5对引物序列(SeqID No.1～10)；本发明实施例中针对模拟抗体基因设计了6对引物序列(Seq ID No.11～22)。
本发明还提供了制备本发明所述抗肿瘤多肽的方法，是将上述获得的重组质粒转染入大肠杆菌BL21(DE3)工程菌中，筛选出阳性克隆，分离纯化阳性克隆表达的蛋白即能得到为本发明新型抗EB病毒所致肿瘤多肽。
本发明提供的新型抗EB病毒所致肿瘤多肽，可在制备治疗或预防EB病毒所致肿瘤的药物中应用。可以通过将本发明中获得的新型抗生素的多肽添加到药学上可接受的载体或者赋形剂或可选的其它成分而制成临床上适用的药物组合物。
本发明还提供了大肠菌素Ia变构多肽的氨基酸序列和基因序列，该变构多肽不仅可用于本发明中，还可以与其他引导多肽构成抗体多肽，本发明实施例3的实验数据一方面证明了含有该变构多肽的多肽药物具有较低的抗原性，也证明该变构多肽与其他引导多肽构成抗体多肽具有杀菌能力，而制备方法是本领域的常规实验操作。
本发明提供的新型抗肿瘤多肽，具有专利号ZL200410081446.8的发明所公开的抗肿瘤多肽的优点，即高特异性的靶向性和对正常细胞的安全性，不易产生耐药性等优点，同时本发明的抗肿瘤多肽通过对大肠菌素多肽中易引起超敏反应的氨基酸残基进行了突变，降低了含该变构多肽的抗肿瘤多肽的免疫原性，即降低了引起过敏反应的可能性，改进了现有该类多肽的药物使用安全性和杀肿瘤效果，还为其他含大肠菌素多肽的药物提供了改进的参考。
附图说明
图1.含有模拟抗体多肽VHCDR1-VHFR2-VLCDR3的基因和大肠菌素Ia变构多肽基因的重组质粒pCHCEB11的结构示意图
图2.含有模拟抗体多肽VHCDR1-VHFR2-(Rev)VLCDR3的基因和大肠菌素Ia变构多肽基因的重组质粒pCHCEB22的结构示意图
图3.大肠菌素Ia变构多肽的致敏效果实验1
(A)昆明小鼠腹腔注射致死剂量的耐甲氧西林金葡菌(ATCC BAA42)，随机分组为(1)对照组，(2)氨苄青霉素组，(3)抗金葡菌多肽(ZL 01128836.1)组，(4)抗金葡菌多肽1组。
(B)14天后，再取昆明小鼠一批作为对照和氨苄青霉素组，抗金葡菌多肽组及抗金葡菌多肽1组存活鼠作为抗金葡菌多肽组及抗金葡菌多肽1组重复上述试验。
(C)41天后，再取昆明小鼠一批作为(1)对照组、(2)左氧氟沙星组和(3)头孢曲松钠组，(4)抗金葡菌多肽组及(5)抗金葡菌多肽1组存活鼠作为抗绿脓杆菌多肽2组及抗绿脓杆菌多肽1组。。
图4.大肠菌素Ia变构多肽的低致敏效果实验2
(A)抗金葡菌多肽/抗绿脓杆菌多肽2组血清，1∶50,000滴度；
(B)抗金葡菌多肽1/抗绿脓杆菌多肽1组血清，1∶50,000滴度。
(1)第一周，(2)第二周，(3)第7周血清。(4)阴性对照。
图5.新型抗肿瘤多肽对EB病毒所致人恶性淋巴肉瘤(Burkitt’s lymphoma)体外杀伤效果比较
(A)对照组，(B)新型抗肿瘤多肽1处理组，(C)新型抗肿瘤多肽2处理组。
图6.新型抗肿瘤多肽对EB病毒所致Burkitt’s人恶性淋巴肉瘤细胞和其它肿瘤细胞的体外杀伤作用
(A)EBV病毒阳性的Burkitt’s人恶性淋巴肉瘤细胞，
(B)EBV病毒阴性的Burkitt’s人恶性淋巴肉瘤细胞，
(C)EBV病毒阳性的爱滋病人(AIDS)恶性淋巴肉瘤细胞。
(1)对照组，(2)新型抗肿瘤多肽1处理组。。
图7新型抗肿瘤多肽对EB病毒所致Burkitt’s人恶性淋巴肉瘤细胞种植到裸鼠体内生长出的实体肿瘤的杀伤作用
(A)对照组。
(B)新型抗肿瘤多肽1处理组的SCID免疫缺陷鼠，鼠双腋下均接种Burkitt’s人恶性淋巴肉瘤细胞。左边箭头，EBV病毒阴性的淋巴肉瘤，右边箭头，EBV病毒阳性的淋巴肉瘤。
图8新型抗肿瘤多肽对EB病毒所致Burkitts人恶性淋巴肉瘤细胞种植到裸鼠体内生长出的实体肿瘤的杀伤作用
(A)对照鼠EBV病毒阴性的淋巴肉瘤切片，(B)对照鼠EBV病毒阳性的淋巴肉瘤切片，(C)新型抗肿瘤多肽1处理鼠EBV病毒阴性的淋巴肉瘤切片，(D)新型抗肿瘤多肽1处理鼠EBV病毒阳性的淋巴肉瘤切片。
具体实施方式
结合附图，通过对本发明较佳实施例的描述具体说明本发明。
本发明所用的原始质粒：pSELECTTM-1购于Promega公司。
工程菌：E.coli BL-21(DE3)工程菌，购于Novagen公司。
实施例1.构建含编码突变大肠菌素Ia的基因的重组质粒
原始质粒为原始质粒为装载了大肠菌素多肽Ia和immunity蛋白基因的pSELECTTM-1质粒(8.3kb)(购于Promega公司)，经双链寡聚核苷酸点突变技术(QuickChangeTM Kit，Strategene公司)分别将编码突变氨基酸的基因如：SEQ ID NO 1～10所示的寡聚核苷酸引物序列与野生型大肠菌素Ia的基因可操作地连接，获得如SEQ ID NO.23所示编码大肠菌素Ia变构多肽的基因，同时得到突变质粒；再将编码模拟抗体的基因SEQ ID NO.26或SEQ IDNO.28插入到突变质粒中大肠菌素Ia变构多肽的基因的I626位密码子之后，制备出到新型抗EB病毒所致肿瘤多肽的两种重组质粒pCHCEB11(如图1所示)，pCHCEB22(如图2所示)，为制备重组质粒中编码抗EB病毒抗体的模拟抗体基因所设计的6条寡聚核苷酸引物序列如SEQ ID NO11～22所示。重组质粒转染入E.coli BL21(DE3)工程菌(购于Novagen公司)里制备多肽，获得序列表中SEQ ID NO.25(在后面的实施例中称为“新型抗肿瘤多肽1”)和SEQID NO.27(在后面的实施例中称为“新型抗肿瘤多肽2”)所示。
双链寡聚核苷酸点突变程序按Strategene QuickChang Site-Directed MutagenesisKit(catalog#200518)试剂盒进行。
1.准备点突变反应物：
5ul 10X buffer
2ul(10ng)装载了野生型大肠菌素变构多肽和immunity蛋白基因的原始质粒pSELECTTM-1。
1.25ul(125ng)设计的5’-3’寡聚核苷酸引物
1.25ul(125ng)设计的3’-5’寡聚核苷酸引物
1ul dNTP
双蒸水50ul
1ul pfu
(除质粒、引物和双蒸水外，均为试剂盒所备试剂)
2.进行PCR扩增，扩增条件：变性95℃，35秒，退火53℃，70秒，延伸68℃，17分，共20个循环；
3.加入Dpn 1内切酶1ul消化母体DNA链(37℃，1小时)，取1ul反应物与XL1-Blue感受态细胞50ul冰孵30分钟，热冲击42℃，45秒，再置入冰中2分钟；
4.加入NZY培基0.5ml，220rpm，37℃摇菌1小时，取50-100ul反应物铺板(LB培基加1％琼脂加50ug/ml氨苄青霉素，37℃过夜)；
5.18小时后挑菌，提取质粒后测序确定突变成功；
6.将完成多个位点突变的最终获得的重组质粒50ng与制备的E.coli BL-21(DE3)工程菌感受态细胞40ul冰孵5分钟，42℃热冲击30秒，再置入冰中2分钟，加入Novagen公司SOC培养液160ul后220rpm，37℃摇菌1小时后铺板(LB培基加1％琼脂，加50ug/ml氨苄青霉素)37℃过夜。
7.挑取单克隆菌落大量增菌，8-16升FB培基，250rpm，30℃，4-5小时，热冲击250rpm，42℃，30分钟，250rpm，37℃，2小时；离心沉淀菌体，4℃，6000g，20分钟，取4℃，50mM硼酸缓冲液(2mM EDTA+2mM DTT)50-80ml悬浮菌体，加入0.2M PMSF 250毫升后，使用超声破碎(4℃，400W，2分钟，)，高速离心沉淀破碎的菌体(4℃，75,000g，90分钟)，取上清加入硫酸链霉素500万单位沉淀DNA，15000g，4℃，10分钟离心沉淀后，取上清装入分子量15,000透析袋于4℃，50mM硼酸缓冲液4升透析过夜后，再次15000g，4℃，10分钟离心沉淀，取上清上样于CM离子交换柱，经0.1-0.3M NaCl+50mM硼酸缓冲液梯度洗脱即可得到重组抗肿瘤多肽。
点突变设计的引物序列如下：
Seq ID NO.1突变大肠菌素基因中G11A所设计的寡聚引物5’-3’
cgt att aca aat ccc GCA gca gaa tcg ctg ggg
Seq ID NO.2突变大肠菌素基因中G11A所设计的寡聚引物3’-5’
ccc cag cga ttc tgc TGC ggg att tgt aat acg
Seq ID NO.3突变大肠菌素基因中H22G所设计的寡聚引物5’-3’
gat tca gat ggc GGT aaa tta tgg gtg
Seq ID NO.4突变大肠菌素基因中H22G所设计的寡聚引物3’-5’
cac cca taa ttt ACC gcc atc tga atc
Seq ID NO.5突变大肠菌素基因中A26G所设计的寡聚引物5’-3’
gaaa ttatgGGTgt tgatatttat
Seq ID NO.6突变大肠菌素基因中A26G所设计的寡聚引物3’-5’
ataaatatacaacACCcataatttc
Seq ID NO.7突变大肠菌素基因中V31L所设计的寡聚引物5’-3’
gt tgatatttat CTC aaccctc cacgtgtc
Seq ID NO.8突变大肠菌素基因中V31L所设计的寡聚引物3’-5’
gacacgtggagggttGAGataaatatcaac
Seq ID NO.9突变大肠菌素基因中H40D所设计的寡聚引物5’-3’
cgtgtcga tgtctttGATggtaccccgc ctgcat
Seq ID NO.10突变大肠菌素基因中H40D所设计的寡聚引物3’-5’
atgcaggcggggtaccATCaaagacatcgacacg
Seq ID NO.11重组质粒pCHCEB11中VHCDR1基因引物5’-3’
gcg aat aag ttc tgg ggt att TCC TTC GGT ATG CAT TGG GTG CGTCAGtaa ata aaa tat aag
aca ggc
Seq ID NO.12重组质粒pCHCEB11中VHCDR1基因引物3’-5’
gcc tgt ctt ata ttt tat tta CTG ACG CAC CCA ATG CAT ACC GAA GGA aat acc cca gaa
ctt att cgc
Seq ID NO.13重组质粒pCHCEB11中VHFR2基因引物5’-3’
ggt atg cat tgg gtg cgt cag GCC CCC GAG AAA GGT CTG GAG TGG GTG GCC taa ata aaa
tat aag aca ggc
Seq ID NO.14重组质粒pCHCEB11中VHFR2基因引物3’-5’
gcc tgt ctt ata ttt tat tta GGC CAC CCA CTC CAG ACCT TTT CTC GGG GGC ctg acg cac
cca atg cat acc
Seq ID NO.15重组质粒pCHCEB11中(Rev)VLCDR3基因引物5’-3’
aaa ggt ctg gag tgg gtg gcc ACC TAC CCC TAC TCC TAC GGT CAG GGT taa ata aaa tat
aag aca ggc
Seq ID NO.16重组质粒pCHCEB11中(Rev)VLCDR3基因引物3’-5’
gcc tgt ctt ata ttt tat tta ACC CTG ACC GTA GGA GTA GGG GGT ggc cac cca ctc cag
acc ttt
Seq ID NO.17重组质粒pCHCEB22中VHCDR1基因引物5’-3’
gcg aat aag ttc tgg ggt att TCC TTC GGT ATG CAT TGG GTG CGT CAG taa ata aaa tat
aag aca ggc
SeqID NO.18重组质粒pCHCEB22中VHCDR1基因引物3’-5’
gcc tgt ctt ata ttt tat tta CTG ACG CAC CCA ATG CAT ACC GAA GGA aat acc cca gaa
ctt att cgc
Seq ID NO.19重组质粒pCHCEB22中VHFR2基因引物5’-3’
ggt atg cat tgg gtg cgt cag GCC CCC GAG AAA GGT CTG GAG TGG GTG GCC taa ataaaa
tat aag aca ggc
Seq ID NO.20重组质粒pCHCEB22中VHFR2基因引物3’-5’
gcc tgt ctt ata ttt tat tta GGC CAC CCA CTC CAG ACCT TTT CTC GGG GGC ctg acg cac
cca atg cat acc
Seq ID NO.21重组质粒pCHCEB22中VLCDR3基因引物5’-3’
aaa ggt ctg gag tgg gtg gcc GGT CAG GGT TAC TCC TAC CCC TAC ACC taa ata aaa tat
aag aca ggc
Seq ID NO.22重组质粒pCHCEB22中VLCDR3基因引物3’-5’
gcc tgt ctt ata ttt tat tta GGT GTA GGG GTA GGA GTA ACC CTG ACC ggc cac cca ctc
cag acc ttt
实施例2.重组质粒pCHCEB11、pCHCEB22制备的新型抗肿瘤多肽的免疫效果观察
取实施例1制备获得重组质粒pCHCEB 11、pCHCEB22制备得到的新型抗肿瘤多肽1，新型抗肿瘤多肽2，发明人的前期专利中的抗肿瘤多肽1、抗肿瘤多肽2(ZL200410081446.8)各一份免疫小鼠：上述各蛋白与佐剂混合后，基础量和追加量为腹腔注射每只50μg(0.5ml)1次。间隔两周，免疫5针。ELISA间接法检测小鼠血清效价，本发明制得的新型抗肿瘤多肽1和2所免疫小鼠血清效价为10-3至10-4而抗肿瘤多肽1、抗肿瘤多肽2所免疫小鼠的血清效价为10-4至10-5。
可见本发明新型抗肿瘤多肽造成宿主致敏反应的可能性要比含野生型大肠菌素Ia的抗肿瘤多肽造成宿主致敏反应的可能性低一至两个数量级。
实施例3.构成新型抗肿瘤多肽的大肠菌素Ia变构多肽的低致敏效果实验
取实施例1中大肠菌素Ia变构多肽(其水性孔道结构域的肽链中突变了氨基酸残基G11A、H22G、A26G、V31L和H40D)的突变质粒，在其氨基端或羧基端可操作地连接金黄色葡萄球菌信息素AgrD1(YSTCDFIM)，制备出两种抗菌多肽。AgrD1连接在变构的大肠菌素Ia羧基端制备而得的多肽命名为抗金葡多肽1，AgrD1连接在变构的大肠菌素Ia氨基端制备而得的多肽命名为抗绿脓杆菌多肽1。取野生型大肠菌素Ia的质粒，在其氨基端连接金黄色葡萄球菌信息素AgrD1制备出抗绿脓杆菌多肽2。
实验1：取昆明小鼠一批，腹腔注射致死剂量耐甲氧西林金葡菌(ATCC BAA42)，随机分组为(1)对照组，(2)氨苄青霉素组，(3)抗金葡菌多肽组，(4)抗金葡菌多肽1组。每组小鼠均为10只。
处理方法：
腹腔注射致死剂量耐甲氧西林金葡菌(ATCC BAA42)一小时后，
对照组：尾静脉注射0.5毫升0.3M NaCl+50mM硼酸缓冲液一次；
氨苄青霉素组：尾静脉注射氨苄青霉素2.5mg/kg一次；
抗金葡菌多肽组：尾静脉注射发明人发明的抗金葡菌多肽(ZL 01128836.1)6mg/kg一次；
抗金葡菌多肽1组：尾静脉注射抗金葡菌多肽16mg/kg一次。
结果：对照组及氨苄青霉素组鼠在两天内全部死亡。抗金葡菌多肽组及抗金葡菌多肽1组有85％的鼠存活。
实验2：实验1的第14天后，再取昆明小鼠一批作为对照和氨苄青霉素组，抗金葡菌多肽组及抗金葡菌多肽1组存活鼠作为抗金葡菌多肽组及抗金葡菌多肽1组重复上述试验。对照组及氨苄青霉素组鼠在两天内全部死亡。抗金葡菌多肽组有75％的鼠存活，抗金葡菌多肽1组有90％的鼠存活。
实验3：实验1的41天后，再取昆明小鼠一批作为对照组、左氧氟沙星组和头孢曲松钠组，抗金葡菌多肽组及抗金葡菌多肽1组存活鼠作为抗绿脓杆菌多肽2组及抗绿脓杆菌多肽1组。
小鼠腹腔注射致死剂量多重耐药绿脓杆菌(四川大学华西医院试验医学系临床分离株13578)一小时后，
对照组尾静脉注射0.5毫升0.3M NaCl+50mM硼酸缓冲液一次，
左氧氟沙星组尾静脉注射左氧氟沙星5mg/kg一次，
头孢曲松钠组尾静脉注射头孢曲松钠30mg/kg一次，
抗绿脓杆菌多肽2组尾静脉注射绿脓杆菌多肽28mg/kg一次，
抗绿脓杆菌多肽1组尾静脉注射抗绿脓杆菌多肽18mg/kg一次。对照组和左氧氟沙星组鼠在一天内全部死亡。头孢曲松钠组有25％的鼠存活。抗绿脓杆菌多肽2组有60％的鼠存活。抗绿脓杆菌多肽1组鼠全部存活，说明宿主抗体对变构多肽杀伤效用的干扰比对野生型多肽的干扰要低。
见附图3。
在试验第一周、第二周和第7周分别采取上述抗金葡菌多肽/抗绿脓杆菌多肽2组和抗金葡菌多肽1/抗绿脓杆菌多肽1组存活鼠的血清进行ELISA间接法检测其血中的抗体，酶标板的孔中分别包被野生型大肠菌素Ia和大肠菌素Ia变构多肽，100ng/well，一抗分别为抗金葡菌多肽/抗绿脓杆菌多肽2组和抗金葡菌多肽1/抗绿脓杆菌多肽1组存活鼠血清，2抗为山羊抗小鼠标记抗体，阴性对照以5％牛奶-PBS为一抗，1∶50,000滴度的所得结果如下(见附图4)
| A(抗金葡多肽/抗绿脓多肽2组) | (抗金葡多肽1/抗绿脓多肽1) | |
| 1(第1周) | 0.914 | 0.254 |
| 2(第2周) | 1.623 | 0.598 |
| 3(第7周) | 2.911 | 1.41 |
| 4(对照) | 0.065 | 0.069 |
可见本发明所制备的大肠菌素Ia变构多肽造成宿主致敏反应的可能性要比野生型大肠菌素Ia造成宿主致敏反应的可能性低；
实施例4新型抗肿瘤多肽对EBV所致人恶性淋巴肉瘤(Burkitt’s lymphoma)体外杀伤效果EB病毒阳性及阴性细胞株：为美国ATCC标准细胞株。
细胞培养：取出0.1ml复苏培养的Raji细胞悬浮液，缓缓加入含3ml 1640液体培养基(加10％血清)的培养皿中(稀释比例为1∶30)，混合均匀，放入37℃ CO2培养箱中培养。实验使用一株EB病毒阳性细胞株：ATCC CCL-86(即全世界细胞培养室使用的标准人Burkitt’s恶性淋巴肉瘤细胞，Raji细胞，1963年分离自12岁非洲男性患儿)。
受试细胞共分3组，第一组为空白组，即加入抗肿瘤多肽空白保存液(10mMPB+0.2MNaCI磷酸盐缓冲液(pH7.4))。
第二组为加入200μg/ml的新型抗肿瘤多肽1(质粒为pCHCEB11，保存液为10mMPB+0.2M NaCI磷酸缓冲液pH7.4)。
第三组为加入200μg/ml的新型抗肿瘤多肽2(质粒为pCHCEB22，保存液为10mMPB+0.2M NaCI磷酸缓冲液pH7.4)。
细胞在培养24小时后，分别加入上述各组处理物于培养皿中，在加入处理物后的第72小时加入100uMol碘化丙啶(Propidium Iodide，PI)20ul，10分钟后在荧光显微镜下观察。结果显示空白组细胞生长良好，唯新型抗肿瘤多肽1组中绝大部分细胞被PI染成了红色，提示这些细胞膜已被抗肿瘤多肽破坏，造成肿瘤细胞死亡。从细胞死亡数量来比较，两种新型抗肿瘤多肽中新型抗肿瘤多肽2效果较差，见附图5。
实施例5.新型抗肿瘤多肽对EB病毒所致Burkitt’s人恶性淋巴肉瘤细胞和其它肿瘤细胞的体外杀伤作用之多重荧光染色观察。
细胞培养条件同实施例2。实验共使用三株细胞，EB病毒阳性细胞株：ATCC CCL-86(Raji细胞，Burkitt’s恶性淋巴肉瘤细胞)；ATCC CRL-2230，46岁男性爱滋病人(AIDS)恶性淋巴肉瘤细胞株，EB病毒和Kaposi肉瘤病毒(HHV8)均阳性；EB病毒阴性细胞株：ATCCCRL-1648(CA-46，细胞分离自美国型Burkitt’s恶性淋巴肉瘤病人的腹水)。
每株细胞分为二个实验组，第一组为加入新型抗肿瘤多肽空白保存液(10mMPB+0.2MNaCI磷酸盐缓冲液(pH7.4))。第二组为加入200μg/ml的新型抗肿瘤多肽1(质粒为pCHCEB11)，保存液为10mMPB+0.2M NaCI磷酸缓冲液pH7.4。
细胞在培养24小时后，分别加入上述各组处理物于培养皿中，在加入处理物后的第72小时分别加入50uMol FITC 20ul及50uMol Rodamin-12320ul两种荧光染料。10分钟后在Olympus IX-71荧光显微镜下观察。
结果显示：EB病毒阴性的肿瘤细胞株被新型抗肿瘤多肽1处理后仍生长良好。而EB病毒阳性的各肿瘤细胞株被新型抗肿瘤多肽1处理后，绝大多数细胞出现线粒体及胞核结构消失，明显肿胀和坏死，细胞几乎全部死亡。显然多重荧光染色的结果比实施例4碘化丙啶染色的结果更为精确的展示了新型抗肿瘤多肽1对EB病毒阳性肿瘤细胞的强大杀伤作用，见图6。
EB病毒阴性的肿瘤细胞生长良好，表明新型抗肿瘤多肽并不攻击细胞膜上不带有EB病毒表面抗原的细胞。这提示本发明新型抗肿瘤多肽具有理想的靶向特异性和安全性。
实施例6.新型抗肿瘤多肽对EB病毒所致Burkitt’s人恶性淋巴肉瘤细胞种植到裸鼠体内生长出的实体肿瘤的杀伤作用
SCID免疫缺陷小鼠购自中国科学院上海实验动物中心，鼠喂养按标准饲养要求，水、垫草和饲料均经高温或紫外线灭菌。在相对无菌条件下饲养一周，无异常后进行接种实验。
收集指数生长期的Raji(ATCC CCL-86)和1648(ATCC CRL-1648)细胞悬液于50毫升离心管中，4℃离心，弃上清后，用1640液体培养基(加小牛血清)重悬细胞，使之达到1.0×107/ml个细胞。在鼠左腋处皮下注射Raji细胞悬液0.1ml，在鼠右腋处皮下注射1648细胞悬液0.1ml。
注射细胞后3-4日肿瘤即长到约2×2mm，将荷瘤裸鼠随机分为：
(A组)抗肿瘤多肽空白保存液(10mM PBS+0.2M NaCI磷酸盐缓冲液(pH7.4))为对照组；
(B组)新型抗肿瘤多肽1(质粒为pCHCEB11)治疗组，300μg/鼠(以25克重计算)/日，连续20日；
每组10只荷瘤鼠，给药方式为腹腔注射，每天注射2次，每次0.5ml，连续给药20天。。每天观察鼠活动情况，并作记录，隔天精确测量肿瘤大小并照相。
结果显示：(见图7)B组新型抗肿瘤多肽组的鼠肿瘤生长明显受到抑制，其中7只鼠的瘤块消失，其余3只的瘤块明显小于对照组。新型抗肿瘤多肽在鼠体内可以有效地抑制EBV病毒阳性淋巴肉瘤细胞所致的实体瘤块生长。但对同体鼠内接种的EBV病毒阴性淋巴肉瘤细胞所致的实体瘤块却无抑制作用。
实施例7.体内实体肿瘤消除实验的病理观察.
瘤体病理组织学观察：实施例6实验到期后处死小鼠，取出瘤体于10％福尔马林中固定，石蜡切片，HE染色常规光镜观察。
镜下观察对照组鼠的实体肿瘤增殖旺盛；新型抗肿瘤多肽组鼠的EBV病毒阳性实体肿瘤细胞显著减小，标本中缩小的肿瘤细胞团中几乎均为坏死的肿瘤细胞，周边可见大量淋巴细胞浸润。病理组织学结果提示在20日处理期限中，新型抗肿瘤多肽几乎杀灭了实体肿瘤中的所有肿瘤细胞(见图8、D)。
SEQUENCE LISTING
<110>畿晋庆三联(北京)生物技术有限公司
<120>新型抗EB病毒所致肿瘤多肽及其应用与制备方法
<130>P09551/JJQ
<160>32
<170>PatentIn version 3.3
<210>1
<211>33
<212>DNA
<213>突变大肠菌素基因中g11a所设计的寡聚引物5’-3’
<400>1
cgtattacaa atcccgcagc agaatcgctg ggg 33
<210>2
<211>33
<212>DNA
<213>突变大肠菌素基因中G11A所设计的寡聚引物3’-5’
<400>2
ccccagcgat tctgctgcgg gatttgtaat acg 33
<210>3
<211>27
<212>DNA
<213>突变大肠菌素基因中H22G所设计的寡聚引物5’-3’
<400>3
gattcagatg gcggtaaatt atgggtg 27
<210>4
<211>27
<212>DNA
<213>突变大肠菌素基因中H22G所设计的寡聚引物3’-5’
<400>4
gattcagatg gcaccaaatt atgggtg 27
<210>5
<211>24
<212>DNA
<213>突变大肠菌素基因中A26G所设计的寡聚引物5’-3’
<400>5
gaaattatgg gtgttgatat ttat 24
<210>6
<211>24
<212>DNA
<213>突变大肠菌素基因中A26G所设计的寡聚引物3’-5’
<400>6
gaaattatga ccgttgatat ttat 24
<210>7
<211>30
<212>DNA
<213>突变大肠菌素基因中V31L所设计的寡聚引物5’-3’
<400>7
gttgatattt atctcaaccc tccacgtgtc 30
<210>8
<211>30
<212>DNA
<213>突变大肠菌素基因中V31L所设计的寡聚引物3’-5’
<400>8
gacacgtgga gggttgagat aaatatcaac 30
<210>9
<211>34
<212>DNA
<213>突变大肠菌素基因中H40D所设计的寡聚引物5’-3’
<400>9
cgtgtcgatg tctttgatgg taccccgcct gcat 34
<210>10
<211>34
<212>DNA
<213>突变大肠菌素基因中H40D所设计的寡聚引物3’-5’
<400>10
atgcaggcgg ggtaccatca aagacatcga cacg 34
<210>11
<211>69
<212>DNA
<213>重组质粒pCHCEB11中VHCDR1基因引物5’-3’
<400>11
gcgaataagt tctggggtat ttccttcggt atgcattggg tgcgtcagta aataaaatat 60
aagacaggc 69
<210>12
<211>69
<212>DNA
<213>重组质粒pCHCEB11中VHCDR1基因引物3’-5’
<400>12
gcctgtctta tattttattt actgacgcac ccaatgcata ccgaaggaaa taccccagaa 60
cttattcgc 69
<210>13
<211>72
<212>DNA
<213>重组质粒pCHCEB11中VHFR2基因引物5’-3’
<400>13
ggtatgcatt gggtgcgtca ggcccccgag aaaggtctgg agtgggtggc ctaaataaaa 60
tataagacag gc 72
<210>14
<211>73
<212>DNA
<213>重组质粒pCHCEB11中VHFR2基因引物3’-5’
<400>14
gcctgtctta tattttattt aggccaccca ctccagacct tttctcgggg gcctgacgca 60
cccaatgcat acc 73
<210>15
<211>69
<212>DNA
<213>重组质粒pCHCEB11中(Rev)VHCDR3基因引物5’-3’
<400>15
aaaggtctgg agtgggtggc cacctacccc tactcctacg gtcagggtta aataaaatat 60
aagacaggc 69
<210>16
<211>66
<212>DNA
<213>重组质粒pCHCEB11中(Rev)VHCDR3基因引物3’-5’
<400>16
gcctgtctta tattttattt aaccctgacc gtaggagtag ggggtggcca cccactccag 60
accttt 66
<210>17
<211>69
<212>DNA
<213>重组质粒pCHCEB22中VHCDR1基因引物5’-3’
<400>17
gcgaataagt tctggggtat ttccttcggt atgcattggg tgcgtcagta aataaaatat 60
aagacaggc 69
<210>18
<211>69
<212>DNA
<213>重组质粒pCHCEB22中VHCDR1基因引物3’-5’
<400>18
gcctgtctta tattttattt actgacgcac ccaatgcata ccgaaggaaa taccccagaa 60
cttattcgc 69
<210>19
<211>72
<212>DNA
<213>重组质粒pCHCEB22中VHFR2基因引物5’-3’
<400>19
ggtatgcatt gggtgcgtca ggcccccgag aaaggtctgg agtgggtggc ctaaataaaa 60
tataagacag gc 72
<210>20
<211>73
<212>DNA
<213>重组质粒pCHCEB22中VHFR2基因引物3’-5’
<400>20
gcctgtctta tattttattt aggccaccca ctccagacct tttctcgggg gcctgacgca 60
cccaatgcat acc 73
<210>21
<211>69
<212>DNA
<213>重组质粒pCHCEB22中VLCDR3基因引物5’-3’
<400>21
aaaggtctgg agtgggtggc cggtcagggt tactcctacc cctacaccta aataaaatat 60
aagacaggc 69
<210>22
<211>69
<212>DNA
<213>重组质粒pCHCEB22中VLCDR3基因引物3’-5’
<400>22
gcctgtctta tattttattt aggtgtaggg gtaggagtaa ccctgaccgg ccacccactc 60
cagaccttt 69
<210>23
<211>1878
<212>DNA
<213>大肠菌素Ia变构多肽基因序列
<400>23
atgtctgacc ctgtacgtat tacaaatccc gcagcagaat cgctggggta tgattcagat 60
ggcggtgaaa ttatgggtgt tgatatttat ctcaaccctc cacgtgtcga tgtctttgat 120
ggtaccccgc ctgcatggag ttccttcggg aacaaaacca tctggggcgg aaacgagtgg 180
gttgatgatt ccccaacccg aagtgatatc gaaaaaaggg acaaggaaat cacagcgtac 240
aaaaacacgc tcagcgcgca gcagaaagag aatgagaata agcgtactga agccggaaaa 300
cgcctctctg cggcgattgc tgcaagggaa aaagatgaaa acacactgaa aacactccgt 360
gccggaaacg cagatgccgc tgatattaca cgacaggagt tcagactcct gcaggcagag 420
ctgagagaat acggattccg tactgaaatc gccggatatg acgccctccg gctgcataca 480
gagagccgga tgctgtttgc tgatgctgat tctcttcgta tatctccccg ggaggccagg 540
tcgttaatcg aacaggctga aaaacggcag aaggatgcgc agaacgcaga caagaaggcc 600
gctgatatgc ttgctgaata cgagcgcaga aaaggtattc tggacacccg gttgtcagag 660
ctggaaaaaa atggcggggc agcccttgcc gttcttgatg cacaacaggc ccgtctgctc 720
gggcagcaga cacggaatga cagggccatt tcagaggccc ggaataaact cagttcagtg 780
acggaatcgc ttaacacggc ccgtaatgca ttaaccagag ctgaacaaca gctgacgcaa 840
cagaaaaaca cgcctgacgg caaaacgata gtttcccctg aaaaattccc ggggcgttca 900
tcaacaaatc attctattgt tgtgagcggt gatccgagat ttgccggtac gataaaaatc 960
acaaccagcg cagtcatcga taaccgtgca aacctgaatt atcttctgag ccattccggt 1020
ctggactata aacgcaatat tctgaatgac cggaatccgg tggtgacaga ggatgtggaa 1080
ggtgacaaga aaatttataa tgctgaagtt gctgaatggg ataagttacg gcaaagattg 1140
cttgatgcca gaaataaaat cacctctgct gaatctgcgg taaattcggc gagaaataac 1200
ctcagtgcca gaacaaatga gcaaaagcat gcaaatgacg ctcttaatgc cctgttgaag 1260
gaaaaagaga atatacgtaa ccagctttcc ggcatcaatc agaagatagc ggaagagaaa 1320
agaaaacagg atgaactgaa ggcaacgaaa gacgcaatta atttcacaac agagttcctg 1380
aaatcagttt cagaaaaata tggtgcaaaa gctgagcagt tagccagaga gatggccggg 1440
caggctaaag ggaagaaaat acgtaatgtt gaagaggcat taaaaacgta tgaaaagtac 1500
cgggctgaca ttaacaaaaa aattaatgca aaagatcgtg cagcgattgc cgcagccctt 1560
gagtctgtga agctgtctga tatatcgtct aatctgaaca gattcagtcg gggactggga 1620
tatgcaggaa aatttacaag tcttgctgac tggatcactg agtttggtaa ggctgtccgg 1680
acagagaact ggcgtcctct ttttgttaaa acagaaacca tcatagcagg caatgccgca 1740
acggctcttg tggcactggt cttcagtatt cttaccggaa gcgctttagg cattatcggg 1800
tatggtttac tgatggctgt caccggtgcg ctgattgatg aatcgcttgt ggaaaaagcg 1860
aataagttct ggggtatt 1878
<210>24
<211>625
<212>PRT
<213>大肠菌素Ia变构多肽氨基酸序列
<400>24
Ser Asp Pro Val Arg Ile Thr Asn Pro Ala Ala Glu Ser Leu Gly Tyr
Asp Ser Asp Gly Gly Glu Ile Met Gly Val Asp Ile Tyr Leu Asn Pro
Pro Arg Val Asp Val Phe Asp Gly Thr Pro Pro Ala Trp Ser Ser Phe
Gly Asn Lys Thr Ile Trp Gly Gly Asn Glu Trp Val Asp Asp Ser Pro
Thr Arg Ser Asp Ile Glu Lys Arg Asp Lys Glu Ile Thr Ala Tyr Lys
Asn Thr Leu Ser Ala Gln Gln Lys Glu Asn Glu Asn Lys Arg Thr Glu
Ala Gly Lys Arg Leu Ser Ala Ala Ile Ala Ala Arg Glu Lys Asp Glu
Asn Thr Leu Lys Thr Leu Arg Ala Gly Asn Ala Asp Ala Ala Asp Ile
Thr Arg Gln Glu Phe Arg Leu Leu Gln Ala Glu Leu Arg Glu Tyr Gly
Phe Arg Thr Glu Ile Ala Gly Tyr Asp Ala Leu Arg Leu His Thr Glu
Ser Arg Met Leu Phe Ala Asp Ala Asp Ser Leu Arg Ile Ser Pro Arg
Glu Ala Arg Ser Leu Ile Glu Gln Ala Glu Lys Arg Gln Lys Asp Ala
Gln Asn Ala Asp Lys Lys Ala Ala Asp Met Leu Ala Glu Tyr Glu Arg
Arg Lys Gly Ile Leu Asp Thr Arg Leu Ser Glu Leu Glu Lys Asn Gly
Gly Ala Ala Leu Ala Val Leu Asp Ala Gln Gln Ala Arg Leu Leu Gly
Gln Gln Thr Arg Asn Asp Arg Ala Ile Ser Glu Ala Arg Asn Lys Leu
Ser Ser Val Thr Glu Ser Leu Asn Thr Ala Arg Asn Ala Leu Thr Arg
Ala Glu Gln Gln Leu Thr Gln Gln Lys Asn Thr Pro Asp Gly Lys Thr
Ile Val Ser Pro Glu Lys Phe Pro Gly Arg Ser Ser Thr Asn His Ser
Ile Val Val Ser Gly Asp Pro Arg Phe Ala Gly Thr Ile Lys Ile Thr
Thr Ser Ala Val Ile Asp Asn Arg Ala Asn Leu Asn Tyr Leu Leu Ser
His Ser Gly Leu Asp Tyr Lys Arg Asn Ile Leu Asn Asp Arg Asn Pro
Val Val Thr Glu Asp Val Glu Gly Asp Lys Lys Ile Tyr Asn Ala Glu
Val Ala Glu Trp Asp Lys Leu Arg Gln Arg Leu Leu Asp Ala Arg Asn
Lys Ile Thr Ser Ala Glu Ser Ala Val Asn Ser Ala Arg Asn Asn Leu
Ser Ala Arg Thr Asn Glu Gln Lys His Ala Asn Asp Ala Leu Asn Ala
Leu Leu Lys Glu Lys Glu Asn Ile Arg Asn Gln Leu Ser Gly Ile Asn
Gln Lys Ile Ala Glu Glu Lys Arg Lys Gln Asp Glu Leu Lys Ala Thr
Lys Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly Gln
Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys Thr Tyr
Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala Lys Asp Arg
Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu Ser Asp Ile Ser
Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly Tyr Ala Gly Lys Phe
Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe Gly Lys Ala Val Arg Thr
Glu Asn Trp Arg Pro Leu Phe Val Lys Thr Glu Thr Ile Ile Ala Gly
Asn Ala Ala Thr Ala Leu Val Ala Leu Val Phe Ser Ile Leu Thr Gly
Ser Ala Leu Gly Ile Ile Gly Tyr Gly Leu Leu Met Ala Val Thr Gly
Ala Leu Ile Asp Glu Ser Leu Val Glu Lys Ala Asn Lys Phe Trp Gly
Ile
<210>25
<211>28
<212>PRT
<213>模拟抗体物VHCDR1-VHFR2-VLCDR3氨基酸序列
<400>25
Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val Ala
Gly Gln Gly Tyr Ser Tyr Pro Tyr Thr
<210>26
<211>84
<212>DNA
<213>编码模拟抗体物VHCDR1-VHFR2-VLCDR3的核苷酸序列
<400>26
tccttcggta tgcattgggt gcgtcaggcc cccgagaaag gtctggagtg ggtggccggt 60
cagggttact cctaccccta cacc 84
<210>27
<211>28
<212>DNA
<213>模拟抗体物VHCDR1-VHFR2-(Rev)VLCDR3的氨基酸序列
<400>27
Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val Ala
Thr Tyr Pro Tyr Ser Tyr Gly Gln Gly
<210>28
<211>84
<212>DNA
<213>编码模拟抗体物VHCDR1-VHFR2-(Rev)VLCDR3的核苷酸序列
<400>28
tccttcggta tgcattgggt gcgtcaggcc cccgagaaag gtctggagtg ggtggccacc 60
tacccctact cctacggtca gggt 84
<210>29
<211>653
<212>PRT
<213>抗EB病毒所致肿瘤多肽的氨基酸序列1
<400>29
Ser Asp Pro Val Arg Ile Thr Asn Pro Ala Ala Glu Ser Leu Gly Tyr
Asp Ser Asp Gly Gly Glu Ile Met Gly Val Asp Ile Tyr Leu Asn Pro
Pro Arg Val Asp Val Phe Asp Gly Thr Pro Pro Ala Trp Ser Ser Phe
Gly Asn Lys Thr Ile Trp Gly Gly Asn Glu Trp Val Asp Asp Ser Pro
Thr Arg Ser Asp Ile Glu Lys Arg Asp Lys Glu Ile Thr Ala Tyr Lys
Asn Thr Leu Ser Ala Gln Gln Lys Glu Asn Glu Asn Lys Arg Thr Glu
Ala Gly Lys Arg Leu Ser Ala Ala Ile Ala Ala Arg Glu Lys Asp Glu
Asn Thr Leu Lys Thr Leu Arg Ala Gly Asn Ala Asp Ala Ala Asp Ile
Thr Arg Gln Glu Phe Arg Leu Leu Gln Ala Glu Leu Arg Glu Tyr Gly
Phe Arg Thr Glu Ile Ala Gly Tyr Asp Ala Leu Arg Leu His Thr Glu
Ser Arg Met Leu Phe Ala Asp Ala Asp Ser Leu Arg Ile Ser Pro Arg
Glu Ala Arg Ser Leu Ile Glu Gln Ala Glu Lys Arg Gln Lys Asp Ala
Gln Asn Ala Asp Lys Lys Ala Ala Asp Met Leu Ala Glu Tyr Glu Arg
Arg Lys Gly Ile Leu Asp Thr Arg Leu Ser Glu Leu Glu Lys Asn Gly
Gly Ala Ala Leu Ala Val Leu Asp Ala Gln Gln Ala Arg Leu Leu Gly
Gln Gln Thr Arg Asn Asp Arg Ala Ile Ser Glu Ala Arg Asn Lys Leu
Ser Ser Val Thr Glu Ser Leu Asn Thr Ala Arg Asn Ala Leu Thr Arg
Ala Glu Gln Gln Leu Thr Gln Gln Lys Asn Thr Pro Asp Gly Lys Thr
Ile Val Ser Pro Glu Lys Phe Pro Gly Arg Ser Ser Thr Asn His Ser
Ile Val Val Ser Gly Asp Pro Arg Phe Ala Gly Thr Ile Lys Ile Thr
Thr Ser Ala Val Ile Asp Asn Arg Ala Asn Leu Asn Tyr Leu Leu Ser
His Ser Gly Leu Asp Tyr Lys Arg Asn Ile Leu Asn Asp Arg Asn Pro
Val Val Thr Glu Asp Val Glu Gly Asp Lys Lys Ile Tyr Asn Ala Glu
Val Ala Glu Trp Asp Lys Leu Arg Gln Arg Leu Leu Asp Ala Arg Asn
Lys Ile Thr Ser Ala Glu Ser Ala Val Asn Ser Ala Arg Asn Asn Leu
Ser Ala Arg Thr Asn Glu Gln Lys His Ala Asn Asp Ala Leu Asn Ala
Leu Leu Lys Glu Lys Glu Asn Ile Arg Asn Gln Leu Ser Gly Ile Asn
Gln Lys Ile Ala Glu Glu Lys Arg Lys Gln Asp Glu Leu Lys Ala Thr
Lys Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly Gln
Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys Thr Tyr
Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala Lys Asp Arg
Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu Ser Asp Ile Ser
Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly Tyr Ala Gly Lys Phe
Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe Gly Lys Ala Val Arg Thr
Glu Asn Trp Arg Pro Leu Phe Val Lys Thr Glu Thr Ile Ile Ala Gly
Asn Ala Ala Thr Ala Leu Val Ala Leu Val Phe Ser Ile Leu Thr Gly
Ser Ala Leu Gly Ile Ile Gly Tyr Gly Leu Leu Met Ala Val Thr Gly
Ala Leu Ile Asp Glu Ser Leu Val Glu Lys Ala Asn Lys Phe Trp Gly
Ile Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu
Glu Trp Mal Ala Gly Gln Gly Tyr Ser Tyr Pro Tyr Thr
<210>30
<211>1962
<212>DNA
<213>编码抗EB病毒所致肿瘤多肽的氨基酸序列1的核苷酸序列
<400>30
atgtctgacc ctgtacgtat tacaaatccc gcagcagaat cgctggggta tgattcagat 60
ggcggtgaaa ttatgggtgt tgatatttat ctcaaccctc cacgtgtcga tgtctttgat 120
ggtaccccgc ctgcatggag ttccttcggg aacaaaacca tctggggcgg aaacgagtgg 180
gttgatgatt ccccaacccg aagtgatatc gaaaaaaggg acaaggaaat cacagcgtac 240
aaaaacacgc tcagcgcgca gcagaaagag aatgagaata agcgtactga agccggaaaa 300
cgcctctctg cggcgattgc tgcaagggaa aaagatgaaa acacactgaa aacactccgt 360
gccggaaacg cagatgccgc tgatattaca cgacaggagt tcagactcct gcaggcagag 420
ctgagagaat acggattccg tactgaaatc gccggatatg acgccctccg gctgcataca 480
gagagccgga tgctgtttgc tgatgctgat tctcttcgta tatctccccg ggaggccagg 540
tcgttaatcg aacaggctga aaaacggcag aaggatgcgc agaacgcaga caagaaggcc 600
gctgatatgc ttgctgaata cgagcgcaga aaaggtattc tggacacccg gttgtcagag 660
ctggaaaaaa atggcggggc agcccttgcc gttcttgatg cacaacaggc ccgtctgctc 720
gggcagcaga cacggaatga cagggccatt tcagaggccc ggaataaact cagttcagtg 780
acggaatcgc ttaacacggc ccgtaatgca ttaaccagag ctgaacaaca gctgacgcaa 840
cagaaaaaca cgcctgacgg caaaacgata gtttcccctg aaaaattccc ggggcgttca 900
tcaacaaatc attctattgt tgtgagcggt gatccgagat ttgccggtac gataaaaatc 960
acaaccagcg cagtcatcga taaccgtgca aacctgaatt atcttctgag ccattccggt 1020
ctggactata aacgcaatat tctgaatgac cggaatccgg tggtgacaga ggatgtggaa 1080
ggtgacaaga aaatttataa tgctgaagtt gctgaatggg ataagttacg gcaaagattg 1140
cttgatgcca gaaataaaat cacctctgct gaatctgcgg taaattcggc gagaaataac 1200
ctcagtgcca gaacaaatga gcaaaagcat gcaaatgacg ctcttaatgc cctgttgaag 1260
gaaaaagaga atatacgtaa ccagctttcc ggcatcaatc agaagatagc ggaagagaaa 1320
agaaaacagg atgaactgaa ggcaacgaaa gacgcaatta atttcacaac agagttcctg 1380
aaatcagttt cagaaaaata tggtgcaaaa gctgagcagt tagccagaga gatggccggg 1440
caggctaaag ggaagaaaat acgtaatgtt gaagaggcat taaaaacgta tgaaaagtac 1500
cgggctgaca ttaacaaaaa aattaatgca aaagatcgtg cagcgattgc cgcagccctt 1560
gagtctgtga agctgtctga tatatcgtct aatctgaaca gattcagtcg gggactggga 1620
tatgcaggaa aatttacaag tcttgctgac tggatcactg agtttggtaa ggctgtccgg 1680
acagagaact ggcgtcctct ttttgttaaa acagaaacca tcatagcagg caatgccgca 1740
acggctcttg tggcactggt cttcagtatt cttaccggaa gcgctttagg cattatcggg 1800
tatggtttac tgatggctgt caccggtgcg ctgattgatg aatcgcttgt ggaaaaagcg 1860
aataagttct ggggtatttc cttcggtatg cattgggtgc gtcaggcccc cgagaaaggt 1920
ctggagtggg tggccggtca gggttactcc tacccctaca cc 1962
<210>31
<211>653
<212>PRT
<213>新型抗EB病毒所致肿瘤多肽2的氨基酸序列
<400>31
Ser Asp Pro Val Arg Ile Thr Asn Pro Ala Ala Glu Ser Leu Gly Tyr
Asp Ser Asp Gly Gly Glu Ile Met Gly Val Asp Ile Tyr Leu Asn Pro
Pro Arg Val Asp Val Phe Asp Gly Thr Pro Pro Ala Trp Ser Ser Phe
Gly Asn Lys Thr Ile Trp Gly Gly Asn Glu Trp Val Asp Asp Ser Pro
Thr Arg Ser Asp Ile Glu Lys Arg Asp Lys Glu Ile Thr Ala Tyr Lys
Asn Thr Leu Ser Ala Gln Gln Lys Glu Asn Glu Asn Lys Arg Thr Glu
Ala Gly Lys Arg Leu Ser Ala Ala Ile Ala Ala Arg Glu Lys Asp Glu
Asn Thr Leu Lys Thr Leu Arg Ala Gly Asn Ala Asp Ala Ala Asp Ile
Thr Arg Gln Glu Phe Arg Leu Leu Gln Ala Glu Leu Arg Glu Tyr Gly
Phe Arg Thr Glu Ile Ala Gly Tyr Asp Ala Leu Arg Leu His Thr Glu
Ser Arg Met Leu Phe Ala Asp Ala Asp Ser Leu Arg Ile Ser Pro Arg
Glu Ala Arg Ser Leu Ile Glu Gln Ala Glu Lys Arg Gln Lys Asp Ala
Gln Asn Ala Asp Lys Lys Ala Ala Asp Met Leu Ala Glu Tyr Glu Arg
Arg Lys Gly Ile Leu Asp Thr Arg Leu Ser Glu Leu Glu Lys Asn Gly
Gly Ala Ala Leu Ala Val Leu Asp Ala Gln Gln Ala Arg Leu Leu Gly
Gln Gln Thr Arg Asn Asp Arg Ala Ile Ser Glu Ala Arg Asn Lys Leu
Ser Ser Val Thr Glu Ser Leu Asn Thr Ala Arg Asn Ala Leu Thr Arg
Ala Glu Gln Gln Leu Thr Gln Gln Lys Asn Thr Pro Asp Gly Lys Thr
Ile Val Ser Pro Glu Lys Phe Pro Gly Arg Ser Ser Thr Asn His Ser
Ile Val Val Ser Gly Asp Pro Arg Phe Ala Gly Thr Ile Lys Ile Thr
Thr Ser Ala Val Ile Asp Asn Arg Ala Asn Leu Asn Tyr Leu Leu Ser
His Ser Gly Leu Asp Tyr Lys Arg Asn Ile Leu Asn Asp Arg Asn Pro
Val Val Thr Glu Asp Val Glu Gly Asp Lys Lys Ile Tyr Asn Ala Glu
Val Ala Glu Trp Asp Lys Leu Arg Gln Arg Leu Leu Asp Ala Arg Asn
Lys Ile Thr Ser Ala Glu Ser Ala Val Asn Ser Ala Arg Asn Asn Leu
Ser Ala Arg Thr Asn Glu Gln Lys His Ala Asn Asp Ala Leu Asn Ala
Leu Leu Lys Glu Lys Glu Asn Ile Arg Asn Gln Leu Ser Gly Ile Asn
Gln Lys Ile Ala Glu Glu Lys Arg Lys Gln Asp Glu Leu Lys Ala Thr
Lys Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly Gln
Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys Thr Tyr
Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala Lys Asp Arg
Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu Ser Asp Ile Ser
Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly Tyr Ala Gly Lys Phe
Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe Gly Lys Ala Val Arg Thr
Glu Asn Trp Arg Pro Leu Phe Val Lys Thr Glu Thr Ile Ile Ala Gly
Asn Ala Ala Thr Ala Leu Val Ala Leu Val Phe Ser Ile Leu Thr Gly
Ser Ala Leu Gly Ile Ile Gly Tyr Gly Leu Leu Met Ala Val Thr Gly
Ala Leu Ile Asp Glu Ser Leu Val Glu Lys Ala Asn Lys Phe Trp Gly
Ile Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu
Glu Trp Val Ala Thr Tyr Pro Tyr Ser Tyr Gly Gln Gly
<210>32
<211>1962
<212>DNA
<213>编码抗EB病毒所致肿瘤多肽的氨基酸序列2的核苷酸序列
<400>32
atgtctgacc ctgtacgtat tacaaatccc gcagcagaat cgctggggta tgattcagat 60
ggcggtgaaa ttatgggtgt tgatatttat ctcaaccctc cacgtgtcga tgtctttgat 120
ggtaccccgc ctgcatggag ttccttcggg aacaaaacca tctggggcgg aaacgagtgg 180
gttgatgatt ccccaacccg aagtgatatc gaaaaaaggg acaaggaaat cacagcgtac 240
aaaaacacgc tcagcgcgca gcagaaagag aatgagaata agcgtactga agccggaaaa 300
cgcctctctg cggcgattgc tgcaagggaa aaagatgaaa acacactgaa aacactccgt 360
gccggaaacg cagatgccgc tgatattaca cgacaggagt tcagactcct gcaggcagag 420
ctgagagaat acggattccg tactgaaatc gccggatatg acgccctccg gctgcataca 480
gagagccgga tgctgtttgc tgatgctgat tctcttcgta tatctccccg ggaggccagg 540
tcgttaatcg aacaggctga aaaacggcag aaggatgcgc agaacgcaga caagaaggcc 600
gctgatatgc ttgctgaata cgagcgcaga aaaggtattc tggacacccg gttgtcagag 660
ctggaaaaaa atggcggggc agcccttgcc gttcttgatg cacaacaggc ccgtctgctc 720
gggcagcaga cacggaatga cagggccatt tcagaggccc ggaataaact cagttcagtg 780
acggaatcgc ttaacacggc ccgtaatgca ttaaccagag ctgaacaaca gctgacgcaa 840
cagaaaaaca cgcctgacgg caaaacgata gtttcccctg aaaaattccc ggggcgttca 900
tcaacaaatc attctattgt tgtgagcggt gatccgagat ttgccggtac gataaaaatc 960
acaaccagcg cagtcatcga taaccgtgca aacctgaatt atcttctgag ccattccggt 1020
ctggactata aacgcaatat tctgaatgac cggaatccgg tggtgacaga ggatgtggaa 1080
ggtgacaaga aaatttataa tgctgaagtt gctgaatggg ataagttacg gcaaagattg 1140
cttgatgcca gaaataaaat cacctctgct gaatctgcgg taaattcggc gagaaataac 1200
ctcagtgcca gaacaaatga gcaaaagcat gcaaatgacg ctcttaatgc cctgttgaag 1260
gaaaaagaga atatacgtaa ccagctttcc ggcatcaatc agaagatagc ggaagagaaa 1320
agaaaacagg atgaactgaa ggcaacgaaa gacgcaatta atttcacaac agagttcctg 1380
aaatcagttt cagaaaaata tggtgcaaaa gctgagcagt tagccagaga gatggccggg 1440
caggctaaag ggaagaaaat acgtaatgtt gaagaggcat taaaaacgta tgaaaagtac 1500
cgggctgaca ttaacaaaaa aattaatgca aaagatcgtg cagcgattgc cgcagccctt 1560
gagtctgtga agctgtctga tatatcgtct aatctgaaca gattcagtcg gggactggga 1620
tatgcaggaa aatttacaag tcttgctgac tggatcactg agtttggtaa ggctgtccgg 1680
acagagaact ggcgtcctct ttttgttaaa acagaaacca tcatagcagg caatgccgca 1740
acggctcttg tggcactggt cttcagtatt cttaccggaa gcgctttagg cattatcggg 1800
tatggtttac tgatggctgt caccggtgcg ctgattgatg aatcgcttgt ggaaaaagcg 1860
aataagttct ggggtatttc cttcggtatg cattgggtgc gtcaggcccc cgagaaaggt 1920
ctggagtggg tggccaccta cccctactcc tacggtcagg gt 1962
Claims (9)
1.一种新型抗EB病毒所致肿瘤多肽，其氨基酸序列如SEQ ID NO.29所示；由可形成离子通道的大肠菌素变构多肽与抗EB病毒抗体多肽或者抗EB病毒抗体的模拟抗体多肽可操作地连接构成，所述可形成离子通道的大肠菌素变构多肽由野生型大肠菌素Ia突变了氨基酸残基G11A、H22G、A26G、V31L和H40D而获得，所述抗EB病毒抗体的氨基酸序列与ATCC HB-168杂交瘤分泌的单克隆抗体相同,所述模拟抗体多肽指所述抗EB病毒抗体的重链CDR1区、重链CDR1-CDR2连接肽段和轻链CDR3的连接肽。
2.编码权利要求1所述的新型抗EB病毒所致肿瘤多肽的基因。
3.根据权利要求2所述的基因，其核苷酸序列如SEQ ID NO.30所示。
4.含有权利要求3所述基因的重组质粒。
5.权利要求1所述新型抗EB病毒所致肿瘤多肽的制备方法，步骤如下：将权利要求4所述的重组质粒转化到表达系统中进行表达，分离纯化表达的多肽。
6.权利要求1所述新型抗EB病毒所致肿瘤多肽在制备治疗和预防EB病毒所致肿瘤的药物中的应用。
7.一种大肠菌素Ia的变构多肽，其氨基酸序列如SEQ ID NO.24所示。
8.编码权利要求7所述的大肠菌素Ia的变构多肽的基因。
9.权利要求8所述的基因在制备多肽药物中的应用，指将所述基因与诱导多肽的基因可操作地连接并克隆到表达载体中，然后将表达载体转化到表达系统中，分离纯化表达的多肽。
Priority Applications (30)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102428380A CN102101888B (zh) | 2009-12-17 | 2009-12-17 | 一种新型抗eb病毒所致肿瘤多肽及其应用与制备方法 |
| MA35062A MA33921B1 (fr) | 2009-12-17 | 2010-02-26 | Polypeptide de fusion dirigé contre une tumeur induite par le virus eb et mutant de la colicine ia |
| US13/516,605 US8883161B2 (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide against EB virus-induced tumor and colicin Ia mutant |
| BR112012017350-2A BR112012017350A2 (pt) | 2009-12-17 | 2010-02-26 | "polipeptídeo de fusão contra tumor induzido por vírus eb e mutante de colicina ia". |
| SG2012041786A SG181553A1 (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide against eb virus-induced tumor and colicin ia mutant |
| JP2012543448A JP5683603B2 (ja) | 2009-12-17 | 2010-02-26 | Ｅｂウィルスにより誘発される腫瘍に対する融合ポリペプチドとコリシンｉａ変異体 |
| AU2010333588A AU2010333588B2 (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide against EB virus-induced tumor and colicin Ia mutant |
| ES10836940.6T ES2634944T3 (es) | 2009-12-17 | 2010-02-26 | Polipéptido de fusión frente a un tumor inducido por el virus de EB y un mutante de la colicina Ia |
| CA2784784A CA2784784C (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide against eb virus-induced tumor and colicin ia mutant |
| PE2012000834A PE20121722A1 (es) | 2009-12-17 | 2010-02-26 | Polipeptido de fusion contra tumor inducido por virus eb y mutante de colicina ia |
| AP2012006327A AP3535A (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide against eb virus-induced tumor and colicin ia mutant |
| HUE10836940A HUE033298T2 (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide EB virus-induced tumor and colic and mutant |
| DK10836940.6T DK2514768T3 (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide against EB virus-induced tumor and colicin Ia mutant |
| UAA201208633A UA104933C2 (uk) | 2009-12-17 | 2010-02-26 | ЗЛИТИЙ ПОЛІПЕПТИД ПРОТИ ПУХЛИНИ, ІНДУКОВАНОЇ ВІРУСОМ EB, І МУТАНТ КОЛІЦИНУ Ia |
| GEAP201012791A GEP20156228B (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide against eb virus-induced tumor and colicin ia mutant |
| EP10836940.6A EP2514768B1 (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide against eb virus-induced tumor and colicin ia mutant |
| NZ600729A NZ600729A (en) | 2009-12-17 | 2010-02-26 | Fusion polypeptide against eb virus-induced tumor and colicin ia mutant |
| MX2012006952A MX2012006952A (es) | 2009-12-17 | 2010-02-26 | Polipeptido de fusion contra tumor inducido por virus eb y mutante de colicina ia. |
| PCT/CN2010/070762 WO2011072501A1 (zh) | 2009-12-17 | 2010-02-26 | 抗EB病毒诱发的肿瘤的融合多肽和大肠菌素Ia突变体 |
| EA201270655A EA030638B1 (ru) | 2009-12-17 | 2010-02-26 | Полипептид для лечения и профилактики опухоли, вызванной вирусом эпштейна-барр, способ его получения и применение |
| KR1020127018638A KR101464842B1 (ko) | 2009-12-17 | 2010-02-26 | ＥＢ 바이러스에 의해 유도된 종양에 대한 융합 폴리펩티드 및 콜리신 Ｉａ 돌연변이체 |
| HK11113462.9A HK1159123A1 (en) | 2009-12-17 | 2011-12-14 | Novel polypeptide for resisting tumors caused by eb (epstein-barr) viruses, and application and preparation method thereof |
| TNP2012000253A TN2012000253A1 (en) | 2009-12-17 | 2012-05-24 | Fusion polypeptide against eb virus-induced tumor and colicin ia mutant |
| IL220296A IL220296A (en) | 2009-12-17 | 2012-06-11 | Polypeptide Protected against Epstein-Bar Virus Virus and Colicin ia Mutation |
| CU2012000096A CU20120096A7 (es) | 2009-12-17 | 2012-06-12 | Polipéptido de fusión contra tumor inducido por virus eb y mutante de colicina ia |
| CO12098450A CO6541633A2 (es) | 2009-12-17 | 2012-06-12 | Polipetido de fusión contra tumor inducido por virus eb y mutante de colicina ia |
| DO2012000164A DOP2012000164A (es) | 2009-12-17 | 2012-06-13 | Polipeptido de fusion contra tumor inducido por virus eb y mutante de colicina ia |
| CL2012001609A CL2012001609A1 (es) | 2009-12-17 | 2012-06-14 | Polipéptido de fusión contra tumor inducido por virus epstein-barr (eb) formado por la unión de polipéptido mutante de colicina ia, el cual pude formar canales iónicos, y que tiene las mutaciones g11a, h22g, a26g, v31l y h40d, con un anticuerpo anti-virus eb o un polipéptido mimético de anticuerpo anti-virus eb; gen codificante de dicho polipéptido; plásmido de recombinación que comprende dicho gen; método de preparación de dicho polipéptido; uso médico de dicho polipéptido; polipéptido mutante de colicina ia con sec id n°24 (con mutaciones mutaciones g11a, h22g, a26g, v31l y h40d); gen codificante de dicho polipéptido; uso médico de dicho gen. |
| CR20120329A CR20120329A (es) | 2009-12-17 | 2012-06-15 | Polipéptido de fusión contra tumor inducido por virus eb y mutante de colicina ia |
| ZA2012/05217A ZA201205217B (en) | 2009-12-17 | 2012-07-13 | Fusion polypeptide against eb virus-induced tumor and colicin ia mutant |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102428380A CN102101888B (zh) | 2009-12-17 | 2009-12-17 | 一种新型抗eb病毒所致肿瘤多肽及其应用与制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102101888A CN102101888A (zh) | 2011-06-22 |
| CN102101888B true CN102101888B (zh) | 2013-03-20 |
Family
ID=44154977
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009102428380A Expired - Fee Related CN102101888B (zh) | 2009-12-17 | 2009-12-17 | 一种新型抗eb病毒所致肿瘤多肽及其应用与制备方法 |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US8883161B2 (zh) |
| EP (1) | EP2514768B1 (zh) |
| JP (1) | JP5683603B2 (zh) |
| KR (1) | KR101464842B1 (zh) |
| CN (1) | CN102101888B (zh) |
| AP (1) | AP3535A (zh) |
| AU (1) | AU2010333588B2 (zh) |
| BR (1) | BR112012017350A2 (zh) |
| CA (1) | CA2784784C (zh) |
| CL (1) | CL2012001609A1 (zh) |
| CO (1) | CO6541633A2 (zh) |
| CR (1) | CR20120329A (zh) |
| CU (1) | CU20120096A7 (zh) |
| DK (1) | DK2514768T3 (zh) |
| DO (1) | DOP2012000164A (zh) |
| EA (1) | EA030638B1 (zh) |
| ES (1) | ES2634944T3 (zh) |
| GE (1) | GEP20156228B (zh) |
| HK (1) | HK1159123A1 (zh) |
| HU (1) | HUE033298T2 (zh) |
| IL (1) | IL220296A (zh) |
| MA (1) | MA33921B1 (zh) |
| MX (1) | MX2012006952A (zh) |
| NZ (1) | NZ600729A (zh) |
| PE (1) | PE20121722A1 (zh) |
| SG (1) | SG181553A1 (zh) |
| TN (1) | TN2012000253A1 (zh) |
| UA (1) | UA104933C2 (zh) |
| WO (1) | WO2011072501A1 (zh) |
| ZA (1) | ZA201205217B (zh) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9200251B1 (en) | 2011-03-31 | 2015-12-01 | David Gordon Bermudes | Bacterial methionine analogue and methionine synthesis inhibitor anticancer, antiinfective and coronary heart disease protective microcins and methods of treatment therewith |
| KR20140104475A (ko) * | 2011-12-08 | 2014-08-28 | 프로틴 디자인 랩, 리미티드 | 신규 항생제 제조방법 및 이 방법에 기초한 플랫폼 시스템 |
| CN107106578B (zh) * | 2014-08-12 | 2020-12-25 | 香港大学 | 治疗厄泼斯坦-巴尔病毒相关疾病的双膦酸盐化合物和γδT细胞-介导的疗法 |
| CN104604799B (zh) * | 2015-02-05 | 2017-11-21 | 南华大学 | 一种鉴定eb病毒对淋巴瘤的诱发性的方法 |
| EP3957995A1 (en) * | 2018-11-19 | 2022-02-23 | Bioaster | Methods and reagents for multiplex binding experiments |
| CN111333724B (zh) * | 2018-12-19 | 2022-03-15 | 中国人民解放军军事科学院军事医学研究院 | 一种抗金黄色葡萄球菌肠毒素b的单克隆抗体yg11-1及其应用 |
| CN111848817B (zh) * | 2020-07-28 | 2021-11-09 | 中国农业大学 | 一种兼具抗菌、抗病毒、免疫调节和抗炎活性的多功能杂合肽及其制备方法和应用 |
| CN112125959B (zh) * | 2020-10-10 | 2022-07-29 | 中山大学肿瘤防治中心 | 一种抑制eb病毒的肽和编码该肽的dna及其应用 |
| CN113880914B (zh) * | 2021-04-25 | 2023-11-21 | 内蒙古农业大学 | 一种抗肿瘤多肽及其衍生物 |
| CN114369158B (zh) * | 2021-09-28 | 2024-04-19 | 北京亦科信息菌素研究院有限公司 | 一种抗新冠病毒的信息菌素及其应用 |
| CN113999304B (zh) * | 2021-10-13 | 2023-10-24 | 北京市农林科学院 | 抗肠菌素单克隆抗体mAb4及其在肠菌素检测中的应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1641024A (zh) * | 2004-12-10 | 2005-07-20 | 四川大学华西医院 | 抗eb病毒所致肿瘤多肽及其应用与制备方法 |
| WO2007083175A1 (en) * | 2006-01-17 | 2007-07-26 | West China Hospital, Sichuan University | Antiviral bifunctional molecules, methods of construction and methods of treating virus-induced cancer therewith |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1164612C (zh) | 2001-09-11 | 2004-09-01 | 四川新泰克控股有限责任公司 | 人工组合的抗菌工程多肽及其制备方法 |
| CN1314806C (zh) * | 2005-01-14 | 2007-05-09 | 四川大学 | 小型化抗eb病毒肿瘤多肽及其应用与制备方法 |
| CN101643501B (zh) * | 2008-11-07 | 2012-06-20 | 畿晋庆三联（北京）生物技术有限公司 | 一种新型抗生素及其核苷酸序列、制备方法与应用 |
| CN101633699B (zh) * | 2009-09-02 | 2012-02-15 | 畿晋庆堂国际生物技术有限公司 | 一种含抗体模拟物的新型抗生素及其制备方法与应用 |
-
2009
- 2009-12-17 CN CN2009102428380A patent/CN102101888B/zh not_active Expired - Fee Related
-
2010
- 2010-02-26 BR BR112012017350-2A patent/BR112012017350A2/pt not_active Application Discontinuation
- 2010-02-26 MX MX2012006952A patent/MX2012006952A/es active IP Right Grant
- 2010-02-26 SG SG2012041786A patent/SG181553A1/en unknown
- 2010-02-26 NZ NZ600729A patent/NZ600729A/en not_active IP Right Cessation
- 2010-02-26 UA UAA201208633A patent/UA104933C2/uk unknown
- 2010-02-26 WO PCT/CN2010/070762 patent/WO2011072501A1/zh active Application Filing
- 2010-02-26 AU AU2010333588A patent/AU2010333588B2/en not_active Ceased
- 2010-02-26 JP JP2012543448A patent/JP5683603B2/ja not_active Expired - Fee Related
- 2010-02-26 EA EA201270655A patent/EA030638B1/ru not_active IP Right Cessation
- 2010-02-26 CA CA2784784A patent/CA2784784C/en not_active Expired - Fee Related
- 2010-02-26 AP AP2012006327A patent/AP3535A/xx active
- 2010-02-26 PE PE2012000834A patent/PE20121722A1/es active IP Right Grant
- 2010-02-26 KR KR1020127018638A patent/KR101464842B1/ko active IP Right Grant
- 2010-02-26 DK DK10836940.6T patent/DK2514768T3/en active
- 2010-02-26 US US13/516,605 patent/US8883161B2/en not_active Expired - Fee Related
- 2010-02-26 HU HUE10836940A patent/HUE033298T2/en unknown
- 2010-02-26 EP EP10836940.6A patent/EP2514768B1/en active Active
- 2010-02-26 MA MA35062A patent/MA33921B1/fr unknown
- 2010-02-26 GE GEAP201012791A patent/GEP20156228B/en unknown
- 2010-02-26 ES ES10836940.6T patent/ES2634944T3/es active Active
-
2011
- 2011-12-14 HK HK11113462.9A patent/HK1159123A1/xx not_active IP Right Cessation
-
2012
- 2012-05-24 TN TNP2012000253A patent/TN2012000253A1/en unknown
- 2012-06-11 IL IL220296A patent/IL220296A/en not_active IP Right Cessation
- 2012-06-12 CU CU2012000096A patent/CU20120096A7/es active IP Right Grant
- 2012-06-12 CO CO12098450A patent/CO6541633A2/es unknown
- 2012-06-13 DO DO2012000164A patent/DOP2012000164A/es unknown
- 2012-06-14 CL CL2012001609A patent/CL2012001609A1/es unknown
- 2012-06-15 CR CR20120329A patent/CR20120329A/es unknown
- 2012-07-13 ZA ZA2012/05217A patent/ZA201205217B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1641024A (zh) * | 2004-12-10 | 2005-07-20 | 四川大学华西医院 | 抗eb病毒所致肿瘤多肽及其应用与制备方法 |
| WO2007083175A1 (en) * | 2006-01-17 | 2007-07-26 | West China Hospital, Sichuan University | Antiviral bifunctional molecules, methods of construction and methods of treating virus-induced cancer therewith |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102101888B (zh) | 一种新型抗eb病毒所致肿瘤多肽及其应用与制备方法 | |
| Uchida et al. | Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus | |
| CN100424096C (zh) | 含有hiv转导结构域的生存素突变体及制备方法和应用 | |
| CN104884084A (zh) | 鱼用亚单位浸泡疫苗 | |
| CN101633699B (zh) | 一种含抗体模拟物的新型抗生素及其制备方法与应用 | |
| CN101139613B (zh) | 抗肿瘤二元多肽及其应用与制备方法 | |
| CN103667199B (zh) | 体外制备轮状病毒双层类病毒颗粒的方法 | |
| KR101751501B1 (ko) | 리피바디-단백질 독소 복합체, 그 제조방법 및 용도 | |
| CN106552259A (zh) | 一种融合蛋白及其治疗疾病的用途 | |
| CN101899466B (zh) | 登革病毒-日本脑炎病毒嵌合假病毒疫苗及其制备方法 | |
| US7763581B2 (en) | Mutants of trichosanthin with anti-tumor activity and lowered side-effects | |
| WO2017152873A1 (zh) | 微小rna31前体编码多肽在制备免疫调节药物中的应用 | |
| CN110891597A (zh) | 防治家禽滑膜霉浆菌感染的组合物 | |
| TWI418630B (zh) | A novel anti-EB virus-induced tumor polypeptide, a gene encoding it and a plastid containing the gene, and its application and its preparation method | |
| CN102321178B (zh) | 一种新的促性腺激素释放激素导向融合蛋白突变体 | |
| CN108864300A (zh) | 鸡白蛋白-干扰素α-白介素2融合蛋白、制备方法及其编码基因、一种鸡长效干扰素 | |
| CN116785402B (zh) | 预防和/或治疗乳腺癌的多肽及其应用 | |
| US11352445B2 (en) | Method for preparing recombinant protein from bacterium and composition containing the same | |
| RU2471869C1 (ru) | РЕКОМБИНАНТНЫЕ ПЛАЗМИДНЫЕ ДНК pQE-60-TNFR-CrmB-Ind-67 И pFastBac1-G2R-dSECRET, СОДЕРЖАЩИЕ ФРАГМЕНТ ГЕНОМА ВИРУСА НАТУРАЛЬНОЙ ОСПЫ, КОДИРУЮЩИЙ ФАКТОР НЕКРОЗА ОПУХОЛЕЙ СВЯЗЫВАЮЩИЙ ДОМЕН БЕЛКА CrmB И ШТАММ БАКУЛОВИРУСА Bv/G2R-dSECRET, ПРОДУЦИРУЮЩИЙ СЕКРЕТИРУЕМЫЙ ФНО-СВЯЗЫВАЮЩИЙ БЕЛОК CrmB ВИРУСА НАТУРАЛЬНОЙ ОСПЫ С ДЕЛЕТИРОВАННЫМ SECRET-ДОМЕНОМ | |
| CN102526707B (zh) | 共刺激因子及融合蛋白的新用途 | |
| CN116789750A (zh) | 预防和/或治疗宫颈癌的多肽及其应用 | |
| CN102643346A (zh) | 一种含抗体模拟物的新型抗生素及其制备方法与应用 | |
| CN101139399A (zh) | 重组靶向杀伤白血病细胞的融合蛋白及其制备方法和用途 | |
| CN102558361A (zh) | 一种含抗体模拟物的新型抗生素及其制备方法与应用 | |
| CN101143222A (zh) | p53表达产物在制备治疗肿瘤药剂中的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1159123 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1159123 Country of ref document: HK |
|
| ASS | Succession or assignment of patent right |
Owner name: AMERICA INFORMATION RHZOMORPH BIOLOGICAL TECHNOLOG Free format text: FORMER OWNER: JIJINQING SANLIAN (BEIJNG) BIO-TECHNOLOGY CO., LTD. Effective date: 20131024 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20131024 Address after: Wilsher Losangeles Avenue, California No. 2404 6E Patentee after: American pheromone biotechnology Co Address before: 100095, Beijing, Haidian District before the town of Su Tuo Sand Village Patentee before: Jinjinqing Sanlian (Beijing) Biotechnology Co., Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130320 Termination date: 20191217 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |