CN1805757A - 重组抗体及组合物及其制备和使用方法 - Google Patents
重组抗体及组合物及其制备和使用方法 Download PDFInfo
- Publication number
- CN1805757A CN1805757A CNA2004800165846A CN200480016584A CN1805757A CN 1805757 A CN1805757 A CN 1805757A CN A2004800165846 A CNA2004800165846 A CN A2004800165846A CN 200480016584 A CN200480016584 A CN 200480016584A CN 1805757 A CN1805757 A CN 1805757A
- Authority
- CN
- China
- Prior art keywords
- antibody
- seq
- aminoacid sequence
- basically
- sequence seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 72
- 238000000034 method Methods 0.000 title claims abstract description 56
- 206010037742 Rabies Diseases 0.000 claims abstract description 120
- 241000711798 Rabies lyssavirus Species 0.000 claims abstract description 97
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 92
- 238000011282 treatment Methods 0.000 claims abstract description 34
- 239000002773 nucleotide Substances 0.000 claims abstract description 31
- 125000003729 nucleotide group Chemical group 0.000 claims abstract description 31
- 239000013604 expression vector Substances 0.000 claims abstract description 15
- 210000004962 mammalian cell Anatomy 0.000 claims abstract description 13
- 239000002574 poison Substances 0.000 claims description 73
- 231100000614 poison Toxicity 0.000 claims description 73
- 210000004027 cell Anatomy 0.000 claims description 70
- 241000700605 Viruses Species 0.000 claims description 35
- 238000002360 preparation method Methods 0.000 claims description 35
- 230000014509 gene expression Effects 0.000 claims description 33
- 230000000694 effects Effects 0.000 claims description 22
- 230000037396 body weight Effects 0.000 claims description 21
- 230000003472 neutralizing effect Effects 0.000 claims description 14
- 241000699800 Cricetinae Species 0.000 claims description 12
- 108090000288 Glycoproteins Proteins 0.000 claims description 11
- 241000282472 Canis lupus familiaris Species 0.000 claims description 10
- 238000006386 neutralization reaction Methods 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000013598 vector Substances 0.000 claims description 8
- 102000003886 Glycoproteins Human genes 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 230000010412 perfusion Effects 0.000 claims description 7
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 6
- 229910052709 silver Inorganic materials 0.000 claims description 6
- 239000004332 silver Substances 0.000 claims description 6
- 208000003265 stomatitis Diseases 0.000 claims description 6
- 241001529453 unidentified herpesvirus Species 0.000 claims description 6
- 210000003501 vero cell Anatomy 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 230000000968 intestinal effect Effects 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 241000282461 Canis lupus Species 0.000 claims description 2
- 230000008021 deposition Effects 0.000 claims description 2
- 239000007928 intraperitoneal injection Substances 0.000 claims description 2
- 239000007929 subcutaneous injection Substances 0.000 claims description 2
- 238000010254 subcutaneous injection Methods 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 238000003259 recombinant expression Methods 0.000 abstract description 3
- 238000011321 prophylaxis Methods 0.000 abstract description 2
- 150000007523 nucleic acids Chemical class 0.000 description 49
- 108020004707 nucleic acids Proteins 0.000 description 36
- 102000039446 nucleic acids Human genes 0.000 description 36
- 108090000765 processed proteins & peptides Proteins 0.000 description 32
- 108090000623 proteins and genes Proteins 0.000 description 27
- 108020004414 DNA Proteins 0.000 description 25
- 241001465754 Metazoa Species 0.000 description 24
- 229940024606 amino acid Drugs 0.000 description 24
- 235000001014 amino acid Nutrition 0.000 description 23
- 150000001413 amino acids Chemical class 0.000 description 21
- 241000862632 Soja Species 0.000 description 19
- 108091028043 Nucleic acid sequence Proteins 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 14
- 239000013612 plasmid Substances 0.000 description 14
- 230000002064 post-exposure prophylaxis Effects 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- 208000024891 symptom Diseases 0.000 description 13
- 241000588724 Escherichia coli Species 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 241000880493 Leptailurus serval Species 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 11
- 108060003951 Immunoglobulin Proteins 0.000 description 10
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 10
- 239000002299 complementary DNA Substances 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 102000018358 immunoglobulin Human genes 0.000 description 10
- 108020004635 Complementary DNA Proteins 0.000 description 9
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 9
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 108010076504 Protein Sorting Signals Proteins 0.000 description 8
- 210000003169 central nervous system Anatomy 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 230000036039 immunity Effects 0.000 description 8
- 108020004999 messenger RNA Proteins 0.000 description 8
- 241000699802 Cricetulus griseus Species 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000003550 marker Substances 0.000 description 7
- 210000001672 ovary Anatomy 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 108010073969 valyllysine Proteins 0.000 description 7
- 230000003612 virological effect Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003623 enhancer Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 5
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 5
- 102100032611 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short Human genes 0.000 description 5
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 5
- 108020005091 Replication Origin Proteins 0.000 description 5
- 230000010530 Virus Neutralization Effects 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 108010060199 cysteinylproline Proteins 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 210000004408 hybridoma Anatomy 0.000 description 5
- 238000002649 immunization Methods 0.000 description 5
- 230000003053 immunization Effects 0.000 description 5
- 230000008520 organization Effects 0.000 description 5
- 108010031719 prolyl-serine Proteins 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 229940081969 saccharomyces cerevisiae Drugs 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 229960005486 vaccine Drugs 0.000 description 5
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 4
- 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 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- 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 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 4
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 4
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 4
- 241001460678 Napo <wasp> Species 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 4
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 108010087924 alanylproline Proteins 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- -1 dimethyl sulfoxine Chemical compound 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 108010015792 glycyllysine Proteins 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 108010017391 lysylvaline Proteins 0.000 description 4
- 230000035479 physiological effects, processes and functions Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 238000010839 reverse transcription Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 108010061238 threonyl-glycine Proteins 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 210000005253 yeast cell Anatomy 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 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
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 206010015548 Euthanasia Diseases 0.000 description 3
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 3
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 3
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 3
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 3
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 3
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 3
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 3
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 3
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 3
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 3
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101900083372 Rabies virus Glycoprotein Proteins 0.000 description 3
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 3
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 3
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 3
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 3
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 3
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 3
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 3
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 3
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 239000012228 culture supernatant Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 3
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 3
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 3
- 108010050848 glycylleucine Proteins 0.000 description 3
- 108010037850 glycylvaline Proteins 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 3
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108010077112 prolyl-proline Proteins 0.000 description 3
- 230000008521 reorganization Effects 0.000 description 3
- 108091008146 restriction endonucleases Proteins 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 230000001131 transforming effect Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- WYMDDFRYORANCC-UHFFFAOYSA-N 2-[[3-[bis(carboxymethyl)amino]-2-hydroxypropyl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)CN(CC(O)=O)CC(O)=O WYMDDFRYORANCC-UHFFFAOYSA-N 0.000 description 2
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 2
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 2
- WQLDNOCHHRISMS-NAKRPEOUSA-N Ala-Pro-Ile Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WQLDNOCHHRISMS-NAKRPEOUSA-N 0.000 description 2
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 2
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 2
- PHQXWZGXKAFWAZ-ZLIFDBKOSA-N Ala-Trp-Lys Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 PHQXWZGXKAFWAZ-ZLIFDBKOSA-N 0.000 description 2
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 2
- 206010002199 Anaphylactic shock Diseases 0.000 description 2
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-N 0.000 description 2
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 2
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 2
- APHUDFFMXFYRKP-CIUDSAMLSA-N Asn-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N APHUDFFMXFYRKP-CIUDSAMLSA-N 0.000 description 2
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 2
- MJIJBEYEHBKTIM-BYULHYEWSA-N Asn-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MJIJBEYEHBKTIM-BYULHYEWSA-N 0.000 description 2
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 2
- DPNWSMBUYCLEDG-CIUDSAMLSA-N Asp-Lys-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O DPNWSMBUYCLEDG-CIUDSAMLSA-N 0.000 description 2
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 2
- RSMZEHCMIOKNMW-GSSVUCPTSA-N Asp-Thr-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RSMZEHCMIOKNMW-GSSVUCPTSA-N 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000282552 Chlorocebus aethiops Species 0.000 description 2
- VPQZSNQICFCCSO-BJDJZHNGSA-N Cys-Leu-Ile Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VPQZSNQICFCCSO-BJDJZHNGSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 101150082239 G gene Proteins 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
- ZFADFBPRMSBPOT-KKUMJFAQSA-N Gln-Arg-Phe Chemical compound N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](Cc1ccccc1)C(O)=O ZFADFBPRMSBPOT-KKUMJFAQSA-N 0.000 description 2
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 2
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 2
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 2
- RAUDKMVXNOWDLS-WDSKDSINSA-N Glu-Gly-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O RAUDKMVXNOWDLS-WDSKDSINSA-N 0.000 description 2
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 2
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 2
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 2
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 2
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 2
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 2
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 2
- HZWWOGWOBQBETJ-CUJWVEQBSA-N His-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N)O HZWWOGWOBQBETJ-CUJWVEQBSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 2
- OMDWJWGZGMCQND-CFMVVWHZSA-N Ile-Tyr-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N OMDWJWGZGMCQND-CFMVVWHZSA-N 0.000 description 2
- 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 2
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 2
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 2
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 2
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 2
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 2
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[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 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 2
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 2
- NNCDAORZCMPZPX-GUBZILKMSA-N Lys-Gln-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N NNCDAORZCMPZPX-GUBZILKMSA-N 0.000 description 2
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 2
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 2
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 2
- CTJUSALVKAWFFU-CIUDSAMLSA-N Lys-Ser-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N CTJUSALVKAWFFU-CIUDSAMLSA-N 0.000 description 2
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 2
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 2
- 241000711828 Lyssavirus Species 0.000 description 2
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 241001631646 Papillomaviridae Species 0.000 description 2
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 2
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 2
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- OLHDPZMYUSBGDE-GUBZILKMSA-N Pro-Arg-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O OLHDPZMYUSBGDE-GUBZILKMSA-N 0.000 description 2
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 2
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 2
- VDGTVWFMRXVQCT-GUBZILKMSA-N Pro-Glu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 VDGTVWFMRXVQCT-GUBZILKMSA-N 0.000 description 2
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 2
- MHHQQZIFLWFZGR-DCAQKATOSA-N Pro-Lys-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O MHHQQZIFLWFZGR-DCAQKATOSA-N 0.000 description 2
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 2
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 2
- 241000242743 Renilla reniformis Species 0.000 description 2
- 241000711931 Rhabdoviridae Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 2
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 2
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-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)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 2
- OLIJLNWFEQEFDM-SRVKXCTJSA-N Ser-Asp-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OLIJLNWFEQEFDM-SRVKXCTJSA-N 0.000 description 2
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 2
- SNVIOQXAHVORQM-WDSKDSINSA-N Ser-Gly-Gln Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O SNVIOQXAHVORQM-WDSKDSINSA-N 0.000 description 2
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 2
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 2
- GYDFRTRSSXOZCR-ACZMJKKPSA-N Ser-Ser-Glu Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GYDFRTRSSXOZCR-ACZMJKKPSA-N 0.000 description 2
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 2
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 2
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 2
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 2
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 2
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 2
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 2
- KERCOYANYUPLHJ-XGEHTFHBSA-N Thr-Pro-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O KERCOYANYUPLHJ-XGEHTFHBSA-N 0.000 description 2
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 2
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 2
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 2
- KPMIQCXJDVKWKO-IFFSRLJSSA-N Thr-Val-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O KPMIQCXJDVKWKO-IFFSRLJSSA-N 0.000 description 2
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 2
- 101710120037 Toxin CcdB Proteins 0.000 description 2
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 2
- ULHASJWZGUEUNN-XIRDDKMYSA-N Trp-Lys-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O ULHASJWZGUEUNN-XIRDDKMYSA-N 0.000 description 2
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-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
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 2
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 2
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 2
- ZLFHAAGHGQBQQN-GUBZILKMSA-N Val-Ala-Pro Natural products CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O ZLFHAAGHGQBQQN-GUBZILKMSA-N 0.000 description 2
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 2
- UMPVMAYCLYMYGA-ONGXEEELSA-N Val-Leu-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O UMPVMAYCLYMYGA-ONGXEEELSA-N 0.000 description 2
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 2
- CKTMJBPRVQWPHU-JSGCOSHPSA-N Val-Phe-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)O)N CKTMJBPRVQWPHU-JSGCOSHPSA-N 0.000 description 2
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 2
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 2
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 2
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 2
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 2
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 2
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 2
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 2
- 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 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 108010081404 acein-2 Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000011543 agarose gel Substances 0.000 description 2
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 2
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 2
- 108010041407 alanylaspartic acid Proteins 0.000 description 2
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108010008355 arginyl-glutamine Proteins 0.000 description 2
- 108010092854 aspartyllysine Proteins 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 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 2
- MURGITYSBWUQTI-UHFFFAOYSA-N fluorescin Chemical compound OC(=O)C1=CC=CC=C1C1C2=CC=C(O)C=C2OC2=CC(O)=CC=C21 MURGITYSBWUQTI-UHFFFAOYSA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 2
- 108010049041 glutamylalanine Proteins 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 230000003862 health status Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 108010078274 isoleucylvaline Proteins 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 108010057821 leucylproline Proteins 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 108010003700 lysyl aspartic acid Proteins 0.000 description 2
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 2
- 108010064235 lysylglycine Proteins 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 2
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 229940036105 rabies immunoglobulin Drugs 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 239000006152 selective media Substances 0.000 description 2
- 108010048818 seryl-histidine Proteins 0.000 description 2
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 239000013595 supernatant sample Substances 0.000 description 2
- 239000003104 tissue culture media Substances 0.000 description 2
- 230000005026 transcription initiation Effects 0.000 description 2
- 230000005030 transcription termination Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 108010038745 tryptophylglycine Proteins 0.000 description 2
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 2
- 108010051110 tyrosyl-lysine Proteins 0.000 description 2
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 2
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 2
- 230000029812 viral genome replication Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 108010027345 wheylin-1 peptide Proteins 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- IQRXZEJYKNXFNQ-PSHWWVSLSA-N (2S)-2-aminobutanedioic acid (2S)-2-aminopentanedioic acid (2S)-2,6-diaminohexanoic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O IQRXZEJYKNXFNQ-PSHWWVSLSA-N 0.000 description 1
- JNTMAZFVYNDPLB-PEDHHIEDSA-N (2S,3S)-2-[[[(2S)-1-[(2S,3S)-2-amino-3-methyl-1-oxopentyl]-2-pyrrolidinyl]-oxomethyl]amino]-3-methylpentanoic acid Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JNTMAZFVYNDPLB-PEDHHIEDSA-N 0.000 description 1
- YUXKOWPNKJSTPQ-AXWWPMSFSA-N (2s,3r)-2-amino-3-hydroxybutanoic acid;(2s)-2-amino-3-hydroxypropanoic acid Chemical compound OC[C@H](N)C(O)=O.C[C@@H](O)[C@H](N)C(O)=O YUXKOWPNKJSTPQ-AXWWPMSFSA-N 0.000 description 1
- LXJXRIRHZLFYRP-VKHMYHEASA-L (R)-2-Hydroxy-3-(phosphonooxy)-propanal Natural products O=C[C@H](O)COP([O-])([O-])=O LXJXRIRHZLFYRP-VKHMYHEASA-L 0.000 description 1
- WNQJZQMIEZWFIN-UHFFFAOYSA-N 1-(benzenesulfonyl)-4-(2-chlorobenzoyl)piperazine Chemical compound ClC1=CC=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=CC=CC=2)CC1 WNQJZQMIEZWFIN-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CVOFKRWYWCSDMA-UHFFFAOYSA-N 2-chloro-n-(2,6-diethylphenyl)-n-(methoxymethyl)acetamide;2,6-dinitro-n,n-dipropyl-4-(trifluoromethyl)aniline Chemical compound CCC1=CC=CC(CC)=C1N(COC)C(=O)CCl.CCCN(CCC)C1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O CVOFKRWYWCSDMA-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 1
- 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 1
- XQGIRPGAVLFKBJ-CIUDSAMLSA-N Ala-Asn-Lys Chemical compound N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)O XQGIRPGAVLFKBJ-CIUDSAMLSA-N 0.000 description 1
- XQJAFSDFQZPYCU-UWJYBYFXSA-N Ala-Asn-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N XQJAFSDFQZPYCU-UWJYBYFXSA-N 0.000 description 1
- WJRXVTCKASUIFF-FXQIFTODSA-N Ala-Cys-Arg Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WJRXVTCKASUIFF-FXQIFTODSA-N 0.000 description 1
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 1
- SMCGQGDVTPFXKB-XPUUQOCRSA-N Ala-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N SMCGQGDVTPFXKB-XPUUQOCRSA-N 0.000 description 1
- ZPXCNXMJEZKRLU-LSJOCFKGSA-N Ala-His-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CN=CN1 ZPXCNXMJEZKRLU-LSJOCFKGSA-N 0.000 description 1
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 1
- 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 1
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 1
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 1
- 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 1
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 1
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- AWNAEZICPNGAJK-FXQIFTODSA-N Ala-Met-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O AWNAEZICPNGAJK-FXQIFTODSA-N 0.000 description 1
- 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 1
- FFZJHQODAYHGPO-KZVJFYERSA-N Ala-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N FFZJHQODAYHGPO-KZVJFYERSA-N 0.000 description 1
- YHBDGLZYNIARKJ-GUBZILKMSA-N Ala-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N YHBDGLZYNIARKJ-GUBZILKMSA-N 0.000 description 1
- VJVQKGYHIZPSNS-FXQIFTODSA-N Ala-Ser-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N VJVQKGYHIZPSNS-FXQIFTODSA-N 0.000 description 1
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 1
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 1
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 1
- SAHQGRZIQVEJPF-JXUBOQSCSA-N Ala-Thr-Lys Chemical compound C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN SAHQGRZIQVEJPF-JXUBOQSCSA-N 0.000 description 1
- 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 1
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 1
- OTOXOKCIIQLMFH-KZVJFYERSA-N Arg-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N OTOXOKCIIQLMFH-KZVJFYERSA-N 0.000 description 1
- YWENWUYXQUWRHQ-LPEHRKFASA-N Arg-Cys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CS)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O YWENWUYXQUWRHQ-LPEHRKFASA-N 0.000 description 1
- GOWZVQXTHUCNSQ-NHCYSSNCSA-N Arg-Glu-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O GOWZVQXTHUCNSQ-NHCYSSNCSA-N 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- ITHMWNNUDPJJER-ULQDDVLXSA-N Arg-His-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ITHMWNNUDPJJER-ULQDDVLXSA-N 0.000 description 1
- JEXPNDORFYHJTM-IHRRRGAJSA-N Arg-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCN=C(N)N JEXPNDORFYHJTM-IHRRRGAJSA-N 0.000 description 1
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 1
- ADPACBMPYWJJCE-FXQIFTODSA-N Arg-Ser-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O ADPACBMPYWJJCE-FXQIFTODSA-N 0.000 description 1
- LRPZJPMQGKGHSG-XGEHTFHBSA-N Arg-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N)O LRPZJPMQGKGHSG-XGEHTFHBSA-N 0.000 description 1
- BECXEHHOZNFFFX-IHRRRGAJSA-N Arg-Ser-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BECXEHHOZNFFFX-IHRRRGAJSA-N 0.000 description 1
- OQPAZKMGCWPERI-GUBZILKMSA-N Arg-Ser-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O OQPAZKMGCWPERI-GUBZILKMSA-N 0.000 description 1
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 1
- UVTGNSWSRSCPLP-UHFFFAOYSA-N Arg-Tyr Natural products NC(CCNC(=N)N)C(=O)NC(Cc1ccc(O)cc1)C(=O)O UVTGNSWSRSCPLP-UHFFFAOYSA-N 0.000 description 1
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 1
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DNYRZPOWBTYFAF-IHRRRGAJSA-N Asn-Arg-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)N)N)O DNYRZPOWBTYFAF-IHRRRGAJSA-N 0.000 description 1
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 1
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 1
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 1
- XVBDDUPJVQXDSI-PEFMBERDSA-N Asn-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N XVBDDUPJVQXDSI-PEFMBERDSA-N 0.000 description 1
- BXUHCIXDSWRSBS-CIUDSAMLSA-N Asn-Leu-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O BXUHCIXDSWRSBS-CIUDSAMLSA-N 0.000 description 1
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 1
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 1
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 1
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 1
- WLVLIYYBPPONRJ-GCJQMDKQSA-N Asn-Thr-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O WLVLIYYBPPONRJ-GCJQMDKQSA-N 0.000 description 1
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 1
- ANRZCQXIXGDXLR-CWRNSKLLSA-N Asn-Trp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC(=O)N)N)C(=O)O ANRZCQXIXGDXLR-CWRNSKLLSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- RTFXPCYMDYBZNQ-SRVKXCTJSA-N Asn-Tyr-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O RTFXPCYMDYBZNQ-SRVKXCTJSA-N 0.000 description 1
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 1
- DBWYWXNMZZYIRY-LPEHRKFASA-N Asp-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)O)N)C(=O)O DBWYWXNMZZYIRY-LPEHRKFASA-N 0.000 description 1
- KNMRXHIAVXHCLW-ZLUOBGJFSA-N Asp-Asn-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N)C(=O)O KNMRXHIAVXHCLW-ZLUOBGJFSA-N 0.000 description 1
- VAWNQIGQPUOPQW-ACZMJKKPSA-N Asp-Glu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VAWNQIGQPUOPQW-ACZMJKKPSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- KHBLRHKVXICFMY-GUBZILKMSA-N Asp-Glu-Lys Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O KHBLRHKVXICFMY-GUBZILKMSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- SEMWSADZTMJELF-BYULHYEWSA-N Asp-Ile-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O SEMWSADZTMJELF-BYULHYEWSA-N 0.000 description 1
- DONWIPDSZZJHHK-HJGDQZAQSA-N Asp-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)O DONWIPDSZZJHHK-HJGDQZAQSA-N 0.000 description 1
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 1
- 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 1
- OZBXOELNJBSJOA-UBHSHLNASA-N Asp-Ser-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N OZBXOELNJBSJOA-UBHSHLNASA-N 0.000 description 1
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 1
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 1
- PDIYGFYAMZZFCW-JIOCBJNQSA-N Asp-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N)O PDIYGFYAMZZFCW-JIOCBJNQSA-N 0.000 description 1
- GCACQYDBDHRVGE-LKXGYXEUSA-N Asp-Thr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC(O)=O GCACQYDBDHRVGE-LKXGYXEUSA-N 0.000 description 1
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 1
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 1
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 1
- ALMIMUZAWTUNIO-BZSNNMDCSA-N Asp-Tyr-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ALMIMUZAWTUNIO-BZSNNMDCSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- MFXSFNYSJPNOHH-BKUDZZDWSA-N C(C)(C)C1(O)[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO Chemical compound C(C)(C)C1(O)[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO MFXSFNYSJPNOHH-BKUDZZDWSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282421 Canidae Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- UISYPAHPLXGLNH-ACZMJKKPSA-N Cys-Asn-Gln Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O UISYPAHPLXGLNH-ACZMJKKPSA-N 0.000 description 1
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 1
- ASHTVGGFIMESRD-LKXGYXEUSA-N Cys-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N)O ASHTVGGFIMESRD-LKXGYXEUSA-N 0.000 description 1
- SFRQEQGPRTVDPO-NRPADANISA-N Cys-Gln-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O SFRQEQGPRTVDPO-NRPADANISA-N 0.000 description 1
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 1
- ZOKPRHVIFAUJPV-GUBZILKMSA-N Cys-Pro-Arg Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CS)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O ZOKPRHVIFAUJPV-GUBZILKMSA-N 0.000 description 1
- MBRWOKXNHTUJMB-CIUDSAMLSA-N Cys-Pro-Glu Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O MBRWOKXNHTUJMB-CIUDSAMLSA-N 0.000 description 1
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 1
- YXQDRIRSAHTJKM-IMJSIDKUSA-N Cys-Ser Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(O)=O YXQDRIRSAHTJKM-IMJSIDKUSA-N 0.000 description 1
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- LXJXRIRHZLFYRP-VKHMYHEASA-N D-glyceraldehyde 3-phosphate Chemical compound O=C[C@H](O)COP(O)(O)=O LXJXRIRHZLFYRP-VKHMYHEASA-N 0.000 description 1
- 108010008286 DNA nucleotidylexotransferase Proteins 0.000 description 1
- 102100029764 DNA-directed DNA/RNA polymerase mu Human genes 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 229920002491 Diethylaminoethyl-dextran Polymers 0.000 description 1
- 240000001879 Digitalis lutea Species 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 241000282323 Felidae Species 0.000 description 1
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 1
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 1
- 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 1
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 1
- IKFZXRLDMYWNBU-YUMQZZPRSA-N Gln-Gly-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N IKFZXRLDMYWNBU-YUMQZZPRSA-N 0.000 description 1
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 1
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 1
- KQOPMGBHNQBCEL-HVTMNAMFSA-N Gln-His-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KQOPMGBHNQBCEL-HVTMNAMFSA-N 0.000 description 1
- ZNTDJIMJKNNSLR-RWRJDSDZSA-N Gln-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N ZNTDJIMJKNNSLR-RWRJDSDZSA-N 0.000 description 1
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 1
- XUMFMAVDHQDATI-DCAQKATOSA-N Gln-Pro-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XUMFMAVDHQDATI-DCAQKATOSA-N 0.000 description 1
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 1
- MFORDNZDKAVNSR-SRVKXCTJSA-N Gln-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCC(N)=O MFORDNZDKAVNSR-SRVKXCTJSA-N 0.000 description 1
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 1
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 1
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 1
- WPJDPEOQUIXXOY-AVGNSLFASA-N Gln-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O WPJDPEOQUIXXOY-AVGNSLFASA-N 0.000 description 1
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- WZZSKAJIHTUUSG-ACZMJKKPSA-N Glu-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O WZZSKAJIHTUUSG-ACZMJKKPSA-N 0.000 description 1
- UTKUTMJSWKKHEM-WDSKDSINSA-N Glu-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O UTKUTMJSWKKHEM-WDSKDSINSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 1
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 1
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 1
- DNPCBMNFQVTHMA-DCAQKATOSA-N Glu-Leu-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O DNPCBMNFQVTHMA-DCAQKATOSA-N 0.000 description 1
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 1
- ZIYGTCDTJJCDDP-JYJNAYRXSA-N Glu-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZIYGTCDTJJCDDP-JYJNAYRXSA-N 0.000 description 1
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 1
- BFEZQZKEPRKKHV-SRVKXCTJSA-N Glu-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O BFEZQZKEPRKKHV-SRVKXCTJSA-N 0.000 description 1
- JWNZHMSRZXXGTM-XKBZYTNZSA-N Glu-Ser-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWNZHMSRZXXGTM-XKBZYTNZSA-N 0.000 description 1
- CAQXJMUDOLSBPF-SUSMZKCASA-N Glu-Thr-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAQXJMUDOLSBPF-SUSMZKCASA-N 0.000 description 1
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 1
- ZSIDREAPEPAPKL-XIRDDKMYSA-N Glu-Trp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N ZSIDREAPEPAPKL-XIRDDKMYSA-N 0.000 description 1
- 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 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000005731 Glucose-6-phosphate isomerase Human genes 0.000 description 1
- 108010070600 Glucose-6-phosphate isomerase Proteins 0.000 description 1
- 102000004366 Glucosidases Human genes 0.000 description 1
- 108010056771 Glucosidases Proteins 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- QGZSAHIZRQHCEQ-QWRGUYRKSA-N Gly-Asp-Tyr Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QGZSAHIZRQHCEQ-QWRGUYRKSA-N 0.000 description 1
- CQZDZKRHFWJXDF-WDSKDSINSA-N Gly-Gln-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CN CQZDZKRHFWJXDF-WDSKDSINSA-N 0.000 description 1
- GNPVTZJUUBPZKW-WDSKDSINSA-N Gly-Gln-Ser Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GNPVTZJUUBPZKW-WDSKDSINSA-N 0.000 description 1
- DHDOADIPGZTAHT-YUMQZZPRSA-N Gly-Glu-Arg Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DHDOADIPGZTAHT-YUMQZZPRSA-N 0.000 description 1
- STVHDEHTKFXBJQ-LAEOZQHASA-N Gly-Glu-Ile Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O STVHDEHTKFXBJQ-LAEOZQHASA-N 0.000 description 1
- 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 1
- XMPXVJIDADUOQB-RCOVLWMOSA-N Gly-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C([O-])=O)NC(=O)CNC(=O)C[NH3+] XMPXVJIDADUOQB-RCOVLWMOSA-N 0.000 description 1
- KAJAOGBVWCYGHZ-JTQLQIEISA-N Gly-Gly-Phe Chemical compound [NH3+]CC(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 KAJAOGBVWCYGHZ-JTQLQIEISA-N 0.000 description 1
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 1
- LPCKHUXOGVNZRS-YUMQZZPRSA-N Gly-His-Ser Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O LPCKHUXOGVNZRS-YUMQZZPRSA-N 0.000 description 1
- BHPQOIPBLYJNAW-NGZCFLSTSA-N Gly-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN BHPQOIPBLYJNAW-NGZCFLSTSA-N 0.000 description 1
- TWTPDFFBLQEBOE-IUCAKERBSA-N Gly-Leu-Gln Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O TWTPDFFBLQEBOE-IUCAKERBSA-N 0.000 description 1
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 1
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 1
- GGAPHLIUUTVYMX-QWRGUYRKSA-N Gly-Phe-Ser Chemical compound OC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)C[NH3+])CC1=CC=CC=C1 GGAPHLIUUTVYMX-QWRGUYRKSA-N 0.000 description 1
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 1
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 1
- POJJAZJHBGXEGM-YUMQZZPRSA-N Gly-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)CN POJJAZJHBGXEGM-YUMQZZPRSA-N 0.000 description 1
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 1
- ABPRMMYHROQBLY-NKWVEPMBSA-N Gly-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)CN)C(=O)O ABPRMMYHROQBLY-NKWVEPMBSA-N 0.000 description 1
- YJDALMUYJIENAG-QWRGUYRKSA-N Gly-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN)O YJDALMUYJIENAG-QWRGUYRKSA-N 0.000 description 1
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 1
- RYAOJUMWLWUGNW-QMMMGPOBSA-N Gly-Val-Gly Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O RYAOJUMWLWUGNW-QMMMGPOBSA-N 0.000 description 1
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 102000005548 Hexokinase Human genes 0.000 description 1
- 108700040460 Hexokinases Proteins 0.000 description 1
- ZPVJJPAIUZLSNE-DCAQKATOSA-N His-Arg-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O ZPVJJPAIUZLSNE-DCAQKATOSA-N 0.000 description 1
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 1
- HVCRQRQPIIRNLY-IUCAKERBSA-N His-Gln-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N HVCRQRQPIIRNLY-IUCAKERBSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- QCBYAHHNOHBXIH-UWVGGRQHSA-N His-Pro-Gly Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)C1=CN=CN1 QCBYAHHNOHBXIH-UWVGGRQHSA-N 0.000 description 1
- FOCSWPCHUDVNLP-PMVMPFDFSA-N His-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC4=CN=CN4)N FOCSWPCHUDVNLP-PMVMPFDFSA-N 0.000 description 1
- 241000701109 Human adenovirus 2 Species 0.000 description 1
- FDGQSTZJBFJUBT-UHFFFAOYSA-N Hypoxanthine Natural products O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 1
- ASCFJMSGKUIRDU-ZPFDUUQYSA-N Ile-Arg-Gln Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O ASCFJMSGKUIRDU-ZPFDUUQYSA-N 0.000 description 1
- YOTNPRLPIPHQSB-XUXIUFHCSA-N Ile-Arg-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N YOTNPRLPIPHQSB-XUXIUFHCSA-N 0.000 description 1
- RSDHVTMRXSABSV-GHCJXIJMSA-N Ile-Asn-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N RSDHVTMRXSABSV-GHCJXIJMSA-N 0.000 description 1
- FADXGVVLSPPEQY-GHCJXIJMSA-N Ile-Cys-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N FADXGVVLSPPEQY-GHCJXIJMSA-N 0.000 description 1
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 1
- FGBRXCZYVRFNKQ-MXAVVETBSA-N Ile-Phe-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N FGBRXCZYVRFNKQ-MXAVVETBSA-N 0.000 description 1
- CAHCWMVNBZJVAW-NAKRPEOUSA-N Ile-Pro-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)O)N CAHCWMVNBZJVAW-NAKRPEOUSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 101710203526 Integrase Proteins 0.000 description 1
- 102000004195 Isomerases Human genes 0.000 description 1
- 108090000769 Isomerases Proteins 0.000 description 1
- 241001331012 Kotonkan virus Species 0.000 description 1
- 101150062031 L gene Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 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 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- LZDNBBYBDGBADK-UHFFFAOYSA-N L-valyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C(C)C)C(O)=O)=CNC2=C1 LZDNBBYBDGBADK-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001520693 Lagos bat lyssavirus Species 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 241000270322 Lepidosauria Species 0.000 description 1
- WSGXUIQTEZDVHJ-GARJFASQSA-N Leu-Ala-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O WSGXUIQTEZDVHJ-GARJFASQSA-N 0.000 description 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- CLVUXCBGKUECIT-HJGDQZAQSA-N Leu-Asp-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CLVUXCBGKUECIT-HJGDQZAQSA-N 0.000 description 1
- PNUCWVAGVNLUMW-CIUDSAMLSA-N Leu-Cys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O PNUCWVAGVNLUMW-CIUDSAMLSA-N 0.000 description 1
- VQPPIMUZCZCOIL-GUBZILKMSA-N Leu-Gln-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O VQPPIMUZCZCOIL-GUBZILKMSA-N 0.000 description 1
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 1
- YVKSMSDXKMSIRX-GUBZILKMSA-N Leu-Glu-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O YVKSMSDXKMSIRX-GUBZILKMSA-N 0.000 description 1
- NRFGTHFONZYFNY-MGHWNKPDSA-N Leu-Ile-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NRFGTHFONZYFNY-MGHWNKPDSA-N 0.000 description 1
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 1
- UBZGNBKMIJHOHL-BZSNNMDCSA-N Leu-Leu-Phe Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 UBZGNBKMIJHOHL-BZSNNMDCSA-N 0.000 description 1
- IEWBEPKLKUXQBU-VOAKCMCISA-N Leu-Leu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IEWBEPKLKUXQBU-VOAKCMCISA-N 0.000 description 1
- FOBUGKUBUJOWAD-IHPCNDPISA-N Leu-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FOBUGKUBUJOWAD-IHPCNDPISA-N 0.000 description 1
- HVHRPWQEQHIQJF-AVGNSLFASA-N Leu-Lys-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HVHRPWQEQHIQJF-AVGNSLFASA-N 0.000 description 1
- LVTJJOJKDCVZGP-QWRGUYRKSA-N Leu-Lys-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O LVTJJOJKDCVZGP-QWRGUYRKSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- 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 1
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 1
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 1
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 1
- MVHXGBZUJLWZOH-BJDJZHNGSA-N Leu-Ser-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MVHXGBZUJLWZOH-BJDJZHNGSA-N 0.000 description 1
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 1
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 1
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 1
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 1
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 1
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 1
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- XFIHDSBIPWEYJJ-YUMQZZPRSA-N Lys-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN XFIHDSBIPWEYJJ-YUMQZZPRSA-N 0.000 description 1
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 1
- IXHKPDJKKCUKHS-GARJFASQSA-N Lys-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IXHKPDJKKCUKHS-GARJFASQSA-N 0.000 description 1
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 1
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 1
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 1
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 1
- ORVFEGYUJITPGI-IHRRRGAJSA-N Lys-Leu-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCCN ORVFEGYUJITPGI-IHRRRGAJSA-N 0.000 description 1
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 1
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- VHTOGMKQXXJOHG-RHYQMDGZSA-N Lys-Thr-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O VHTOGMKQXXJOHG-RHYQMDGZSA-N 0.000 description 1
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- DNDVVILEHVMWIS-LPEHRKFASA-N Met-Asp-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N DNDVVILEHVMWIS-LPEHRKFASA-N 0.000 description 1
- MCNGIXXCMJAURZ-VEVYYDQMSA-N Met-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)N)O MCNGIXXCMJAURZ-VEVYYDQMSA-N 0.000 description 1
- UYAKZHGIPRCGPF-CIUDSAMLSA-N Met-Glu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCSC)N UYAKZHGIPRCGPF-CIUDSAMLSA-N 0.000 description 1
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 1
- RNAGAJXCSPDPRK-KKUMJFAQSA-N Met-Glu-Phe Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 RNAGAJXCSPDPRK-KKUMJFAQSA-N 0.000 description 1
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 1
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 1
- UROWNMBTQGGTHB-DCAQKATOSA-N Met-Leu-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O UROWNMBTQGGTHB-DCAQKATOSA-N 0.000 description 1
- MQASRXPTQJJNFM-JYJNAYRXSA-N Met-Pro-Phe Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MQASRXPTQJJNFM-JYJNAYRXSA-N 0.000 description 1
- RIIFMEBFDDXGCV-VEVYYDQMSA-N Met-Thr-Asn Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(N)=O RIIFMEBFDDXGCV-VEVYYDQMSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000725171 Mokola lyssavirus Species 0.000 description 1
- 241000699729 Muridae Species 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 1
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 1
- 108010066427 N-valyltryptophan Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- SFGHOPCYYSBLNF-MTPJMXSYSA-N OC(=O)[C@@H]1CCCN1.CC[C@H](C)[C@H](N)C(O)=O.CSCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 Chemical compound OC(=O)[C@@H]1CCCN1.CC[C@H](C)[C@H](N)C(O)=O.CSCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 SFGHOPCYYSBLNF-MTPJMXSYSA-N 0.000 description 1
- 101150012394 PHO5 gene Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 1
- QPVFUAUFEBPIPT-CDMKHQONSA-N Phe-Gly-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O QPVFUAUFEBPIPT-CDMKHQONSA-N 0.000 description 1
- WZEWCHQHNCMBEN-PMVMPFDFSA-N Phe-Lys-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N WZEWCHQHNCMBEN-PMVMPFDFSA-N 0.000 description 1
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 1
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 1
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 1
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 1
- IEIFEYBAYFSRBQ-IHRRRGAJSA-N Phe-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N IEIFEYBAYFSRBQ-IHRRRGAJSA-N 0.000 description 1
- 102000001105 Phosphofructokinases Human genes 0.000 description 1
- 108010069341 Phosphofructokinases Proteins 0.000 description 1
- 102000012288 Phosphopyruvate Hydratase Human genes 0.000 description 1
- 108010022181 Phosphopyruvate Hydratase Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000254064 Photinus pyralis Species 0.000 description 1
- 108010053210 Phycocyanin Proteins 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- AJLVKXCNXIJHDV-CIUDSAMLSA-N Pro-Ala-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O AJLVKXCNXIJHDV-CIUDSAMLSA-N 0.000 description 1
- HQVPQXMCQKXARZ-FXQIFTODSA-N Pro-Cys-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O HQVPQXMCQKXARZ-FXQIFTODSA-N 0.000 description 1
- PULPZRAHVFBVTO-DCAQKATOSA-N Pro-Glu-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PULPZRAHVFBVTO-DCAQKATOSA-N 0.000 description 1
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-N 0.000 description 1
- MGDFPGCFVJFITQ-CIUDSAMLSA-N Pro-Glu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MGDFPGCFVJFITQ-CIUDSAMLSA-N 0.000 description 1
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 1
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 1
- HAAQQNHQZBOWFO-LURJTMIESA-N Pro-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H]1CCCN1 HAAQQNHQZBOWFO-LURJTMIESA-N 0.000 description 1
- DXTOOBDIIAJZBJ-BQBZGAKWSA-N Pro-Gly-Ser Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CO)C(O)=O DXTOOBDIIAJZBJ-BQBZGAKWSA-N 0.000 description 1
- FXGIMYRVJJEIIM-UWVGGRQHSA-N Pro-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FXGIMYRVJJEIIM-UWVGGRQHSA-N 0.000 description 1
- OFGUOWQVEGTVNU-DCAQKATOSA-N Pro-Lys-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OFGUOWQVEGTVNU-DCAQKATOSA-N 0.000 description 1
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 1
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 1
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 description 1
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 1
- SBVPYBFMIGDIDX-SRVKXCTJSA-N Pro-Pro-Pro Chemical compound OC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)[C@H]2NCCC2)CCC1 SBVPYBFMIGDIDX-SRVKXCTJSA-N 0.000 description 1
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 1
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 1
- HRIXMVRZRGFKNQ-HJGDQZAQSA-N Pro-Thr-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HRIXMVRZRGFKNQ-HJGDQZAQSA-N 0.000 description 1
- IURWWZYKYPEANQ-HJGDQZAQSA-N Pro-Thr-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O IURWWZYKYPEANQ-HJGDQZAQSA-N 0.000 description 1
- DMNANGOFEUVBRV-GJZGRUSLSA-N Pro-Trp-Gly Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)O)C(=O)[C@@H]1CCCN1 DMNANGOFEUVBRV-GJZGRUSLSA-N 0.000 description 1
- LEBTWGWVUVJNTA-FKBYEOEOSA-N Pro-Trp-Phe Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@@H](CC4=CC=CC=C4)C(=O)O LEBTWGWVUVJNTA-FKBYEOEOSA-N 0.000 description 1
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 241000282325 Proteles cristata Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 108010053763 Pyruvate Carboxylase Proteins 0.000 description 1
- 102000013009 Pyruvate Kinase Human genes 0.000 description 1
- 108020005115 Pyruvate Kinase Proteins 0.000 description 1
- 102100039895 Pyruvate carboxylase, mitochondrial Human genes 0.000 description 1
- 108010003201 RGH 0205 Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 101100191147 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PHO3 gene Proteins 0.000 description 1
- WTWGOQRNRFHFQD-JBDRJPRFSA-N Ser-Ala-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WTWGOQRNRFHFQD-JBDRJPRFSA-N 0.000 description 1
- 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 1
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 1
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 1
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 1
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- ICHZYBVODUVUKN-SRVKXCTJSA-N Ser-Asn-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ICHZYBVODUVUKN-SRVKXCTJSA-N 0.000 description 1
- BNFVPSRLHHPQKS-WHFBIAKZSA-N Ser-Asp-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O BNFVPSRLHHPQKS-WHFBIAKZSA-N 0.000 description 1
- SWSRFJZZMNLMLY-ZKWXMUAHSA-N Ser-Asp-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O SWSRFJZZMNLMLY-ZKWXMUAHSA-N 0.000 description 1
- KNCJWSPMTFFJII-ZLUOBGJFSA-N Ser-Cys-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KNCJWSPMTFFJII-ZLUOBGJFSA-N 0.000 description 1
- TUYBIWUZWJUZDD-ACZMJKKPSA-N Ser-Cys-Gln Chemical compound OC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(N)=O TUYBIWUZWJUZDD-ACZMJKKPSA-N 0.000 description 1
- MPPHJZYXDVDGOF-BWBBJGPYSA-N Ser-Cys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CO MPPHJZYXDVDGOF-BWBBJGPYSA-N 0.000 description 1
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 1
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 1
- 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 1
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 1
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 1
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 1
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 1
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 1
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 1
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 1
- RRVFEDGUXSYWOW-BZSNNMDCSA-N Ser-Phe-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RRVFEDGUXSYWOW-BZSNNMDCSA-N 0.000 description 1
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 1
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 1
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 1
- 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 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- OLKICIBQRVSQMA-SRVKXCTJSA-N Ser-Ser-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OLKICIBQRVSQMA-SRVKXCTJSA-N 0.000 description 1
- 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 1
- PURRNJBBXDDWLX-ZDLURKLDSA-N Ser-Thr-Gly Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CO)N)O PURRNJBBXDDWLX-ZDLURKLDSA-N 0.000 description 1
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 1
- DYEGLQRVMBWQLD-IXOXFDKPSA-N Ser-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CO)N)O DYEGLQRVMBWQLD-IXOXFDKPSA-N 0.000 description 1
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 1
- AXKJPUBALUNJEO-UBHSHLNASA-N Ser-Trp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O AXKJPUBALUNJEO-UBHSHLNASA-N 0.000 description 1
- PIQRHJQWEPWFJG-UWJYBYFXSA-N Ser-Tyr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O PIQRHJQWEPWFJG-UWJYBYFXSA-N 0.000 description 1
- PLQWGQUNUPMNOD-KKUMJFAQSA-N Ser-Tyr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O PLQWGQUNUPMNOD-KKUMJFAQSA-N 0.000 description 1
- HAYADTTXNZFUDM-IHRRRGAJSA-N Ser-Tyr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O HAYADTTXNZFUDM-IHRRRGAJSA-N 0.000 description 1
- 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 1
- 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 1
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 1
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 101150006914 TRP1 gene Proteins 0.000 description 1
- MQCPGOZXFSYJPS-KZVJFYERSA-N Thr-Ala-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MQCPGOZXFSYJPS-KZVJFYERSA-N 0.000 description 1
- NJEMRSFGDNECGF-GCJQMDKQSA-N Thr-Ala-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O NJEMRSFGDNECGF-GCJQMDKQSA-N 0.000 description 1
- 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 1
- JNQZPAWOPBZGIX-RCWTZXSCSA-N Thr-Arg-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)O)CCCN=C(N)N JNQZPAWOPBZGIX-RCWTZXSCSA-N 0.000 description 1
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 1
- UHBPFYOQQPFKQR-JHEQGTHGSA-N Thr-Gln-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O UHBPFYOQQPFKQR-JHEQGTHGSA-N 0.000 description 1
- DIPIPFHFLPTCLK-LOKLDPHHSA-N Thr-Gln-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O DIPIPFHFLPTCLK-LOKLDPHHSA-N 0.000 description 1
- MSIYNSBKKVMGFO-BHNWBGBOSA-N Thr-Gly-Pro Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N1CCC[C@@H]1C(=O)O)N)O MSIYNSBKKVMGFO-BHNWBGBOSA-N 0.000 description 1
- DJDSEDOKJTZBAR-ZDLURKLDSA-N Thr-Gly-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O DJDSEDOKJTZBAR-ZDLURKLDSA-N 0.000 description 1
- SXAGUVRFGJSFKC-ZEILLAHLSA-N Thr-His-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SXAGUVRFGJSFKC-ZEILLAHLSA-N 0.000 description 1
- MEJHFIOYJHTWMK-VOAKCMCISA-N Thr-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)[C@@H](C)O MEJHFIOYJHTWMK-VOAKCMCISA-N 0.000 description 1
- IJVNLNRVDUTWDD-MEYUZBJRSA-N Thr-Leu-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IJVNLNRVDUTWDD-MEYUZBJRSA-N 0.000 description 1
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 1
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- QFEYTTHKPSOFLV-OSUNSFLBSA-N Thr-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H]([C@@H](C)O)N QFEYTTHKPSOFLV-OSUNSFLBSA-N 0.000 description 1
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 1
- MXDOAJQRJBMGMO-FJXKBIBVSA-N Thr-Pro-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O MXDOAJQRJBMGMO-FJXKBIBVSA-N 0.000 description 1
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 1
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 1
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 1
- JAWUQFCGNVEDRN-MEYUZBJRSA-N Thr-Tyr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N)O JAWUQFCGNVEDRN-MEYUZBJRSA-N 0.000 description 1
- LVRFMARKDGGZMX-IZPVPAKOSA-N Thr-Tyr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=C(O)C=C1 LVRFMARKDGGZMX-IZPVPAKOSA-N 0.000 description 1
- BKIOKSLLAAZYTC-KKHAAJSZSA-N Thr-Val-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O BKIOKSLLAAZYTC-KKHAAJSZSA-N 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 102000005924 Triose-Phosphate Isomerase Human genes 0.000 description 1
- 108700015934 Triose-phosphate isomerases Proteins 0.000 description 1
- WFZYXGSAPWKTHR-XEGUGMAKSA-N Trp-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N WFZYXGSAPWKTHR-XEGUGMAKSA-N 0.000 description 1
- VEYXZZGMIBKXCN-UBHSHLNASA-N Trp-Asp-Asp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N VEYXZZGMIBKXCN-UBHSHLNASA-N 0.000 description 1
- DVAAUUVLDFKTAQ-VHWLVUOQSA-N Trp-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N DVAAUUVLDFKTAQ-VHWLVUOQSA-N 0.000 description 1
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-N 0.000 description 1
- WLQRIHCMPFHGKP-PMVMPFDFSA-N Trp-Leu-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)CC(C)C)C(O)=O)C1=CC=CC=C1 WLQRIHCMPFHGKP-PMVMPFDFSA-N 0.000 description 1
- GQEXFCQNAJHJTI-IHPCNDPISA-N Trp-Phe-Asp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N GQEXFCQNAJHJTI-IHPCNDPISA-N 0.000 description 1
- YXSSXUIBUJGHJY-SFJXLCSZSA-N Trp-Thr-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)[C@H](O)C)C(O)=O)C1=CC=CC=C1 YXSSXUIBUJGHJY-SFJXLCSZSA-N 0.000 description 1
- RWTFCAMQLFNPTK-UMPQAUOISA-N Trp-Val-Thr Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)=CNC2=C1 RWTFCAMQLFNPTK-UMPQAUOISA-N 0.000 description 1
- VCXWRWYFJLXITF-AUTRQRHGSA-N Tyr-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VCXWRWYFJLXITF-AUTRQRHGSA-N 0.000 description 1
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 1
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 1
- CGDZGRLRXPNCOC-SRVKXCTJSA-N Tyr-Cys-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 CGDZGRLRXPNCOC-SRVKXCTJSA-N 0.000 description 1
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 1
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 1
- GULIUBBXCYPDJU-CQDKDKBSSA-N Tyr-Leu-Ala Chemical compound [O-]C(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CC1=CC=C(O)C=C1 GULIUBBXCYPDJU-CQDKDKBSSA-N 0.000 description 1
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 1
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 1
- UPODKYBYUBTWSV-BZSNNMDCSA-N Tyr-Phe-Cys Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CS)C(O)=O)C1=CC=C(O)C=C1 UPODKYBYUBTWSV-BZSNNMDCSA-N 0.000 description 1
- SZEIFUXUTBBQFQ-STQMWFEESA-N Tyr-Pro-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O SZEIFUXUTBBQFQ-STQMWFEESA-N 0.000 description 1
- KWKJGBHDYJOVCR-SRVKXCTJSA-N Tyr-Ser-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N)O KWKJGBHDYJOVCR-SRVKXCTJSA-N 0.000 description 1
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 1
- LTFLDDDGWOVIHY-NAKRPEOUSA-N Val-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N LTFLDDDGWOVIHY-NAKRPEOUSA-N 0.000 description 1
- GNWUWQAVVJQREM-NHCYSSNCSA-N Val-Asn-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N GNWUWQAVVJQREM-NHCYSSNCSA-N 0.000 description 1
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 1
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 1
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 1
- LMSBRIVOCYOKMU-NRPADANISA-N Val-Gln-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N LMSBRIVOCYOKMU-NRPADANISA-N 0.000 description 1
- PWRITNSESKQTPW-NRPADANISA-N Val-Gln-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N PWRITNSESKQTPW-NRPADANISA-N 0.000 description 1
- WDIGUPHXPBMODF-UMNHJUIQSA-N Val-Glu-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N WDIGUPHXPBMODF-UMNHJUIQSA-N 0.000 description 1
- XWYUBUYQMOUFRQ-IFFSRLJSSA-N Val-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N)O XWYUBUYQMOUFRQ-IFFSRLJSSA-N 0.000 description 1
- JVYIGCARISMLMV-HOCLYGCPSA-N Val-Gly-Trp Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N JVYIGCARISMLMV-HOCLYGCPSA-N 0.000 description 1
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 1
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 1
- BZWUSZGQOILYEU-STECZYCISA-N Val-Ile-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BZWUSZGQOILYEU-STECZYCISA-N 0.000 description 1
- FEXILLGKGGTLRI-NHCYSSNCSA-N Val-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N FEXILLGKGGTLRI-NHCYSSNCSA-N 0.000 description 1
- DAVNYIUELQBTAP-XUXIUFHCSA-N Val-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N DAVNYIUELQBTAP-XUXIUFHCSA-N 0.000 description 1
- BTWMICVCQLKKNR-DCAQKATOSA-N Val-Leu-Ser Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C([O-])=O BTWMICVCQLKKNR-DCAQKATOSA-N 0.000 description 1
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 1
- VCIYTVOBLZHFSC-XHSDSOJGSA-N Val-Phe-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N VCIYTVOBLZHFSC-XHSDSOJGSA-N 0.000 description 1
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 1
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 1
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 1
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 1
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 1
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 1
- WUFHZIRMAZZWRS-OSUNSFLBSA-N Val-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)N WUFHZIRMAZZWRS-OSUNSFLBSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-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](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 241000608575 Vespertilio Species 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- VEUACKUBDLVUAC-UHFFFAOYSA-N [Na].[Ca] Chemical compound [Na].[Ca] VEUACKUBDLVUAC-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 108010038633 aspartylglutamate Proteins 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011692 calcium ascorbate Substances 0.000 description 1
- 235000010376 calcium ascorbate Nutrition 0.000 description 1
- 229940047036 calcium ascorbate Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- BLORRZQTHNGFTI-ZZMNMWMASA-L calcium-L-ascorbate Chemical compound [Ca+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] BLORRZQTHNGFTI-ZZMNMWMASA-L 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000012832 cell culture technique Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- RGWHQCVHVJXOKC-SHYZEUOFSA-J dCTP(4-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 RGWHQCVHVJXOKC-SHYZEUOFSA-J 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 108010054812 diprotin A Proteins 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 235000012489 doughnuts Nutrition 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical group CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 230000009395 genetic defect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 108010010096 glycyl-glycyl-tyrosine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 108010084389 glycyltryptophan Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 210000004201 immune sera Anatomy 0.000 description 1
- 229940042743 immune sera Drugs 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 108010053037 kyotorphin Proteins 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 108010091871 leucylmethionine Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 108010005942 methionylglycine Proteins 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 210000003360 nephrocyte Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 101150115693 ompA gene Proteins 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 108010087558 pectate lyase Proteins 0.000 description 1
- 101150050446 pelB gene Proteins 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 1
- 101150009573 phoA gene Proteins 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 108700004029 pol Genes Proteins 0.000 description 1
- 101150088264 pol gene Proteins 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 1
- 108700042769 prolyl-leucyl-glycine Proteins 0.000 description 1
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 229960003127 rabies vaccine Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003161 ribonuclease inhibitor Substances 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 206010040400 serum sickness Diseases 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 108010005834 tyrosyl-alanyl-glycine Proteins 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
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
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
-
- 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
- A61P31/14—Antivirals for RNA viruses
-
- 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
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
为狂犬病毒中和抗体在对暴露于狂犬病毒的受试者进行暴露后预防治疗中的应用提供了方法和组合物。包含狂犬病毒中和抗体混合物的组合物以及编码这些抗体的核苷酸和氨基酸序列可用于对暴露于狂犬病毒的受试者的治疗。本发明还提供了使用重组表达载体在哺乳动物细胞内制备重组狂犬病毒中和人抗体的方法。
Description
政府基金声明
在此说明的发明部分地受到从美国政府获得的资金(国家卫生研究院基金AI450079)的支持。美国政府对本发明拥有一定权利。
技术领域
本发明涉及抗体,包括人狂犬病毒中和抗体的核酸和氨基酸序列,以及使用重组表达载体对其进行的制备。更具体地,本发明涉及针对狂犬病毒的抗体混合物的应用,该混合物可在受试者暴露于狂犬病毒后用于预防治疗。
背景技术
狂犬病是由于中枢神经系统受到狂犬病毒的感染而引起的急性神经性疾病,狂犬病毒是棒状病毒科(Rhabdoviridae)狂犬病毒属(Lyssavirus)中的病毒。在于病毒的古老以及疾病的可怕性而具有重要历史意义的狂犬病毒一直是人类和动物感染的重要威胁,因为其在各种野生动物中存在着广泛的宿主。在世界的大部分地区,狂犬病毒在地区物种中是地方病,而不同地区的病毒变异体之间相似性很小。虽然在包括联合王国,澳大利亚,日本,以及各个岛屿上没有地方性狂犬病,英国和澳大利亚也已发现了狂犬病和蝙蝠相关的狂犬相关病毒。
尽管抗体能够提供即时免疫,被动免疫已被广泛地用于治疗传染性疾病,包括狂犬病(Casadeval,A.,Emerg.Infect.Dis.2002,8:833-41)。根据世界卫生组织(WHO)指导方针,3类狂犬病的暴露需要狂犬病暴露后预防(PEP),这些暴露被定义为或单次或多次经皮咬伤或黏膜被患有狂犬病动物的唾液污染(Human rabiesprevention-United States,2000:Recommendations of the AdvisoryCommittee on Immunization Practices.MMWR 2000)。狂犬病的暴露后预防包括疫苗和抗狂犬病免疫球蛋白(RIG)的给药。目前,从狂犬病毒免疫的人(人RIG[HRIG])或狂犬病毒免疫的马(马RIG[ERIG])的血清样品中制备用于暴露后预防的RIG。由于与ERIG的使用相关的潜在不良效应(例如过敏性休克),在美国仅使用HRIG,暴露于狂犬病动物的人(每年~39,000人)接受HRIG和狂犬病毒(RV)疫苗的治疗(Human rabies prevention-United States,2000:Recommendations ofthe Advisory Committee on Immunization Practices.MMWR 2000)。然而,在发展中国家,因为没有足够量的可供使用的HRIG和ERIG或因为它们,特别是HRIG,过于昂贵,所有PEP中<1%包括了RIG的给药(Human rabies prevention-United States,1999:Recommendations of theAdvisory Committee on Immunization Practices(ACIP).MMWR Recomm.Rep.1999,48:1-21)。此外,一些动物保护团体对于饲养动物用于血清制备的行为进行了声讨(Human rabies prevention-United States,1999:Recommendations of the Advisory Committee on Immunization Practices(ACIP).MMWR Recomm.Rep.1999 48:1-21)。另外,由已知或未知病原体造成HRIG污染的可能性是管理机构关心的问题。通过制备人RV-中和单克隆抗体(MAbs)可以克服经济有效而安全的RIG在全球有限的供应,该抗体可被用于与生物反应器技术结合的高产表达系统(例如使用transfectomas的系统)。
一旦个体暴露于狂犬病毒,可以通过合适的治疗包括被动和主动免疫,容易地防止疾病(Human rabies prevention-United States,2000:Recommendations of the Advisory Committee on Immunization Practices.MMWR 2000)。人们相信抗体的被动给药对于在进入位点中和病毒以及干扰病毒向中枢神经系统(CNS)的扩散很重要(Dietzschold等,Proc.Natl.Acad.Sci.USA 1992,89:7252-6)。这两种作用很可能为发展对病毒的主动免疫提供时间,该免疫最终清除病毒。
RV-中和鼠或人单克隆抗体(MAbs)的给药在鼠的暴露后预防中显得很有效(WHO consultation on a monoclonal antibody cocktail forrabies post exposure treatment,WHO,2002年5月23-24日;Schumacher等,J.Clin.Invest.1989 84:971-5;Dietzschold等,J.Virol.1990 64:3087-90)。随着人单克隆抗体制备技术的进步,考虑在人体中使用鼠单克隆抗体可能是不必要的。在人体中使用鼠单克隆抗体可能带来问题,因为它们对于人而言是是免疫原性的且其半衰期是有限的,可能造成血清病或过敏性休克。此外,人单克隆抗体和Fc受体之间的相互作用和相应的鼠试剂之间的作用相比可能是更合适的。
目前,使用从混合人血清或从免疫的马中制备的抗体治疗受试者。但是,这些试剂中没有任何试剂是可以轻易获得、完全安全或生物活性稳定的。
对于暴露于狂犬病毒的个体的暴露后预防治疗需要新的方法。同样需要新的方法治疗存在暴露于狂犬病毒的风险的受试者。本发明满足了这些需要。
发明内容
本发明为狂犬病的治疗和预防提供了狂犬病毒中和抗体的混合物。本发明还提供了含有编码抗狂犬病抗体的核酸的重组棒状病毒表达系统以及这些抗体的组合物和在哺乳动物细胞内制备这些抗体的方法。
在此提供的重组狂犬病毒中和人抗体包括人抗体SOJA、SOJB和SO57。这三个抗体也分别被称作MAb JA、MAb JB.1和MAb 57。
本发明因此提供了包含一种药学上可接受的载体和至少两种狂犬病毒中和人抗体的药物组合物,其中至少两种抗体中的至少一种选自:
a)包含具有氨基酸序列SEQ ID NO:2或与SEQ ID NO:2基本上同源的序列的抗体轻链和具有氨基酸序列SEQ ID NO:1或与SEQ IDNO:1基本上同源的序列的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6或与SEQ ID NO:6基本上同源的序列的抗体轻链和具有氨基酸序列SEQ ID NO:4或与SEQ IDNO:4基本上同源的序列的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7或与SEQ ID NO:7基本上同源的序列的抗体轻链和具有氨基酸序列SEQ ID NO:9或与SEQ IDNO:9基本上同源的序列的抗体重链的抗体。
本发明提供了对需要治疗的受试者治疗或预防狂犬病毒感染的方法。该方法包括对受试者以至少两种重组狂犬病毒中和人抗体的有效量给药,其中抗体选自:
a)包含具有氨基酸序列SEQ ID NO:2或与SEQ ID NO:2基本上同源的序列的抗体轻链和具有氨基酸序列SEQ ID NO:1或与SEQ IDNO:1基本上同源的序列的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6或与SEQ ID NO:6基本上同源的序列的抗体轻链和具有氨基酸序列SEQ ID NO:4或与SEQ IDNO:4基本上同源的序列的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7或与SEQ ID NO:7基本上同源的序列的抗体轻链和具有氨基酸序列SEQ ID NO:9或与SEQ IDNO:9成分同源的序列的抗体重链的抗体。
在一个具体实施方案中,至少两种,更优选三种抗体选自前述组。
在一个具体实施方案中,用至少三种不同的重组狂犬病毒中和人抗体进行给药。
在一个具体实施方案中,抗体以至少两种不同组合物的方式分别给药。
在一个具体实施方案中,重组狂犬病毒中和人抗体对至少两种或多种狂犬病毒呈现中和活性。
在本发明的一个方面中,不同的重组狂犬病毒中和人抗体以大约等摩尔浓度给药。
在一个具体实施方案中,用重组狂犬病毒中和人抗体给药,其中各重组狂犬病毒中和人抗体以与给药的其它重组狂犬病毒中和人抗体大约相等的蛋白量给药。一方面,重组狂犬病毒中和人抗体的给药量在大约0.001mg/kg体重至大约100mg/kg体重之间。在本发明的另一方面中,重组狂犬病毒中和人抗体的给药量在大约0.01mg/kg体重至大约60mg/kg体重之间。
在另一个具体实施方案中,重组狂犬病毒中和人抗体的给药量基于重组狂犬病毒中和人抗体混合物的狂犬病毒中和活性。一方面,混合物活性在大约1IU/kg体重至大约50IU/kg体重之间。
在一个具体实施方案中,本发明提供了通过重组狂犬病毒中和抗体混合物给药对受试者进行治疗的方法,其中受治疗的病毒为一种狂犬病毒街毒。在一些具体实施方案中,病毒选自银毛蝠狂犬病毒、土狼狂犬病毒街毒/墨西哥狗狂犬病毒和狗狂犬病毒。
在另一个具体实施方案中,本发明提供了通过重组狂犬病毒中和抗体混合物的给药对受试者进行治疗的方法,其中受治疗的病毒是狂犬病毒固定毒。
接受治疗的受试者优选是人。
在一个具体实施方案中,本发明提供了重组棒状病毒表达载体,包含编码疱疹性口炎病毒糖蛋白序列的核酸序列,且进一步包含含有编码重组狂犬病毒中和人抗体的抗体轻链和抗体重链的核酸序列的核酸。在另一个具体实施方案中,核酸序列编码狂犬病毒中和人抗体的轻链而不是重链。在另一个具体实施方案中,核酸序列编码狂犬病毒中和人抗体的重链而不是轻链。一方面,抗体是SOJA单克隆抗体。另一方面,抗体是SOJB单克隆抗体。再一方面,抗体是SO57单克隆抗体。一方面,核酸只编码抗体轻链。另一方面,核酸仅编码抗体重链。
在本发明的实践中,提供了包含本发明重组棒状病毒表达载体的哺乳动物宿主细胞。在本发明的一个具体实施方案中,哺乳动物宿主细胞是BSR细胞、幼仓鼠肾细胞、VERO细胞、或中国仓鼠卵巢细胞。
本发明还提供了使用本发明的重组棒状病毒表达载体在哺乳动物宿主细胞中制备重组狂犬病毒中和人抗体的方法。本方法包括用本发明的重组棒状病毒表达载体感染哺乳动物细胞,该载体包含含有编码重组狂犬病毒中和人抗体的抗体轻链和抗体重链的核酸序列的核酸,以及在允许抗体表达的条件下培养哺乳动物细胞。一方面,抗体是SOJA单克隆抗体。另一方面,抗体是SOJB单克隆抗体。再一方面,抗体是SO57单克隆抗体。一方面,核酸仅编码抗体轻链。另一方面,核酸仅编码重链。
在本发明的一个具体实施方案中,制备重组狂犬病毒中和人抗体的哺乳动物细胞是BSR细胞、幼仓鼠肾细胞、VERO细胞、或中国仓鼠卵巢细胞。
缩写和简写形式
在本说明书中使用以下缩写和简写形式。
“BHK”指幼仓鼠肾。
“BSR”指BHK细胞亚克隆。
“CHO”指中国仓鼠卵巢。
“CNS”指中枢神经系统。
“COSRV”指犬类狂犬病毒变体。
“CVS”指标准攻击毒株(challenge-virrus standard)。
“DRV-4”指狗狂犬病毒4。
“EBV-2”指欧洲蝙蝠病毒2。
“ED50”指50%受治疗动物被保护的有效量。
“ERIG”指马狂犬病免疫球蛋白。
“G”指糖蛋白。
“GSP”指基因特异性启动子。
“HRIG”指人狂犬病免疫球蛋白。
“huMAb”指人单克隆抗体。
“Ig H”指免疫球蛋白重链。
“Lg L”指免疫球蛋白轻链。
“IU”指国际单位。
“MAb”指单克隆抗体。
“MIC LD50”指杀死50%的颅内受感染小鼠的病毒剂量,即,小鼠颅内LD50。
“MOI”指感染的多重性。
“PCR”指聚合酶链式反应。
“PEP”指暴露后预防。
“RIG”指狂犬病免疫球蛋白。
“rhuMAb”指重组人单克隆抗体。
“RhV”指棒状病毒载体。
“RV”指狂犬病毒。
“SHBRV”指银毛蝠狂犬病毒。
“VNA”指病毒中和抗体。
“VSV”指疱疹性口炎病毒。
“WHO”指世界卫生组织。
定义
本申请中使用的定义以说明为目的不对本发明的范围进行限制。
在此使用的冠词“一”指该冠词的一或多于一个(即至少一个)的语法宾语。举例来说,“一种成分”指一种或多于一种成分。
在此使用的各“氨基酸”由其全称表示、通过其相应的三字母代码表示、或由其相应的单字母代码表示,如下表所示:
全称 | 三字母代码 | 单字母代码 |
天冬氨酸谷氨酸赖氨酸精氨酸组氨酸酪氨酸半胱氨酸天冬酰胺谷酰胺丝氨酸苏氨酸甘氨酸丙氨酸缬氨酸亮氨酸异亮氨酸甲硫氨酸脯氨酸苯丙氨酸色氨酸 | AspGluLysArgHisTyrCysAsnGlnSerThrGlyAlaValLeuIleMetProPheTrp | DEKRHYCNQSTGAVLIMPFW |
在此使用的表达“氨基酸”包括天然的和合成的氨基酸,以及D型和L型氨基酸。“标准氨基酸”指在天然生成的肽中经常发现的20种L-氨基酸中的任何一种。“非标准氨基酸”指除了标准氨基酸之外的任何氨基酸,无论其是通过合成制备的还是从天然来源衍生出来的。在此使用的“合成氨基酸”也包括化学修饰的氨基酸,包括但不限于盐、氨基酸衍生物(例如酰胺)以及取代物。本发明的肽所包含的氨基酸,特别是位于羧基末端或氨基末端的氨基酸,可通过甲基化、酰胺化、乙酰化或由能够改变肽的循环半衰期而对肽活性不发生负面影响的其它化学基团取代而进行修饰。此外,在本发明的肽中可以出现或不出现二硫键。
术语“氨基酸”可与“氨基酸残基”交替使用,可指代游离氨基酸和肽的氨基酸残基。从使用该术语的上下文可以明显看出该术语指游离氨基酸或肽的残基。
氨基酸具有以下普遍的结构:
根据侧链R可将氨基酸分为七类:(1)脂肪族侧链,(2)含有羟基(OH)的侧链,(3)含有硫原子的侧链,(4)含有酸性或酰胺基团的侧链,(5)含有碱性基团的侧链,(6)含有芳香环的侧链,以及(7)脯氨酸,其侧链与氨基基团结合的亚氨基酸。
用于描述本发明的肽化合物的命名法沿袭传统习惯,其中氨基基团和羧基基团分别位于各氨基酸残基的左边和右边。在表示所选的本发明特定具体实施方案的结构式中,尽管没有特别表示,除非特别说明,应当明白氨基和羧基末端基团以其在生理pH值呈现的形式存在。
在此使用的“抗体”,包括多克隆和单克隆抗体;重组抗体;以及嵌合、单链、人源化抗体,以及人抗体。“抗体”不仅包括完整的抗原结合免疫球蛋白分子,还包括其与抗原结合的片段,如Fv、Fab、Fab’以及F(ab’)2片段、单链Fv或免疫球蛋白表达文库的产物。
在此使用的“抗体重链”指存在于所有抗体分子中的两类多肽链中较大的一类。
在此使用的“抗体轻链”指存在于所有抗体分子中的两类多肽链中较小的一类。
在此使用的关于狂犬病毒中和重组抗体的“生物活性”指用作狂犬病毒活性中和剂的能力。
在此使用的狂犬病毒中和抗体的“有效量”或“治疗有效量”是在暴露于狂犬病的受试者体内足以抑制狂犬病毒感染进程的量或在有暴露于狂犬病风险的受试者体内足以预防狂犬病毒进程的量。
使用的关于狂犬病毒中和抗体mRNA的术语“表达”指狂犬病毒中和重链或轻链核酸序列的转录,造成狂犬病毒中和抗体mRNA的合成。使用的关于狂犬病毒中和抗体的“表达”指狂犬病毒中和抗体mRNA的翻译,造成狂犬病毒中和抗体的合成。
在此使用的“同源”指两个聚合分子之间的亚单元序列相似性,例如在两个核酸分子如两个DNA分子或两个RNA分子之间,或在两个多肽分子之间。当两分子中的亚单元位点被相同的单体亚单元占据,例如两DNA分子中的位置均被腺嘌呤占据,在该位点它们就是同源的。两序列间的同源性是匹配或同源位点数目的直接函数;例如如果两序列中一半的位点(例如,长度为10个亚单元的聚合物中的5个位点)是同源的,两序列为50%同源的;如果90%的位点(例如10个中的9个)是匹配或同源的,两序列为90%同源的。举例来说,DNA序列3’ATTGCC 5’和3’TATGGC 5’为50%同源的。
在此使用的核酸分子的“亚单元”是核苷酸,多肽的“亚单元”是氨基酸。
在此使用的“同源性”与“等同性”同义。
在此使用的术语“抑制”指相对于对照值以至少10%的比例抑制或阻断活性或功能。优选地,活性与对照值相比被抑制或阻断50%,更优选地为75%,甚至更优选地为95%。
“分离的”指通过人的行为从天然状态改变的或离开的。例如,天然存在于活体动物内的核酸或肽不是“分离的”,但从其天然状态的共存材料中部分或完全分离出的相同的核酸或肽是“分离的”。分离的核酸或蛋白质可以充分纯化的形式存在,或存在于非天然环境中,例如宿主细胞中。
在此使用的关于狂犬病毒的“中和”,指在暴露于狂犬病的受试者体内降低或抑制狂犬病毒的感染进程或在有暴露于狂犬病毒风险的受试者体内降低或预防进程。
“核酸”指聚核苷酸,包括聚核糖核苷酸和聚脱氧核糖核苷酸。
在此使用的术语“肽”、“多肽”和“蛋白质”可交替使用,指由氨基酸残基通过肽键共价连接组成的化合物。蛋白质或肽必须包含至少2个氨基酸,对于可以组成蛋白质或肽序列的氨基酸的最大数目没有设限。
“药学上可接受的”指对于人或动物应用在生理学上可容忍的。
在此使用的“药物组合物”包括用于人或动物的配方。
“预防性的”或“预防的”治疗是对没有出现狂犬病毒暴露或感染的症状或仅出现早期症状的受试者进行的治疗。进行预防的或预防性的治疗的目的是降低发展狂犬病毒感染相关病原体的风险。
在此使用的“狂犬病毒相关紊乱”指狂犬病毒的存在和狂犬病临床症状之间存在关联的紊乱。
在此使用的关于重组人抗体“狂犬病毒中和”指能够降低狂犬病毒感染细胞或引起狂犬病程度的抗体或抗体的混合物。“狂犬病毒中和”和“狂犬病毒中和活性”可以交替使用。
在此使用的“样品”指取自受试者的生物样品,包括正常组织样品、血液、唾液、粪便或尿液。样品还可以是取自受试者的其它任何含有感兴趣的化合物或细胞的材料。
在此使用的“受试者”可以是人或非人动物。非人动物包括,例如家畜和宠物,如绵羊、牛、猪、犬科、猫科和鼠科哺乳动物以及爬行动物、鸟类和鱼。优选地,受试者是人。
“充分纯化的”指由于去除了初始存在的其它化合物(例如其它肽、核酸、碳水化合物、脂肪)或其它细胞而在性质上基本上同源的肽或核酸序列。“充分纯化的”不意味着将人工的或合成的混合物与其它化合物一起排除,也不排除对生物活性不发生干扰的杂质的存在,以及例如因为不完全纯化、稳定剂的加入或配制药学上可接受的制剂而可能存在的杂质。
在此使用的“基本上同源的氨基酸序列”包括与参照抗体链的氨基酸序列至少具有大约95%同源性,优选地至少有大约96%同源性,更优选地至少有大约97%同源性,甚至更优选地至少有大约98%同源性,以及最优地至少具有大约99%或更高同源性的氨基酸序列。氨基酸序列的相似性或等同性可以通过采用BLASTP和TBLASTN程序计算,这些程序采用BLAST(基本局部相似性比对搜索工具)2.0.14运算法则。用于这些程序的默认设置适用于为本发明目的而识别充分相似的氨基酸序列。
“基本上同源核酸序列”指与参照核酸序列对应的核酸序列,其中对应序列编码的肽与参照核酸序列编码的肽具有基本上相同的结构和功能;例如,仅有不会显著影响肽功能的氨基酸发生改变的情况下。优选地,充分相似的核酸序列编码由参照核酸序列编码的肽。充分相似的核酸序列和参照核酸序列之间的等同性的百分比为至少大约50%、65%、75%、85%、95%、99%或更高。核酸序列的充分相似性可以通过比较两序列的序列等同性确定,例如通过物理/化学方法(即杂交法)或通过计算机算法的序列相似性比对。确定核苷酸序列和参照核苷酸序列充分相似的合适的核酸杂交条件为:50℃的7%十二烷基磺酸钠SDS、0.5M NaPO4、1mM EDTA,并于50℃用2X标准柠檬酸钠(SSC)、0.1%SDS洗涤;优选地在50℃的7%(SDS)、0.5M NaPO4、1mM EDTA中并于50℃用1X SSC、0.1%SDS洗涤;优选地在50℃的7%(SDS)、0.5M NaPO4、1mM EDTA中并于50℃用0.5X SSC、0.1%SDS洗涤;以及更优选地在50℃的7%(SDS)、0.5M NaPO4、1mM EDTA中并于65℃用0.1X SSC、0.1%SDS洗涤。合适的用于确定两核酸序列之间充分相似性的计算机算法包括GCS程序包(Devereux等,1984 Nucl.Acids Res.12:387)以及BLASTN或FASTA程序(Altschul等,1990 Proc.Natl.Acad.Sci.USA.1990 87:14:5509-13;Altschul等,J.Mol.Biol.1990 215:3:403-10;Altschul等,1997 NucleicAcids Res.25:3389-3402)。这些程序提供的默认设置适于为本发明目的确定核酸序列间的充分相似性。
在此使用的术语“治疗(动词)”或“治疗(名词)”指进行狂犬病毒中和抗体或化合物的给药以降低经受狂犬病毒感染的效应或症状的频率,减轻症状的严重性,或防止效应或症状的发生。
具体实施方式
在本发明的实践中,通过对需要治疗的受试者进行重组狂犬病毒中和人抗体的给药对狂犬病毒感染进行了治疗或预防。重组狂犬病毒中和人抗体与各种狂犬病毒株的糖蛋白特异性的结合。使用两种或多种不同抗体的暴露后治疗可以在进入位点中和狂犬病毒并能防止病毒扩散进中枢神经系统(CNS)。因为病毒复制几乎专门地限制在神经细胞中,用本发明的抗体在病毒进入CNS前中和及清除病毒是有效的暴露后预防。
在本发明的实践中,用重组狂犬病毒中和人抗体混合物的暴露后预防治疗对狂犬病毒相关紊乱进行治疗。该治疗获得安全的水平以及重复了HRIG的保护活性。
在一个具体实施方案中,用两种或多种不同的重组狂犬病毒中和人抗体对受试者给药。重组狂犬病毒中和人抗体不必以单一组合物给药。例如,各不同的重组狂犬病毒中和人抗体可以通过分离的组合物给药,或重组狂犬病毒中和人抗体以含有两种或多种重组狂犬病毒中和人抗体的组合物形式一同给药。另一方面,将三种或更多种不同的重组狂犬病毒中和人抗体给予受试者。
在本发明的一个具体实施方案中,通过至少两种不同的重组狂犬病毒中和人抗体的给药,在暴露于狂犬病毒的受试者体内防止了狂犬病毒感染、或狂犬病临床症状的发展。在本发明的另一个具体实施方案中,通过至少两种不同重组狂犬病毒中和人抗体的给药,在存在暴露于狂犬病毒的风险的受试者体内预防了狂犬病毒的感染。
被选择用于给药的人抗体混合物优选地应当:1)是IgG同型抗体;2)中和多于一种狂犬病毒株,优选地为数种及其它狂犬病毒;以及3)其抗原决定簇识别专一性存在差异,以防止中和一抗性变体的逃脱(WHO consultation on a monoclonal antibody cocktail for rabies postexposure treatment,WHO,2002年5月23-24日)。
在本发明的一个具体实施方案中,重组狂犬病毒中和人抗体衍生自杂交瘤JA、JB和J57的单克隆抗体。重组狂犬病毒中和人抗体分别命名为“SOJA”、“SOJB”和“SO57”。各人抗体中和多于一种狂大病毒株:1)人单克隆抗体SO57中和RV固定毒株(例如Pitman-Moore、标准攻击毒株[CVS]以及Evelyn-Rokitnicki-Abelseth)和街毒株(例如狗RV4[DRV-4]和银毛蝠狂犬病毒18[SHBRV-18])(Dietzschold等,J.Virol.1990 64:3087-90);2)人单克隆抗体SOJB中和欧洲蝙蝠病毒2(EBV-2);以及3)人单克隆抗体SOJA中和EBV-2、Lagos蝙蝠病毒和Mokola病毒(Champion等,J.Immunol.Methods 2000 235:81-90;Hanlon等,Vaccine 2001 19:3834-42)。这表明这三种人单克隆抗体识别不同的抗原决定簇。
单克隆抗体SOJA包括含有氨基酸序列SEQ ID NO:2(Genbank进入号AAO17825)的轻链和含有氨基酸序列SEQ ID NO:1(Genbank进入号AAO17823)的重链。单克隆抗体SOJB包括含有氨基酸序列SEQ ID NO:6(Genbank进入号AAO17826)的轻链和含有氨基酸序列SEQ ID NO:4(Genbank进入号AAO17822)的重链。单克隆抗体SO57包括含有氨基酸序列SEQ ID NO:7(Genbank进入号AAO17824)的轻链和含有氨基酸序列SEQ ID NO:9(Genbank进入号AAO17821)的重链。
单克隆抗体SOJA的轻链由含有核酸序列SEQ ID NO:10(Genbank进入号AY172961)的核酸编码且重链由含有核酸序列SEQ ID NO:11(Genbank进入号AY172959)的核酸编码。单克隆抗体SOJB的轻链由含有核酸序列SEQ ID NO:5(Genbank进入号AY172962)的核酸编码且重链由含有核酸序列SEQ ID NO:3(Genbank进入号AY172958)的核酸编码。单克隆抗体SO57的轻链由含有核酸序列SEQ ID NO:12(Genbank进入号AY172960)的核酸编码且重链由含有核酸序列SEQID NO:8(Genbank进入号AY172957)的核酸编码。
在本发明的一个具体实施方案中,使用的重组狂犬病毒中和人抗体轻链或抗体重链是与参照抗体轻链或抗体重链的氨基酸序列具有实质的序列同源性或等同性的抗体轻链或抗体重链。参照氨基酸序列是SEQ ID NOs:1、2、4、6、7和9。基本上同源的氨基酸序列指与参照肽具有至少95%、96%、97%、98%、99%或更多氨基酸序列等同性或相似性的肽或肽的部分。
多于一个核酸序列能编码特定的氨基酸序列。因此,多于一个核酸序列能编码一抗体轻链且多于一个核酸序列能编码一抗体重链。由于在某些情况下核苷酸可以在不造成初始编码氨基酸序列改变的情况下由其它核苷酸取代,简并序列可以在遗传密码意义内简并。
在一个优选具体实施方案中,给药的不同重组狂犬病毒中和人抗体是SOJA、SOJB和SO57。重组SOJA和SO57 IgG1抗体是IgG1抗体,而SOJB是IgG3抗体。
根据一些具体实施方案,重组抗体是单链抗体,其中重链可变区域和轻链可变区域由一间隔基团(spacer group)优选地为肽连接。单链重组抗体可进一步包含效应分子和/或信号序列,这些序列促进制备抗体的宿主细胞对抗体的加工。
在一个具体实施方案中,重组狂犬病毒中和人抗体通过重组DNA技术制备,该技术包括在允许重组抗体表达的条件下培养转化后的宿主细胞并分离抗体。
一方面,通过培养宿主细胞制备重组狂犬病毒中和人抗体,该宿主细胞已被转化了含有表达框的杂交载体。该表达框含有启动子和编码重组抗体的核酸序列。另一方面,启动子与编码信号肽的第一核酸序列连接,该序列在合适的阅读框内与编码重组抗体的第二核酸序列连接。启动子控制表达。随后分离重组狂犬病毒中和人抗体。
通过体外制备技术可以获得相对纯的抗体制剂,该技术可以使制备扩大以产生大量的需要的抗体。本领域已知细菌细胞、酵母细胞或哺乳动物细胞培养技术,包括均匀悬浮式培养,例如在气举式反应器或连续搅拌反应器内,或固定或截留细胞培养,例如在中空纤维、微囊体内、在琼脂糖微粒或陶瓷芯上。
可通过本领域技术人员已知的其它技术制备抗体,包括例如标准重组核酸技术和化学合成技术。
随后根据实施例中说明的分析方法以及本领域技术人员已知的方法可对纯化后抗体的生物学活性进行分析。
在一个具体实施方案中,包含核酸的杂交载体可用于制备抗体,该核酸进一步地包含编码重组狂犬病毒中和人抗体的核酸序列。选择性地,杂交载体包含复制原点或自主复制序列、一个或多个显性标记序列、表达控制序列、信号序列和附加的限制性酶切位点。
编码抗体轻链、抗体重链或两者的重组表达载体系统可以与相容宿主细胞一起行使两项功能。一项功能是促进编码抗体链的核酸的克隆,即制备可利用量的核酸(克隆载体)。另一项功能是通过保持为染色体外遗传因子或整合进宿主染色体在合适的宿主内进行重组基因构建体的复制和表达(表达载体)。克隆载体包括上述的重组核酸构建体、复制原点或自主复制序列、显性标记序列和选择性地,信号序列和附加的限制性酶切位点。表达载体还包含重组核酸转录和翻译所必需的表达控制序列,由此制备重组狂犬病毒中和人抗体。
使用重组技术,可以构建高水平表达(大约60pg/细胞)狂犬病毒中和人抗体的狂犬病毒载体(Morimoto等,J.Neurovirol.6:373-812000;Morimoto等,J.Immunol.Methods 252:199-206 2001;Schnell等,Proc.Natl.Acad.Sci.USA 97:3544-3549 2000)。
在一个具体实施方案中,重组人抗体由棒状病毒(RhV)表达系统制备,该系统从疫苗株狂犬病毒载体表达系统制备。制备狂犬病毒中和人抗体的RhV表达系统具有以下特征:1)因为本发明的RhV表达系统不会引起细胞病变,受感染细胞可以长时间(>2周)连续制备抗体,该状况实现了经济有效的单克隆抗体制备;2)多种哺乳动物细胞培养物易受到重组RhV表达系统的感染,因此已被批准用作疫苗或抗体制备的细胞系(例如Vero非洲绿猴细胞和CHO细胞)可用于RhV对单克隆抗体的制备;以及3)使用UV照射或不改变抗体活性的化学试剂(例如非离子去污剂或乙醇)可以轻易地破坏RhV。此外,可以修饰RhV使其含有疱疹性口炎病毒糖蛋白(G)蛋白基因,而不是携有负责RV病原性的主要决定子的狂犬病毒G基因(Schnell等,Proc.Natl.Acad.Sci.USA 2000 97:3544-49;Dietzschold等,Proc.Natl.Acad.Sci.USA 1983 80:70-4)。因此,制备狂犬病毒中和人抗体的重组棒状病毒表达系统仅呈现有限的生物安全顾虑。
编码人抗体重链和轻链肽的重链和轻链抗体序列可被插入重组棒状病毒表达系统中糖蛋白基因和聚合酶基因之间经修饰的位点(Schnell等,Proc.Natl.Acad.Sci.USA 97:3544-3549 2000)。此外,该重组棒状病毒表达系统能感染各种哺乳动物细胞系且不是溶细胞的,由此允许使用常规用于制备狂犬病疫苗的细胞培养技术(Morimoto等,J.Neurovirol.6:373-81 2000;Morimoto等,J.Immunol.Methods 252:199-206 2001;Schnell等,Proc.Natl.Acad.Sci.USA 97:3544-35492000)。
在一个具体实施方案中,通过构建含有外源的如来自猿猴病毒40(SV 40)或其它病毒源的复制原点的载体或通过宿主细胞的染色体机制提供复制原点或自主复制序列。
在另一个具体实施方案中,载体中的选择标记实现了对含有载体的宿主细胞的选择。选择标记包括赋予重金属如铜或抗生素如Geneticin(G-418)或潮霉素抗性的基因或弥补宿主细胞遗传缺陷如缺乏胸苷激酶、次黄嘌呤磷酰基转移酶、二氢叶酸还原酶等的基因。
在一些具体实施方案中,重组抗体的分泌被定向。例如信号序列可以是前序列或引导重组抗体分泌的分泌前导序列、剪切信号等。引导重组抗体分泌的信号序列的例子为衍生自ompA基因、pelB基因(果胶酸酯裂解酶)基因或phoA基因的序列。
抗体序列的转录由启动子和转录起始和终止以及稳定mRNA所必需的序列调节,以及选择性地,由增强子和进一步的调节序列调节。根据宿主细胞的性质可以使用多种启动子序列。强启动子且同时被很好调节的启动子是最有用的。例如翻译起始序列是Shine-Dalgarno序列。转录起始和终止以及稳定mRNA所必需的序列通常分别来自病毒或真核cDNA例如表达宿主的非编码5’-区域和3’-区域。增强子是源自病毒的转录激活DNA序列,例如来自猿猴病毒、多瘤病毒、牛乳突淋瘤病毒或莫氏(Moloney)肉瘤病毒的,或源自基因组的,特别是鼠的。
载体的各种核酸片段可操作地连接,即这些片段相邻并相互形成具有功能的关系。适用于在E.coli菌株中复制和表达的载体的实施例是噬菌体例如λ噬菌体的衍生物、或质粒例如特别是质粒ColE1及其衍生质粒例如pMB9、pSF2124、pBR317或pBR322以及衍生自pBR322的质粒例如pUC9、pUCK0、pHRil48和pLc24。合适的载体包含完整的复制子、标记基因、限制性核酸内切酶识别序列,因此外源DNA以及如果合适,表达控制序列以及选择性的信号序列和增强子可被插入这些位点。
例如微生物启动子是由温度敏感抑制子控制的噬菌体λ的强左向启动子PL。同样合适的还有E.coli启动子例如由lac抑制子调节并由异丙基-β-D-硫代半乳糖苷诱导的lac(乳糖)启动子,由trp抑制子调节并由例如色氨酸饥饿诱导的trp(色氨酸)启动子,以及由lac抑制子调节的tac(杂交trp-lac启动子)。
多种载体也适于在酵母中的复制和表达且载体含有酵母复制起点和酵母的选择性遗传标记。这些载体中的一组包含所谓ars序列(自主复制序列)作为复制原点。这些载体在转化后在酵母细胞内保持在染色体外且自主复制。此外,可以使用含有酿酒酵母(Saccharomycescerevisiae)全部或部分2μm质粒的载体。这些载体将通过重组整合进已经存在于细胞内的2μm质粒,或自主复制。在要实现高的转化频率和高拷贝数目时,2μm序列特别适用。
例如,适于在酵母内表达的表达控制序列是那些高水平表达的酵母基因的表达控制序列。因此,可以使用的启动子有TRP1基因、ADHI或ADHII基因、酸性磷酸酯酶(PHO3或PHO5)基因、异细胞色素(isocytochrome)基因的启动子或糖酵解通路中的启动子,例如烯醇酶、甘油醛-3-磷酸激酶(PGK)、己糖激酶、丙酮酸脱羧酶、磷酸果糖激酶、葡萄糖-6-磷酸异构酶、3-磷酸甘油变位酶、丙酮酸激酶、磷酸丙糖异构酶、磷酸葡萄糖异构酶和葡糖激酶基因的启动子。
优选的适于在哺乳动物细胞内复制和表达的载体来自衍生自病毒源DNA的启动序列,例如来自猿猴病毒40(SV40)、鲁斯氏(Rous)肉瘤病毒(RSV)、腺病毒2、牛乳突淋瘤病毒(BPV)、乳多空泡病毒(papova-virus)BK突变体(BKV)、棒状病毒、狂犬病毒、或鼠或人细胞巨化病毒(CMV)。可选择地,载体可以包含来自哺乳动物表达产物的启动子,例如肌动蛋白、胶原蛋白、肌浆球蛋白等,或与所需基因序列正常相关的天然启动子和控制序列,即免疫球蛋白H-链或L-链启动子。
其它载体适用于原核和真核宿主且基于病毒复制系统。特别优选的是含有猿猴病毒启动子例如pSVgpt或pSVneo的载体,载体进一步包含增强子,例如与免疫球蛋白基因序列正常相关的增强子,特别是鼠Ig H-或L-链增强子。
可以按照不同的方法获得完整的四聚体轻链和重链抗体。在一个具体实施方案中,抗体轻链和抗体重链在相同的细胞中共表达实现胞内结合和抗体轻链与抗体重链连接形成完整的四聚体轻链和重链抗体。
在一个具体实施方案中,编码抗体轻链的核酸和编码抗体重链的核酸出现在两个相互兼容的表达载体上,其中各核酸受到不同或相同启动子的控制。在该具体实施方案中,表达载体共转化或分别转化。
在本发明的具体实施方案中,用重组弹状表达系统转化宿主细胞,该表达系统含有编码所需重组抗体的抗体轻链和/或抗体重链的核酸序列。因此,一方面,核酸序列能编码单链重组抗体。
合适宿主的实施例为细菌,特别是大肠杆菌菌株例如E.coliX1776、E.coli Y1090、E.coli HB 101、E.coli W3110、E.coli HB101/LM1035、E.coli JA 221、E.coli DH5α、E.coli K12或E.coli CC118菌株,枯草杆菌、嗜热杆菌、假单胞菌、嗜血杆菌、链球菌及其它,以及酵母例如酿酒酵母如酿酒酵母GRF 18。进一步适用的宿主细胞是更高等生物的细胞,特别是已建立的人或动物连续细胞系,例如人胚胎肺纤维原细胞L132、人恶性黑素瘤Bowes细胞、Hela细胞、被SV40病毒转化的非洲绿猴COS-7肾细胞、BHK细胞、BSR细胞、VERO细胞、或中国仓鼠卵巢(CHO)细胞、或源自淋巴的细胞,例如淋巴瘤、骨髓瘤、杂交瘤、三体瘤(trioma)或四体瘤(quadroma)细胞,例如PAI、Sp2/0或X63-Ag8.653细胞。
在一个具体实施方案中,制备了转化后的宿主细胞,其中合适的受体宿主细胞被杂交载体转化,且使用本领域已知标准选择转化后的细胞。按照文献中的说明进行微生物的转化,例如对酿酒酵母(A.Hinnen等,Proc.Natl.Acad.Sci.USA 75:1929 1978)、枯草杆菌(Anagnostopoulos等,J.Bacteriol.81:741 1961)和大肠杆菌(M.Mandel等,J.Mol.Biol.53:159 1970)的转化。
相应地,例如E.coli细胞的转化步骤包括用Ca2+对细胞进行预处理从而允许DNA的摄入以及将细胞与杂交载体培育。随后例如通过将细胞转移至选择性培养基可以实现对转化后细胞的选择,该培养基根据载体DNA的标记序列的性质可以将转化细胞从亲代细胞中分离出来。优选地,使用的培养基不允许不含载体的细胞的生长。例如酵母细胞的转化包含步骤有使用葡糖苷酶酶解去除酵母细胞壁,在聚乙二醇和Ca2+离子存在下用载体处理获得的原生质,以及将原生质埋入琼脂再生细胞壁。优选地,以允许上述转化细胞的再生和选择同时进行的方法制备再生琼脂。
对更高级的真核细胞例如哺乳动物细胞系的转化通过诸如感染或转染的方法实现。使用传统技术进行转染,例如磷酸钙沉淀、微注射、原生质体融合、电穿孔法,即通过能瞬间提高细胞膜通透性的短电脉冲,或在帮助化合物例如二乙氨乙基葡聚糖、二甲亚砜、甘油或聚乙二醇等的存在下引入DNA。在转染步骤之后,通过例如在根据选择标记性质所选择的选择性培养基中培养细胞识别和选择被转染细胞,例如含有相应的抗生素的标准培养基如Dulbecco改良细胞培养基(DMEM)、最低必需培养基、RPMI 1640培养基等。
在一优选具体实施方案中,重组棒状病毒表达系统包括使用核酸感染哺乳动物细胞例如BSR细胞、CHO细胞、VERO细胞和BHK细胞或其它经批准用于抗体制备的细胞,该核酸包含编码抗体轻链或抗体重链或编码两者的核酸序列。细胞可以在允许制备本发明抗体的条件下培养。抗体可以使用本领域已知技术分离和纯化。
用于给药的重组狂犬病毒中和人抗体的抗体轻链或抗体重链可以被其它物质修饰。使用其它物质修饰抗体的方法,特别是标记,是本领域技术人员所熟知的。抗体修饰可以改变抗体活性,例如通过改变其特征诸如体内组织分配、肽的降解速率或狂犬病毒中和活性。修饰还可以赋予化合物额外的特性,例如被观测、操作或定位的能力。
重组狂犬病毒中和人抗体可用聚合和大分子结构(例如脂质体、沸石、树枝状聚合物、磁性微粒以及金属珠)或靶基团(例如信号肽序列、配体、外源凝集素或抗体)加以修饰。修饰物可以例如通过化学方法(例如通过共价键、静电作用、范德华力、氢键、离子键、螯合作用等)或通过物理包埋与链相结合。例如抗体可以用标记物修饰(例如具有磁共振活性的物质;辐射密度物质;荧光物质;放射性物质;超声可探测物质;可见、红外或紫外光可探测物质)。合适的标记物包括例如异硫氰酸荧光素、肽发色团如藻红蛋白或藻蓝蛋白等;生物发光肽如源自北美萤火虫(Photinus pyrali)的荧光素酶;或源自海肾(Renilla reniformi)的荧光蛋白。
本发明的一方面,抗体可以包含天冬氨酸(D)残基以提高抗体的溶解度。另一方面,可以通过添加加合物如蔗糖或聚乙二醇以延长抗体寿命。
本领域技术人员在考虑到受试者的身材和体重、疾病渗透程度、受试者年龄、健康状况和性别、给药途径、以及给药是局部的还是系统的等因素后可以容易地确定对受试者给药的重组狂犬病毒中和人抗体的有效量。一般地,对受试者的抗体给药量依赖于需要被中和的狂犬病毒的量和抗体呈现的狂犬病毒中和活性量。本领域技术人员可以推导出给药的合适剂量和计划以适应特定情况和受试者的需要。例如,根据受试者暴露的狂犬病毒量或受试者存在暴露风险的狂犬病毒量可以估计用于共同给药的各抗体的合适剂量。典型地,抗体剂量在大约0.001mg/kg和大约100mg/kg体重之间。在某些特定具体实施方案中,剂量在大约0.01mg/kg和大约60mg/kg体重之间。
应当明白有效量将依赖于受药者的年龄、性别、健康状况和体重,同期治疗的种类,如果有的话,治疗的频率以及需要实现的效应性质。最优选的剂量将根据受试者个体裁定,本领域技术人员在没有不当实验的情况下可以理解和确定该剂量。
重组狂犬病毒中和人抗体的混合物可以等摩尔浓度对需要该治疗的受试者给药。在另一个实施例中,抗体可以非等摩尔浓度给药。在其它实施例中,抗体可以相对于每千克体重的等质量蛋白给药。例如,抗体可以根据受试者的体重等量给药。在另一个实施例中,抗体可以非等量给药。在其它实施例中,各抗体的给药量可以根据抗体的中和活性。例如,给药的混合物的狂犬病毒中和活性可在大约1IU/kg体重和大约50IU/kg体重之间。
一般地,狂犬病毒中和人抗体混合物给药的计划和时间根据所进行步骤可接受的操作确定。
当在体内使用时,抗体优选地作为药物组合物给药,该组合物包含一种混合物和一种药学上可接受的载体。药物组合物中存在的抗体量可以在0.001至99.9wt%,更优选地在大约0.01至99.0wt%,以及甚至更优选地在0.1至50wt%。为了实现好的血浆浓度,抗体或抗体的混合物例如可作为含有0.1至1.0%活性试剂的溶液通过静脉注射给药。
所有不同的重组狂犬病毒中和人抗体的给药不必在单个组合物中一同给药。不同的重组狂犬病毒中和人抗体可以在分开的组合物中给药。例如,如果对三种不同抗体给药,三种不同抗体可以三种在分开的组合物中给药。此外,各抗体可以同时给药,或抗体可以依次连续给药。这样,重组狂犬病毒中和人抗体混合物可以以单个组合物给药,或以包含一种或多种重组狂犬病毒中和人抗体的多种组合物给药。
重组狂犬病毒中和人抗体和包含这些化合物的药物组合物可以通过经设计可使化合物具有生理学效应的任何方法给药。可以以肠道或非肠道给药;例如口服、直肠、潴泡内(intracistemally)、阴道内、腹腔内、局部(例如粉剂、软膏或滴液)给药。肠道内给药为优选。特别优选的肠道内给药方法包括血管内给药(例如静脉内高剂量注射、静脉灌注、动脉内高剂量注射、动脉灌注和用滴药导管滴入脉管系统)、靶组织周边和靶组织内注射、皮下注射或沉积包括皮下灌注(例如通过渗透泵)、肌肉内注射、腹腔内注射以及例如通过导管或其它放置装置直接应用在靶区域。
药学上可接受的载体包括生理学上可容忍或可接受的稀释剂、赋形剂、溶剂或佐剂。组合物优选地是无菌的和非致热性的。合适载体的实施例包括但不限于水、常规盐、右旋糖、甘露醇、乳糖或其它糖、卵磷脂、白蛋白、谷氨酸钠、盐酸半胱氨酸、乙醇、多羟基化合物(丙二醇、聚乙二醇、甘油等)、植物油(例如橄榄油)、可注射有机酯例如油酸乙酯、乙氧基化异十八醇、聚氧乙烯山梨醇及山梨醇酐酯、微晶纤维素、甲羟基铝(aluminum methahydroxide)、膨润土、高岭土、琼脂以及黄蓍胶或这些物质的混合物等。
药物组合物还可以包含少量的无毒辅助药物或赋形剂以及/或添加剂,例如润湿剂、乳化剂、pH缓冲试剂、抗菌和抗真菌试剂(例如对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸等)。合适的添加剂包括但不限于生理学上生物相容的缓冲液(例如氨基丁三醇盐酸)、螯合剂(例如DTPA或DPTA双酰胺)或钙螯合络合物(例如钙-DPTA或钙钠DPTA双酰胺)的加入(例如0.01至10摩尔百分比)或选择性地加入(例如1至50摩尔百分比)钙或钠盐(例如氯化钙、抗坏血酸钙、葡糖酸钙或乳酸钙)。如果需要,可以使用吸收增强或延缓试剂(例如脂质体、单硬脂酸铝或凝胶)。组合物可以制备成传统形式,抑或是液体溶液或悬浮剂、在注射前适于形成溶液或悬浮剂的固体形式或乳剂。肌肉内、腹腔内、皮下或静脉内组合物是例如等渗水溶液或悬浮剂,选择性地在使用之前不久从冻干或浓缩制剂制备。油悬浮剂包含作为油性成分的常规用于注射的蔬菜、合成或半合成油。药物化合物可以是无菌的且含有例如用于保存、稳定、润湿、乳化或溶解成分的添加剂、调节渗透压的盐、调节粘度的缓冲液和/或化合物,例如羧基纤维素钠、羧甲基纤维素、羧甲基纤维素钠、右旋糖苷、聚乙烯吡咯烷酮或凝胶。根据本发明的药物化合物可以以本领域熟知的技术方式制备。
在抗体通过注射或直接使用进行给药时,注射或直接使用可以是一剂或多剂。在化合物的给药是通过灌注时,灌注可以是在延长的时间区间内的单剂持续剂或多次灌注。
本发明不应被理解为仅限于在此说明的实验和方法,而应理解为也包括其它实验和分析。本领域的技术人员将明白其它的实验和方法可用于实现在此说明的步骤。
没有进一步的说明,应当相信本领域的普通技术人员通过使用之前的说明和之后的说明性实施例能够制备和利用重组狂犬病毒中和人抗体并操作权利要求的方法。因此以下的操作实施例特别指出了本发明的优选实施方案,但不应理解为以任何方式对公开的其它内容的限制。
实施例1-抗狂犬病毒重组表达人抗体(rhuMAbs)的制备和病毒中和活性
抗体cDNA的制备
三个杂交瘤,JA、JB和J57分泌命名为“SOJA”、“SOJB”和“SO57”的人单克隆抗体。这些单克隆抗体的生成和分析的具体细节在其它地方已被报道(Dietzschold等,J.Virol.1990 64:3087-90;Champion等,J.Immunol.Methods 2000 235:81-90)。从JA、JB和J57杂交瘤中分离免疫球蛋白重链(Ig H)和免疫球蛋白轻链(Ig L)mRNA,使用棒状病毒载体(RhV)在BSR或CHO细胞中高水平表达抗体。
为获得Ig H和Ig L mRNA的完整核酸序列,根据生产商的建议,使用Tri-Reagent手册(Sigma)和RNeasy RNA提取试剂盒(Qiagen)从各杂交瘤细胞系中分离总RNA。
使用cDNA末端快速扩增试剂盒(GIBCO-BRL)和Ig H和Ig L基因恒定区3’端的基因专一性引物(GSPs)扩增Ig L和Ig H cDNA片段。简言之,使用ThermoScript反转录酶(Life Technology)和GSP在55℃对2.5μg总RNA反转录60分钟。随后用核糖核酸酶H降解mRNA,且使用GlassMAX离心管(spin cartridges)纯化cDNA。在用脱氧核苷末端转移酶和dCTP在cDNA上加上dC尾巴后,用精简锚定引物(GIBCO-BRL)和第二GSP对cDNA进行PCR扩增以获得巢式产物。使用第三GSP对PCR产物再扩增,并用凝胶电泳纯化产物并测序。作为最后一步,用DNASTAR软件(DNAstar)和国家生物技术信息中心的网站工具对序列进行分析。
为克隆全长的Ig H和Ig L cDNAs,使用10pmol寡dT引物、200单位Superscript II以及20单位核糖核酸酶抑制剂在含有第一链缓冲液、200μM dNTP和10mM二硫苏糖醇的40μl的反应体系中对1μg的总RNA进行反转录。随后使用Expand高保真PCR系统(Roche)和10pmol与Ig L和Ig H cDNAs的5’端和3’端互补的引物对5μl反转录反应物进行扩增。
对克隆的Ig cDNAs进行测序且GenBank的进入号如下:SOJA IgL,AY172961(SEQ ID NO:10);SOJA Ig H,AY172959(SEQ ID NO:11);SOJB Ig L,AY172962(SEQ ID NO:5);SOJB Ig H,AY172958(SEQ ID NO:3);SO57 Ig L,AY172960(SEQ ID NO:12);以及SO57 Ig H,AY172957(SEQ ID NO:8)。为了基因组装,使用对应于cDNAs的5’端(JAHF,5′-AAACGTACGATGGAGTTTGGG-CTGAGCTGGCTT-3′(SEQ ID NO:13);JBHF,5′-AACGTACGA-TGGACACACTTTGCTCCACGCTCCT-3′(SEQ ID NO:14);以及J57HF,5′-AAACGTACGACCATGGACTGGACCTGGAGGTTCCT-3′(SEQ ID NO:15))的引物以及与各Ig H cDNAs的3’端互补和与由狂犬病毒转录中止/起始信号组成的连接序列互补的HR引物5′-GCTAGGGGTGTTAGTTTTTTTCATGACTCATTTACCCGGGGACAGGG A-3′(SEQ ID NO:16)对JA、JB和J57 Ig H的cDNAs进行扩增(Morimoto等,J.Immunol.Methods 2001 252:199-206)。
使用LF引物以及cDNAs的3’端引物(JALR,5′-AAAGCTAGCCTAACACTCTCCCCTGTTGAAGCTC-3′(SEQ IDNO:18);JBLR,5′-AAAGCTAGCCTATGAACATTCTGTAGGGGCCA-CTGT-3′(SEQ ID NO:19)以及J57LR,5′-AAATCTAGACTATGAACA-TTCTGTAGGGGCCAC-3′(SEQ ID NO:20))对Ig L的cDNA进行再扩增,LF引物包含连接区域和对不同轻链cDNAs的5’端的具有专一性的区域(5′-GGTAAATGAGTCATGAAAAAAACTAACACCCC-TAGCNNNNNNNNNN NNNNNNNNNN-3′(SEQ ID NO:17),其中N是cDNA轻链的5’端)。
重组棒状病毒载体的构建
使用前述的狂犬病毒载体制备重组棒状病毒载体(RhV)(Foley等,Proc.Natl.Acad.Sci.USA 200097:14680-14685)。狂犬病毒糖蛋白基因(GenBank进入号NP 056796)的膜外和跨膜结构域(GenBank进入号NC 001542)由疱疹性口炎病毒糖蛋白基因(VSV G)(GenBank进入号J02428)的膜外和跨膜结构域取代(Foley等,Proc.Natl.Acad.Sci.USA 2000 97:14680-14685;Schnell等,J.Virology 1996 70:2318-2323;Lawson等,Proc.Natl.Acad.Sci.USA 1995 92:4477-4481),在载体中生成嵌合的糖蛋白基因。生成的质粒命名为pSN-VSV-G。
狂犬病毒糖蛋白基因带有负责狂犬病毒的病原性的主要决定子(Dietzschold等,Proc.Natl.Acad.Sci.USA 1983 80:70-74)。通过使用疱疹性口炎病毒糖蛋白基因膜外和跨膜序列替换狂犬病毒糖蛋白基因膜外和跨膜序列,形成了只存在有限的生物安全顾虑的重组棒状病毒表达系统。
为构建pSN-VSV-G载体,狂犬病毒G的胞质尾巴从pSN用引物RP8,5′-CCTCTAGATTACAGTCTGGTCTCACCCCC-3′(XbaI,粗体)(SEQ ID NO:21)和RP29,5′-CCCGGGTTAACAGAAGA-GTCAATCGATCAGAAC-3′(HpaI,粗体)(SEQ ID NO:22)PCR扩增(Foley等,Proc.Natl.Acad.Sci.USA 2000 97:14680-14685)。VSV G基因的膜外和跨膜结构域(GenBank进入号J02428)用引物RP33,5′-TTAAGTTAACCAAGAATAGTCCAATGA-3′(HpaI,粗体)(SEQ ID NO:23)和RP34,5′-TCTCGAGCCCGGGACTATGAAGTGCCTT-TTGTAC-3′(XbaI,粗体)(SEQ ID NO:24)从pVSV-XN1扩增(Schnell等,J.Virology 199670:2318-2323)。两PCR产物均用HpaI酶切并连接。连接产物用引物RP8和RP34再次扩增,且将PCR产物克隆进pSN的XmaI和XbaI位点。生成的质粒命名为pSV-VSV-G(Foley等,Proc.Natl.Acad.Sci.USA 2000 97:14680-1468)。
进一步修饰上述质粒pSN-VSV-G(此后称作pSPBN)从而允许插入和表达包含编码抗体轻链序列、重链序列或两者的核酸。使用PCR策略在糖蛋白(G)基因和聚合酶(L)基因之间引入BsiWI和NheI位点对质粒进行修饰(见例如Foley等,Proc.Natl.Acad.Sci.USA 200097:14680-1468和Schnell等,Proc.Natl.Acad.Sci.USA 2000 97:3544-3549)。生成的重组棒状病毒载体被称作RhV。
包含轻链和重链核酶序列的质粒和重组病毒的制备
通过PCR连接以上制备的Ig H和Ig L的cDNAs,且用BsiWI和NheI酶切生成的Ig L+连接子+Ig H cDNA并插入上述质粒pSPNB的相应位点。插入三种不同的Ig L+Ig H cDNAs,生成质粒pSPBN-SOJA、pSPBN-SOJB以及pSPBN-SO57。
通过哺乳动物细胞制备抗体
由上述质粒产生的重组病毒按别处说明的方法(Morimoto等,J.Neurovirol.20006:373-81)回收并用于以0.1MOI感染幼仓鼠肾(BHK)细胞的亚克隆BSR细胞或感染CHO细胞。在感染后,用Cellgro-FREE培养基(Mediatech)在34℃培养细胞。在培养3天后,收集组织培养上清并进行UV照射将病毒灭活。
表1证实了由受感染BSR细胞分泌至组织培养上清液中的三种不同重组表达人抗体的量。可以看出由包含编码SOJA、SOJB或SO57抗体的核酸的重组病毒感染的各BSR细胞以大约40μg/ml/48小时的速率生成重组人抗体。BSR细胞或CHO细胞的感染导致高水平的制备(≤40μg/ml/48小时)。
表1 抗狂犬病毒重组表达人单克隆抗体(rhuMAbs)的制备和病毒中和活性
抗体(同型) | 在BSR细胞中的制备,μg/mL/48小时 | 攻击病毒 | |||
CVS-11 | CVS-N2c | SHBRV-18 | DRV-4 | ||
SOJA(IgG1)aSOJB(IgG3)aSO57(IgG1)arhuMAb混合物aHRIGb | 403740-- | 302402200720110 | 12036016201080202 | 6060360180108 | 405401080810108 |
注:“CVS”是标准攻击毒株;“DRV-4”是狗狂犬病毒4;“HRIG”是人狂犬病免疫球蛋白;“SHBRV-18”银毛蝠狂犬病毒。
a在测试前,将纯化的rhuMAbs和rhuMAb混合物(SOJA∶SOJB∶SO57蛋白质比例1∶1∶1)调节至1mg/ml的蛋白浓度。
bHRIG按生产商制备的进行使用(150IU/ml;Bayer)。
亲和层析对抗体的纯化
随后从培养上清中纯化出分泌至组织培养基中的各重组人抗体且将各样品校准并调整至相同的蛋白含量。
使用蛋白A柱(蛋白A琼脂糖凝胶,Amersham Pharmacia Biotech)纯化IgG1抗体。简言之,经过0.45μm膜过滤使上清澄清并用1N NaOH将pH调整至8.0。上清以大约100cm/小时的线性流速经过柱体。用PBS(pH 8)洗涤后,用0.1M柠檬酸溶液将抗体从柱上洗脱并对PBS进行透析。
IgG3抗体用蛋白G柱(蛋白G琼脂糖凝胶,Amersham PharmaciaBiotech)纯化。含有IgG3的上清通过0.45μm膜过滤澄清且用1N NaOH将pH调至7.0。上清以大约11cm/小时的线性流速流经柱体。在用PBS洗涤后,用0.1M甘氨酸缓冲液,pH 3.0将抗体从柱上洗脱并随后对PBS进行透析。
透析后的抗体制剂的蛋白浓度用以下蛋白质检测实验确定(Bio-Rad Laboratories,Hercules CA)。将100μl样品加入5ml染料浓缩剂的1/5稀释液并在室温放置10分钟。在各试验中包括阴性PBS对照和各种牛血清白蛋白(BSA)标准。在放置后,用分光光度计在595nm对样品读数。测试样品的蛋白浓度参考BSA标准的吸收值计算。所有抗体制剂的纯度用还原条件下的12.5%聚丙烯酰胺凝胶电泳(SDS-PAGE)确定。纯化后的抗体在SDS-PAGE上出现两条主带,对应于分离出的免疫球蛋白重链和轻链。
病毒中和活性
由包含重组狂犬病毒中和人抗体的重组棒状病毒表达系统感染的哺乳动物细胞产生的病毒中和活性量由快速荧光聚焦抑制实验(RFFIT)确定(Morimoto等,J.Immunol.Methods 2001 252:199-206)。确定病毒滴度降低是否为真的一种方法是当病毒滴度降低>100个感染单位实现的时候(Dietzschold等,J.Virol.1990 64:3087-3090)。此外,病毒中和抗体(VNA)滴度可以以国家健康研究所的参考血清作为标准用国际单位表达。中和活性典型地表达为单位每克蛋白或单位每毫升。用于病毒中和的狂犬病毒株在别处有所说明(Dietzschold等,J.Hum.Virol.2000 3:50-7;Morimoto等,Proc.Natl.Acad.Sci.USA 199895:3152-6)。用RFFIT分析各转化细胞系的上清样品中狂犬病毒中和抗体的存在。在96孔平底板(Nunc)中稀释上清样品(50μl)。在各测试样品中加入已知能造成指示细胞80-90%感染的狂犬病毒稀释液,将板在37℃培养1小时。在各实验中包括了阴性培养基和阳性狂犬病免疫血清对照样品。在培养后,在各孔中加入30μl浓度为1.8×106细胞/ml的BHK细胞并在37℃将培养物过夜培养。随后用冰冷的PBS将板洗涤一次并用冰冷的90%丙酮在-20℃固定20分钟。在固定后,去除丙酮将板风干。为检测受感染的BHK细胞,将40μl FITC抗狂犬病核蛋白单克隆球蛋白(Centocor,Malvern PA)在37℃加入各孔45分钟。随后用蒸馏水将板洗涤3次并在荧光显微镜下检测。
对已从培养物上清中纯化出的各重组人抗体测试它们中和狂犬病毒固定株(例如CVS-N2c和CVS-11)和街毒株(例如SHBRV-18和DRV-4)的能力。如同快速荧光聚焦抑制实验所测试的,三种重组人抗体在中和不同狂犬病毒的能力上呈现出质和量上的差异(表1)。此外,通过含有等摩尔浓度的三种重组人抗体的混合物获得的狂犬病毒株的病毒中和抗体(VNA)滴度相对率与从HRIG获得的相似,除了抗SHBRV-18 HRIG VNA滴度略高之外。
实施例2 用抗狂犬病人单克隆抗体混合物对小鼠的暴露后预防
为确定SOJA、SOJB和SO57的重组人抗体混合物在体内的保护活性,用10LD50狂犬病毒CVS-N2c鼻腔内感染雌性Swiss Webster小鼠(10只/组)。1小时后,小鼠接受混合物或HRIG的单次治疗。各治疗后小组接受含有不同活性的混合物。制备的混合物中SOJA∶SOJB∶SO57蛋白比例为1∶1∶1。各抗体或抗体混合物的活性以国际单位(IU)表示。通过对WHO标准抗血清的滴定确定抗体的IU。小鼠接受的混合物的范围在0-20IU/kg体重之间。随后对小鼠进行5周观察确定它们是否发展了狂犬病的临床症状。计算接受SOJA∶SOJB∶SO57混合物治疗的动物和接受HRIG治疗的动物的治疗有效量,在该剂量50%动物受到保护避免致命攻击(ED50)。
如果狂犬病的临床症状变得明显,用CO2中毒对小鼠实施安乐死。在疑似患有狂犬病的动物脑组织印模上进行直接荧光抗体实验对狂犬病的诊断进行确认。
用重组狂犬病毒中和人抗体混合物进行的暴露后预防治疗在体内预防了致命的狂犬病毒感染(表2)。此外,发现人抗体混合物的保护活性与HRIG的保护活性相当(表2)。在使用20IU/kg时混合物保护了10只小鼠中的8只没有发展狂犬病的临床症状,但在2.5IU/kg的浓度下,没有任何小鼠受保护未发展狂犬病临床症状。小鼠发展狂犬病症状的ED50剂量是3.38IU/kg的HRIG和4.47IU/kg的rhuMAB混合物。
表2.用人狂犬病毒免疫球蛋白(HRIG)和抗狂犬病重组表达人单克隆抗体(rhuMAB)混合物进行小鼠的暴露后预防
浓度a | 抗体 | |
HRIG | rhuMAb混合物b | |
20IU/kg10IU/kg5IU/kg2.5IU/kgED50,IU/kg | 9/106/106/100/103.38 | 8/107/104/100/104.47 |
aHRIG或混合物的给药量。bSOJA∶SOJB∶SO57蛋白比例1∶1∶1。数据表示为出现狂犬病临床症状的小鼠数目/测试小鼠数目。
实施例3-用重组抗狂犬病人单克隆抗体混合物进行仓鼠的暴露后预防在仓鼠暴露后预防模型中进一步检测重组人抗体混合物的功效。
用50μl取自天然感染狂犬病的山狼的唾液腺组织匀浆攻击2月大(100克;10只/组)的雌性叙利亚仓鼠(Harlan-Sprague-Dawley)。在左腓肠肌对动物进行接种。在用狂犬病毒接种4小时后,在10只仓鼠中起始含有20IU/kg rhuMAb混合物(如实施例2中所述)的暴露后预防治疗。用50微升抗体制剂在动物接种病毒的相同位点进行一次给药。没有接受暴露后预防治疗混合物的10只仓鼠作为对照动物。
此后,每日观察动物共90天。如果在一只动物中的狂犬病临床症状变得明显,通过CO2中毒对该动物施行安乐死。在安乐死后对狂犬病的诊断进行确认。使用直接荧光抗体实验对狂犬病诊断进行确认,该实验在疑似患有狂犬病的动物脑组织压模上进行。
用SOJA/SOJB/SO57抗体混合物给药的所有10只仓鼠均存活。但是,所有的对照动物均死于狂犬病。使用的病毒剂量含有~106.8MICLD50/ml浓度的犬类RV变体(COSRV),该变体在美国/墨西哥接壤地区流行,因此成为公共健康的重要关注。预计该剂量在肌肉内接种后导致80-100%的死亡率。
在此引用的各专利、专利申请以及公开物的公开内容由此完整地作为参考加以引用。
尽管参考特定具体实施方案对本发明进行了公开,很明显的,在不悖离本发明的真正精神和范围的基础上本领域的其它技术人员可以实现其它具体实施方案和本发明的变化。所附权利要求书应当被理解为包括所有这些具体实施方案和等同的变化。
序列表
<110>托马斯杰斐逊大学(Thomas Jefferson University)
<120>重组抗体及组合物及其制备和使用方法
<130>EP05-2817-XC20
<150>US 10/461,148
<151>2003-06-13
<160>24
<170>FastSEQ for Windows Version 4.0
<210>1
<211>474
<212>PRT
<213>人
<400>1
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Ala Ile Ser Ala Ser Gly His Ser Thr Tyr Leu Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Lys Asp Arg Glu Val Thr Met Ile Val Val Leu Asn
115 120 125
Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Arg Val Thr Val Ser Ser
130 135 140
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
145 150 155 160
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
165 170 175
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
180 185 190
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
195 200 205
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
210 215 220
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
225 230 235 240
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
245 250 255
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
260 265 270
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
275 280 285
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
290 295 300
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
305 310 315 320
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
325 330 335
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
340 345 350
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
355 360 365
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
370 375 380
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
385 390 395 400
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
405 410 415
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
420 425 430
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
435 440 445
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
450 455 460
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210>2
<211>234
<212>PRT
<213>人
<400>2
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ala Cys Arg Ala Ser Gln Thr
35 40 45
Ala Ser Arg Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Asp Thr Ser Asn Arg Ala Thr Gly Ile Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Ser
85 90 95
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Phe
100 105 110
Asn Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Phe Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu AsnAsn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210>3
<211>1557
<212>DNA
<213>人
<400>3
atggacacac tttgctccac gctcctgctg ctgaccatcc cttcatgggt cttgtcccaa 60
attaccttga aggagactgg tcctacgctg gtgaaaccca cacagaccct cacgctgacc 120
tgcaccttct cggggttctc actcagcact agtggagtgg gtgtgggctg gatccgtcag 180
cccccaggaa aggccctgga gtgggttaca ctcatttatt gggatgatga taagcgttac 240
agtccatctc tggagaacag ggtcaccatc aggaaggaca cctccaaaaa ccaggtggct 300
cttacaatga cgaacatgga ccctttggac acaggcacat actactgtgc gcacagacaa 360
catatcagca gcttcccgtg gttcgattcc tggggccagg gaaccctggt caccgtctcc 420
tcagcttcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctct 480
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgagcc ggtgacggtg 540
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 600
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 660
acctacacct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag 720
ctcaaaaccc cacttggtga cacaactcac acatgcccac ggtgcccaga gcccaaatct 780
tgtgacacac ctcccccgtg cccacggtgc ccagagccca aatcttgtga cacacctccc 840
ccgtgcccac ggtgcccaga gcccaaatct tgtgacacac ctcccccatg cccacggtgc 900
ccagcacctg aactcctggg aggaccgtca gtcttcctct tccccccaaa acccaaggat 960
acccttatga tttcccggac ccctgaggtc acgtgcgtgg tggtggacgt gagccacgaa 1020
gaccccgagg tccagttcaa gtggtacgtg gacggcgtgg aggtgcataa tgccaagaca 1080
aagccgcggg aggagcagtt caacagcacg ttccgtgtgg tcagcgtcct caccgtcctg 1140
caccaggact ggctgaacgg taaggagtac aagtgcaagg tctccaacaa agccctccca 1200
gcccccatcg agaaaaccat ctccaaaacc aaaggacagc cccgagaacc acaggtgtac 1260
accctgcccc catcccggga ggagatgacc aagaaccagg tcagcctgac ctgcctggtc 1320
aaaggcttct accccagcga catcgccgtg gagtgggaga gcagcgggca gccggagaac 1380
aactacaaca ccacgcctcc catgctggac tccgacggct ccttcttcct ctacagcaag 1440
ctcaccgtgg acaagagcag gtggcagcag gggaacatct tctcatgctc cgtgatgcat 1500
gaggctctgc acaaccgctt cacgcagaag agcctctccc tgtctccggg taaatga 1557
<2l0>4
<211>518
<212>PRT
<213>人
<400>4
Met Asp Thr Leu Cys Ser Thr Leu Leu Leu Leu Thr Ile Pro Ser Trp
1 5 10 15
Val Leu Ser Gln Ile Thr Leu Lys Glu Thr Gly Pro Thr Leu Val Lys
20 25 30
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
35 40 45
Ser Thr Ser Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Val Thr Leu Ile Tyr Trp Asp Asp Asp Lys Arg Tyr
65 70 75 80
Ser Pro Ser Leu Glu Asn Arg Val Thr Ile Arg Lys Asp Thr Ser Lys
85 90 95
Asn Gln Val Ala Leu Thr Met Thr Asn Met Asp Pro Leu Asp Thr Gly
100 105 110
Thr Tyr Tyr Cys Ala HisArg Gln His Ile Ser Ser Phe Pro Trp Phe
115 120 125
Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
110 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
225 230 235 240
Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro Arg Cys Pro
245 250 255
Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu
260 265 270
Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu Pro
275 280 285
Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Ala Pro Glu
290 295 300
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
305 310 315 320
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
325 330 335
Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr Val Asp Gly
340 345 350
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
355 360 365
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
370 375 380
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
385 390 395 400
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
405 410 415
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
420 425 430
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
435 440 445
Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn Tyr Asn Thr
450 455 460
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
465 470 475 480
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile Phe Ser Cys
485 490 495
Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu
500 505 510
Ser Leu Ser Pro Gly Lys
515
<210>5
<211>699
<212>DNA
<213>人
<400>5
atggcctgga ccgttctcct cctcggcctc ctctctcact gcacagggtc tgtgacgtcc 60
tatgtgctga ctcagccacc ctcggtgtca gtggccccag gaaagacggc caggattaac 120
tgtgggggaa acaacattga atatagaagt gtgcactggt accagcagaa gtcaggccag 180
gcccctgtag cggtcatcta tgataatagt gaccggccct cagggatccc tgagcgattc 240
tctggttcca aatctgggaa cacggccacc ctgaccatca gcagggtcga agccggggat 300
gaggccgact attactgtca ggtgtgggat attagtagtg atgtggtctt cggcggaggg 360
accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 420
tcctctgagg agcttcaagc caacaaggcc acactggtgt gtctcataag tgacttctac 480
ccgggagccg tgacagtggc ctggaaggca gatagcagcc ccgtcaaggc gggagtggag 540
accaccacac cctccaaaca aagcaacaac aagtacgcgg ccagcagcta tctgagcctg 600
acgcctgagc agtggaagtc ccacagaagc tacagctgcc aggtcacgca tgaagggagc 660
accgtggaga agacagtggc ccctacagaa tgttcatag 699
<210>6
<211>232
<212>PRT
<213>人
<400>6
Met Ala Trp Thr Val Leu Leu Leu Gly Leu Leu Ser His Cys Thr Gly
1 5 10 15
Ser Val Thr Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala
20 25 30
Pro Gly Lys Thr Ala Arg Ile Asn Cys Gly Gly Asn Asn Ile Glu Tyr
35 40 45
Arg Ser Val His Trp Tyr Gln Gln Lys Ser Gly Gln Ala Pro Val Ala
50 55 60
Val Ile Tyr Asp Asn Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe
65 70 75 80
Ser Gly Ser Lys Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val
85 90 95
Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ile Ser
100 105 110
Ser Asp Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
115 120 125
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
130 135 140
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
145 150 155 160
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
165 170 175
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
180 185 190
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
195 200 205
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
210 215 220
Thr Val Ala Pro Thr Glu Cys Ser
225 230
<210>7
<211>242
<212>PRT
<213>人
<400>7
Met Ser Val Pro Thr Met Ala Trp Ala Leu Leu Leu Leu Ser Leu Leu
1 5 10 15
Thr Gln Gly Thr Gly Ser Trp Ala Gln Ser Ala Leu Thr Gln Pro Arg
20 25 30
Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly
35 40 45
Thr Ser Ser Asp Ile Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln
50 55 60
His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Ala Thr Lys Arg
65 70 75 80
Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr
85 90 95
Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr
100 105 110
Tyr Cys Cys Ser Tyr Ala Gly Asp Tyr Thr Pro Gly Val Val Phe Gly
115 120 125
Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser
130 135 140
Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val
165 170 175
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr
180 185 190
Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu
195 200 205
Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln
210 215 220
Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu
225 230 235 240
Cys Ser
<210>8
<211>1431
<212>DNA
<213>人
<400>8
atggactgga cctggaggtt cctctttgtg gtggcagcag ctacaggtgt ccagtcccag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg ggtcctcggt gaaggtctcc 120
tgcaaggctt ctggaggcac cttcaacagg tatactgtca actgggtgcg acaggcccct 180
ggacaagggc ttgagtggat gggaggcatc atccctatct ttggtacagc aaactacgca 240
cagaggttcc agggcagact caccattacc gcggacgaat ccacgagcac agcctacatg 300
gagctgagca gcctgagatc tgatgacacg gccgtgtatt tctgtgcgag agagaatctc 360
gataattcgg ggacttatta ttatttctca ggctggttcg acccctgggg ccagggaacc 420
ctggtcaccg tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 480
tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 540
gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 600
gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 660
agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 720
gacaagagag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 780
cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 840
atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 900
gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 960
cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1020
gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1080
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1140
cccccatccc gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1200
ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1260
aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctatag caagctcacc 1320
gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1380
ctgcacaacc actacacgca gaagagcctc tccctgtccc cgggtaaatg a 1431
<210>9
<211>476
<212>PRT
<213>人
<400>9
Met Asp Trp Thr Trp Arg Phe Leu Phe Val Val Ala Ala Ala Thr Gly
1 5 10 15
Val Gln Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
35 40 45
Asn Arg Tyr Thr Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala
65 70 75 80
Gln Arg Phe Gln Gly Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Phe Cys Ala Arg Glu Asn Leu Asp Asn Ser Gly Thr Tyr Tyr Tyr
115 120 125
Phe Ser Gly Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val
130 135 140
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
145 150 155 160
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
165 170 175
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
180 185 190
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
195 200 205
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
210 215 220
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
225 230 235 240
Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
245 250 255
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
260 265 270
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
275 280 285
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
290 295 300
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
305 310 315 320
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
325 330 335
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
340 345 350
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
355 360 365
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
370 375 380
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
385 390 395 400
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
405 410 415
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
420 425 430
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
435 440 445
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
450 455 460
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210>10
<211>705
<212>DNA
<213>人
<400>10
atggaagccc cagctcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60
gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 120
ctcgcctgca gggccagtca gactgctagc aggtacttag cctggtacca acagaaacct 180
ggccaggctc ccagactcct catctatgat acatccaaca gggccactgg catcccagcc 240
aggttcagtg gcagtgggtc tgggacagac ttcactctct ccatcagcag cctggagcct 300
gaagattttg cagtttatta ctgtcagcag cgtttcaact ggccgtggac gttcggccaa 360
gggaccaagg tggaattcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 420
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 705
<210>11
<211>1425
<212>DNA
<213>人
<400>11
atggagtttg ggctgagctg gctttttctt gtggctattt taaaaggtgt ccagtgtgag 60
gtgcagctgt tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc 120
tgtgcagcct ctggattcac ctttagcaac tatgccatga gctgggtccg ccaggctcca 180
gggaaggggc tggagtgggt ctcagctatt agtgctagtg gtcatagcac atatttggca 240
gactccgtga agggccggtt caccatctcc agagacaatt ccaagaacac gctgtatctg 300
caaatgaaca gcctgagagc cgaggacacg gccgtatatt actgtgcgaa agatcgagag 360
gttactatga tagttgtact taatggaggc tttgactact ggggccaggg aacccgggtc 420
accgtctcct ccgcctccac caagggccca tcggtcttcc ccctggcacc ctcctccaag 480
agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 540
gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 600
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 660
ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 720
agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 780
ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 840
tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 900
aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 960
gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1020
ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 1080
aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1140
tcccgggagg agatgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1200
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1260
acgcctcccg tgctggactc cgacggctcc ttcttcctct atagcaagct caccgtggac 1320
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1380
aaccactaca cgcagaagag cctctccctg tccccgggta aatga 1425
<210>12
<211>729
<212>DNA
<213>人
<400>12
atgagtgtcc ccaccatggc ctgggctctg ctcctcctca gcctcctcac tcagggcaca 60
ggatcctggg ctcagtctgc cctgactcag cctcgctcag tgtccgggtc tcctggacag 120
tcagtcacca tctcctgcac tggaaccagc agtgatattg gtggttataa ctttgtctcc 180
tggtaccaac aacacccagg caaagccccc aaactcatga tttatgatgc cactaagcgg 240
ccctcagggg tccctgatcg cttctctggc tccaagtctg gcaacacggc ctccctgacc 300
atctctgggc tccaggctga ggatgaggct gattattact gctgctcata tgcaggcgac 360
tacaccccgg gcgtggtttt cggcggaggg accaagctga ccgtcctagg tcagcccaag 420
gctgccccct cggtcactct gttcccgccc tcctctgagg agcttcaagc caacaaggcc 480
acactggtgt gtctcataag tgacttctac ccgggagccg tgacagtggc ctggaaggca 540
gatagcagcc ccgtcaaggc gggagtggag accaccacac cctccaaaca aagcaacaac 600
aagtacgcgg ccagcagcta cctgagcctg acgcctgagc agtggaagtc ccacagaagc 660
tacagctgcc aggtcacgca tgaagggagc accgtggaga agacagtggc ccctacagaa 720
tgttcatag 729
<210>13
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物
<400>13
aaacgtacga tggagtttgg gctgagctgg ctt 33
<210>14
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物
<400>14
aacgtacgat ggacacactt tgctccacgc tcct 34
<210>15
<211>35
<212>DNA
<213>人工序列
<220>
<223>引物
<400>15
aaacgtacga ccatggactg gacctggagg ttcct 35
<210>16
<211>49
<212>DNA
<213>人工序列
<220>
<223>引物
<400>16
tgctaggggt gttagttttt ttcatgactc atttacccgg ggacaggga 49
<210>17
<211>56
<212>DNA
<213>人工序列
<220>
<223>引物,其中n是轻链cDNAs的5’端
<221>misc_feature
<222>(1)...(56)
<223>n=A,T,C or G
<400>17
ggtaaatgag tcatgaaaaa aactaacacc cctagcnnnn nnnnnnnnnn nnnnnn 56
<210>18
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物
<400>18
aaagctagcc taacactctc ccctgttgaa gctc 34
<210>19
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物
<400>19
aaagctagcc tatgaacatt ctgtaggggc cactgt 36
<210>20
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物
<400>20
aaatctagac tatgaacatt ctgtaggggc cac 33
<210>21
<211>29
<212>DNA
<213>人工序列
<220>
<223>引物
<400>21
cctctagatt acagtctggt ctcaccccc 29
<210>22
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物
<400>22
cccgggttaa cagaagagtc aatcgatcag aac 33
<210>23
<211>27
<212>DNA
<213>人工序列
<220>
<223>引物
<400>23
ttaagttaac caagaatagt ccaatga 27
<210>24
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物
<400>24
tctcgagccc gggactatga agtgcctttt gtac 34
Claims (34)
1.一种药物组合物,含有药学上可接受的载体和至少两种重组狂犬病毒中和人抗体,其中至少两种抗体中的至少一种选自:
a)包含具有氨基酸序列SEQ ID NO:2或与SEQ ID NO:2基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:1或与SEQID NO:1基本上同源的序列的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6或与SEQ ID NO:6基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:4或与SEQID NO:4基本上同源的序列的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7或与SEQ ID NO:7基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:9或与SEQID NO:9基本上同源的序列的抗体重链的抗体。
2.如权利要求1所述的药物组合物,包含:
a)包含具有氨基酸序列SEQ ID NO:2或与SEQ ID NO:2基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:1或与SEQID NO:1基本上同源的序列的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6或与SEQ ID NO:6基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:4或与SEQID NO:4基本上同源的序列的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7或与SEQ ID NO:7基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:9或与SEQID NO:9基本上同源的序列的抗体重链的抗体。
3.如权利要求2所述的药物组合物,包含:
a)包含具有氨基酸序列SEQ ID NO:2的抗体轻链以及具有氨基酸序列SEQ ID NO:1的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6的抗体轻链以及具有氨基酸序列SEQ ID NO:4的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7的抗体轻链以及具有氨基酸序列SEQ ID NO:9的抗体重链的抗体。
4.一种在需要治疗的受试者体内治疗或预防狂犬病毒感染的方法,包括以至少两种重组狂犬病毒中和人抗体的有效量对受试者给药,其中至少两种抗体中至少一种选自:
a)包含具有氨基酸序列SEQ ID NO:2或与SEQ ID NO:2基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:1或与SEQID NO:1基本上同源的序列的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6或与SEQ ID NO:6基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:4或与SEQID NO:4基本上同源的序列的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7或与SEQ ID NO:7基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:9或与SEQID NO:9基本上同源的序列的抗体重链的抗体。
5.如权利要求4所述的方法,其中至少两种重组狂犬病毒中和人抗体呈现出对不同狂犬病毒的中和活性。
6.如权利要求5所述的方法,其中用至少两种不同重组狂犬病毒中和人抗体分别给药。
7.如权利要求5所述的方法,其中用至少三种不同重组狂犬病毒中和人抗体给药。
8.如权利要求4所述的方法,其中重组狂犬病毒中和人抗体包含:
a)包含具有氨基酸序列SEQ ID NO:2或与SEQ ID NO:2基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:1或与SEQID NO:1基本上同源的序列的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6或与SEQ ID NO:6基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:4或与SEQID NO:4基本上同源的序列的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7或与SEQ ID NO:7基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:9或与SEQID NO:9基本上同源的序列的抗体重链的抗体。
9.如权利要求8所述的方法,其中重组狂犬病毒中和人抗体包含:
a)包含具有氨基酸序列SEQ ID NO:2的抗体轻链以及具有氨基酸序列SEQ ID NO:1的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6的抗体轻链以及具有氨基酸序列SEQ ID NO:4的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7的抗体轻链以及具有氨基酸序列SEQ ID NO:9的抗体重链的抗体。
10.如权利要求5所述的方法,其中重组狂犬病毒中和人抗体以大约等摩尔浓度的混合物给药。
11.如权利要求5所述的方法,其中重组狂犬病毒中和人抗体以大约等重量给药。
12.如权利要求11所述的方法,其中给药的抗体量在大约0.001mg/kg体重至大约100mg/kg体重之间。
13.如权利要求12所述的方法,其中给药的抗体量在大约0.01mg/kg体重至大约60mg/kg体重之间。
14.如权利要求5所述的方法,其中至少三种不同重组狂犬病毒中和人抗体包含大约1IU/kg体重至大约50IU/kg体重之间的狂犬病毒中和活性。
15.如权利要求5所述的方法,其中狂犬病毒是狂犬病毒固定毒株或街毒株。
16.如权利要求15所述的方法,其中狂犬病毒街毒株选自银毛蝠狂犬病毒、山狼狂犬病毒街毒/墨西哥狗狂犬病毒以及狗狂犬病毒。
17.如权利要求16所述的方法,其中银毛蝠狂犬病毒是银毛蝠狂犬病毒-18。
18.如权利要求16所述的方法,其中狗狂犬病毒是狗狂犬病毒-4。
19.如权利要求5所述的方法,其中受试者是人。
20.如权利要求5所述的方法,其中至少两种重组狂犬病毒中和人抗体肠道外给药。
21.如权利要求20所述的方法,其中肠道外给药方式选自血管内给药、组织周边和组织内注射、腹腔内注射、皮下注射、皮下沉积和皮下灌注。
22.一种重组棒状病毒表达载体,包含:(i)编码疱疹性口炎病毒糖蛋白序列的核酸序列;以及(ii)编码重组狂犬病毒中和人抗体的抗体轻链或抗体重链或抗体轻链和抗体重链两者的核酸序列。
23.如权利要求22所述的重组棒状病毒表达载体,其中载体进一步包含编码启动子序列的核酸序列,所述序列与(i)编码疱疹性口炎病毒糖蛋白序列的核酸序列;以及(ii)编码重组狂犬病毒中和人抗体的抗体轻链、或抗体重链、或抗体轻链以及抗体重链两者的核酸序列可操作地连接。
24.如权利要求23所述的重组棒状病毒表达载体,其中载体编码抗体轻链,所述抗体轻链选自:
a)包含具有氨基酸序列SEQ ID NO:2或与SEQ ID NO:2基本上同源的序列的抗体轻链;
b)包含具有氨基酸序列SEQ ID NO:6或与SEQ ID NO:6基本上同源的序列的抗体轻链;以及
c)包含具有氨基酸序列SEQ ID NO:7或与SEQ ID NO:7基本上同源的序列的抗体轻链。
25.如权利要求23所述的重组棒状病毒表达载体,其中载体编码抗体重链,所述抗体重链选自:
a)包含具有氨基酸序列SEQ ID NO:1或与SEQ ID NO:1基本上同源的序列的抗体重链;
b)包含具有氨基酸序列SEQ ID NO:4或与SEQ ID NO:4基本上同源的序列的抗体重链;以及
c)包含具有氨基酸序列SEQ ID NO:9或与SEQ ID NO:9基本上同源的序列的抗体重链。
26.一种宿主哺乳动物细胞,包含重组棒状病毒表达载体,所述载体选自如权利要求22、23、24和25所述的重组棒状病毒表达载体。
27.如权利要求26所述的宿主哺乳动物细胞,其中哺乳动物细胞选自BSR细胞、幼仓鼠细胞、VERO细胞和中国仓鼠卵巢细胞。
28.一种在哺乳动物细胞中制备重组狂犬病毒中和人抗体的方法,包含在允许重组狂犬病毒中和人抗体表达的条件下培养如权利要求26所述的细胞。
29.如权利要求28所述的方法,其中重组狂犬病毒中和人抗体在哺乳动物细胞内制备,所述哺乳动物细胞选自BSR细胞、幼仓鼠细胞、VERO细胞以及中国仓鼠卵巢细胞。
30.至少两种重组狂犬病毒中和人抗体的混合物在制备用于治疗和预防需要治疗的受试者体内的狂犬病毒感染的药物上的应用,其中至少一种抗体选自:
a)包含具有氨基酸序列SEQ ID NO:2或与SEQ ID NO:2基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:1或与SEQID NO:1基本上同源的序列的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6或与SEQ ID NO:6基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:4或与SEQID NO:4基本上同源的序列的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7或与SEQ ID NO:7基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:9或与SEQID NO:9基本上同源的序列的抗体重链的抗体。
31.如权利要求30所述的抗体混合物的应用,其中至少两种重组狂犬病毒中和人抗体呈现出对不同狂犬病毒的中和活性。
32.如权利要求30所述的抗体混合物的应用,其中混合物包含至少三种不同的重组狂犬病毒中和抗体。
33.如权利要求32所述的抗体混合物的应用,其中抗体包含:
a)包含具有氨基酸序列SEQ ID NO:2或与SEQ ID NO:2基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:1或与SEQID NO:1基本上同源的序列的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6或与SEQ ID NO:6基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:4或与SEQID NO:4基本上同源的序列的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7或与SEQ ID NO:7基本上同源的序列的抗体轻链以及具有氨基酸序列SEQ ID NO:9或与SEQID NO:9基本上同源的序列的抗体重链的抗体。
34.如权利要求33所述的抗体混合物的应用,其中抗体包含:
a)包含具有氨基酸序列SEQ ID NO:2的抗体轻链以及具有氨基酸序列SEQ ID NO:1的抗体重链的抗体;
b)包含具有氨基酸序列SEQ ID NO:6的抗体轻链以及具有氨基酸序列SEQ ID NO:4的抗体重链的抗体;以及
c)包含具有氨基酸序列SEQ ID NO:7的抗体轻链以及具有氨基酸序列SEQ ID NO:9的抗体重链的抗体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/461,148 | 2003-06-13 | ||
US10/461,148 US20040013672A1 (en) | 2000-05-16 | 2003-06-13 | Recombinant antibodies, and compositions and methods for making and using the same |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1805757A true CN1805757A (zh) | 2006-07-19 |
Family
ID=33563696
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2004800165846A Pending CN1805757A (zh) | 2003-06-13 | 2004-06-10 | 重组抗体及组合物及其制备和使用方法 |
Country Status (8)
Country | Link |
---|---|
US (2) | US20040013672A1 (zh) |
EP (1) | EP1633399A4 (zh) |
CN (1) | CN1805757A (zh) |
AU (1) | AU2004253464A1 (zh) |
BR (1) | BRPI0410655A (zh) |
CA (1) | CA2528860A1 (zh) |
RU (1) | RU2006101166A (zh) |
WO (1) | WO2005002511A2 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101337990B (zh) * | 2008-06-25 | 2011-04-06 | 中国人民解放军军事医学科学院微生物流行病研究所 | 人源抗狂犬病毒中和性抗体及其制备方法与用途 |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040013672A1 (en) * | 2000-05-16 | 2004-01-22 | Thomas Jefferson University | Recombinant antibodies, and compositions and methods for making and using the same |
CA2568162C (en) * | 2004-05-27 | 2013-04-16 | Crucell Holland B.V. | Binding molecules capable of neutralizing rabies virus and uses thereof |
ES2453973T3 (es) | 2005-02-02 | 2014-04-09 | University Of Massachusetts | Anticuerpos humanos contra la rabia y usos de los mismos |
EA018030B1 (ru) | 2006-06-06 | 2013-05-30 | Круселл Холланд Б.В. | Связывающие молекулы человека, имеющие убивающую активность против стафилококков, и их применения |
EP2088997B1 (en) * | 2006-12-05 | 2016-08-24 | Janssen Vaccines & Prevention B.V. | Liquid anti-rabies antibody formulations |
KR101495019B1 (ko) * | 2011-09-30 | 2015-02-24 | (주)셀트리온 | 광견병 바이러스를 중화시킬 수 있는 결합 분자 |
CN103214571B (zh) * | 2013-03-22 | 2014-09-24 | 华北制药集团新药研究开发有限责任公司 | 一种鼠源单克隆抗体及其制备方法和用途 |
CN103467598B (zh) * | 2013-09-26 | 2017-02-08 | 北京泰诺迪生物科技有限公司 | 一种全人源抗狂犬病毒的中和抗体 |
WO2022090484A2 (en) * | 2020-10-29 | 2022-05-05 | The Secretary Of State For Environment, Food And Rural Affairs | Viral vector |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7071319B2 (en) * | 2000-05-16 | 2006-07-04 | Thomas Jefferson University | Recombinant antibodies, and compositions and methods for making and using the same |
US20040013672A1 (en) * | 2000-05-16 | 2004-01-22 | Thomas Jefferson University | Recombinant antibodies, and compositions and methods for making and using the same |
CA2419148C (en) * | 2000-05-16 | 2011-07-12 | Thomas Jefferson University | Rabies virus-specific neutralizing human monoclonal antibodies and nucleic acids and related methods |
CA2457362C (en) * | 2001-08-21 | 2012-01-17 | Thomas Jefferson University | Human monoclonal rabies virus neutralizing antibodies, and methods for making and using the same |
-
2003
- 2003-06-13 US US10/461,148 patent/US20040013672A1/en not_active Abandoned
-
2004
- 2004-06-10 US US10/560,299 patent/US20060216300A1/en not_active Abandoned
- 2004-06-10 BR BRPI0410655-5A patent/BRPI0410655A/pt not_active IP Right Cessation
- 2004-06-10 RU RU2006101166/13A patent/RU2006101166A/ru not_active Application Discontinuation
- 2004-06-10 WO PCT/US2004/018613 patent/WO2005002511A2/en active Application Filing
- 2004-06-10 EP EP04755016A patent/EP1633399A4/en not_active Withdrawn
- 2004-06-10 CN CNA2004800165846A patent/CN1805757A/zh active Pending
- 2004-06-10 CA CA002528860A patent/CA2528860A1/en not_active Abandoned
- 2004-06-10 AU AU2004253464A patent/AU2004253464A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101337990B (zh) * | 2008-06-25 | 2011-04-06 | 中国人民解放军军事医学科学院微生物流行病研究所 | 人源抗狂犬病毒中和性抗体及其制备方法与用途 |
Also Published As
Publication number | Publication date |
---|---|
EP1633399A4 (en) | 2007-01-24 |
CA2528860A1 (en) | 2005-01-13 |
BRPI0410655A (pt) | 2006-06-20 |
AU2004253464A1 (en) | 2005-01-13 |
WO2005002511A2 (en) | 2005-01-13 |
US20060216300A1 (en) | 2006-09-28 |
WO2005002511A3 (en) | 2005-09-15 |
RU2006101166A (ru) | 2006-05-27 |
EP1633399A2 (en) | 2006-03-15 |
US20040013672A1 (en) | 2004-01-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1211123C (zh) | 抗白细胞粘附分子vla-4的人源化抗体 | |
CN1902231A (zh) | 具有增加的Fc受体结合亲和性和效应子功能的CD20抗体 | |
KR20220012231A (ko) | 완전-인간 번역 후 변형된 항체 치료제 | |
CN1547486A (zh) | 抗opgl抗体 | |
CN1656122A (zh) | 人源抗白细胞介素5单克隆抗体及其制备方法和包含这些抗体的组合物 | |
CN1303431A (zh) | 抗人组织因子和人源化抗体以及人源化抗体的制作方法 | |
CN1599754A (zh) | 抗trail-r抗体 | |
CN1191855C (zh) | 淋巴细胞系肿瘤的治疗剂 | |
CN101035809A (zh) | 抗tag-72的人源化单克隆抗体 | |
CN1537164A (zh) | 治疗和诊断Her-2/neu相关恶性肿瘤的组合物和方法 | |
CN101052654A (zh) | 具有改变的效应子功能的多肽变体 | |
CN1816566A (zh) | Vegf捕获剂及其治疗用途 | |
CN1522264A (zh) | 抗cd40单克隆抗体 | |
CN1146442C (zh) | 作为抗肿瘤剂的淋巴毒素-α/β复合体和抗淋巴毒素-β受体抗体 | |
CN1820026A (zh) | 作为选择性IFN-γ途径抑制剂的人抗IFN-γ中和性抗体 | |
CN1803842A (zh) | 一种治疗或预防老年性痴呆的抗体及其表达载体和在制药中的应用 | |
CN1342202A (zh) | 可溶性受体br43×2和应用方法 | |
CN1439022A (zh) | 抗协同刺激信号转导分子ailim的人单克隆抗体及其药物用途 | |
CN1213312A (zh) | 用于治疗血栓形成的抗凝血剂 | |
CN1547590A (zh) | 人源化抗-LT-β-R抗体 | |
CN1753911A (zh) | 调节血管生成的α5β1整合素的嵌合的和人源化的抗体 | |
CN1891714A (zh) | 单纯疱疹病毒进入介体的配体和使用方法 | |
CN1805757A (zh) | 重组抗体及组合物及其制备和使用方法 | |
CN1838965A (zh) | 用于癌症治疗的药品 | |
CN1531554A (zh) | 血纤维蛋白d-二聚体片段特异性的、来源于dd-3b6/22的人源化抗体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |