CN1973040A - EphA4作为PRC和PDACa的治疗靶 - Google Patents
EphA4作为PRC和PDACa的治疗靶 Download PDFInfo
- Publication number
- CN1973040A CN1973040A CNA2005800135582A CN200580013558A CN1973040A CN 1973040 A CN1973040 A CN 1973040A CN A2005800135582 A CNA2005800135582 A CN A2005800135582A CN 200580013558 A CN200580013558 A CN 200580013558A CN 1973040 A CN1973040 A CN 1973040A
- Authority
- CN
- China
- Prior art keywords
- epha4
- prc
- cell
- sequence
- sirna
- 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
- 108010055179 EphA4 Receptor Proteins 0.000 title claims abstract description 277
- 102000021727 EphA4 Receptor Human genes 0.000 title claims abstract 21
- 230000001225 therapeutic effect Effects 0.000 title description 16
- 210000004027 cell Anatomy 0.000 claims abstract description 211
- 230000014509 gene expression Effects 0.000 claims abstract description 196
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 171
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 171
- 238000000034 method Methods 0.000 claims abstract description 152
- 108020004459 Small interfering RNA Proteins 0.000 claims abstract description 127
- 238000011282 treatment Methods 0.000 claims abstract description 91
- 150000007523 nucleic acids Chemical group 0.000 claims abstract description 76
- 239000000203 mixture Substances 0.000 claims abstract description 62
- 239000003814 drug Substances 0.000 claims abstract description 61
- 238000012216 screening Methods 0.000 claims abstract description 18
- 239000013598 vector Substances 0.000 claims abstract description 10
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 160
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 79
- 239000002773 nucleotide Substances 0.000 claims description 76
- 125000003729 nucleotide group Chemical group 0.000 claims description 74
- 102000039446 nucleic acids Human genes 0.000 claims description 73
- 108020004707 nucleic acids Proteins 0.000 claims description 73
- 229920001184 polypeptide Polymers 0.000 claims description 60
- 230000000694 effects Effects 0.000 claims description 59
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 58
- 230000000692 anti-sense effect Effects 0.000 claims description 50
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 claims description 45
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 claims description 45
- 102000004169 proteins and genes Human genes 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 44
- 108020004414 DNA Proteins 0.000 claims description 42
- 239000000523 sample Substances 0.000 claims description 30
- 108020004999 messenger RNA Proteins 0.000 claims description 28
- 238000001514 detection method Methods 0.000 claims description 25
- 108091034117 Oligonucleotide Proteins 0.000 claims description 23
- 230000002265 prevention Effects 0.000 claims description 23
- 239000012634 fragment Substances 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims description 20
- 239000002342 ribonucleoside Substances 0.000 claims description 20
- 230000000295 complement effect Effects 0.000 claims description 19
- 102000040430 polynucleotide Human genes 0.000 claims description 19
- 108091033319 polynucleotide Proteins 0.000 claims description 19
- 239000002157 polynucleotide Substances 0.000 claims description 19
- 238000001890 transfection Methods 0.000 claims description 19
- 210000002919 epithelial cell Anatomy 0.000 claims description 18
- 230000002068 genetic effect Effects 0.000 claims description 18
- 229960005486 vaccine Drugs 0.000 claims description 18
- 230000004071 biological effect Effects 0.000 claims description 16
- 239000012472 biological sample Substances 0.000 claims description 15
- 108091081021 Sense strand Proteins 0.000 claims description 14
- 238000009396 hybridization Methods 0.000 claims description 14
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 13
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 13
- 230000001105 regulatory effect Effects 0.000 claims description 12
- 108700008625 Reporter Genes Proteins 0.000 claims description 9
- 238000013518 transcription Methods 0.000 claims description 9
- 230000035897 transcription Effects 0.000 claims description 9
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 5
- 239000012745 toughening agent Substances 0.000 claims description 5
- 108020004635 Complementary DNA Proteins 0.000 claims description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 4
- 230000000975 bioactive effect Effects 0.000 claims description 4
- 230000002103 transcriptional effect Effects 0.000 claims description 3
- 108091028664 Ribonucleotide Proteins 0.000 claims 1
- 239000002336 ribonucleotide Substances 0.000 claims 1
- 125000002652 ribonucleotide group Chemical group 0.000 claims 1
- 102100021616 Ephrin type-A receptor 4 Human genes 0.000 abstract description 196
- 206010028980 Neoplasm Diseases 0.000 abstract description 80
- 201000011510 cancer Diseases 0.000 abstract description 61
- 210000004881 tumor cell Anatomy 0.000 abstract description 14
- 230000012010 growth Effects 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 201000008129 pancreatic ductal adenocarcinoma Diseases 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 101150078651 Epha4 gene Proteins 0.000 abstract 1
- 238000002405 diagnostic procedure Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 56
- 210000001519 tissue Anatomy 0.000 description 40
- 239000003795 chemical substances by application Substances 0.000 description 39
- 208000021046 prostate intraepithelial neoplasia Diseases 0.000 description 36
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 33
- 238000002360 preparation method Methods 0.000 description 25
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 24
- 230000001939 inductive effect Effects 0.000 description 20
- 210000000612 antigen-presenting cell Anatomy 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 201000010099 disease Diseases 0.000 description 16
- 238000003757 reverse transcription PCR Methods 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- 239000002299 complementary DNA Substances 0.000 description 13
- 210000004443 dendritic cell Anatomy 0.000 description 13
- 230000000118 anti-neoplastic effect Effects 0.000 description 12
- 230000008859 change Effects 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 230000009467 reduction Effects 0.000 description 12
- 238000002560 therapeutic procedure Methods 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 230000003321 amplification Effects 0.000 description 11
- 239000000427 antigen Substances 0.000 description 11
- 108091007433 antigens Proteins 0.000 description 11
- 102000036639 antigens Human genes 0.000 description 11
- 230000010261 cell growth Effects 0.000 description 11
- 108060002566 ephrin Proteins 0.000 description 11
- 102000012803 ephrin Human genes 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 238000003199 nucleic acid amplification method Methods 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 10
- 241000282414 Homo sapiens Species 0.000 description 10
- 210000001744 T-lymphocyte Anatomy 0.000 description 10
- 210000000981 epithelium Anatomy 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000009736 wetting Methods 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 238000011156 evaluation Methods 0.000 description 9
- 238000002493 microarray Methods 0.000 description 9
- 238000011275 oncology therapy Methods 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000004393 prognosis Methods 0.000 description 9
- -1 stablizer Substances 0.000 description 9
- 241000282326 Felis catus Species 0.000 description 8
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 238000013461 design Methods 0.000 description 8
- 238000003745 diagnosis Methods 0.000 description 8
- 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 8
- 238000001727 in vivo Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 108091008815 Eph receptors Proteins 0.000 description 7
- 108700020796 Oncogene Proteins 0.000 description 7
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 7
- 239000004141 Sodium laurylsulphate Substances 0.000 description 7
- 238000001574 biopsy Methods 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 238000012151 immunohistochemical method Methods 0.000 description 7
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 210000002307 prostate Anatomy 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 208000005623 Carcinogenesis Diseases 0.000 description 5
- 101150029707 ERBB2 gene Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 241000880493 Leptailurus serval Species 0.000 description 5
- 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 5
- 230000002159 abnormal effect Effects 0.000 description 5
- 108010047495 alanylglycine Proteins 0.000 description 5
- 239000003098 androgen Substances 0.000 description 5
- 239000000074 antisense oligonucleotide Substances 0.000 description 5
- 238000012230 antisense oligonucleotides Methods 0.000 description 5
- 230000036952 cancer formation Effects 0.000 description 5
- 230000005907 cancer growth Effects 0.000 description 5
- 231100000504 carcinogenesis Toxicity 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 231100000433 cytotoxic Toxicity 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 238000003197 gene knockdown Methods 0.000 description 5
- 238000002649 immunization Methods 0.000 description 5
- 230000003053 immunization Effects 0.000 description 5
- 230000003211 malignant effect Effects 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- 238000012384 transportation and delivery Methods 0.000 description 5
- 229960000575 trastuzumab Drugs 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 238000000134 MTT assay Methods 0.000 description 4
- 231100000002 MTT assay Toxicity 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 4
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 4
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 4
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 4
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 4
- 108091081024 Start codon Proteins 0.000 description 4
- DNOOLPROHJWCSQ-RCWTZXSCSA-N Val-Arg-Thr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DNOOLPROHJWCSQ-RCWTZXSCSA-N 0.000 description 4
- 238000010317 ablation therapy Methods 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 230000005809 anti-tumor immunity Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 238000004590 computer program Methods 0.000 description 4
- 238000012790 confirmation Methods 0.000 description 4
- 239000000824 cytostatic agent Substances 0.000 description 4
- 230000001085 cytostatic effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 230000009368 gene silencing by RNA Effects 0.000 description 4
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 238000003018 immunoassay Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000008595 infiltration Effects 0.000 description 4
- 238000001764 infiltration Methods 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 238000001531 micro-dissection Methods 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 208000023958 prostate neoplasm Diseases 0.000 description 4
- 238000010839 reverse transcription Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000001550 testis Anatomy 0.000 description 4
- 238000013519 translation Methods 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 3
- HHGYNJRJIINWAK-FXQIFTODSA-N Ala-Ala-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N HHGYNJRJIINWAK-FXQIFTODSA-N 0.000 description 3
- NIZKGBJVCMRDKO-KWQFWETISA-N Ala-Gly-Tyr Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NIZKGBJVCMRDKO-KWQFWETISA-N 0.000 description 3
- RZZMZYZXNJRPOJ-BJDJZHNGSA-N Ala-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](C)N RZZMZYZXNJRPOJ-BJDJZHNGSA-N 0.000 description 3
- MFMDKJIPHSWSBM-GUBZILKMSA-N Ala-Lys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O MFMDKJIPHSWSBM-GUBZILKMSA-N 0.000 description 3
- OOWSBIOUKIUWLO-RCOVLWMOSA-N Asn-Gly-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O OOWSBIOUKIUWLO-RCOVLWMOSA-N 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- 108090000994 Catalytic RNA Proteins 0.000 description 3
- 102000053642 Catalytic RNA Human genes 0.000 description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- CVLIHKBUPSFRQP-WHFBIAKZSA-N Cys-Gly-Ala Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](C)C(O)=O CVLIHKBUPSFRQP-WHFBIAKZSA-N 0.000 description 3
- 239000004278 EU approved seasoning Substances 0.000 description 3
- 102000050554 Eph Family Receptors Human genes 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 108010013476 HLA-A24 Antigen Proteins 0.000 description 3
- 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 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 3
- 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 3
- 239000012097 Lipofectamine 2000 Substances 0.000 description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 3
- 108010079364 N-glycylalanine Proteins 0.000 description 3
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 241000009328 Perro Species 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- QJKPECIAWNNKIT-KKUMJFAQSA-N Ser-Lys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QJKPECIAWNNKIT-KKUMJFAQSA-N 0.000 description 3
- 102000039471 Small Nuclear RNA Human genes 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 3
- 241000700618 Vaccinia virus Species 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 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 3
- 230000008485 antagonism Effects 0.000 description 3
- 239000003005 anticarcinogenic agent Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 239000010839 body fluid Substances 0.000 description 3
- 201000010989 colorectal carcinoma Diseases 0.000 description 3
- 230000001934 delay Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000013020 embryo development Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 235000011194 food seasoning agent Nutrition 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 108010049041 glutamylalanine Proteins 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 229940022353 herceptin Drugs 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 108010038320 lysylphenylalanine Proteins 0.000 description 3
- 206010025482 malaise Diseases 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 210000004923 pancreatic tissue Anatomy 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 108091092562 ribozyme Proteins 0.000 description 3
- 108091029842 small nuclear ribonucleic acid Proteins 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 108010080629 tryptophan-leucine Proteins 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 2
- PIPTUBPKYFRLCP-NHCYSSNCSA-N Ala-Ala-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PIPTUBPKYFRLCP-NHCYSSNCSA-N 0.000 description 2
- WDIYWDJLXOCGRW-ACZMJKKPSA-N Ala-Asp-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WDIYWDJLXOCGRW-ACZMJKKPSA-N 0.000 description 2
- SGYSTDWPNPKJPP-GUBZILKMSA-N Arg-Ala-Arg Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SGYSTDWPNPKJPP-GUBZILKMSA-N 0.000 description 2
- XPSGESXVBSQZPL-SRVKXCTJSA-N Arg-Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XPSGESXVBSQZPL-SRVKXCTJSA-N 0.000 description 2
- CYXCAHZVPFREJD-LURJTMIESA-N Arg-Gly-Gly Chemical compound NC(=N)NCCC[C@H](N)C(=O)NCC(=O)NCC(O)=O CYXCAHZVPFREJD-LURJTMIESA-N 0.000 description 2
- HNJNAMGZQZPSRE-GUBZILKMSA-N Arg-Pro-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O HNJNAMGZQZPSRE-GUBZILKMSA-N 0.000 description 2
- 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 2
- 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 2
- FXGMURPOWCKNAZ-JYJNAYRXSA-N Arg-Val-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FXGMURPOWCKNAZ-JYJNAYRXSA-N 0.000 description 2
- 241000796533 Arna Species 0.000 description 2
- JRVABKHPWDRUJF-UBHSHLNASA-N Asn-Asn-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N JRVABKHPWDRUJF-UBHSHLNASA-N 0.000 description 2
- FAEFJTCTNZTPHX-ACZMJKKPSA-N Asn-Gln-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FAEFJTCTNZTPHX-ACZMJKKPSA-N 0.000 description 2
- JTXVXGXTRXMOFJ-FXQIFTODSA-N Asn-Pro-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O JTXVXGXTRXMOFJ-FXQIFTODSA-N 0.000 description 2
- HPASIOLTWSNMFB-OLHMAJIHSA-N Asn-Thr-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O HPASIOLTWSNMFB-OLHMAJIHSA-N 0.000 description 2
- FMNBYVSGRCXWEK-FOHZUACHSA-N Asn-Thr-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O FMNBYVSGRCXWEK-FOHZUACHSA-N 0.000 description 2
- LKIYSIYBKYLKPU-BIIVOSGPSA-N Asp-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)O)N)C(=O)O LKIYSIYBKYLKPU-BIIVOSGPSA-N 0.000 description 2
- DTNUIAJCPRMNBT-WHFBIAKZSA-N Asp-Gly-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O DTNUIAJCPRMNBT-WHFBIAKZSA-N 0.000 description 2
- RPUYTJJZXQBWDT-SRVKXCTJSA-N Asp-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](CC(=O)O)N RPUYTJJZXQBWDT-SRVKXCTJSA-N 0.000 description 2
- QPDUWAUSSWGJSB-NGZCFLSTSA-N Asp-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N QPDUWAUSSWGJSB-NGZCFLSTSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- BVFQOPGFOQVZTE-ACZMJKKPSA-N Cys-Gln-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O BVFQOPGFOQVZTE-ACZMJKKPSA-N 0.000 description 2
- XCDDSPYIMNXECQ-NAKRPEOUSA-N Cys-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CS XCDDSPYIMNXECQ-NAKRPEOUSA-N 0.000 description 2
- DQUWSUWXPWGTQT-DCAQKATOSA-N Cys-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CS DQUWSUWXPWGTQT-DCAQKATOSA-N 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108010090461 DFG peptide Proteins 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 108010042407 Endonucleases Proteins 0.000 description 2
- 102000004533 Endonucleases Human genes 0.000 description 2
- 102400001368 Epidermal growth factor Human genes 0.000 description 2
- 101800003838 Epidermal growth factor Proteins 0.000 description 2
- 108700039887 Essential Genes Proteins 0.000 description 2
- 241001145021 Ferula feruloides Species 0.000 description 2
- GHYJGDCPHMSFEJ-GUBZILKMSA-N Gln-Gln-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N GHYJGDCPHMSFEJ-GUBZILKMSA-N 0.000 description 2
- MFJAPSYJQJCQDN-BQBZGAKWSA-N Gln-Gly-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O MFJAPSYJQJCQDN-BQBZGAKWSA-N 0.000 description 2
- RUFHOVYUYSNDNY-ACZMJKKPSA-N Glu-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O RUFHOVYUYSNDNY-ACZMJKKPSA-N 0.000 description 2
- SYWCGQOIIARSIX-SRVKXCTJSA-N Glu-Pro-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O SYWCGQOIIARSIX-SRVKXCTJSA-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
- HFPVRZWORNJRRC-UWVGGRQHSA-N Gly-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN HFPVRZWORNJRRC-UWVGGRQHSA-N 0.000 description 2
- 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 2
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 2
- HQSKKSLNLSTONK-JTQLQIEISA-N Gly-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 HQSKKSLNLSTONK-JTQLQIEISA-N 0.000 description 2
- MUGLKCQHTUFLGF-WPRPVWTQSA-N Gly-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)CN MUGLKCQHTUFLGF-WPRPVWTQSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VYMGAXSNYUFVCK-GUBZILKMSA-N His-Gln-Asn Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N VYMGAXSNYUFVCK-GUBZILKMSA-N 0.000 description 2
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-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](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 2
- 108700020121 Human Immunodeficiency Virus-1 rev Proteins 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- HDOYNXLPTRQLAD-JBDRJPRFSA-N Ile-Ala-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)O)N HDOYNXLPTRQLAD-JBDRJPRFSA-N 0.000 description 2
- GYAFMRQGWHXMII-IUKAMOBKSA-N Ile-Asp-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N GYAFMRQGWHXMII-IUKAMOBKSA-N 0.000 description 2
- SLQVFYWBGNNOTK-BYULHYEWSA-N Ile-Gly-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N SLQVFYWBGNNOTK-BYULHYEWSA-N 0.000 description 2
- FJWALBCCVIHZBS-QXEWZRGKSA-N Ile-Met-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)O)N FJWALBCCVIHZBS-QXEWZRGKSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 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 2
- WGNOPSQMIQERPK-UHFFFAOYSA-N Leu-Asn-Pro Natural products CC(C)CC(N)C(=O)NC(CC(=O)N)C(=O)N1CCCC1C(=O)O WGNOPSQMIQERPK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JRJLGNFWYFSJHB-HOCLYGCPSA-N Leu-Gly-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JRJLGNFWYFSJHB-HOCLYGCPSA-N 0.000 description 2
- AVEGDIAXTDVBJS-XUXIUFHCSA-N Leu-Ile-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AVEGDIAXTDVBJS-XUXIUFHCSA-N 0.000 description 2
- IZPVWNSAVUQBGP-CIUDSAMLSA-N Leu-Ser-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IZPVWNSAVUQBGP-CIUDSAMLSA-N 0.000 description 2
- 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 2
- KPJJOZUXFOLGMQ-CIUDSAMLSA-N Lys-Asp-Asn Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N KPJJOZUXFOLGMQ-CIUDSAMLSA-N 0.000 description 2
- HIIZIQUUHIXUJY-GUBZILKMSA-N Lys-Asp-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HIIZIQUUHIXUJY-GUBZILKMSA-N 0.000 description 2
- IZJGPPIGYTVXLB-FQUUOJAGSA-N Lys-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IZJGPPIGYTVXLB-FQUUOJAGSA-N 0.000 description 2
- RPWQJSBMXJSCPD-XUXIUFHCSA-N Lys-Val-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)C(C)C)C(O)=O RPWQJSBMXJSCPD-XUXIUFHCSA-N 0.000 description 2
- OZVXDDFYCQOPFD-XQQFMLRXSA-N Lys-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N OZVXDDFYCQOPFD-XQQFMLRXSA-N 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- 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 2
- 108010066427 N-valyltryptophan Proteins 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 108700026244 Open Reading Frames Proteins 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- GNRMAQSIROFNMI-IXOXFDKPSA-N Phe-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O GNRMAQSIROFNMI-IXOXFDKPSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- HFNPOYOKIPGAEI-SRVKXCTJSA-N Pro-Leu-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 HFNPOYOKIPGAEI-SRVKXCTJSA-N 0.000 description 2
- 108010079005 RDV peptide Proteins 0.000 description 2
- 108010025216 RVF peptide Proteins 0.000 description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 2
- TYYBJUYSTWJHGO-ZKWXMUAHSA-N Ser-Asn-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O TYYBJUYSTWJHGO-ZKWXMUAHSA-N 0.000 description 2
- OHKLFYXEOGGGCK-ZLUOBGJFSA-N Ser-Asp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O OHKLFYXEOGGGCK-ZLUOBGJFSA-N 0.000 description 2
- IXZHZUGGKLRHJD-DCAQKATOSA-N Ser-Leu-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IXZHZUGGKLRHJD-DCAQKATOSA-N 0.000 description 2
- 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 2
- CRJZZXMAADSBBQ-SRVKXCTJSA-N Ser-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO CRJZZXMAADSBBQ-SRVKXCTJSA-N 0.000 description 2
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- NLSNVZAREYQMGR-HJGDQZAQSA-N Thr-Asp-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NLSNVZAREYQMGR-HJGDQZAQSA-N 0.000 description 2
- QWMPARMKIDVBLV-VZFHVOOUSA-N Thr-Cys-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O QWMPARMKIDVBLV-VZFHVOOUSA-N 0.000 description 2
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 2
- VTMGKRABARCZAX-OSUNSFLBSA-N Thr-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O VTMGKRABARCZAX-OSUNSFLBSA-N 0.000 description 2
- NBIIPOKZPUGATB-BWBBJGPYSA-N Thr-Ser-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N)O NBIIPOKZPUGATB-BWBBJGPYSA-N 0.000 description 2
- KZTLZZQTJMCGIP-ZJDVBMNYSA-N Thr-Val-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KZTLZZQTJMCGIP-ZJDVBMNYSA-N 0.000 description 2
- ZOBLBMGJKVJVEV-BZSNNMDCSA-N Tyr-Lys-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N)O ZOBLBMGJKVJVEV-BZSNNMDCSA-N 0.000 description 2
- TYFLVOUZHQUBGM-IHRRRGAJSA-N Tyr-Ser-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 TYFLVOUZHQUBGM-IHRRRGAJSA-N 0.000 description 2
- KLQPIEVIKOQRAW-IZPVPAKOSA-N Tyr-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O KLQPIEVIKOQRAW-IZPVPAKOSA-N 0.000 description 2
- JQOMHZMWQHXALX-FHWLQOOXSA-N Tyr-Tyr-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JQOMHZMWQHXALX-FHWLQOOXSA-N 0.000 description 2
- 108091023045 Untranslated Region Proteins 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- KKHRWGYHBZORMQ-NHCYSSNCSA-N Val-Arg-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KKHRWGYHBZORMQ-NHCYSSNCSA-N 0.000 description 2
- XIFAHCUNWWKUDE-DCAQKATOSA-N Val-Cys-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N XIFAHCUNWWKUDE-DCAQKATOSA-N 0.000 description 2
- SDUBQHUJJWQTEU-XUXIUFHCSA-N Val-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](C(C)C)N SDUBQHUJJWQTEU-XUXIUFHCSA-N 0.000 description 2
- OVBMCNDKCWAXMZ-NAKRPEOUSA-N Val-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N OVBMCNDKCWAXMZ-NAKRPEOUSA-N 0.000 description 2
- LYERIXUFCYVFFX-GVXVVHGQSA-N Val-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N LYERIXUFCYVFFX-GVXVVHGQSA-N 0.000 description 2
- YDVDTCJGBBJGRT-GUBZILKMSA-N Val-Met-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N YDVDTCJGBBJGRT-GUBZILKMSA-N 0.000 description 2
- 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 2
- GTACFKZDQFTVAI-STECZYCISA-N Val-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CC=C(O)C=C1 GTACFKZDQFTVAI-STECZYCISA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 238000011319 anticancer therapy Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 108010013835 arginine glutamate Proteins 0.000 description 2
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 2
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 2
- 108010060035 arginylproline Proteins 0.000 description 2
- 108010077245 asparaginyl-proline Proteins 0.000 description 2
- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical compound C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000003327 cancerostatic effect Effects 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000003632 chemoprophylactic effect Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 230000005757 colony formation Effects 0.000 description 2
- 238000010293 colony formation assay Methods 0.000 description 2
- 230000001332 colony forming effect Effects 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 230000001276 controlling effect Effects 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
- 238000005520 cutting process Methods 0.000 description 2
- 108010016616 cysteinylglycine Proteins 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 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 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 108010054812 diprotin A Proteins 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229940116977 epidermal growth factor Drugs 0.000 description 2
- 230000000763 evoking effect Effects 0.000 description 2
- 230000006126 farnesylation Effects 0.000 description 2
- 244000144992 flock Species 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 2
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 2
- 108010072405 glycyl-aspartyl-glycine Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 239000003163 gonadal steroid hormone Substances 0.000 description 2
- 108010025306 histidylleucine Proteins 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000002991 immunohistochemical analysis Methods 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 238000012744 immunostaining Methods 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 238000001001 laser micro-dissection Methods 0.000 description 2
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 2
- 108010009298 lysylglutamic acid Proteins 0.000 description 2
- 108010017391 lysylvaline Proteins 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 108010005942 methionylglycine Proteins 0.000 description 2
- 238000010208 microarray analysis Methods 0.000 description 2
- 210000001982 neural crest cell Anatomy 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 235000010603 pastilles Nutrition 0.000 description 2
- 238000000059 patterning Methods 0.000 description 2
- 210000003668 pericyte Anatomy 0.000 description 2
- 230000000505 pernicious effect Effects 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 108091005981 phosphorylated proteins Proteins 0.000 description 2
- 238000013439 planning Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 238000011472 radical prostatectomy Methods 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 210000001202 rhombencephalon Anatomy 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 230000014621 translational initiation Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 231100000588 tumorigenic Toxicity 0.000 description 2
- 230000000381 tumorigenic effect Effects 0.000 description 2
- 108010051110 tyrosyl-lysine Proteins 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- 108010027345 wheylin-1 peptide Proteins 0.000 description 2
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- SZDLYOHKAVLHRP-BFLQJQPQSA-N 3-[4-[(2s,3s)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]piperazin-1-yl]-2-methyl-1-phenylpropan-1-one Chemical compound C1CN([C@@H]2[C@H](CC3=CC=CC=C3C2)O)CCN1CC(C)C(=O)C1=CC=CC=C1 SZDLYOHKAVLHRP-BFLQJQPQSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 108010013043 Acetylesterase Proteins 0.000 description 1
- 102000057234 Acyl transferases Human genes 0.000 description 1
- 108700016155 Acyl transferases Proteins 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
- DVWVZSJAYIJZFI-FXQIFTODSA-N Ala-Arg-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O DVWVZSJAYIJZFI-FXQIFTODSA-N 0.000 description 1
- SKHCUBQVZJHOFM-NAKRPEOUSA-N Ala-Arg-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SKHCUBQVZJHOFM-NAKRPEOUSA-N 0.000 description 1
- PXKLCFFSVLKOJM-ACZMJKKPSA-N Ala-Asn-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PXKLCFFSVLKOJM-ACZMJKKPSA-N 0.000 description 1
- GSCLWXDNIMNIJE-ZLUOBGJFSA-N Ala-Asp-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GSCLWXDNIMNIJE-ZLUOBGJFSA-N 0.000 description 1
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 1
- NJIFPLAJSVUQOZ-JBDRJPRFSA-N Ala-Cys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C)N NJIFPLAJSVUQOZ-JBDRJPRFSA-N 0.000 description 1
- CXQODNIBUNQWAS-CIUDSAMLSA-N Ala-Gln-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N CXQODNIBUNQWAS-CIUDSAMLSA-N 0.000 description 1
- JPGBXANAQYHTLA-DRZSPHRISA-N Ala-Gln-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JPGBXANAQYHTLA-DRZSPHRISA-N 0.000 description 1
- BTBUEVAGZCKULD-XPUUQOCRSA-N Ala-Gly-His Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BTBUEVAGZCKULD-XPUUQOCRSA-N 0.000 description 1
- NJWJSLCQEDMGNC-MBLNEYKQSA-N Ala-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C)N)O NJWJSLCQEDMGNC-MBLNEYKQSA-N 0.000 description 1
- PNALXAODQKTNLV-JBDRJPRFSA-N Ala-Ile-Ala Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O PNALXAODQKTNLV-JBDRJPRFSA-N 0.000 description 1
- CKLDHDOIYBVUNP-KBIXCLLPSA-N Ala-Ile-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O CKLDHDOIYBVUNP-KBIXCLLPSA-N 0.000 description 1
- LXAARTARZJJCMB-CIQUZCHMSA-N Ala-Ile-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LXAARTARZJJCMB-CIQUZCHMSA-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
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 1
- OMFMCIVBKCEMAK-CYDGBPFRSA-N Ala-Leu-Val-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O OMFMCIVBKCEMAK-CYDGBPFRSA-N 0.000 description 1
- NLOMBWNGESDVJU-GUBZILKMSA-N Ala-Met-Arg Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NLOMBWNGESDVJU-GUBZILKMSA-N 0.000 description 1
- KYDYGANDJHFBCW-DRZSPHRISA-N Ala-Phe-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N KYDYGANDJHFBCW-DRZSPHRISA-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
- ADSGHMXEAZJJNF-DCAQKATOSA-N Ala-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N ADSGHMXEAZJJNF-DCAQKATOSA-N 0.000 description 1
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 1
- RMAWDDRDTRSZIR-ZLUOBGJFSA-N Ala-Ser-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O RMAWDDRDTRSZIR-ZLUOBGJFSA-N 0.000 description 1
- AUFACLFHBAGZEN-ZLUOBGJFSA-N Ala-Ser-Cys Chemical compound N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O AUFACLFHBAGZEN-ZLUOBGJFSA-N 0.000 description 1
- OMCKWYSDUQBYCN-FXQIFTODSA-N Ala-Ser-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(O)=O OMCKWYSDUQBYCN-FXQIFTODSA-N 0.000 description 1
- MTDDMSUUXNQMKK-BPNCWPANSA-N Ala-Tyr-Arg Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N MTDDMSUUXNQMKK-BPNCWPANSA-N 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
- 241000415078 Anemone hepatica Species 0.000 description 1
- 101100046775 Arabidopsis thaliana TPPA gene Proteins 0.000 description 1
- BIOCIVSVEDFKDJ-GUBZILKMSA-N Arg-Arg-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O BIOCIVSVEDFKDJ-GUBZILKMSA-N 0.000 description 1
- BVBKBQRPOJFCQM-DCAQKATOSA-N Arg-Asn-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BVBKBQRPOJFCQM-DCAQKATOSA-N 0.000 description 1
- RCAUJZASOAFTAJ-FXQIFTODSA-N Arg-Asp-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)CN=C(N)N RCAUJZASOAFTAJ-FXQIFTODSA-N 0.000 description 1
- VXXHDZKEQNGXNU-QXEWZRGKSA-N Arg-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N VXXHDZKEQNGXNU-QXEWZRGKSA-N 0.000 description 1
- PTVGLOCPAVYPFG-CIUDSAMLSA-N Arg-Gln-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O PTVGLOCPAVYPFG-CIUDSAMLSA-N 0.000 description 1
- RKRSYHCNPFGMTA-CIUDSAMLSA-N Arg-Glu-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O RKRSYHCNPFGMTA-CIUDSAMLSA-N 0.000 description 1
- PBSOQGZLPFVXPU-YUMQZZPRSA-N Arg-Glu-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O PBSOQGZLPFVXPU-YUMQZZPRSA-N 0.000 description 1
- RFXXUWGNVRJTNQ-QXEWZRGKSA-N Arg-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)N RFXXUWGNVRJTNQ-QXEWZRGKSA-N 0.000 description 1
- HAVKMRGWNXMCDR-STQMWFEESA-N Arg-Gly-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HAVKMRGWNXMCDR-STQMWFEESA-N 0.000 description 1
- FFEUXEAKYRCACT-PEDHHIEDSA-N Arg-Ile-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(O)=O FFEUXEAKYRCACT-PEDHHIEDSA-N 0.000 description 1
- OKKMBOSPBDASEP-CYDGBPFRSA-N Arg-Ile-Met Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(O)=O OKKMBOSPBDASEP-CYDGBPFRSA-N 0.000 description 1
- NMRHDSAOIURTNT-RWMBFGLXSA-N Arg-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N NMRHDSAOIURTNT-RWMBFGLXSA-N 0.000 description 1
- NIELFHOLFTUZME-HJWJTTGWSA-N Arg-Phe-Ile 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)CC)C(O)=O NIELFHOLFTUZME-HJWJTTGWSA-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
- FOQFHANLUJDQEE-GUBZILKMSA-N Arg-Pro-Cys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCCN=C(N)N)N)C(=O)N[C@@H](CS)C(=O)O FOQFHANLUJDQEE-GUBZILKMSA-N 0.000 description 1
- FVBZXNSRIDVYJS-AVGNSLFASA-N Arg-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCN=C(N)N FVBZXNSRIDVYJS-AVGNSLFASA-N 0.000 description 1
- YCYXHLZRUSJITQ-SRVKXCTJSA-N Arg-Pro-Pro Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 YCYXHLZRUSJITQ-SRVKXCTJSA-N 0.000 description 1
- OWSMKCJUBAPHED-JYJNAYRXSA-N Arg-Pro-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OWSMKCJUBAPHED-JYJNAYRXSA-N 0.000 description 1
- DNLQVHBBMPZUGJ-BQBZGAKWSA-N Arg-Ser-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O DNLQVHBBMPZUGJ-BQBZGAKWSA-N 0.000 description 1
- WCZXPVPHUMYLMS-VEVYYDQMSA-N Arg-Thr-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O WCZXPVPHUMYLMS-VEVYYDQMSA-N 0.000 description 1
- LYJXHXGPWDTLKW-HJGDQZAQSA-N Arg-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O LYJXHXGPWDTLKW-HJGDQZAQSA-N 0.000 description 1
- UZSQXCMNUPKLCC-FJXKBIBVSA-N Arg-Thr-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O UZSQXCMNUPKLCC-FJXKBIBVSA-N 0.000 description 1
- OGZBJJLRKQZRHL-KJEVXHAQSA-N Arg-Thr-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OGZBJJLRKQZRHL-KJEVXHAQSA-N 0.000 description 1
- AZHXYLJRGVMQKW-UMPQAUOISA-N Arg-Trp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCCN=C(N)N)N)O AZHXYLJRGVMQKW-UMPQAUOISA-N 0.000 description 1
- ANAHQDPQQBDOBM-UHFFFAOYSA-N Arg-Val-Tyr Natural products CC(C)C(NC(=O)C(N)CCNC(=N)N)C(=O)NC(Cc1ccc(O)cc1)C(=O)O ANAHQDPQQBDOBM-UHFFFAOYSA-N 0.000 description 1
- HZPSDHRYYIORKR-WHFBIAKZSA-N Asn-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O HZPSDHRYYIORKR-WHFBIAKZSA-N 0.000 description 1
- KXFCBAHYSLJCCY-ZLUOBGJFSA-N Asn-Asn-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O KXFCBAHYSLJCCY-ZLUOBGJFSA-N 0.000 description 1
- XSGBIBGAMKTHMY-WHFBIAKZSA-N Asn-Asp-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O XSGBIBGAMKTHMY-WHFBIAKZSA-N 0.000 description 1
- HJRBIWRXULGMOA-ACZMJKKPSA-N Asn-Gln-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJRBIWRXULGMOA-ACZMJKKPSA-N 0.000 description 1
- VJTWLBMESLDOMK-WDSKDSINSA-N Asn-Gln-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VJTWLBMESLDOMK-WDSKDSINSA-N 0.000 description 1
- PPMTUXJSQDNUDE-CIUDSAMLSA-N Asn-Glu-Arg Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N PPMTUXJSQDNUDE-CIUDSAMLSA-N 0.000 description 1
- GFFRWIJAFFMQGM-NUMRIWBASA-N Asn-Glu-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GFFRWIJAFFMQGM-NUMRIWBASA-N 0.000 description 1
- DMLSCRJBWUEALP-LAEOZQHASA-N Asn-Glu-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O DMLSCRJBWUEALP-LAEOZQHASA-N 0.000 description 1
- HYQYLOSCICEYTR-YUMQZZPRSA-N Asn-Gly-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O HYQYLOSCICEYTR-YUMQZZPRSA-N 0.000 description 1
- GQRDIVQPSMPQME-ZPFDUUQYSA-N Asn-Ile-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O GQRDIVQPSMPQME-ZPFDUUQYSA-N 0.000 description 1
- PNHQRQTVBRDIEF-CIUDSAMLSA-N Asn-Leu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)N PNHQRQTVBRDIEF-CIUDSAMLSA-N 0.000 description 1
- BZWRLDPIWKOVKB-ZPFDUUQYSA-N Asn-Leu-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BZWRLDPIWKOVKB-ZPFDUUQYSA-N 0.000 description 1
- TZFQICWZWFNIKU-KKUMJFAQSA-N Asn-Leu-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 TZFQICWZWFNIKU-KKUMJFAQSA-N 0.000 description 1
- NCFJQJRLQJEECD-NHCYSSNCSA-N Asn-Leu-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O NCFJQJRLQJEECD-NHCYSSNCSA-N 0.000 description 1
- BYLSYQASFJJBCL-DCAQKATOSA-N Asn-Pro-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O BYLSYQASFJJBCL-DCAQKATOSA-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
- 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
- ZUFPUBYQYWCMDB-NUMRIWBASA-N Asn-Thr-Glu Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZUFPUBYQYWCMDB-NUMRIWBASA-N 0.000 description 1
- BCADFFUQHIMQAA-KKHAAJSZSA-N Asn-Thr-Val 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)C)C(O)=O BCADFFUQHIMQAA-KKHAAJSZSA-N 0.000 description 1
- XEGZSHSPQNDNRH-JRQIVUDYSA-N Asn-Tyr-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XEGZSHSPQNDNRH-JRQIVUDYSA-N 0.000 description 1
- SYZWMVSXBZCOBZ-QXEWZRGKSA-N Asn-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC(=O)N)N SYZWMVSXBZCOBZ-QXEWZRGKSA-N 0.000 description 1
- WQAOZCVOOYUWKG-LSJOCFKGSA-N Asn-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CC(=O)N)N WQAOZCVOOYUWKG-LSJOCFKGSA-N 0.000 description 1
- KRXIWXCXOARFNT-ZLUOBGJFSA-N Asp-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O KRXIWXCXOARFNT-ZLUOBGJFSA-N 0.000 description 1
- NECWUSYTYSIFNC-DLOVCJGASA-N Asp-Ala-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 NECWUSYTYSIFNC-DLOVCJGASA-N 0.000 description 1
- RGKKALNPOYURGE-ZKWXMUAHSA-N Asp-Ala-Val Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O RGKKALNPOYURGE-ZKWXMUAHSA-N 0.000 description 1
- HMQDRBKQMLRCCG-GMOBBJLQSA-N Asp-Arg-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HMQDRBKQMLRCCG-GMOBBJLQSA-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
- ILJQISGMGXRZQQ-IHRRRGAJSA-N Asp-Arg-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ILJQISGMGXRZQQ-IHRRRGAJSA-N 0.000 description 1
- QRULNKJGYQQZMW-ZLUOBGJFSA-N Asp-Asn-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O QRULNKJGYQQZMW-ZLUOBGJFSA-N 0.000 description 1
- NZJDBCYBYCUEDC-UBHSHLNASA-N Asp-Cys-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)O)N NZJDBCYBYCUEDC-UBHSHLNASA-N 0.000 description 1
- DXQOQMCLWWADMU-ACZMJKKPSA-N Asp-Gln-Ser Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O DXQOQMCLWWADMU-ACZMJKKPSA-N 0.000 description 1
- GHODABZPVZMWCE-FXQIFTODSA-N Asp-Glu-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O GHODABZPVZMWCE-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
- DGKCOYGQLNWNCJ-ACZMJKKPSA-N Asp-Glu-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O DGKCOYGQLNWNCJ-ACZMJKKPSA-N 0.000 description 1
- VIRHEUMYXXLCBF-WDSKDSINSA-N Asp-Gly-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O VIRHEUMYXXLCBF-WDSKDSINSA-N 0.000 description 1
- KLYPOCBLKMPBIQ-GHCJXIJMSA-N Asp-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N KLYPOCBLKMPBIQ-GHCJXIJMSA-N 0.000 description 1
- JNNVNVRBYUJYGS-CIUDSAMLSA-N Asp-Leu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O JNNVNVRBYUJYGS-CIUDSAMLSA-N 0.000 description 1
- QNIACYURSSCLRP-GUBZILKMSA-N Asp-Lys-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O QNIACYURSSCLRP-GUBZILKMSA-N 0.000 description 1
- VSMYBNPOHYAXSD-GUBZILKMSA-N Asp-Lys-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O VSMYBNPOHYAXSD-GUBZILKMSA-N 0.000 description 1
- IOXWDLNHXZOXQP-FXQIFTODSA-N Asp-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N IOXWDLNHXZOXQP-FXQIFTODSA-N 0.000 description 1
- LTCKTLYKRMCFOC-KKUMJFAQSA-N Asp-Phe-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O LTCKTLYKRMCFOC-KKUMJFAQSA-N 0.000 description 1
- FAUPLTGRUBTXNU-FXQIFTODSA-N Asp-Pro-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O FAUPLTGRUBTXNU-FXQIFTODSA-N 0.000 description 1
- KBJVTFWQWXCYCQ-IUKAMOBKSA-N Asp-Thr-Ile 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)CC)C(O)=O KBJVTFWQWXCYCQ-IUKAMOBKSA-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
- KACWACLNYLSVCA-VHWLVUOQSA-N Asp-Trp-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KACWACLNYLSVCA-VHWLVUOQSA-N 0.000 description 1
- XWKPSMRPIKKDDU-RCOVLWMOSA-N Asp-Val-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O XWKPSMRPIKKDDU-RCOVLWMOSA-N 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 101150010856 CRT gene Proteins 0.000 description 1
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 101800004637 Communis Proteins 0.000 description 1
- VNLYIYOYUNGURO-ZLUOBGJFSA-N Cys-Asp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N VNLYIYOYUNGURO-ZLUOBGJFSA-N 0.000 description 1
- FWYBFUDWUUFLDN-FXQIFTODSA-N Cys-Asp-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N FWYBFUDWUUFLDN-FXQIFTODSA-N 0.000 description 1
- DYBIDOHFRRUMLW-CIUDSAMLSA-N Cys-Leu-Cys Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CS)C(O)=O DYBIDOHFRRUMLW-CIUDSAMLSA-N 0.000 description 1
- KCPOQGRVVXYLAC-KKUMJFAQSA-N Cys-Leu-Phe Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CS)N KCPOQGRVVXYLAC-KKUMJFAQSA-N 0.000 description 1
- YXPNKXFOBHRUBL-BJDJZHNGSA-N Cys-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N YXPNKXFOBHRUBL-BJDJZHNGSA-N 0.000 description 1
- KGIHMGPYGXBYJJ-SRVKXCTJSA-N Cys-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CS KGIHMGPYGXBYJJ-SRVKXCTJSA-N 0.000 description 1
- XMVZMBGFIOQONW-GARJFASQSA-N Cys-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N)C(=O)O XMVZMBGFIOQONW-GARJFASQSA-N 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-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
- YWEHYKGJWHPGPY-XGEHTFHBSA-N Cys-Thr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CS)N)O YWEHYKGJWHPGPY-XGEHTFHBSA-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
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000007317 Farnesyltranstransferase Human genes 0.000 description 1
- 108010007508 Farnesyltranstransferase Proteins 0.000 description 1
- 241000700662 Fowlpox virus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 244000059224 Gaultheria adenothrix Species 0.000 description 1
- 235000001721 Gaultheria adenothrix Nutrition 0.000 description 1
- 230000010558 Gene Alterations Effects 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- IGNGBUVODQLMRJ-CIUDSAMLSA-N Gln-Ala-Met Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O IGNGBUVODQLMRJ-CIUDSAMLSA-N 0.000 description 1
- KWUSGAIFNHQCBY-DCAQKATOSA-N Gln-Arg-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O KWUSGAIFNHQCBY-DCAQKATOSA-N 0.000 description 1
- CITDWMLWXNUQKD-FXQIFTODSA-N Gln-Gln-Asn Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CITDWMLWXNUQKD-FXQIFTODSA-N 0.000 description 1
- MCAVASRGVBVPMX-FXQIFTODSA-N Gln-Glu-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O MCAVASRGVBVPMX-FXQIFTODSA-N 0.000 description 1
- CGVWDTRDPLOMHZ-FXQIFTODSA-N Gln-Glu-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CGVWDTRDPLOMHZ-FXQIFTODSA-N 0.000 description 1
- KHNJVFYHIKLUPD-SRVKXCTJSA-N Gln-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCC(=O)N)N KHNJVFYHIKLUPD-SRVKXCTJSA-N 0.000 description 1
- HPCOBEHVEHWREJ-DCAQKATOSA-N Gln-Lys-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HPCOBEHVEHWREJ-DCAQKATOSA-N 0.000 description 1
- SWDSRANUCKNBLA-AVGNSLFASA-N Gln-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](CCC(=O)N)N SWDSRANUCKNBLA-AVGNSLFASA-N 0.000 description 1
- OZEQPCDLCDRCGY-SOUVJXGZSA-N Gln-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCC(=O)N)N)C(=O)O OZEQPCDLCDRCGY-SOUVJXGZSA-N 0.000 description 1
- QFXNFFZTMFHPST-DZKIICNBSA-N Gln-Phe-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CCC(=O)N)N QFXNFFZTMFHPST-DZKIICNBSA-N 0.000 description 1
- VDMABHYXBULDGN-LAEOZQHASA-N Gln-Val-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O VDMABHYXBULDGN-LAEOZQHASA-N 0.000 description 1
- KHHDJQRWIFHXHS-NRPADANISA-N Gln-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)N)N KHHDJQRWIFHXHS-NRPADANISA-N 0.000 description 1
- RLZBLVSJDFHDBL-KBIXCLLPSA-N Glu-Ala-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RLZBLVSJDFHDBL-KBIXCLLPSA-N 0.000 description 1
- MXOODARRORARSU-ACZMJKKPSA-N Glu-Ala-Ser Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)O)N MXOODARRORARSU-ACZMJKKPSA-N 0.000 description 1
- NCWOMXABNYEPLY-NRPADANISA-N Glu-Ala-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O NCWOMXABNYEPLY-NRPADANISA-N 0.000 description 1
- WOSRKEJQESVHGA-CIUDSAMLSA-N Glu-Arg-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O WOSRKEJQESVHGA-CIUDSAMLSA-N 0.000 description 1
- MLCPTRRNICEKIS-FXQIFTODSA-N Glu-Asn-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O MLCPTRRNICEKIS-FXQIFTODSA-N 0.000 description 1
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 1
- 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 1
- ILGFBUGLBSAQQB-GUBZILKMSA-N Glu-Glu-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ILGFBUGLBSAQQB-GUBZILKMSA-N 0.000 description 1
- LGYZYFFDELZWRS-DCAQKATOSA-N Glu-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O LGYZYFFDELZWRS-DCAQKATOSA-N 0.000 description 1
- QJCKNLPMTPXXEM-AUTRQRHGSA-N Glu-Glu-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O QJCKNLPMTPXXEM-AUTRQRHGSA-N 0.000 description 1
- AIGROOHQXCACHL-WDSKDSINSA-N Glu-Gly-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O AIGROOHQXCACHL-WDSKDSINSA-N 0.000 description 1
- XMPAXPSENRSOSV-RYUDHWBXSA-N Glu-Gly-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XMPAXPSENRSOSV-RYUDHWBXSA-N 0.000 description 1
- HILMIYALTUQTRC-XVKPBYJWSA-N Glu-Gly-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HILMIYALTUQTRC-XVKPBYJWSA-N 0.000 description 1
- LGYCLOCORAEQSZ-PEFMBERDSA-N Glu-Ile-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O LGYCLOCORAEQSZ-PEFMBERDSA-N 0.000 description 1
- YVYVMJNUENBOOL-KBIXCLLPSA-N Glu-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N YVYVMJNUENBOOL-KBIXCLLPSA-N 0.000 description 1
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 1
- SWRVAQHFBRZVNX-GUBZILKMSA-N Glu-Lys-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O SWRVAQHFBRZVNX-GUBZILKMSA-N 0.000 description 1
- YGLCLCMAYUYZSG-AVGNSLFASA-N Glu-Lys-His Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 YGLCLCMAYUYZSG-AVGNSLFASA-N 0.000 description 1
- YRMZCZIRHYCNHX-RYUDHWBXSA-N Glu-Phe-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O YRMZCZIRHYCNHX-RYUDHWBXSA-N 0.000 description 1
- FGSGPLRPQCZBSQ-AVGNSLFASA-N Glu-Phe-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O FGSGPLRPQCZBSQ-AVGNSLFASA-N 0.000 description 1
- BIYNPVYAZOUVFQ-CIUDSAMLSA-N Glu-Pro-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O BIYNPVYAZOUVFQ-CIUDSAMLSA-N 0.000 description 1
- VNCNWQPIQYAMAK-ACZMJKKPSA-N Glu-Ser-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O VNCNWQPIQYAMAK-ACZMJKKPSA-N 0.000 description 1
- CQGBSALYGOXQPE-HTUGSXCWSA-N Glu-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](CCC(=O)O)N)O CQGBSALYGOXQPE-HTUGSXCWSA-N 0.000 description 1
- MXJYXYDREQWUMS-XKBZYTNZSA-N Glu-Thr-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O MXJYXYDREQWUMS-XKBZYTNZSA-N 0.000 description 1
- DXMOIVCNJIJQSC-QEJZJMRPSA-N Glu-Trp-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)O)N DXMOIVCNJIJQSC-QEJZJMRPSA-N 0.000 description 1
- MLILEEIVMRUYBX-NHCYSSNCSA-N Glu-Val-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O MLILEEIVMRUYBX-NHCYSSNCSA-N 0.000 description 1
- KCCNSVHJSMMGFS-NRPADANISA-N Glu-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N KCCNSVHJSMMGFS-NRPADANISA-N 0.000 description 1
- 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 1
- QXUPRMQJDWJDFR-NRPADANISA-N Glu-Val-Ser Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O QXUPRMQJDWJDFR-NRPADANISA-N 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
- RLFSBAPJTYKSLG-WHFBIAKZSA-N Gly-Ala-Asp Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O RLFSBAPJTYKSLG-WHFBIAKZSA-N 0.000 description 1
- GZUKEVBTYNNUQF-WDSKDSINSA-N Gly-Ala-Gln Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O GZUKEVBTYNNUQF-WDSKDSINSA-N 0.000 description 1
- RQZGFWKQLPJOEQ-YUMQZZPRSA-N Gly-Arg-Gln Chemical compound C(C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)CN)CN=C(N)N RQZGFWKQLPJOEQ-YUMQZZPRSA-N 0.000 description 1
- OVSKVOOUFAKODB-UWVGGRQHSA-N Gly-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N OVSKVOOUFAKODB-UWVGGRQHSA-N 0.000 description 1
- MXXXVOYFNVJHMA-IUCAKERBSA-N Gly-Arg-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CN MXXXVOYFNVJHMA-IUCAKERBSA-N 0.000 description 1
- LXXLEUBUOMCAMR-NKWVEPMBSA-N Gly-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)CN)C(=O)O LXXLEUBUOMCAMR-NKWVEPMBSA-N 0.000 description 1
- JPWIMMUNWUKOAD-STQMWFEESA-N Gly-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)CN JPWIMMUNWUKOAD-STQMWFEESA-N 0.000 description 1
- BPQYBFAXRGMGGY-LAEOZQHASA-N Gly-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)CN BPQYBFAXRGMGGY-LAEOZQHASA-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
- JNGJGFMFXREJNF-KBPBESRZSA-N Gly-Glu-Trp Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JNGJGFMFXREJNF-KBPBESRZSA-N 0.000 description 1
- UPADCCSMVOQAGF-LBPRGKRZSA-N Gly-Gly-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)CNC(=O)CN)C(O)=O)=CNC2=C1 UPADCCSMVOQAGF-LBPRGKRZSA-N 0.000 description 1
- LUJVWKKYHSLULQ-ZKWXMUAHSA-N Gly-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN LUJVWKKYHSLULQ-ZKWXMUAHSA-N 0.000 description 1
- SCWYHUQOOFRVHP-MBLNEYKQSA-N Gly-Ile-Thr Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SCWYHUQOOFRVHP-MBLNEYKQSA-N 0.000 description 1
- COVXELOAORHTND-LSJOCFKGSA-N Gly-Ile-Val Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O COVXELOAORHTND-LSJOCFKGSA-N 0.000 description 1
- LLZXNUUIBOALNY-QWRGUYRKSA-N Gly-Leu-Lys Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN LLZXNUUIBOALNY-QWRGUYRKSA-N 0.000 description 1
- CLNSYANKYVMZNM-UWVGGRQHSA-N Gly-Lys-Arg Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N CLNSYANKYVMZNM-UWVGGRQHSA-N 0.000 description 1
- YHYDTTUSJXGTQK-UWVGGRQHSA-N Gly-Met-Leu Chemical compound CSCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(C)C)C(O)=O YHYDTTUSJXGTQK-UWVGGRQHSA-N 0.000 description 1
- ZWRDOVYMQAAISL-UWVGGRQHSA-N Gly-Met-Lys Chemical compound CSCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CCCCN ZWRDOVYMQAAISL-UWVGGRQHSA-N 0.000 description 1
- OMOZPGCHVWOXHN-BQBZGAKWSA-N Gly-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)CN OMOZPGCHVWOXHN-BQBZGAKWSA-N 0.000 description 1
- FEUPVVCGQLNXNP-IRXDYDNUSA-N Gly-Phe-Phe Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 FEUPVVCGQLNXNP-IRXDYDNUSA-N 0.000 description 1
- QAMMIGULQSIRCD-IRXDYDNUSA-N Gly-Phe-Tyr Chemical compound C([C@H](NC(=O)C[NH3+])C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C([O-])=O)C1=CC=CC=C1 QAMMIGULQSIRCD-IRXDYDNUSA-N 0.000 description 1
- LBDXVCBAJJNJNN-WHFBIAKZSA-N Gly-Ser-Cys Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O LBDXVCBAJJNJNN-WHFBIAKZSA-N 0.000 description 1
- ZKJZBRHRWKLVSJ-ZDLURKLDSA-N Gly-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN)O ZKJZBRHRWKLVSJ-ZDLURKLDSA-N 0.000 description 1
- NIOPEYHPOBWLQO-KBPBESRZSA-N Gly-Trp-Glu Chemical compound NCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(O)=O NIOPEYHPOBWLQO-KBPBESRZSA-N 0.000 description 1
- GWNIGUKSRJBIHX-STQMWFEESA-N Gly-Tyr-Arg Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)CN)O GWNIGUKSRJBIHX-STQMWFEESA-N 0.000 description 1
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 1
- NGBGZCUWFVVJKC-IRXDYDNUSA-N Gly-Tyr-Tyr Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NGBGZCUWFVVJKC-IRXDYDNUSA-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
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 1
- 108010075704 HLA-A Antigens Proteins 0.000 description 1
- 108010088729 HLA-A*02:01 antigen Proteins 0.000 description 1
- SVHKVHBPTOMLTO-DCAQKATOSA-N His-Arg-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O SVHKVHBPTOMLTO-DCAQKATOSA-N 0.000 description 1
- TXLQHACKRLWYCM-DCAQKATOSA-N His-Glu-Glu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O TXLQHACKRLWYCM-DCAQKATOSA-N 0.000 description 1
- PYNUBZSXKQKAHL-UWVGGRQHSA-N His-Gly-Arg Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O PYNUBZSXKQKAHL-UWVGGRQHSA-N 0.000 description 1
- GNBHSMFBUNEWCJ-DCAQKATOSA-N His-Pro-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O GNBHSMFBUNEWCJ-DCAQKATOSA-N 0.000 description 1
- FFKJUTZARGRVTH-KKUMJFAQSA-N His-Ser-Tyr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O FFKJUTZARGRVTH-KKUMJFAQSA-N 0.000 description 1
- GYXDQXPCPASCNR-NHCYSSNCSA-N His-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N GYXDQXPCPASCNR-NHCYSSNCSA-N 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- NKVZTQVGUNLLQW-JBDRJPRFSA-N Ile-Ala-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O)N NKVZTQVGUNLLQW-JBDRJPRFSA-N 0.000 description 1
- SACHLUOUHCVIKI-GMOBBJLQSA-N Ile-Arg-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N SACHLUOUHCVIKI-GMOBBJLQSA-N 0.000 description 1
- ZXJFURYTPZMUNY-VKOGCVSHSA-N Ile-Arg-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)[C@@H](C)CC)C(O)=O)=CNC2=C1 ZXJFURYTPZMUNY-VKOGCVSHSA-N 0.000 description 1
- RPZFUIQVAPZLRH-GHCJXIJMSA-N Ile-Asp-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)O)N RPZFUIQVAPZLRH-GHCJXIJMSA-N 0.000 description 1
- JHCVYQKVKOLAIU-NAKRPEOUSA-N Ile-Cys-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)O)N JHCVYQKVKOLAIU-NAKRPEOUSA-N 0.000 description 1
- KUHFPGIVBOCRMV-MNXVOIDGSA-N Ile-Gln-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(C)C)C(=O)O)N KUHFPGIVBOCRMV-MNXVOIDGSA-N 0.000 description 1
- PHIXPNQDGGILMP-YVNDNENWSA-N Ile-Glu-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N PHIXPNQDGGILMP-YVNDNENWSA-N 0.000 description 1
- KFVUBLZRFSVDGO-BYULHYEWSA-N Ile-Gly-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O KFVUBLZRFSVDGO-BYULHYEWSA-N 0.000 description 1
- MQFGXJNSUJTXDT-QSFUFRPTSA-N Ile-Gly-Ile Chemical compound N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)O MQFGXJNSUJTXDT-QSFUFRPTSA-N 0.000 description 1
- LBRCLQMZAHRTLV-ZKWXMUAHSA-N Ile-Gly-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LBRCLQMZAHRTLV-ZKWXMUAHSA-N 0.000 description 1
- CMNMPCTVCWWYHY-MXAVVETBSA-N Ile-His-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC(C)C)C(=O)O)N CMNMPCTVCWWYHY-MXAVVETBSA-N 0.000 description 1
- YNMQUIVKEFRCPH-QSFUFRPTSA-N Ile-Ile-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)O)N YNMQUIVKEFRCPH-QSFUFRPTSA-N 0.000 description 1
- HUWYGQOISIJNMK-SIGLWIIPSA-N Ile-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N HUWYGQOISIJNMK-SIGLWIIPSA-N 0.000 description 1
- HUORUFRRJHELPD-MNXVOIDGSA-N Ile-Leu-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N HUORUFRRJHELPD-MNXVOIDGSA-N 0.000 description 1
- GVKKVHNRTUFCCE-BJDJZHNGSA-N Ile-Leu-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)O)N GVKKVHNRTUFCCE-BJDJZHNGSA-N 0.000 description 1
- PARSHQDZROHERM-NHCYSSNCSA-N Ile-Lys-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)O)N PARSHQDZROHERM-NHCYSSNCSA-N 0.000 description 1
- FFAUOCITXBMRBT-YTFOTSKYSA-N Ile-Lys-Ile Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FFAUOCITXBMRBT-YTFOTSKYSA-N 0.000 description 1
- WVUDHMBJNBWZBU-XUXIUFHCSA-N Ile-Lys-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)O)N WVUDHMBJNBWZBU-XUXIUFHCSA-N 0.000 description 1
- IDMNOFVUXYYZPF-DKIMLUQUSA-N Ile-Lys-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N IDMNOFVUXYYZPF-DKIMLUQUSA-N 0.000 description 1
- IALVDKNUFSTICJ-GMOBBJLQSA-N Ile-Met-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(=O)O)C(=O)O)N IALVDKNUFSTICJ-GMOBBJLQSA-N 0.000 description 1
- VZSDQFZFTCVEGF-ZEWNOJEFSA-N Ile-Phe-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(O)=O VZSDQFZFTCVEGF-ZEWNOJEFSA-N 0.000 description 1
- WLRJHVNFGAOYPS-HJPIBITLSA-N Ile-Ser-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N WLRJHVNFGAOYPS-HJPIBITLSA-N 0.000 description 1
- COWHUQXTSYTKQC-RWRJDSDZSA-N Ile-Thr-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N COWHUQXTSYTKQC-RWRJDSDZSA-N 0.000 description 1
- YBKKLDBBPFIXBQ-MBLNEYKQSA-N Ile-Thr-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)O)N YBKKLDBBPFIXBQ-MBLNEYKQSA-N 0.000 description 1
- JTBFQNHKNRZJDS-SYWGBEHUSA-N Ile-Trp-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](C)C(=O)O)N JTBFQNHKNRZJDS-SYWGBEHUSA-N 0.000 description 1
- ZYVTXBXHIKGZMD-QSFUFRPTSA-N Ile-Val-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ZYVTXBXHIKGZMD-QSFUFRPTSA-N 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 0.000 description 1
- LJHGALIOHLRRQN-DCAQKATOSA-N Leu-Ala-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N LJHGALIOHLRRQN-DCAQKATOSA-N 0.000 description 1
- PBCHMHROGNUXMK-DLOVCJGASA-N Leu-Ala-His Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 PBCHMHROGNUXMK-DLOVCJGASA-N 0.000 description 1
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 1
- KSZCCRIGNVSHFH-UWVGGRQHSA-N Leu-Arg-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O KSZCCRIGNVSHFH-UWVGGRQHSA-N 0.000 description 1
- YOZCKMXHBYKOMQ-IHRRRGAJSA-N Leu-Arg-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N YOZCKMXHBYKOMQ-IHRRRGAJSA-N 0.000 description 1
- STAVRDQLZOTNKJ-RHYQMDGZSA-N Leu-Arg-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STAVRDQLZOTNKJ-RHYQMDGZSA-N 0.000 description 1
- RFUBXQQFJFGJFV-GUBZILKMSA-N Leu-Asn-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O RFUBXQQFJFGJFV-GUBZILKMSA-N 0.000 description 1
- JKGHDYGZRDWHGA-SRVKXCTJSA-N Leu-Asn-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JKGHDYGZRDWHGA-SRVKXCTJSA-N 0.000 description 1
- WGNOPSQMIQERPK-GARJFASQSA-N Leu-Asn-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N WGNOPSQMIQERPK-GARJFASQSA-N 0.000 description 1
- FGNQZXKVAZIMCI-CIUDSAMLSA-N Leu-Asp-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N FGNQZXKVAZIMCI-CIUDSAMLSA-N 0.000 description 1
- MYGQXVYRZMKRDB-SRVKXCTJSA-N Leu-Asp-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN MYGQXVYRZMKRDB-SRVKXCTJSA-N 0.000 description 1
- MMEDVBWCMGRKKC-GARJFASQSA-N Leu-Asp-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N MMEDVBWCMGRKKC-GARJFASQSA-N 0.000 description 1
- DKEZVKFLETVJFY-CIUDSAMLSA-N Leu-Cys-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N DKEZVKFLETVJFY-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
- NEEOBPIXKWSBRF-IUCAKERBSA-N Leu-Glu-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O NEEOBPIXKWSBRF-IUCAKERBSA-N 0.000 description 1
- OGUUKPXUTHOIAV-SDDRHHMPSA-N Leu-Glu-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N OGUUKPXUTHOIAV-SDDRHHMPSA-N 0.000 description 1
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 1
- LLBQJYDYOLIQAI-JYJNAYRXSA-N Leu-Glu-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LLBQJYDYOLIQAI-JYJNAYRXSA-N 0.000 description 1
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 1
- JLWZLIQRYCTYBD-IHRRRGAJSA-N Leu-Lys-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JLWZLIQRYCTYBD-IHRRRGAJSA-N 0.000 description 1
- DDVHDMSBLRAKNV-IHRRRGAJSA-N Leu-Met-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(O)=O DDVHDMSBLRAKNV-IHRRRGAJSA-N 0.000 description 1
- INCJJHQRZGQLFC-KBPBESRZSA-N Leu-Phe-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O INCJJHQRZGQLFC-KBPBESRZSA-N 0.000 description 1
- PTRKPHUGYULXPU-KKUMJFAQSA-N Leu-Phe-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O PTRKPHUGYULXPU-KKUMJFAQSA-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
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 1
- XZNJZXJZBMBGGS-NHCYSSNCSA-N Leu-Val-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O XZNJZXJZBMBGGS-NHCYSSNCSA-N 0.000 description 1
- FDBTVENULFNTAL-XQQFMLRXSA-N Leu-Val-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N FDBTVENULFNTAL-XQQFMLRXSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 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 1
- JGAMUXDWYSXYLM-SRVKXCTJSA-N Lys-Arg-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O JGAMUXDWYSXYLM-SRVKXCTJSA-N 0.000 description 1
- SVJRVFPSHPGWFF-DCAQKATOSA-N Lys-Cys-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SVJRVFPSHPGWFF-DCAQKATOSA-N 0.000 description 1
- KSFQPRLZAUXXPT-GARJFASQSA-N Lys-Cys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N)C(=O)O KSFQPRLZAUXXPT-GARJFASQSA-N 0.000 description 1
- HWMZUBUEOYAQSC-DCAQKATOSA-N Lys-Gln-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O HWMZUBUEOYAQSC-DCAQKATOSA-N 0.000 description 1
- DRCILAJNUJKAHC-SRVKXCTJSA-N Lys-Glu-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DRCILAJNUJKAHC-SRVKXCTJSA-N 0.000 description 1
- WGLAORUKDGRINI-WDCWCFNPSA-N Lys-Glu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGLAORUKDGRINI-WDCWCFNPSA-N 0.000 description 1
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 1
- OWRUUFUVXFREBD-KKUMJFAQSA-N Lys-His-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O OWRUUFUVXFREBD-KKUMJFAQSA-N 0.000 description 1
- QBEPTBMRQALPEV-MNXVOIDGSA-N Lys-Ile-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCCCN QBEPTBMRQALPEV-MNXVOIDGSA-N 0.000 description 1
- IVFUVMSKSFSFBT-NHCYSSNCSA-N Lys-Ile-Gly Chemical compound OC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCCCN IVFUVMSKSFSFBT-NHCYSSNCSA-N 0.000 description 1
- ZXFRGTAIIZHNHG-AJNGGQMLSA-N Lys-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CCCCN)N ZXFRGTAIIZHNHG-AJNGGQMLSA-N 0.000 description 1
- NJNRBRKHOWSGMN-SRVKXCTJSA-N Lys-Leu-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O NJNRBRKHOWSGMN-SRVKXCTJSA-N 0.000 description 1
- MTBBHUKKPWKXBT-ULQDDVLXSA-N Lys-Met-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MTBBHUKKPWKXBT-ULQDDVLXSA-N 0.000 description 1
- YSPZCHGIWAQVKQ-AVGNSLFASA-N Lys-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCN YSPZCHGIWAQVKQ-AVGNSLFASA-N 0.000 description 1
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 1
- PELXPRPDQRFBGQ-KKUMJFAQSA-N Lys-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](CCCCN)N)O PELXPRPDQRFBGQ-KKUMJFAQSA-N 0.000 description 1
- FPQMQEOVSKMVMA-ACRUOGEOSA-N Lys-Tyr-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)NC(=O)[C@H](CCCCN)N)O FPQMQEOVSKMVMA-ACRUOGEOSA-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
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- GAELMDJMQDUDLJ-BQBZGAKWSA-N Met-Ala-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O GAELMDJMQDUDLJ-BQBZGAKWSA-N 0.000 description 1
- SQUTUWHAAWJYES-GUBZILKMSA-N Met-Asp-Arg Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SQUTUWHAAWJYES-GUBZILKMSA-N 0.000 description 1
- AETNZPKUUYYYEK-CIUDSAMLSA-N Met-Glu-Asn Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O AETNZPKUUYYYEK-CIUDSAMLSA-N 0.000 description 1
- MVMNUCOHQGYYKB-PEDHHIEDSA-N Met-Ile-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)NC(=O)[C@H](CCSC)N MVMNUCOHQGYYKB-PEDHHIEDSA-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
- HSJIGJRZYUADSS-IHRRRGAJSA-N Met-Lys-Leu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HSJIGJRZYUADSS-IHRRRGAJSA-N 0.000 description 1
- AOFZWWDTTJLHOU-ULQDDVLXSA-N Met-Lys-Tyr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AOFZWWDTTJLHOU-ULQDDVLXSA-N 0.000 description 1
- SOAYQFDWEIWPPR-IHRRRGAJSA-N Met-Ser-Tyr Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O SOAYQFDWEIWPPR-IHRRRGAJSA-N 0.000 description 1
- JZXKNNOWPBVZEV-XIRDDKMYSA-N Met-Trp-Glu Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N JZXKNNOWPBVZEV-XIRDDKMYSA-N 0.000 description 1
- YJNDFEWPGLNLNH-IHRRRGAJSA-N Met-Tyr-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CS)C(O)=O)CC1=CC=C(O)C=C1 YJNDFEWPGLNLNH-IHRRRGAJSA-N 0.000 description 1
- VYDLZDRMOFYOGV-TUAOUCFPSA-N Met-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCSC)N VYDLZDRMOFYOGV-TUAOUCFPSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- VUFMYRQVVWYHIJ-UHFFFAOYSA-N P(O)(O)(=O)N.P(O)(=O)N Chemical compound P(O)(O)(=O)N.P(O)(=O)N VUFMYRQVVWYHIJ-UHFFFAOYSA-N 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000008900 Pancreatic Ductal Carcinoma Diseases 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- BBDSZDHUCPSYAC-QEJZJMRPSA-N Phe-Ala-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O BBDSZDHUCPSYAC-QEJZJMRPSA-N 0.000 description 1
- ULECEJGNDHWSKD-QEJZJMRPSA-N Phe-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 ULECEJGNDHWSKD-QEJZJMRPSA-N 0.000 description 1
- DPUOLKQSMYLRDR-UBHSHLNASA-N Phe-Arg-Ala Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 DPUOLKQSMYLRDR-UBHSHLNASA-N 0.000 description 1
- MECSIDWUTYRHRJ-KKUMJFAQSA-N Phe-Asn-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O MECSIDWUTYRHRJ-KKUMJFAQSA-N 0.000 description 1
- VUYCNYVLKACHPA-KKUMJFAQSA-N Phe-Asp-His Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N VUYCNYVLKACHPA-KKUMJFAQSA-N 0.000 description 1
- MGECUMGTSHYHEJ-QEWYBTABSA-N Phe-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 MGECUMGTSHYHEJ-QEWYBTABSA-N 0.000 description 1
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 1
- ZLGQEBCCANLYRA-RYUDHWBXSA-N Phe-Gly-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O ZLGQEBCCANLYRA-RYUDHWBXSA-N 0.000 description 1
- VJLLEKDQJSMHRU-STQMWFEESA-N Phe-Gly-Met Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O VJLLEKDQJSMHRU-STQMWFEESA-N 0.000 description 1
- FXPZZKBHNOMLGA-HJWJTTGWSA-N Phe-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FXPZZKBHNOMLGA-HJWJTTGWSA-N 0.000 description 1
- YCCUXNNKXDGMAM-KKUMJFAQSA-N Phe-Leu-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YCCUXNNKXDGMAM-KKUMJFAQSA-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
- GMWNQSGWWGKTSF-LFSVMHDDSA-N Phe-Thr-Ala 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)C(O)=O GMWNQSGWWGKTSF-LFSVMHDDSA-N 0.000 description 1
- BSTPNLNKHKBONJ-HTUGSXCWSA-N Phe-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=CC=C1)N)O BSTPNLNKHKBONJ-HTUGSXCWSA-N 0.000 description 1
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 1
- VGTJSEYTVMAASM-RPTUDFQQSA-N Phe-Thr-Tyr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VGTJSEYTVMAASM-RPTUDFQQSA-N 0.000 description 1
- FRMKIPSIZSFTTE-HJOGWXRNSA-N Phe-Tyr-Phe Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O FRMKIPSIZSFTTE-HJOGWXRNSA-N 0.000 description 1
- RGMLUHANLDVMPB-ULQDDVLXSA-N Phe-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N RGMLUHANLDVMPB-ULQDDVLXSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 241000282405 Pongo abelii Species 0.000 description 1
- INXAPZFIOVGHSV-CIUDSAMLSA-N Pro-Asn-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1 INXAPZFIOVGHSV-CIUDSAMLSA-N 0.000 description 1
- XWYXZPHPYKRYPA-GMOBBJLQSA-N Pro-Asn-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XWYXZPHPYKRYPA-GMOBBJLQSA-N 0.000 description 1
- TXPUNZXZDVJUJQ-LPEHRKFASA-N Pro-Asn-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)N)C(=O)N2CCC[C@@H]2C(=O)O TXPUNZXZDVJUJQ-LPEHRKFASA-N 0.000 description 1
- FUVBEZJCRMHWEM-FXQIFTODSA-N Pro-Asn-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O FUVBEZJCRMHWEM-FXQIFTODSA-N 0.000 description 1
- WPQKSRHDTMRSJM-CIUDSAMLSA-N Pro-Asp-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 WPQKSRHDTMRSJM-CIUDSAMLSA-N 0.000 description 1
- SFECXGVELZFBFJ-VEVYYDQMSA-N Pro-Asp-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SFECXGVELZFBFJ-VEVYYDQMSA-N 0.000 description 1
- SZZBUDVXWZZPDH-BQBZGAKWSA-N Pro-Cys-Gly Chemical compound OC(=O)CNC(=O)[C@H](CS)NC(=O)[C@@H]1CCCN1 SZZBUDVXWZZPDH-BQBZGAKWSA-N 0.000 description 1
- XJROSHJRQTXWAE-XGEHTFHBSA-N Pro-Cys-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XJROSHJRQTXWAE-XGEHTFHBSA-N 0.000 description 1
- FISHYTLIMUYTQY-GUBZILKMSA-N Pro-Gln-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1 FISHYTLIMUYTQY-GUBZILKMSA-N 0.000 description 1
- AQSMZTIEJMZQEC-DCAQKATOSA-N Pro-His-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CO)C(=O)O AQSMZTIEJMZQEC-DCAQKATOSA-N 0.000 description 1
- SMFQZMGHCODUPQ-ULQDDVLXSA-N Pro-Lys-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SMFQZMGHCODUPQ-ULQDDVLXSA-N 0.000 description 1
- NTXFLJULRHQMDC-GUBZILKMSA-N Pro-Met-Asp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@@H]1CCCN1 NTXFLJULRHQMDC-GUBZILKMSA-N 0.000 description 1
- SPLBRAKYXGOFSO-UNQGMJICSA-N Pro-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@@H]2CCCN2)O SPLBRAKYXGOFSO-UNQGMJICSA-N 0.000 description 1
- QAAYIXYLEMRULP-SRVKXCTJSA-N Pro-Pro-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 QAAYIXYLEMRULP-SRVKXCTJSA-N 0.000 description 1
- 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 1
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 1
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 1
- QMABBZHZMDXHKU-FKBYEOEOSA-N Pro-Tyr-Trp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O QMABBZHZMDXHKU-FKBYEOEOSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102000014450 RNA Polymerase III Human genes 0.000 description 1
- 108010078067 RNA Polymerase III Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 102000003661 Ribonuclease III Human genes 0.000 description 1
- 108010057163 Ribonuclease III Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- BRKHVZNDAOMAHX-BIIVOSGPSA-N Ser-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N BRKHVZNDAOMAHX-BIIVOSGPSA-N 0.000 description 1
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-N 0.000 description 1
- BCKYYTVFBXHPOG-ACZMJKKPSA-N Ser-Asn-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N BCKYYTVFBXHPOG-ACZMJKKPSA-N 0.000 description 1
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 1
- 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 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
- INCNPLPRPOYTJI-JBDRJPRFSA-N Ser-Cys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N INCNPLPRPOYTJI-JBDRJPRFSA-N 0.000 description 1
- SWIQQMYVHIXPEK-FXQIFTODSA-N Ser-Cys-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O SWIQQMYVHIXPEK-FXQIFTODSA-N 0.000 description 1
- SMIDBHKWSYUBRZ-ACZMJKKPSA-N Ser-Glu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O SMIDBHKWSYUBRZ-ACZMJKKPSA-N 0.000 description 1
- UOLGINIHBRIECN-FXQIFTODSA-N Ser-Glu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UOLGINIHBRIECN-FXQIFTODSA-N 0.000 description 1
- AEGUWTFAQQWVLC-BQBZGAKWSA-N Ser-Gly-Arg Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O AEGUWTFAQQWVLC-BQBZGAKWSA-N 0.000 description 1
- MIJWOJAXARLEHA-WDSKDSINSA-N Ser-Gly-Glu Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O MIJWOJAXARLEHA-WDSKDSINSA-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
- SFTZTYBXIXLRGQ-JBDRJPRFSA-N Ser-Ile-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SFTZTYBXIXLRGQ-JBDRJPRFSA-N 0.000 description 1
- YMDNFPNTIPQMJP-NAKRPEOUSA-N Ser-Ile-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(O)=O YMDNFPNTIPQMJP-NAKRPEOUSA-N 0.000 description 1
- UBRMZSHOOIVJPW-SRVKXCTJSA-N Ser-Leu-Lys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O UBRMZSHOOIVJPW-SRVKXCTJSA-N 0.000 description 1
- KCGIREHVWRXNDH-GARJFASQSA-N Ser-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N KCGIREHVWRXNDH-GARJFASQSA-N 0.000 description 1
- JLPMFVAIQHCBDC-CIUDSAMLSA-N Ser-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N JLPMFVAIQHCBDC-CIUDSAMLSA-N 0.000 description 1
- ZSLFCBHEINFXRS-LPEHRKFASA-N Ser-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N ZSLFCBHEINFXRS-LPEHRKFASA-N 0.000 description 1
- FBLNYDYPCLFTSP-IXOXFDKPSA-N Ser-Phe-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FBLNYDYPCLFTSP-IXOXFDKPSA-N 0.000 description 1
- WNDUPCKKKGSKIQ-CIUDSAMLSA-N Ser-Pro-Gln Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O WNDUPCKKKGSKIQ-CIUDSAMLSA-N 0.000 description 1
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-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
- WUXCHQZLUHBSDJ-LKXGYXEUSA-N Ser-Thr-Asp Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC(O)=O)C(O)=O WUXCHQZLUHBSDJ-LKXGYXEUSA-N 0.000 description 1
- FGBLCMLXHRPVOF-IHRRRGAJSA-N Ser-Tyr-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FGBLCMLXHRPVOF-IHRRRGAJSA-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
- PCMZJFMUYWIERL-ZKWXMUAHSA-N Ser-Val-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PCMZJFMUYWIERL-ZKWXMUAHSA-N 0.000 description 1
- LLSLRQOEAFCZLW-NRPADANISA-N Ser-Val-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LLSLRQOEAFCZLW-NRPADANISA-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
- LSHUNRICNSEEAN-BPUTZDHNSA-N Ser-Val-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CO)N LSHUNRICNSEEAN-BPUTZDHNSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 108700025695 Suppressor Genes Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- PXQUBKWZENPDGE-CIQUZCHMSA-N Thr-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)N PXQUBKWZENPDGE-CIQUZCHMSA-N 0.000 description 1
- BSNZTJXVDOINSR-JXUBOQSCSA-N Thr-Ala-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O BSNZTJXVDOINSR-JXUBOQSCSA-N 0.000 description 1
- LVHHEVGYAZGXDE-KDXUFGMBSA-N Thr-Ala-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(=O)O)N)O LVHHEVGYAZGXDE-KDXUFGMBSA-N 0.000 description 1
- UKBSDLHIKIXJKH-HJGDQZAQSA-N Thr-Arg-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UKBSDLHIKIXJKH-HJGDQZAQSA-N 0.000 description 1
- JHBHMCMKSPXRHV-NUMRIWBASA-N Thr-Asn-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O JHBHMCMKSPXRHV-NUMRIWBASA-N 0.000 description 1
- PQLXHSACXPGWPD-GSSVUCPTSA-N Thr-Asn-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PQLXHSACXPGWPD-GSSVUCPTSA-N 0.000 description 1
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 1
- LMMDEZPNUTZJAY-GCJQMDKQSA-N Thr-Asp-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O LMMDEZPNUTZJAY-GCJQMDKQSA-N 0.000 description 1
- GNHRVXYZKWSJTF-HJGDQZAQSA-N Thr-Asp-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N)O GNHRVXYZKWSJTF-HJGDQZAQSA-N 0.000 description 1
- KZUJCMPVNXOBAF-LKXGYXEUSA-N Thr-Cys-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KZUJCMPVNXOBAF-LKXGYXEUSA-N 0.000 description 1
- YAAPRMFURSENOZ-KATARQTJSA-N Thr-Cys-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N)O YAAPRMFURSENOZ-KATARQTJSA-N 0.000 description 1
- MQUZMZBFKCHVOB-HJGDQZAQSA-N Thr-Gln-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O MQUZMZBFKCHVOB-HJGDQZAQSA-N 0.000 description 1
- JMGJDTNUMAZNLX-RWRJDSDZSA-N Thr-Glu-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JMGJDTNUMAZNLX-RWRJDSDZSA-N 0.000 description 1
- ONNSECRQFSTMCC-XKBZYTNZSA-N Thr-Glu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ONNSECRQFSTMCC-XKBZYTNZSA-N 0.000 description 1
- LKEKWDJCJSPXNI-IRIUXVKKSA-N Thr-Glu-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 LKEKWDJCJSPXNI-IRIUXVKKSA-N 0.000 description 1
- SLUWOCTZVGMURC-BFHQHQDPSA-N Thr-Gly-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O SLUWOCTZVGMURC-BFHQHQDPSA-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
- KBBRNEDOYWMIJP-KYNKHSRBSA-N Thr-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KBBRNEDOYWMIJP-KYNKHSRBSA-N 0.000 description 1
- AMXMBCAXAZUCFA-RHYQMDGZSA-N Thr-Leu-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMXMBCAXAZUCFA-RHYQMDGZSA-N 0.000 description 1
- VTVVYQOXJCZVEB-WDCWCFNPSA-N Thr-Leu-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O VTVVYQOXJCZVEB-WDCWCFNPSA-N 0.000 description 1
- NZRUWPIYECBYRK-HTUGSXCWSA-N Thr-Phe-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O NZRUWPIYECBYRK-HTUGSXCWSA-N 0.000 description 1
- HUPLKEHTTQBXSC-YJRXYDGGSA-N Thr-Ser-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUPLKEHTTQBXSC-YJRXYDGGSA-N 0.000 description 1
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 1
- CSNBWOJOEOPYIJ-UVOCVTCTSA-N Thr-Thr-Lys Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O CSNBWOJOEOPYIJ-UVOCVTCTSA-N 0.000 description 1
- KAJRRNHOVMZYBL-IRIUXVKKSA-N Thr-Tyr-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAJRRNHOVMZYBL-IRIUXVKKSA-N 0.000 description 1
- XGFYGMKZKFRGAI-RCWTZXSCSA-N Thr-Val-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N XGFYGMKZKFRGAI-RCWTZXSCSA-N 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 241001150496 Tosapusia duplex Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- BIJDDZBDSJLWJY-PJODQICGSA-N Trp-Ala-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O BIJDDZBDSJLWJY-PJODQICGSA-N 0.000 description 1
- PMIJXCLOQFMOKZ-BPUTZDHNSA-N Trp-Asp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N PMIJXCLOQFMOKZ-BPUTZDHNSA-N 0.000 description 1
- PTAWAMWPRFTACW-SZMVWBNQSA-N Trp-Gln-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N PTAWAMWPRFTACW-SZMVWBNQSA-N 0.000 description 1
- VMBBTANKMSRJSS-JSGCOSHPSA-N Trp-Glu-Gly Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O VMBBTANKMSRJSS-JSGCOSHPSA-N 0.000 description 1
- YDTKYBHPRULROG-LTHWPDAASA-N Trp-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](CC1=CNC2=CC=CC=C21)N YDTKYBHPRULROG-LTHWPDAASA-N 0.000 description 1
- YVXIAOOYAKBAAI-SZMVWBNQSA-N Trp-Leu-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 YVXIAOOYAKBAAI-SZMVWBNQSA-N 0.000 description 1
- WMBFONUKQXGLMU-WDSOQIARSA-N Trp-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N WMBFONUKQXGLMU-WDSOQIARSA-N 0.000 description 1
- ABRICLFKFRFDKS-IHPCNDPISA-N Trp-Ser-Tyr Chemical compound C([C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=C(O)C=C1 ABRICLFKFRFDKS-IHPCNDPISA-N 0.000 description 1
- KDGFPPHLXCEQRN-STECZYCISA-N Tyr-Arg-Ile 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@@H](C)CC)C(O)=O KDGFPPHLXCEQRN-STECZYCISA-N 0.000 description 1
- GFZQWWDXJVGEMW-ULQDDVLXSA-N Tyr-Arg-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O GFZQWWDXJVGEMW-ULQDDVLXSA-N 0.000 description 1
- JRXKIVGWMMIIOF-YDHLFZDLSA-N Tyr-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JRXKIVGWMMIIOF-YDHLFZDLSA-N 0.000 description 1
- HKYTWJOWZTWBQB-AVGNSLFASA-N Tyr-Glu-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 HKYTWJOWZTWBQB-AVGNSLFASA-N 0.000 description 1
- UNUZEBFXGWVAOP-DZKIICNBSA-N Tyr-Glu-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UNUZEBFXGWVAOP-DZKIICNBSA-N 0.000 description 1
- GIOBXJSONRQHKQ-RYUDHWBXSA-N Tyr-Gly-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O GIOBXJSONRQHKQ-RYUDHWBXSA-N 0.000 description 1
- FNWGDMZVYBVAGJ-XEGUGMAKSA-N Tyr-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC1=CC=C(C=C1)O)N FNWGDMZVYBVAGJ-XEGUGMAKSA-N 0.000 description 1
- XDGPTBVOSHKDFT-KKUMJFAQSA-N Tyr-Met-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O XDGPTBVOSHKDFT-KKUMJFAQSA-N 0.000 description 1
- CDBXVDXSLPLFMD-BPNCWPANSA-N Tyr-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 CDBXVDXSLPLFMD-BPNCWPANSA-N 0.000 description 1
- QVYFTFIBKCDHIE-ACRUOGEOSA-N Tyr-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CCCCN)C(=O)O)N)O QVYFTFIBKCDHIE-ACRUOGEOSA-N 0.000 description 1
- RMRFSFXLFWWAJZ-HJOGWXRNSA-N Tyr-Tyr-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 RMRFSFXLFWWAJZ-HJOGWXRNSA-N 0.000 description 1
- 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 1
- NVJCMGGZHOJNBU-UFYCRDLUSA-N Tyr-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N NVJCMGGZHOJNBU-UFYCRDLUSA-N 0.000 description 1
- COYSIHFOCOMGCF-WPRPVWTQSA-N Val-Arg-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N COYSIHFOCOMGCF-WPRPVWTQSA-N 0.000 description 1
- COYSIHFOCOMGCF-UHFFFAOYSA-N Val-Arg-Gly Natural products CC(C)C(N)C(=O)NC(C(=O)NCC(O)=O)CCCN=C(N)N COYSIHFOCOMGCF-UHFFFAOYSA-N 0.000 description 1
- BYOHPUZJVXWHAE-BYULHYEWSA-N Val-Asn-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N BYOHPUZJVXWHAE-BYULHYEWSA-N 0.000 description 1
- GXAZTLJYINLMJL-LAEOZQHASA-N Val-Asn-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N GXAZTLJYINLMJL-LAEOZQHASA-N 0.000 description 1
- LNYOXPDEIZJDEI-NHCYSSNCSA-N Val-Asn-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C(C)C)N LNYOXPDEIZJDEI-NHCYSSNCSA-N 0.000 description 1
- NWDOPHYLSORNEX-QXEWZRGKSA-N Val-Asn-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCSC)C(=O)O)N NWDOPHYLSORNEX-QXEWZRGKSA-N 0.000 description 1
- JLFKWDAZBRYCGX-ZKWXMUAHSA-N Val-Asn-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N JLFKWDAZBRYCGX-ZKWXMUAHSA-N 0.000 description 1
- XLDYBRXERHITNH-QSFUFRPTSA-N Val-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)C(C)C XLDYBRXERHITNH-QSFUFRPTSA-N 0.000 description 1
- DDNIHOWRDOXXPF-NGZCFLSTSA-N Val-Asp-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N DDNIHOWRDOXXPF-NGZCFLSTSA-N 0.000 description 1
- PFMAFMPJJSHNDW-ZKWXMUAHSA-N Val-Cys-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N PFMAFMPJJSHNDW-ZKWXMUAHSA-N 0.000 description 1
- HIZMLPKDJAXDRG-FXQIFTODSA-N Val-Cys-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N HIZMLPKDJAXDRG-FXQIFTODSA-N 0.000 description 1
- DJEVQCWNMQOABE-RCOVLWMOSA-N Val-Gly-Asp Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)O)N DJEVQCWNMQOABE-RCOVLWMOSA-N 0.000 description 1
- WFENBJPLZMPVAX-XVKPBYJWSA-N Val-Gly-Glu Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O WFENBJPLZMPVAX-XVKPBYJWSA-N 0.000 description 1
- FXVDGDZRYLFQKY-WPRPVWTQSA-N Val-Gly-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)C(C)C FXVDGDZRYLFQKY-WPRPVWTQSA-N 0.000 description 1
- OPGWZDIYEYJVRX-AVGNSLFASA-N Val-His-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N OPGWZDIYEYJVRX-AVGNSLFASA-N 0.000 description 1
- FTKXYXACXYOHND-XUXIUFHCSA-N Val-Ile-Leu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O FTKXYXACXYOHND-XUXIUFHCSA-N 0.000 description 1
- VENKIVFKIPGEJN-NHCYSSNCSA-N Val-Met-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VENKIVFKIPGEJN-NHCYSSNCSA-N 0.000 description 1
- MGVYZTPLGXPVQB-CYDGBPFRSA-N Val-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](C(C)C)N MGVYZTPLGXPVQB-CYDGBPFRSA-N 0.000 description 1
- PWCJARIQERIIGF-BZSNNMDCSA-N Val-Met-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N PWCJARIQERIIGF-BZSNNMDCSA-N 0.000 description 1
- UXODSMTVPWXHBT-ULQDDVLXSA-N Val-Phe-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N UXODSMTVPWXHBT-ULQDDVLXSA-N 0.000 description 1
- 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 1
- QSPOLEBZTMESFY-SRVKXCTJSA-N Val-Pro-Val Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O QSPOLEBZTMESFY-SRVKXCTJSA-N 0.000 description 1
- LTTQCQRTSHJPPL-ZKWXMUAHSA-N Val-Ser-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N LTTQCQRTSHJPPL-ZKWXMUAHSA-N 0.000 description 1
- PGQUDQYHWICSAB-NAKRPEOUSA-N Val-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N PGQUDQYHWICSAB-NAKRPEOUSA-N 0.000 description 1
- 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 1
- MNSSBIHFEUUXNW-RCWTZXSCSA-N Val-Thr-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N MNSSBIHFEUUXNW-RCWTZXSCSA-N 0.000 description 1
- YQYFYUSYEDNLSD-YEPSODPASA-N Val-Thr-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O YQYFYUSYEDNLSD-YEPSODPASA-N 0.000 description 1
- 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 1
- SVLAAUGFIHSJPK-JYJNAYRXSA-N Val-Trp-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CO)C(=O)O)N SVLAAUGFIHSJPK-JYJNAYRXSA-N 0.000 description 1
- PMKQKNBISAOSRI-XHSDSOJGSA-N Val-Tyr-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N PMKQKNBISAOSRI-XHSDSOJGSA-N 0.000 description 1
- SSKKGOWRPNIVDW-AVGNSLFASA-N Val-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SSKKGOWRPNIVDW-AVGNSLFASA-N 0.000 description 1
- 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 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 235000021068 Western diet Nutrition 0.000 description 1
- 241000269368 Xenopus laevis Species 0.000 description 1
- HMNZFMSWFCAGGW-XPWSMXQVSA-N [3-[hydroxy(2-hydroxyethoxy)phosphoryl]oxy-2-[(e)-octadec-9-enoyl]oxypropyl] (e)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(COP(O)(=O)OCCO)OC(=O)CCCCCCC\C=C\CCCCCCCC HMNZFMSWFCAGGW-XPWSMXQVSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 210000004381 amniotic fluid Anatomy 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000007503 antigenic stimulation Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000011398 antitumor immunotherapy Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 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
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 108010092854 aspartyllysine Proteins 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 101150036080 at gene Proteins 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 208000019804 backache Diseases 0.000 description 1
- 210000000721 basilar membrane Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-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
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 238000011953 bioanalysis Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 201000010983 breast ductal carcinoma Diseases 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 238000007459 endoscopic retrograde cholangiopancreatography Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 210000000222 eosinocyte Anatomy 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229940089256 fungistat Drugs 0.000 description 1
- 108010006664 gamma-glutamyl-glycyl-glycine Proteins 0.000 description 1
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000012637 gene transfection Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 108010085325 histidylproline Proteins 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 230000002390 hyperplastic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 108010078274 isoleucylvaline Proteins 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 108010012058 leucyltyrosine Proteins 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 238000012775 microarray technology Methods 0.000 description 1
- 238000012737 microarray-based gene expression Methods 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000002625 monoclonal antibody therapy Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 210000002797 pancreatic ductal cell Anatomy 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 210000004332 phalangeal cell Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 108010074082 phenylalanyl-alanyl-lysine Proteins 0.000 description 1
- 108010024607 phenylalanylalanine Proteins 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 108010015796 prolylisoleucine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 108010008790 ribosomal phosphoprotein P1 Proteins 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012772 sequence design Methods 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002563 splenic artery Anatomy 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012033 transcriptional gene silencing Methods 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- XZZNDPSIHUTMOC-UHFFFAOYSA-N triphenyl phosphate Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)(=O)OC1=CC=CC=C1 XZZNDPSIHUTMOC-UHFFFAOYSA-N 0.000 description 1
- 108010015666 tryptophyl-leucyl-glutamic acid Proteins 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57434—Specifically defined cancers of prostate
-
- 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
- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/884—Vaccine for a specifically defined cancer prostate
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/136—Screening for pharmacological compounds
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/10—Screening for compounds of potential therapeutic value involving cells
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Pathology (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Analytical Chemistry (AREA)
- Urology & Nephrology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Public Health (AREA)
- Cell Biology (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Hospice & Palliative Care (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Developmental Biology & Embryology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Engineering & Computer Science (AREA)
- Biophysics (AREA)
- General Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
Abstract
本发明描述了用于诊断患前列腺癌(PRC)倾向性的方法。一个实施方案中所述诊断方法包括测定EphA4的表达水平。本发明还提供筛选用于治疗PRC的治疗剂的方法,治疗PRC的方法。本发明还涉及抑制癌细胞生长的方法,所述方法通过将细胞与EPHA4的siRNA的组合物接触进行。本发明还包括治疗癌症的方法。本发明还涉及用于所述方法的产品,包括核酸序列和载体,以及包含它们的组合物。本发明还提供抑制肿瘤细胞的方法,例如胰腺癌细胞,具体是胰管腺癌(PDACa)的方法。
Description
本申请要求2004年2月27日提交的美国临时申请序列号60/548,335以及2004年3月24日提交的美国临时申请序列号60/555,809的优先权,其全文内容包含在此作为参考。
技术领域
本发明涉及检测和诊断患前列腺癌(PRC)和胰管腺癌(PDACa)的倾向性的方法。本发明还涉及治疗和预防前列腺癌和胰管腺癌(PDACa)的方法,具体地,本发明涉及EphA4。
背景技术
前列腺癌(PRC)是男性最为常见的恶性疾病之一,并且是导致美国和欧洲的癌症相关死亡的第二主要原因(Gronberg et al.,2003)。血清前列腺特异性抗原(PSA)的检测可检出早期PRC,并且现在其已经成为筛选高风险人群中的PRC的金标准。
由于西方饮食方式的流行,前列腺癌的发病率在发展中国家中稳定增加,高龄人群的数目也在增加。通过前列腺特异性抗原(PSA)的血清学检测进行早期诊断为治愈性手术提供机会并且显著改善前列腺癌的预后,但是利用根治性前列腺切除术治疗的患者有30%出现复发(Han et al.,2001)。大多数复发性或晚期癌症应答于雄激素消除疗法(androgen ablation therapy),这是由于前列腺癌生长最初是雄激素依赖型的。但是,它们最终进展为雄激素非依赖型疾病,从而不再应答于雄激素消除疗法。前列腺癌最为严重的临床问题是雄激素依赖型前列腺癌对任何其他治疗不应答(Gronberg,2003),确立除雄激素消除疗法之外的抗前列腺癌新疗法是控制前列腺癌的亟待解决的问题。
广为接受的观点是,高级别前列腺上皮内新生物(PIN)是主要的恶性前病变,其没有对腺泡基底膜的浸润,可能发展成浸润性PRC(McNeal andBostwick et al.1986,DeMarzo et al.2003,Abate-Shen et al.2000,Montironi etal.2002,)。PIN不明显升高血清PSA浓度并且不能被超声检出。
高级别PIN作为PRC标记具有高度预测价值,其鉴定需要对同时出现或随后出现的浸润性PRC进行重复活检。仅仅前列腺针刺活检可识别该微小病变,其鉴定需要对同时出现或随后出现的浸润性PRC进行重复活检(Bostwick 2000)。进行饱和型(saturation)前列腺活检以排除任何共存的前列腺癌然后每3-6个月连续重复前列腺活检是目前控制发现患有高级别PIN的患者的唯一方法。但是该诊断的可信度高度依赖于前列腺针刺活检技术,组织学处理,以及进行观察的病理学家的经验(van der Kwast et al.2003)。它们不能很好地区别PRC病变与PRC,也不能鉴定PIN高风险人群中患有浸润性PRC的患者。
因此PIN和PRC的精确鉴定以及经过PIN的前列腺癌发生的理解对于避免浸润性PRC的诊断以及患者管理中的错误是重要的(Steiner 2001)。但是,PIN的自然病程以及推定的PIN到PRC的过渡形式的分子机制仍不清楚并且这些不具有PRC的PIN病变是否应被治疗仍然有争议。
可选,胰管腺癌(PDACa)是西方世界的第五大致死因素,并且是所有恶性病变中病死率最高的疾病之一,仅仅有5年的生存率。在美国,每年估计有30,700名患者被诊断患有胰腺癌,近30,000人死于这些疾病。大多数患者在疾病晚期才被诊断,其对于目前的治疗不应答并且患者可存活数月。仅仅外科切除术可提供治愈的可能性,但是仅有10-20%PDACa患者可能通过切除治愈,甚至在治愈性切除之后,80-90%的患者会复发并死于该病。外科结果以及生活质量的一些改善出现在也接受了化学治疗包括吉西它滨(gemcitabine)和/或放疗(radiation)的患者中,但是对长期生存的影响由于PDACa对任何治疗的严重抗性而变得非常微小。在这种情况下,大多数患者的管理目标是减轻疾病。
因此,确定PDACa的新分子疗法以及鉴定新的PDACa治疗分子靶是胰腺癌治疗目前的要紧问题。
CDNA微阵列技术已经使得正常和恶性细胞中基因表达的复杂图谱以及恶性与对应正常细胞中基因表达的比较成为可能(Okabe et al.,Cancer Res61:2129-37(2001);Kitahara et al.,Cancer Res 61:3544-9(2001);Lin et al.,Oncogene 21:4120-8(2002);Hasegawa et al.,Cancer Res 62:7012-7(2002))。该方法使得理解癌细胞的复杂性质成为可能,并有助于理解癌发生的机制。鉴定在肿瘤中下调的基因可导致对个体癌症更为精确且准确的诊断,并可开发新的治疗靶(Bienz and Clevers,Cell 103:311-20(2000))。为了从全基因组角度公开机制以及发现用于诊断和开发新的治疗药物的靶分子,本发明人利用23040个基因的cDNA微阵列分析了肿瘤细胞的表达图谱(Okabe et al.,Cancer Res 61:2129-37(2001);Kitahara et al.,Cancer Res 61:3544-9(2001);Lin et al.,Oncogene 21:4120-8(2002);Hasegawa et al.,Cancer Res 62:7012-7(2002))。
意在揭示致癌机理的研究已促进了对抗肿瘤剂分子靶的鉴定。例如,法尼酰转移酶(farnesyltransferase)(FTI)的抑制剂已被有效用于在动物模型中治疗Ras依赖性肿瘤,所述抑制剂最初被发展用于抑制与Ras相关的生长信号通路,Ras的激活依赖翻译后法尼基化(posttranslational farnesylation)(He等,Cell 99:335-45(1999))。已联合利用抗癌药及抗HER2单克隆抗体trastuzumab对人类进行了临床试验,用以拮抗原癌基因受体HER2/neu;并已获得乳癌患者的临床反应和总生存率的改善(Lin等,Cancer Res61:6345-9(2001))。选择性灭活bcr-abl融合蛋白质的酪氨酸激酶抑制剂(STI-571)已被发展用于治疗慢性髓细胞性白血病,在该疾病中,bcr-abl酪氨酸激酶的组成性激活(constitutive activation)在白细胞转化中发挥决定性作用。这类药剂意在抑制特定基因产物的致癌活性(Fujita等,Cancer Res61:7722-6(2001))。因此,在癌性细胞中通常被上调的基因产物可作为发展新抗癌剂的潜在靶点。
已经证实,CD8+细胞毒性T淋巴细胞(CTL)能识别在MHCI类分子上呈递的来源于肿瘤相关抗原(TAAs)的表位肽,并溶解肿瘤细胞。自从MAGE家族作为第一例TAA被发现以来,已经采用免疫学方法发现了许多其它TAA(Boon,Int J Cancer 54:177-80(1993);Boon和van der Bruggen,J Exp Med183:725-9(1996);van der Bruggen等,Science 254:1643-7(1991);Brichard等,J Exp Med 178:489-95(1993);Kawakami等,J Exp Med 180:347-52(1994))。所发现的某些TAA现已作为免疫治疗靶点而处于临床开发阶段。到目前为止发现的TAA包括MAGE(van der Bruggen等,Science 254:1643-7(1991)),gp100(Kawakami等,J Exp Med 180:347-52(1994)),SART(Shichijo等,J Exp Med 187:277-88(1998)),和NY-ESO-1(Chen等,Proc Natl Acad Sci USA 94:1914-8(1997))。另一方面,已被证实在肿瘤细胞中特异性过表达的基因产物已显示出可被识别为诱导细胞免疫反应的靶点。所述基因产物包括p53(Umano等,Brit J Cancer 84:1052-7(2001)),HER2/neu(Tanaka等,Brit J Cancer 84:94-9(2001)),CEA(Nukaya等,Int JCancer 80:92-7(1999)),等。
尽管关于TAA的基础和临床研究已取得显著进展(Rosenbeg等,NatureMed 4:321-7(1998);Mukherji等,Proc Natl Acad Sci USA 92:8078-82(1995);Hu等,Cancer Res 56:2479-83(1996)),但用于治疗腺癌(包括结肠直肠癌)的可用候补(candidate)TAA的数量是有限的。在癌细胞中大量表达,同时其表达限于癌细胞的TAA应该是免疫治疗靶的有希望的候补物(candidate)。此外,对诱导有效且特异性抗肿瘤免疫反应的新型TAA的鉴定被预期能够促进肽接种策略在多种类型癌中的临床使用(Boon和can der Bruggen,J ExpMed 183:725-9(1996);van der Bruggen等,Science 254:1643-7(1991);Brichard等,J Exp Med 178:489-95(1993);Kawakami等,J Exp Med 180:347-52(1994);Shichijo等,J Exp Med 187:277-88(1998);Chen等,Proc NatlAcad Sci USA 94:1914-8(1997);Harris,J Natl Cancer Inst 88:1442-5(1996);Butterfield等,Cancer Res 59:3134-42(1999);Vissers等,Cancer Res 59:5554-9(1999);van der Burg等,J Immunol 156:3308-14(1996);Tanaka等,Cancer Res 57:4465-8(1997);Fujie等,Int J Cancer 80:169-72(1999);Kikuchi等,Int J Cancer 81:459-66(1999);Oiso等,Int J Cancer 81:387-94(1999))。
已有报道重复指出,来自具体健康供体的肽刺激的外周血单核细胞(PBMC)对该肽产生响应而产生显著水平的IFN-γ,但在铬-51释放试验中几乎不以HLA-A24或-A0201限制性图谱发挥针对肿瘤细胞的细胞毒性作用(Kawano等,Cance Res 60:3550-8(2000);Nishizaka等,Cancer Res 60:4830-7(2000);Tamura等,Jpn J Cancer Res 92:762-7(2001))。但是,HLA-A24和HLA-A0201均为一种在日本人以及高加索人群中常见的HLA等位基因(Date等,Tissue Antigens 47:93-101(1996);Kondo等,J Immunol 155:4307-12(1995);Kubo等,J Immunol 152:3913-24(1994);Imanishi等,Proceeding of the eleventh International Hictocompatibility Workshop andConference Oxford University Press,Oxford,1065(1992);Williams等,TissueAntigen 49:129(1997))。因此,由这些HLA所呈递的癌抗原肽特别适用于治疗日本人和高加索人中的癌症。此外,已知在体外诱导低亲和力CTL通常是使用高浓度肽的结果,所述高浓度肽的使用在抗原呈递细胞(APC)上生成高水平特异性肽/MHC复合物,所述复合物将有效激活这些CTL(Alexander-Miller等,Proc Natl Acad Sci USA 93:4102-7(1996))
发明内容
本发明部分基于这样的发现:与非癌性组织相比编码EphA4的基因在前列腺癌或胰管腺癌(PDACa)中过表达。EphA4的cDNA长度为3468个核苷酸。EphA4的核酸和多肽序列分别显示于SEQ ID NO:1和2。序列数据也可通过以下保藏号获得。
EphA4:L36645,NM_004438
相应地,本发明涉及通过测定患者来源的生物样品诸如组织样品中EphA4的表达水平来诊断或测定受试者中患PRC倾向性的方法。与正常对照水平相比EphA4表达水平的改变例如增加表明所述受试者患有或可能患PRC。
本发明术语“对照水平”指对照样品中检测到的蛋白质或基因的表达水平,并包括正常对照水平。对照水平可为源自单个参照群体或多个表达模式的单个表达模式。例如,对照水平可为以前被检测细胞的表达图谱的数据库。“正常对照水平”指在正常、健康个体中或在已知不患有PRC的个体群体中检测到的基因或蛋白表达水平。正常个体是没有PRC或PIN临床症状的个体。
受试样品中检测到的EphA4表达水平与正常对照水平相比增加表明所述受试者(由其获得样品)患有或可能患PRC。
根据本发明,与正常对照水平相比基因表达增加或降低10%,25%,50%或更高时认为基因表达水平“改变”。可选,如果与正常对照水平相比基因表达增加或降低1,2,5或更多倍数则也认为基因表达改变。表达通过例如在阵列上检测EphA4探针与患者来源的组织样品的基因转录物的选择性杂交来确定。
本发明中,患者来源的组织样品是任何获自受试者的组织,例如已知或可疑患有PRC的患者。例如,所述组织含有上皮细胞。更具体地,所述组织是来自前列腺组织的上皮细胞。
本发明还提供鉴定抑制或增强EphA4基因的表达或其基因产物活性的试剂的方法,所述方法通过将表达EphA4基因的受试细胞与靶试剂接触并测定EphA4基因的表达水平或其基因产物的活性来进行。所述受试细胞可为上皮细胞,诸如获自前列腺以及胰腺组织的上皮细胞。EphA4基因的表达水平或其基因产物的活性与PRC中的EphA4基因的表达水平或其基因产物的活性相比降低表明所述受试试剂是EphA4基因表达或功能的抑制剂并可用于减轻PRC的症状。
本发明中,EphA4可优选用作上调的标记基因。此外,与缺乏受试试剂相比存在该试剂时表达水平或生物活性的降低表明所述试剂是EphA4基因的抑制物并可用于抑制PRC。
本发明还提供包含与EphA4多核苷酸或EphA4多肽结合的检测剂的试剂盒。
EphA4基因也可提供鉴定PRC转化的新化学预防药物的信息,这些化学预防药物可给药所选的PRC高风险人群,即患有高级别PIN的人群,以治疗或预防PRC。
本发明的治疗方法包括治疗或预防受试者中的PRC的方法,包括给予受试者抑制性核酸(例如,反义siRNA,或核酶)组合物的步骤。本发明中,反义组合物降低特定靶基因的表达。例如,该反义组合物可含有与EphA4基因序列互补的核苷酸。可选,本发明的方法可包括给予受试者小干扰RNA(siRNA)组合物。本发明中siRNA组合物降低EphA4核酸的表达。另一方法中,治疗受试者中的PRC通过给予受试者核酶组合物进行。本发明中核酸特异性核酶组合物降低EphA4核酸的表达。
本发明提供抑制细胞生长的方法,提供的方法包括包含将细胞与含有EphA4的小干扰RNA(siRNA)的组合物接触的那些方法。本发明还提供抑制受试者中的肿瘤生长的方法。所述方法包括给予受试者包含EphA4的小干扰RNA(siRNA)。本发明另一方面提供抑制EphA4在生物样品细胞中表达的方法。基因的表达可通过将双链核糖核酸(RNA)分子以足以抑制EphA4基因表达的量导入细胞来进行。本发明另一方面涉及用于例如提供的方法中的产品包括核酸序列和载体以及包含它们的组合物。提供的产品中包括在导入表达EphA4基因的细胞时抑制该基因表达的性质的siRNA分子。这些分子包括含有有义链和反义链的分子,其中有义链包含相应于EphA4靶序列的核糖核苷酸序列,反义链包含与所述有义链互补的核糖核苷酸序列。分子的有义和反义链相互杂交形成双链分子。
本发明也包括疫苗和接种方法。例如,治疗或预防受试者的PRC的方法通过给受试者施用含有核酸EphA4编码的多肽或其免疫活性片段的疫苗来进行。一些实施方案中,将编码EphA4多肽的核酸分子或其片段给予患者。本发明中免疫活性片段是长度比全长天然存在蛋白短并且诱导与全长蛋白诱导的免疫反应相似的免疫反应的多肽。例如,长度至少8个残基并能刺激免疫细胞例如T细胞或B细胞的免疫活性片段。通过检测细胞增生、细胞因子(如IL-2)的产生或抗体的产生来测定免疫细胞刺激。
除非另外定义,这里使用的所有专业和科学术语具有与本发明所属领域的普通技术人员通常理解的具有相同意思。尽管相似或等同于本文所描述的方法和材料可以用于实施或检测本发明,但是合适的方法和材料在下面描述。这里提及的所有出版物、专利申请、专利及其它参考文献的全部内容引入作为参考。在冲突的情况下,用本说明书,包括定义来解释。此外,材料、方法和实施例仅仅是说明性的且没有限制的意思。
这里描述的方法的一个优点是在发现明显的临床症状之前鉴定疾病。通过下列详细的说明书和权利要求书,本发明的其它特征和优点将很明显。
附图简述
图1A图示了鉴定为在PIN到PRC的转变中差异表达的基因的免疫组化分析的结果。EphA4蛋白也在PRC细胞中强烈表达,而来自相同患者的PIN和正常前列腺上皮(N)显示没有EphA4蛋白的表达或所述表达非常弱。PRC,PIN和正常前列腺上皮包括在一个前列腺癌组织中。放大率,x200。
图1B图示了PDACa组织中的免疫组化结果。EphA4蛋白的过表达在胰管癌中观察到,但不能在正常胰管中观察到。
图2图示了Northern印迹分析的照片,显示正常成人组织样品中EphA4的表达模式。EphA4仅在成人睾丸中富含,提示对EphA4的靶向预期可导致人体内的毒性降低。
图3是照片,显示前列腺癌细胞系PC3以及PDACa细胞MIA-Paca2中siRNA对击倒(knock-down)内源EphA4的影响。图3(A)显示RT-PCR的结果。证实通过siRNA表达载体1313si的转染对的EphA4 mRNA的击倒效应,但EGFPsi无此效应。1313si被设计为具体用于EphA4 mRNA序列,EGFPsi用于EGFP mRNA序列。RNA在转染后8小时收获并分析。β2-MG和ACTB用于标准化输入cDNA。
图3(B)是照片,显示集落形成实验的结果。显示利用1313si转染后一周细胞中集落数量显著降低,通过RT-PCR有效证实1313si可击倒EphA4。
图3(C)是照片,显示MMT实验的结果。也显示利用1313si转染的生长细胞数目剧烈减少,但利用EGFPsi转染的情况中则并非如此。
发明内容
除非另外特别指出,本文术语“一种”,“该”和“所述”意指“至少一种”。
本文术语“生物体”指任何由至少一个细胞组成的有生命的实体。有生命的生物体可如单个真核细胞那样简单,或如哺乳动物包括人那样复杂。
本文术语“生物样品”指完整生物体或其组织、细胞或组成部分(例如体液,包括但不限于血液,粘液,淋巴液,滑膜液,脑脊液,唾液,羊水,羊膜脐带血,尿液,阴道液体以及精液)。“生物样品”还指从完整生物体或其细胞、组织或组成部分,或其一部分制备的匀浆物,裂解物,提取物,细胞培养物或组织培养物。最后,“生物样品”指培养基,诸如营养液或凝胶,其中繁殖有生物体,其含有细胞成分诸如蛋白质或核酸分子。
本发明部分基于这样的发现,即与非癌组织相比,编码EphA4的基因在胰管腺癌(PDACa)和前列腺癌(PRC)中过表达。EphA4的cDNA长度为3468个核苷酸。EphA4的核酸和多肽序列分别显示于SEQ ID NO:1和2。序列数据也可可通过以下保藏号获得。
EphA4:L36645,NM_004438
EphA4是具有酪氨酸激酶活性的受体家族之一。伴随它们的ephrin配体的功能在神经系统中得到很好的研究,其中Eph受体与ephrin分子参与后脑形成过程的规划(patterning)、轴突路径诱导以及指导神经嵴细胞的迁移(Dodelet VC,and Pasquale EB.Eph receptors and ephrin lignads:embryogenesisto tumorigenesis.Oncogene,19:5614-5619,2000)。这些分子也调节胚胎血管发育,并且存在一些有关Eph/ephrin与肿瘤发生的相关性的报道(Dodelet VC,and Pasquale EB.Eph receptors and ephrin lignads:embryogenesis totumorigenesis.Oncogene,19:5614-5619,2000)。Eph受体家族由13个成员及其配体ephrin组成,其分成两个亚种类,A-亚类(A1-A5)和B-亚类(B1-B3)。受体基于序列相似性以及配体亲和力分成A亚类(EphA41-A8),和B亚类(EphB1-B4,B6)。A型受体通常结合大多数或全部A型配体,B型受体结合A型以及大多数B型配体(Dodelet VC,and Pasquale EB.Ephreceptors and ephrin lignads:embryogenesis to tumorigenesis.Oncogene,19:5614-5619,2000)。
本发明鉴定的差异表达的基因用于诊断目的,其用作患PRC的倾向性的标记并作为基因靶,其表达被改变以治疗或缓解PRC症状。本文术语“倾向性”表明患PRC的可能性。
通过测定EphA4基因在样品细胞中的表达,可诊断PRC。类似地,测定EphA4基因应答于各种药剂的表达可鉴定治疗PRC的药剂。
本发明包括确定(例如,测定)EphA4的表达。使用通过GeneBankTM数据库入口提供的已知序列的序列信息,用本领域普通技术人员熟知的技术检测并测定了EphA4基因。例如,序列数据库入口内相当于EphA4基因的序列用于构建如在Northern印迹杂交分析中检测PRC对应EphA4基因的RNA序列的探针。探针包括参照序列的至少10、20、50、100、200个核苷酸。作为另一个实例,该序列可用于构建如在基于扩增的检测方法如基于反转录的聚合酶链式反应中特异性扩增EphA4核酸的引物。
用于检测EphA4 mRNA序列的探针通常被设计为与靶mRNA特异性杂交。术语“选择性杂交”以及相关术语指探针及其靶在严谨条件下杂交的能力。例如,杂交如下进行:用“Rapid-hyb缓冲液”在68℃预杂交30min或更长,加入标记探针,68℃保温1h或更长。随后的洗涤步骤可在例如低严谨条件进行。低严谨条件是,例如42℃,2×SSC,0.1%SDS,或优选50℃,2×SSC,0.1%SDS。更优选,采用高严谨条件。高严谨条件是,例如室温、于20min间在2×SSC,0.01%SDS中洗涤3次,随后37℃,于20min间在1×SSC,0.1%SDS中洗涤3次,然后50℃,于20min间在1×SSC,0.1%SDS中洗涤2次。虽然一些因素如温度和盐浓度会影响杂交的严谨性,本领域技术人员可以适当的选择这些因素以获得必要的严谨度。
受试细胞群中,如来源于患者组织样品中的EphA4基因的表达水平接着与参照群体中一些基因的表达水平相比较。参照细胞群包括对比参数已知的一个或多个细胞。可同时测定EphA4基因在来自受试细胞群以及参照细胞群的样品中的表达水平。可选,受试细胞群中EphA4基因的表达水平可通过统计学方法测定,其基于通过分析以前收集自前列腺导管癌细胞(例如PRC细胞)或正常前列腺导管上皮细胞(例如,非PRC细胞)的样品中基因的表达水平获得的结果。
与参照细胞群相比,受试细胞群的基因表达模式是否表明患PRC的倾向性依赖于对照细胞群的组成。如果受试细胞群中基因的表达水平不落入参照细胞群的范围,判定受试者具有患PRC的高风险。
此外,如果参照细胞群由PRC细胞组成,受试细胞群和参照细胞群的类似基因表达模式表明受试细胞群包括PRC细胞。
如果受试细胞群中EphA4基因的表达水平与参照细胞群中的相应EphA4基因表达水平的差异在1.0、1.5、2.0、5.0、10.0倍或更高的倍数,则认为受试细胞群中EphA4基因的表达水平“改变”了。
受试细胞群和参比细胞群之间的差异表达可相对于对照核酸例如看家基因标准化。例如,对照核酸是已知根据细胞的癌性或非癌性状态而不同的核酸。对照核酸在受试和参比细胞群中的表达水平可用于标准化受试和参比群中的信号水平。示例性对照基因包括但不限于,例如β-肌动蛋白,甘油醛-3-磷酸脱氢酶和核糖体蛋白P1。
受试细胞群可与多个参照细胞群相对比。多个参照群中每一个的已知参数可能不同。因此,受试细胞群可以与已知含有例如PRC细胞的第二个参照细胞群,以及与已知含有例如非PRC细胞(正常细胞)的第二个参照细胞群相比。受试细胞包括在来自已知含有或怀疑含有PRC细胞的受试者的组织类型或细胞样品中。
受试细胞是从身体组织或身体流体获得的,如生物流体(例如血液或血清)。例如,受试细胞是从前列腺组织纯化的。优选,受试细胞群包含上皮细胞。上皮细胞优选来自已知或怀疑是癌的组织。参照细胞群中的细胞源自于与受试细胞相似的组织类型。任选,参照细胞群是细胞系,如PRC细胞系(阳性对照)或正常非PRC细胞系(阴性对照)。可供选择地,对照细胞群可源自于已知试验参数或条件的细胞的分子信息数据库。
所述个体优选是哺乳动物。示例性哺乳动物包括,但不限于,例如,人类、非人灵长类、小鼠、大鼠、犬、猫、马,或母牛。
用本领域已知方法,可在蛋白或核酸水平确定本文公开基因的表达。例如,使用特异性识别(即选择性杂交于)本发明核酸的探针的Northern杂交分析可用于确定基因表达。可供选择地,使用基于反转录的PCR试验测定基因表达,如使用对EphA4基因序列特异的引物。也在蛋白水平确定表达,即通过测定EphA4基因产物编码的多肽水平或其生物活性。这种方法是本领域熟知的,包括但不限于例如利用抗基因编码的蛋白的抗体的免疫测定。基因编码的蛋白的生物活性也是通常熟知的。
诊断PRC
本发明中,通过检测来自受试细胞群(即,来源于患者的生物样品)的EphA4多核苷酸的表达水平可诊断PRC。优选地,该受试细胞群包括上皮细胞,例如获自前列腺组织的细胞。基因表达也可自血液或其他体液诸如尿液测定。其它生物样品可用于检测蛋白质水平。例如,通过免疫测定法或常规生物分析法可测定来自待诊断的个体的血液或血清中的蛋白质水平。
在受试细胞或生物样品中测定EphA4基因的表达,并将其与正常对照水平的表达进行比较。正常对照水平是指通常见于未患PRC的群体中的EphA4基因的表达分布图。来源于患者的组织样品中EphA4基因表达水平的改变(例如增加或降低)表明该个体患有或易患PRC。例如,受试群体中EphA4的表达与正常对照水平相比的增加表明该个体患有或易患PRC。
与正常对照水平相比EphA4基因在受试群体中的改变表明所述受试者患有或可能患PRC。例如,EphA4基因改变至少1%,至少5%,至少25%,至少50%,至少60%,至少80%,至少90%或更多表明所述受试者患有或可能患PRC。
具体样品中EphA4的表达水平可通过对与其相应的mRNA或由EphA4编码的蛋白质的定量来进行评估。mRNA的定量方法是本领域技术人员已知的。例如,EphA4的相应mRNA水平可通过Northern印迹或RT-PCR进行评估。EphA4的核苷酸序列已被报道。任何本领域技术人员均可设计出用于定量EphA4基因的探针或引物的核苷酸序列。
EphA4的表达水平还可根据所述基因编码的蛋白质的活性或量进行分析。用于测定EphA4蛋白质的量的方法如下所示。例如,免疫测定法可用于测定生物材料中的蛋白质。任何生物材料均可用于测定蛋白质或其活性。例如,分析血液样品可以估计血清标记物所编码的蛋白质。另一方面,可选择适宜的方法从而根据要分析的每种蛋白质的活性来测定由EphA4所编码蛋白质的活性。
在本发明中,还提供了用于诊断患PRC倾向性的诊断剂。本发明的诊断剂包括与本发明的多核苷酸或多肽结合的化合物。优选地,可将与EphA4的多核苷酸杂交的寡核苷酸,或与EphA4的多肽结合的抗体用作所述化合物。
鉴定抑制或增强EphA4基因表达的药剂
抑制EphA4基因的表达或其基因产物活性的药剂可通过如下方法进行鉴定,即通过将表达EphA4基因的受试细胞群与受试药剂接触,并测定EphA4基因的表达水平。与正常对照水平相比(或与缺乏受试药剂时的表达或活性相比),EphA4基因表达水平或其基因产物活性水平的降低表明该药剂是EphA4基因的抑制剂并可用于抑制PRC。
受试细胞群是表达EphA4基因的任何细胞。例如,受试细胞群含有上皮细胞,如来源于前列腺组织的细胞。例如,受试细胞是来源于PRC细胞的无限增殖细胞系。可供选择地,受试细胞是已经被EphA4基因转染或已经被与报道基因可操作连接于报道基因的来自EphA4基因的调节序列(如启动子序列)转染的细胞。
评估对个体中PRC的治疗有效性
本文所鉴定的差异性表达的EphA4序列还可使PRC的疗程得以监测。在该方法中,正在接受PRC治疗的个体提供受试细胞群。如有需要,可在治疗之前、期间或之后的多个时间点从个体取得受试细胞群。然后所述测定细胞群中EphA4基因的表达,并将其与参照细胞群进行比较,所述参照细胞群包括PRC状态已知的细胞。本发明中,所述参照细胞未暴露于治疗。
如果所述参照细胞群不包含PRC细胞,所述受试细胞群和参照细胞群中EphA4基因表达的相似性表明该治疗是有效的。但是,所述试验群和该参照细胞群中EphA4基因的表达有差异,表明临床结果或预后较差。类似地,如果参照细胞群含有PRC细胞,EphA4基因在受试细胞群和参照细胞群中的差异表达表明治疗有效,而EphA4基因在受试细胞群和正常参照细胞群中的表达具有相似性表明临床结果或预后交差。
此外,治疗后获得的受试者来源的生物样品中测定的EphA4基因的表达水平(即治疗后水平)可与获自治疗开始前的受试者来源的生物样品中测定的EphA4基因的表达水平(即治疗前水平)相比较。由于EphA4基因是上调的基因,治疗后样品中表达水平的降低表明目的治疗有效,而治疗后样品中表达水平升高或不变表明临床结果或预后较差。
“有效的”是指治疗导致病理性上调的基因的表达,个体中的PRC大小、患病数或转移可能性降低。当治疗用于预防时,“有效的”是指治疗延缓或阻止PRC形成,或延缓、预防或缓解临床PRC的症状。前列腺肿瘤的评估可利用标准临床方案来进行。
此外,有效性可根据任何诊断和治疗PRC的已知方法关联测定。PRC可例如通过鉴定有症状的异常来诊断,例如体重降低,腹部疼痛,背痛,厌食,恶心,呕吐和全身不适,虚弱以及黄疸。
选择适于具体个体的治疗PRC的治疗剂
个体基因构成的差异可导致其代谢多种药物的相对能力有差异。在个体中被代谢从而作为抗PRC的药剂可通过如下方式使其自身得以显现,即诱导个体细胞中基因表达图谱的变化,即将所述图谱从结肠癌或胃癌癌性状态的特征性图谱改变为非癌性状态的特征性基因表达图谱。由此,本文公开的差异性表达的EphA4使可在来自所选择个体的受试细胞群中检验推定的治疗性或预防性抗PRC剂,以便确定该药剂是否是适于该个体的抗PRC抑制剂。
为鉴定适于PRC抑制剂,将来自该个体的受试细胞群暴露于治疗剂,然后测定EphA4基因的表达。
本发明中,受试细胞群包含表达EphA4基因的PRC细胞。优选地,所述受试细胞是上皮细胞。例如,将受试细胞群在存在候补药剂的情况下进行保温,然后检测受试样品的基因表达图谱并将其与一种或多种参照图(例如PRC参照表达图谱或非PRC参照表达图谱)进行比较。
受试细胞群中EphA4的表达相对于包含PRC的参照细胞群的降低表明该药剂具有治疗性。
本发明中,所述受试药剂可为任何化合物或组合物,示例性受试药剂包括但不限于免疫调节剂。
鉴定治疗剂的筛选试验
本文所述差异性表达的EphA4基因还可用于鉴定用于治疗或预防PRC的候补治疗剂。本发明的方法基于如下方式,即筛选候补治疗剂以便确定其是否将结肠癌或胃癌状态的特征性EphA4基因表达图谱转变为非PRC状态的特征性基因表达图谱。
本发明中,EphA4可用于筛选治疗或预防PRC的治疗剂。
在该方法中,将细胞暴露于受试药剂或多种受试药剂(依序地或联用),然后检测EphA4在细胞中的表达。将试验群中EphA4基因的表达图谱与未暴露于该受试药剂的参照细胞群中EphA4基因的表达水平进行比较。
抑制EphA4基因表达的药剂具有潜在的临床益处。可进一步检测所述药剂预防动物或受试者中PRC的能力。
在其它实施方案中,本发明提供了筛选候补药剂的方法,所述候补药剂是PRC治疗中的潜在靶点。如上面所详述的,通过控制标记基因的表达水平或活性,可以控制PRC的发病和进展。因此,候补药剂(PRC治疗中的潜在靶点)可通过采用表达水平和活性作为指示的筛选方法进行鉴定。在本发明中,所述筛选方法可包括,例如,以下步骤:
a)将受试化合物与多肽接触,所述多肽由选自EphA4的多核苷酸编码;
b)检测所述多肽和受试化合物之间的结合活性;和
c)选择与所述多肽结合的化合物。
或者,本发明的筛选方法可包括以下步骤:
a)将候补化合物与表达EphA4基因的细胞接触,和
b)选择降低EphA4的表达水平的化合物。
表达EphA4基因的细胞包括,例如,由PRC建立的细胞系;所述细胞可用于本发明的上述筛选中。
或者,本发明的筛选方法可包括以下步骤:
a)将受试化合物与多肽接触,所述多肽由EphA4的多核苷酸编码;
b)检测步骤(a)的多肽的生物活性;和
c)选择化合物,其中与不存在该受试化合物时检测到的生物活性相比,所述化合物抑制EphA4的多核苷酸所编码多肽的生物活性。
本发明筛选方法所需要的蛋白质可利用EphA4基因的核苷酸序列作为重组蛋白质而获得。根据EphA4基因及其编码蛋白的信息,本领域技术人员可选择该蛋白质的任何生物活性作为基于所选生物活性的筛选和任何适宜测定所选生物活性的检测方法的指标。
本发明中,EphA4的生物活性优选是酪氨酸激酶活性。本领域技术人员可评估酪氨酸激酶活性。例如,使表达EphA4的细胞与受试化合物在存在[γ-32P]-ATP的条件下接触。然后,测定被EphA4的酪氨酸激酶活性磷酸化的蛋白质。为了检测磷酸化蛋白质,可利用SDS-PAGE或免疫沉淀。此外,可使用识别磷酸化酪氨酸残基的抗体测定磷酸化蛋白质水平。
或者,本发明的筛选方法可包括以下步骤:
a)将候补化合物与细胞接触,所述细胞中已导入载体,所述载体包含EphA4基因的转录调节区以及在该转录调节区控制下表达的报道基因,
b)检测所述报道基因的活性;和
c)选择化合物,其与缺乏受试化合物时相比降低所述报道基因的表达或活性水平。
适宜的报道基因和宿主细胞是本领域中所众所周知的。本发明筛选方法所需要的适宜报告物构建体可通过使用EphA4基因的转录调节区来制备。
本发明的筛选方法中,EphA4可用作优选上调的标记基因。此外,我们鉴定了酪氨酸激酶受体EphA4,其为在浸润性前列腺癌而不是在非浸润性前体PIN(前列腺上皮内肿瘤生成)中特异性过表达的基因,其中利用全基因组cDNA微阵列与激光微光束显微解剖的组合。cDNA阵列和免疫组化证实EphA4在浸润性前列腺癌细胞而不在PIN中特异性过表达,Northern印迹分析显示其表达限于成人睾丸中。EphA4特异性siRNA的击倒效应导致前列腺癌细胞生长的极大抑制。这些发现证实了EphA4与浸润性前列腺癌细胞的生长以及运动性相关,而且酪氨酸激酶受体EphA4可方便地用作新的前列腺癌治疗的分子靶而不产生严重的副作用。因此,抑制EphA4的酪氨酸激酶活性的药剂可用于治疗和预防PRC。
通过筛选而分离的化合物是药物的候补物,所述药物抑制或增强标记基因编码的蛋白质的活性,且可用于治疗或预防PRC。
此外,可通过本发明的筛选方法获得的化合物中还包括其中抑制或增强由标记基因编码的蛋白质的活性的部分结构,通过添加、缺失和/或置换而改变的化合物。
当通过本发明的方法分离的化合物作为药物而施用于人类和其它哺乳动物诸如小鼠、大鼠、豚鼠、兔、鸡、猫、犬、绵羊、猪、牛、猴、狒狒以及猩猩时,该分离的化合物可被直接施用或可采用已知的药物制备方法而被制成剂型。例如,根据需要,该药物可作为糖衣片剂,胶囊剂,酏剂和微囊剂而口服,或以水或任何其它可药用的液体的无菌溶液或悬浮液的注射液形式以非口服施用。例如,该化合物可与可药用的载体或介质,具体而言为无菌水,生理盐水,植物油,乳化剂,悬浮剂,表面活性剂,稳定剂,调味剂,赋形剂,载体,防腐剂,粘合剂,等,在通常可接受的药物制备方法所需的单位剂型中混合。这些制剂中活性成分的量可以得到所述范围内的适宜剂量。
可混合至片剂和胶囊的添加剂的实例是,粘合剂诸如明胶,玉米淀粉,黄蓍胶和阿拉伯胶;赋形剂诸如微晶纤维素;溶胀剂诸如玉米淀粉,明胶和海藻酸;润滑剂诸如硬脂酸镁;增甜剂诸如蔗糖,乳糖或糖精;以及调味剂诸如薄荷,Gaultheria adenothrix油和樱桃红(cherry)。当单位剂型是胶囊时,液体载体诸如油,也可进一步包括在上述成份中。用于注射的无菌组合物可按照标准的药物制备方法采用载体诸如用于注射的蒸馏水进行制备。
生理盐水,葡萄糖,和包含佐剂诸如D-山梨糖醇、D-甘露糖、D-甘露醇和氯化钠的其它等张液可被用作注射用含水溶液。其可与适宜的增溶剂,诸如醇,特别是乙醇,多元醇诸如丙二醇和聚乙二醇,非离子表面活性剂,诸如Polysorbate 80(TM)和HCO-50联合使用。
麻油或大豆油可用作油性液体,其可与用作增溶剂的苯甲酸苄酯或苯甲醇联合使用,且可采用缓冲液诸如磷酸盐缓冲液和醋酸钠缓冲液进行配制;止痛药,诸如盐酸普鲁卡因;稳定剂,诸如苯甲醇和苯酚;和抗氧化剂。可将制备的注射剂装于适宜的安瓿中。
可采用本领域技术人员众所周知的方法将本发明的药物组合物投药患者,例如以动脉内,静脉内,或经皮注射的方式,也可以经鼻内,经支气管,肌内或口服投药。施用的剂量和方法根据患者的体重和年龄以及施用方法而改变;然而,本领域技术人员可常规地选择适宜的施用方法。如果所述化合物可由DNA编码,可将该DNA插入用于基因治疗的载体中,将该载体施用于患者从而实施治疗。施用的剂量和方法根据患者的体重,年龄和症状而改变但本领域技术人员能适当地对其进行选择。
例如,虽然与本发明的蛋白质结合并调节其活性的化合物的剂量依赖于症状,但经口服施用于正常成年个体(体重60kg)时,所述化合物的剂量为约0.1mg-约100mg/日,优选约1.0mg-约50mg/日且更优选约1.0mg-约20mg/日。
当以胃肠外方式(注射剂方式)将化合物施用于正常成年个体(体重60kg)时,虽然根据患者、靶器官、症状和施用方法而存在一些差异,适于静脉内注射的剂量是约0.01mg-约30mg/日,优选约0.1-约20mg/日且更优选约0.1-约10mg/日。而且,当用于其它动物的情况下,适宜的剂量可通过按60kg体重转换来常规计算。
评估患PRC个体的预后
本发明还提供了评估患PRC个体的预后的方法,该方法包括通过在疾病阶段谱期间比较受试细胞群中EphA4基因的表达与来自患者的参照细胞群中所述基因的表达的步骤。通过比较受试细胞群和参照细胞群中EphA4基因的表达,或通过比较来自所述个体的受试细胞群在不同时间的(overtime)基因表达图谱,可对个体的预后进行评估。
例如,与正常对照相比EphA4表达的增加表明预后较为不利。EphA4表达的降低表明受试者的预后较好。分类评分(CS)可用于比较表达图谱。
试剂盒
本发明还提供了PRC-检测试剂,例如,特异性结合或识别EphA4核酸的核酸,诸如与部分EphA4核酸互补的寡核苷酸序列,或结合EphA4核酸所编码的蛋白质的抗体。所述检测试剂可以以试剂盒的形式包装在一起。该试剂盒可在分开的容器中包含核酸或抗体(已结合于固体基质或与将其结合于所述基质的试剂分开包装),对照制剂(阳性和/或阴性),和/或可检测的标记。该试剂盒中可包含实施所述实验的说明书(例如,书面的,磁带,VCR,CD-ROM等)。该实验可以是,例如本领域已知的Northern杂交或夹心ELISA的形式。
例如,将PRC检测试剂固定在固体基质诸如多孔带上从而形成至少一个PRC检测位点。多孔带的测定或检测区可包括多个包含核酸的位点。试验带还可包含阴性和/或阳性对照的位点。或者,对照位点位于与试验带分开的带上。任选地,不同检测位点可包含不同量的固定的核酸,即,第一检测位点上的量较高而随后的位点上的量较低。加入受试样品后,显示可检测信号的位点的数量提供了对样品中存在的PRC量的定量指示。检测位点可被设定为任何适宜的可检测形状,通常为跨越试验带宽度的条或点的形状。
抑制PRC的方法
本发明提供了通过降低EphA4的表达或活性(和其基因产物的活性)治疗或减轻受试者PRC的症状的方法。适宜治疗化合物可预防性或治疗性给予患有或可能患(或易患)PRC的受试者。使用标准临床方法,或通过检测EphA4表达的异常水平或其基因产物的异常活性来鉴定这种受试者。治疗试剂包括细胞周期调节、细胞增殖和蛋白激酶活性的抑制剂。
可选,本发明的治疗方法可包括降低其表达在前列腺细胞中异常升高(“上调的”和“过表达的”)的基因的基因产物的表达和/或功能的步骤。表达可以本领域抑制的多种途径的任意一种来抑制。例如,表达可通过给予受试者抑制或拮抗过表达基因的表达的核酸来抑制,所述核酸例如破坏过表达的基因的表达的反义寡核苷酸或小干扰RNA
反义核酸:
如上述,与EphA4的核苷酸序列对应的反义核酸可用于降低EphA4的表达水平。与在PRC中被上调的EphA4对应的反义核酸可用于治疗PRC。具体来说,本发明的反义核酸可通过如下方式发挥作用,即其与EphA4或与EphA4相应的mRNA结合,由此抑制所述基因的转录或翻译,促进所述mRNA的降解,和/或抑制由核酸EphA4所编码的蛋白质的表达,最终抑制所述蛋白质的功能。术语“反义核酸”包括与靶序列完全互补的核苷酸以及具有一个或多个核苷酸错配的那些核苷酸,只要该反义核酸能与所述靶序列特异性杂交即可。例如,本发明的反义核酸包括在至少15个连续核苷酸的长度上具有至少70%或更高,优选80%或更高,更优选90%或更高,甚至更优选95%或更高同源性的多核苷酸。可将本领域已知的算法用于测定同源性。
百分比同源性(也称为百分比同一性)通常在两条最佳比对的序列之间进行。比对序列(多核苷酸或多肽)以进行比较的方法是本领域已知的。序列的最佳比对和比较可例如利用“Wilbur and Lipman,Proc Natl Acad SciUSA 80:726-30(1983)”中的算法进行。本文术语“基本相同”,“基本同源”以及类似的术语用于利用比较算法诸如本文所述的算法描述两个序列(多肽和多核苷酸),其至少约80%,通常约85%,约90%,约95%,约97%和约99%相同。
本发明的反义核酸衍生物通过以下方式对生成EphA4基因所编码蛋白质的细胞产生作用:与编码所述蛋白质的DNA或mRNA相结合,抑制其转录或翻译,促进所述mRNA降解,抑制所述蛋白质表达,由此抑制该蛋白质的功能。
本发明的反义核酸衍生物可通过与对衍生物无活性的适宜基质混合而被制成外用制剂,诸如搽剂或泥敷剂。
按照需要,该衍生物也可通过加入赋形剂等张剂增溶剂、稳定剂、防腐剂、止痛剂等而被制成片剂、散剂、颗粒剂、胶囊剂、脂质体胶囊剂、注射剂、溶液、滴鼻剂和冻干剂。这些剂型可通过以下已知方法进行制备。
可通过将所述反义核酸衍生物直接施用于患病位点或注射至血管中以便到达患病位点而给予患者。反义封固型介质也可被用于增加耐久性和膜通透性。实例为脂质体、聚左旋赖氨酸、脂质、胆固醇、脂转染素(lipofectin)或这些物质的衍生物。此外,反义寡核苷酸的衍生物和修饰的产物也可用于本发明。所述修饰的产物包括低级烷基膦酸酯修饰,诸如甲基-膦酸酯-型或乙基-膦酸酯-型,磷酸硫化物修饰和膦酰胺(phosphoroamidate)修饰。
本发明的反义核酸衍生物的剂量可根据患者情况进行适当调整并以所需量进行使用。例如,可施用的剂量范围为0.1-100mg/kg,优选0.1-50mg/kg。
本发明的反义核酸抑制本发明的蛋白质的表达,由此可用于抑制本发明的蛋白质的生物活性。而且,由于能够抑制本发明的蛋白质的生物活性,表达抑制剂(包括本发明的反义核酸)是有用的。
本发明的方法可用于改变细胞中EphA4基因的表达。反义核酸与靶细胞中对应EphA4的转录物的结合导致细胞的蛋白质产量减少。寡核苷酸的长度为至少10个核苷酸,并且可与天然存在的转录物一样长。优选,寡核苷酸的长度为大约19到大约25个核苷酸。最优选,寡核苷酸的长度小于大约75,大约50和大约25个核苷酸。
本发明的反义核酸包括修饰的寡核苷酸。例如,硫化的寡核苷酸可用于赋予寡核苷酸核酸酶抗性。
siRNA:
此外,针对EphA4基因的siRNA也可用于降低EphA4基因的表达水平。
本发明的特征在于抑制细胞生长的方法。细胞生长通过将细胞与EphA4的小干扰RNA(siRNA)的组合物接触来抑制。细胞还与转染增强剂接触。细胞可在体内,体外或离体提供。受试者可为哺乳动物,例如人,非人灵长类,小鼠,大鼠,狗,猫,马或牛。所述细胞是胰管腺癌细胞。可选,所述细胞是肿瘤细胞(即癌细胞),诸如癌细胞或腺癌细胞。例如,所述细胞是胰管腺癌细胞。抑制细胞生长是指治疗的细胞以较低速率增殖或其生存力低于未经治疗的细胞。细胞生长可通过本领域已知的增殖试验测定。
术语“siRNA”意指可阻止靶mRNA翻译的双链RNA分子。可以采用将siRNA导入细胞的标准技术,包括其中DNA是RNA转录模板的那些技术。在本发明中,siRNA包括针对上调的基因诸如EphA4的有义核酸序列和反义核酸序列。构建siRNA使其单个转录物具有来自靶基因的有义和互补反义序列例如,发卡结构。
EphA4的siRNA与靶mRNA杂交的并由此通过与正常单链mRNA转录物结合降低或抑制EphA4多肽的产生,从而干扰反义并由此干扰蛋白质的表达。本发明中,siRNA的长度优选低于500,200,100,50,或25个核苷酸。更优选所述siRNA的长度为19-25个核苷酸。为了增强siRNA的抑制活性,核苷酸“u”可添加到靶序列反义链的3’末端。添加的“u”的数目至少微2个通常为2-10个,优选2-5个。添加的“u”在siRNA的反义链的3’末端形成单链。
采用可获自Ambion网站(http://www.ambion.com/techlib/misc/siRNA_finder.html)的siRNA设计计算机程序(design computer program)来设计siRNAs的核苷酸序列。该计算机程序根据以下方案选择用于siRNA合成的核苷酸序列。
siRNA靶部位的选择:
1.从目标转录物的起始密码子AUG开始,扫描下游的AA二核苷酸序列。记录每个AA的存在和3′邻近的19个核苷酸作为潜在的siRNA靶部位。Tuschl等推荐反对设计siRNA接近5′和3′非翻译区(UTRs)和接近起始密码子的区域(75个碱基内),因为这些可能富含调节蛋白结合部位。UTR结合蛋白和/或翻译起始复合物可能妨碍siRNA核酸内切酶复合体的结合。
2.将潜在的靶部位和人的基因组数据库进行比较,并排除考虑与其它编码序列具有显著同源性的任何靶序列。可以使用BLAST进行同源性检索,它可以在NCBI服务器:www.ncbi.nlm.nih.gov/BLAST/找到。
3.选择用于合成的合格靶序列。在Ambion中,沿着用于估计的基因长度可以选择优选的几个靶序列。
本发明还包括含有靶序列核酸序列的分离的核酸分子,例如SEQ ID NO:10或与核酸序列SEQ ID NO:10互补的核酸分子的核苷酸。本文中“分离的核酸”是从其原始环境(例如如果是天然存在的为天然环境)去除的核酸,并由此从其天然状态合成地改变。本发明中,分离的核酸包括DNA,RNA及其衍生物。当分离的核酸是RNA或其衍生物时,核苷酸序列中的碱基“t”被“u”置换。本文术语“互补”是指核酸分子的核苷酸单位间的Watson-Crick或Hoogsteen碱基配对,而术语“结合”是指两种多肽或化合物和/或其相关多肽或化合物间的物理或化学的相互作用。互补核酸在适宜形成含有很少和不含错配的稳定双链体的条件下杂交。此外,本发明分离的核苷酸的有义链和反义链可通过杂交形成双链核苷酸或发夹环结构。在优选实施方案中,所述双链体的每10个配对含有不超过2个错配。在具体优选的实施方案中,双链体的链完全互补时,所述双链体不含错配。对于EphA4该核酸分子的长度小于3468个核苷酸。例如,该核苷酸分子的长度小于大约500,大约200,或大约75个核苷酸。本发明还包括含有本文所述的一或多种核酸的载体,以及含有所述载体的细胞。本发明分离的核酸可用于针对EphA4的siRNA,或编码该siRNA的DNA。当核酸用于siRNA或其编码DNA时,优选有义链的长度不超过约19个核苷酸,更优选不超过约21个核苷酸。
本发明的反义寡核苷酸或siRNA抑制本发明多肽的表达,并有此可用于抑制本发明多肽的生物活性。此外,表达抑制物,包括本发明的反义寡核苷酸或siRNA是有用的,这是由于它们可抑制本发明多肽的生物活性。因此,包含本发明反义寡核苷酸或siRNA的组合物可用于治疗或预防PRC。
抑制细胞生长的方法:
本发明涉及抑制细胞生长,即通过抑制EphA4表达抑制癌细胞生长。EphA4的表达受到特异性靶向EphA4基因的小干扰RNA(siRNA)的抑制。EphA4靶包括,例如SEQ ID NO:10的核苷酸。
非哺乳动物细胞中,双链RNA(dsRNA)对靶基因的表达显示强的特异性沉默效应,其称为RNA干扰(RNAi)(Sharp PA.RNAi and double-strandRNA.Genes Dev.1999 Jan 15;13(2):139-41)。dsRNA通过含有RNase III基序的酶加工成称为小干扰RNA(siRNA)的20-23个核苷酸的dsRNA。siRNA特异性靶向具有多组分核酸酶复合体的互补mRNA(Hammond SM,Bernstein E,Beach D,Hannon GJ.An RNA-directed nuclease mediatespost-transcriptional gene silencing in Drosophila cells.Nature.2000 Mar16;404(6775):293-6.,Hannon GJ. RNA interference.Nature.2002 Jul11;418(6894):244-51.)。哺乳动物细胞中,由20或21mer dsRNA组成并具有19个互补核苷酸以及3’末端非互补胸腺嘧啶或尿嘧啶二聚体的siRNA已经显示具有基因特异性敲除效应而不会诱导基因表达的整体改变(Elbashir SM,Harborth J,Lendeckel W,Yalcin A,Weber K,Tuschl T.Duplexes of21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature.2001 May 24;411(6836):494-8.)。此外,含有小核RNA(snRNA)U6或聚合酶III H1-RNA启动子的质粒有效产生这样的短RNA,起可募集III型RNA聚合酶III并由此可组成性抑制其靶mRNA(Miyagishi M,Taira K.U6promoter-driven siRNAs with four uridine 3′overhangs efficiently suppresstargeted gene expression in mammalian cells.Nat Biotechnol.2002May;20(5):497-500,Brummelkamp TR,Bernards R,Agami R.A System forStable Expression of Short Interfering RNAs in Mammalian Cells Science.296(5567):550-553,April 19,2002.)。
细胞的生长通过将细胞与含有EphA4的siRNA的组合物接触得以抑制。所述细胞进一步与转染药剂接触。适宜的转染药剂是本领域已知的。抑制细胞生长是指细胞以较低速率增殖或与未暴露于所述组合物的细胞相比生存力降低。细胞生长通过本领域已知方法,诸如MTT细胞增殖测定法来测定。
EphA4的siRNA针对EphA4基因序列的单个靶。可选,该siRNA针对EphA4基因序列的多个靶。例如,组合物含有针对EphA4的2,3,4或5或更多个靶序列的EphA4的siRNA。EphA4靶序列是指与EphA4基因部分相同的核苷酸序列。所述靶序列可包括人EphA4基因的5’非翻译(UT)区,开放读框(ORF)或3’未翻译区。可选,该siRNA为与EphA4基因表达的上游或下游调节物互补的核酸序列。上游或下游调节物的实例包括,结合EphA4基因启动子的转录因子,与EphA4多肽相互作用的激酶或磷酸酶,EphA4启动子或增强子。
与靶mRNA选择性杂交的EphA4的siRNA降低或抑制EphA4基因编码的EphA4多肽产物的产生,该过程通过结合通常单链的mrNA转录物,由此干扰翻译并由此干扰蛋白质表达来进行。所述siRNA的长度小于约500,约200,约100,约50,或约25个核苷酸。优选siRNA的长度为19-25个核苷酸。用于制备EphA4 siRNA的示例性核酸序列包括核苷酸序列SEQ IDNO:10作为靶序列的那些。此外,为了增强siRNA的抑制活性,将核苷酸“u”添加到靶序列反义链的3’末端。添加的“u“的数目至少为2,优选2-10,优选2-5。添加的“u”在siRNA的反义链的3’末端形成单链。
所述细胞是任何表达或过表达EphA4的细胞。所述细胞是上皮细胞诸如胰管细胞。可选,所述细胞是肿瘤细胞诸如癌,腺癌,胚细胞瘤,白血病,骨髓瘤或肉瘤的细胞。所述细胞是胰管腺癌细胞。
EphA4的siRNA以能结合mrNA转录物的形式直接引入细胞。可选,编码EphA4的siRNA的DNA是载体。
载体例如通过将EphA4靶序列克隆入表达载体来制备,所述载体与侧接EphA4序列的调控序列以允许两条联表达的方式可操作连接(通过DNA分子的转录)(Lee,N.S.,Dohjima,T.,Bauer,G.,Li,H.,Li,M.-J.,Ehsani,A.,Salvaterra,P.,and Rossi,J.(2002)Expression of小干扰RNAs targetedagainst HIV-1 rev transcripts in human cells.Nature Biotechnology 20:500-505.)。与EphA4 mrNA反义的RNA分子通过第一启动子转录(例如,克隆的DNA 3’的启动子序列),EphA4 mRNA的有义链的RNA分子通过第二启动子(例如克隆的DNA5’的启动子序列)转录。所述有义和反义链在体内杂交产生siRNA以沉默EphA4基因。可选,利用两种构建体产生siRNA构建体的有义和反义链。克隆的EphA4可编码具有二级结构的构建体,例如发夹,其中单个转录物具有靶基因的有义和互补反义序列。
由任意核苷酸序列组成的环序列可位于有义和反义序列之间以形成发夹环结构。因此,本发明还提供具有通式5’-[A]-[B]-[A’]-3’的sirnA,其中[A]是对应SEQ ID NO:10组成的序列的核糖核苷酸序列,
[B]是大约3至大约23个核苷酸的核糖核苷酸序列,和
[A’]是[A]的互补序列组成的核糖核苷酸序列。
[A]区与[A’]杂交,形成[B]区组成的环。环序列的长度优选为3-23个核苷酸。该环序列,例如可选自以下序列组成的组(
http://www.ambion.com/techlib/tb/tb 506.html)。此外,23个核苷酸的环序列也提供活性siRNA(Jacque,J.-M.,Triques,K.,and Stevenson,M.(2002)Modulation of HIV-1 replication by RNA interference.Nature 18:35-438.)。
CCC,CCACC或CCACACC:Jacque,J.M.,Tiiques,K.,and Stevenson,M(2002)Modulation of HIV-1 replication by RNA interference.Nature,Vol.18:35-438。
UUCG:Lee,N.S.,Dohjima,T.,Bauer,G.,Li,H.,Li,M.-J.,Ehsani,A.,Salvaterra,P.,and Rossi,J.(2002)Expression of small interfering RNAs targetedagainst HIV-1 rev transcripts in human cells.Nature Biotechnology 20:500-505.Fruscoloni,P.,Zamboni,M.,and Tocchini-Valentini,G.P.(2003)Exonucleolyticdegradation of double-stranded RNA by an activity in Xenopus laevis germinalvesicles.Proc.Natl.Acad.Sci.USA 100(4):1639-1644。
UUCEPHA42GAGA:Dykxhoorn,D.M.,Novina,C.D.,and Sharp,P.A.(2002)Killing the messenger:Short RNAs that silence gene expression.NatureRevieWs Molecular Cell Biology:57-467。
例如,本发明优选具有发夹环结构的siRNA显示于下文。在下示结构中,环序列可选自CCC,UUCG,CCACC,CCACACC,和UUCEPHA42GAGA组成的组。优选的环序列是UUCEPHA42GAGA(DNA中的“ttcEphA4gaga”)。
GCAGCACCAUCAUCCAUUG-[B]-CEPHA42UGGAUGAUGGUGCUGC(对于靶序列SEQ ID NO:10)
侧接EphA4序列的调控序列是相同或不同的,使得它们的表达独立调控或以时间或空间的方式调控。siRNA在细胞内通过将EphA4基因模板克隆入载体来转录,所述载体含有例如来自小细胞核RNA(snRNA)U6或人H1RNA启动子的RNA聚合酶III转录单元。为将载体引入细胞,使用转染增强剂。FuGENE(Rochediagnostices),Lipofectamine 2000(Invitrogen),Oligofectamine(Invitrogen),and Nucleofector(Wako pure Chemical)可用作转染增强剂。
根据标准方法在体内检测寡核苷酸以及与EphA4 mrNA各部分互补的寡核苷酸降低EphA4在肿瘤细胞(例如,使用诸如胰管腺癌(PDACa)细胞系的胰腺细胞系)中的产生的能力。在与候选siRNA组合物接触的细胞中EphA4基因的产物与缺乏候选组合物的条件下培养的细胞中的情况相比降低利用EphA4的特异性抗体或其它检测策略来检测。检测降低EphA4在基于细胞或无细胞的体外测定法中的产生的序列对细胞生长的抑制效应。在基于细胞的体外测定法中抑制细胞生长的序列在大鼠或小鼠体内检测以证实具有恶性新生物的动物内降低的EphA4产生以及降低的肿瘤细胞生长。
治疗恶性肿瘤的方法;
特征在于EphA4过表达的肿瘤的患者通过给予EphA4的siRNA治疗。siRNA疗法用于抑制EphA4在患有和可能患例如PRC或胰管腺癌(PDACa)的患者中的表达。所述患者通过具体肿瘤类型的标准方法鉴定。,例如通过CT,MRI,ERCP,MRCP,计算机体层照相和超声诊断PRC或胰管腺癌(PDACa)。如果治疗导致治疗益处诸如EphA4表达降低或受试者中的肿瘤大小、发病率和转移可能性降低,则所述治疗有效。当治疗用于防病时,“有效”是指所述治疗延缓和防止肿瘤形成或者防止或缓解肿瘤临床症状。有效性利用任何已知用于诊断或治疗具体肿瘤类型的方法确定。
siRNA疗法通过利用标准载体和/或基因递送系统给予患者siRNA来进行,包括给予已经被修饰以防止其在体内降解的siRNA分子。适宜基因递送系统可包括脂质体,受体介导的递送系统,或病毒载体诸如疱疹病毒,逆转录病毒,腺病毒和腺伴随病毒等。治疗性核酸组合物配制在可药用载体中。所述治疗组合物可包括上述基因递送系统。可药用载体是生物相容性载体,其适于给予动物,例如生理盐水。化合物的治疗有效量是能产生医学所需结果的量,诸如EphA4基因产物减少,细胞生长例如增殖降低,或被治疗动物中肿瘤生长减慢。
胃肠外给药,诸如经静脉内,皮下,肌内和腹腔内递送途径用于递送EphA4的siRNA组合物。对于胰腺肿瘤的治疗,经腹腔动脉、脾动脉和肝总动脉的直接输注是有用的。
任何一名患者的剂量有赖于许多因素,包括患者体积,体表面积,年龄,待给药的具体核酸,性别,给药途径,总体健康状况,同时给药的其它药物。静脉内注射的核酸的剂量为大约106-1022拷贝的核酸分子。
通过标准方法给药多核苷酸,诸如通过注入组织诸如肌肉或皮肤间隙,导入循环或体腔,或通过吸入或吹入。利用可药用液体载体将多核苷酸注入或递送入动物中,例如含水或部分含水的液体载体。所述多核苷酸与脂质体(例如阳离子或阴离子脂质体)结合。所述多核苷酸包括通过靶细胞表达所需的遗传信息,诸如启动子。
抗体:
可供选择地,通过给予结合或否则抑制基因产物功能的化合物来抑制PRC中过表达的基因的基因产物的功能。例如,该化合物是与过表达的基因或基因产物结合的抗体。特异性识别EphA4蛋白的结合药剂也可为例如对于蛋白质特异的配体,或特异性结合蛋白质的合成多肽(见例如,WO2004044011)。
本发明涉及抗体的用途,具体是抗EphA4基因所编码蛋白的抗体,或该抗体的片段。这里使用的术语“抗体”涉及具有特异性结构的免疫球蛋白分子,它仅与用于合成该抗体的抗原(即上调的基因产物)或与其密切相关的抗原相互作用(即结合)。此外,抗体可以是抗体片段或修饰的抗体,只要它结合标志基因所编码的一个或多个蛋白。例如,抗体片段可以是Fab、F(ab)2、Fv或单链Fv(ScFv),其中来自H和L链的Fv片段通过合适的接头连接(Huston J.S.et al.Proc.Natl.Acad.Sci.U.S.A.85:5879-5883(1988))。更具体地说,通过用酶处理抗体,如木瓜蛋白酶或胃蛋白酶,可以产生抗体片段。可供选择地,可以构建编码抗体片段的基因,插入表达载体并在合适的宿主细胞中表达(见例如Co M.S.et al.J.Immunol.152:2968-2976(1994);Better M.and Horwitz A.H.Methods Enzymol.178:476-496(1989);Pluckthun A.and Skerra A.Methods Enzymol.178:497-515(1989);Lamoyi E.Methods Enzymol.121:652-663(1986);Rousseaux J.et al.Methods Enzymol.121:663-669(1986);Bird R.E.and Walker B.W.Trends Biotechnol.9:132-137(1991))。
抗体可以通过与各种分子结合而被修饰,如聚乙二醇(PEG)。本发明提供了这种修饰抗体。修饰抗体可以通过化学修饰抗体获得。这些修饰方法在本领域是常规的。可供选择地,可以获得作为嵌合抗体的抗体,在来源于非人抗体的可变区和来源于人抗体恒定区之间,或作为人源化抗体,包含来源于非人抗体的互补决定区(CDR)、来源于人抗体的框架区(FR),和恒定区。可以使用已知技术制备这种抗体。人源化可通过用人抗体的相应序列取代啮齿类CDR或CDR序列进行(见例如,Verhoeyen et al.,Science239:1534-1536(1988))。因此,所述人源化抗体是嵌合抗体,其中基本上少于完整人抗体可变结构域被来自非人种类的相应序列取代。
包含人可变区以及人框架和恒定区的完整人抗体也可使用。所述抗体可利用本领域已知的各种技术产生。例如,体外方法涉及使用噬菌体上展示的人抗体片段的重组文库(例如,Hoogenboom&Winter,J.Mol.Biol.227:381(1991)。类似地,人抗体可通过将人免疫球蛋白位点引入转基因动物来制备,所述转基因动物例如其中内源免疫球蛋白基因被部分或完全失活的小鼠。所述方法的描述见例如,美国专利6,150,584,5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;5,661,016。
针对癌细胞中所发生的具体分子改变的癌症治疗已经过临床研究和抗癌药的调控性批准而被证实是有效的,所述抗癌药诸如用于治疗晚期乳癌的曲妥单抗(Herceptin),用于治疗慢性髓细胞性白血病(chronic myeloidleukemia)的伊马替尼甲酯(imatinib methylate)(Gleevec),用于治疗非小细胞性肺癌(NSCLC)的吉非替尼(gefitinib)(Iressa),和用于治疗B细胞淋巴瘤和外套细胞淋巴瘤(mantle cell lymphoma)的利妥昔单抗(rabimax)(抗CD20mAb)(Ciardiello F,Tortora G.A novel approach in the treatment of cancer:targeting the epidermal growth factor receptor.Clin Cancer Res.2001 Oct;7(10):2958-70.Review.;Slamon DJ,Leyland-Jones B,Shak S,Fuchs H,PatonV,Bajamonde A,Fleming T,Eiermann W,Wolter J,Pegram M,Baselga J,Norton L.Use of chemotherapy plus a monoclonal antibody against HER2 formetastatic breast cancer that overexpresses HER2.N Engl J Med.2001 Mar 15;344(11):783-92.;Rehwald U,Schulz H,Reiser M,Sieber M,StEphA4k JO,Morschhauser F,Driessen C,Rudiger T,Muller-Hermelink K,Diehl V,EngertA.Treatment of relapsed CD20+Hodgkin lymphoma with the monoclonalantibody rituximab is effective and well tolerated:results of a phase 2 trial of theGerman Hodgkin Lymphoma Study Group.Blood.2003 Jan 15;101(2):420-424.;Fang G,Kim CN,Perkins CL,Ramadevi N,Winton E,Wittmann S和Bhalla KN.(2000).Blood,96,2246-2253.)。这些药物在临床上是有效的,由于其仅靶向转化的细胞,故其耐受性比传统抗癌剂好。因此,所述药物不仅改善了癌症患者的存活率和生活质量,还验证了分子靶向癌症治疗这一概念。此外,在与标准化学疗法联合使用时,经靶向的药物可增强标准化学疗法的功效(Gianni L.(2002).Oncology,63 Suppl 1,47-56.;Klejman A,Rushen L,Morrione A,Slupianek A和Skorski T.(2002).Oncogene,21,5868-5876.)。因此,未来的癌症治疗可涉及传统药物与靶特异性药剂的联用,后者针对肿瘤细胞不同特性诸如血管发生及侵袭力。
这些调节方法可离体或在体外实施(例如,通过在存在所述药剂的条件下培养细胞)或(可选地)在体内实施(例如,通过将药剂施用于个体)。该方法包括施用蛋白质或蛋白质的组合或核酸分子或核酸的组合进行治疗以代偿差异性表达的基因的异常表达或它们的基因产物的异常活性。
特征在于基因的表达水平或基因以及基因产物的生物活性增加(相对于未患有疾病或病症的个体而言)的疾病或病症可用拮抗(即,降低或抑制)一或多种过表达基因的活性的治疗剂来进行治疗。有拮抗活性的治疗剂可在治疗上或预防上进行施用。
因此,可用于本发明的治疗剂包括,例如,(i)过表达或表达低下的基因的多肽,或其类似物、衍生物、片段或同源物;(ii)针对所述过表达的一或多种序列的抗体;(iii)编码表达低下的一或多种基因的核酸;(iv)“功能障碍性(dysfunctional)”反义核酸或核酸(即由于一或多种过表达的序列的编码序列中的异源插入物);(v)小干扰RNA(siRNA);或(vi)调节剂(即,改变过表达/表达低下的多肽与其结合配偶体之间相互作用的抑制剂、激动剂和拮抗剂)。该功能障碍性反义分子可用于通过同源重组而“敲除”多肽的内源功能(参见,例如,Capecchi,Science 244:1288-1292 1989)。
通过定量肽和/或RNA可很容易地检测增加的水平,所述定量可通过获取患者组织样品(例如,从活组织检查组织中),在体外检测其RNA或肽水平、表达的肽的结构和/或活性(或其表达改变的基因的mRNA)来进行。本领域众所周知的方法包括(但不限于)免疫测定法(例如,通过Western印迹分析,免疫沉淀然后进行十二烷基硫酸钠(SDS)聚丙烯酰胺凝胶电泳,免疫细胞化学等)和/或杂交测定法来检测mRNA的表达(例如,Northern测定法,斑点印迹,原位杂交等)。
预防药剂的施用可在异常基因表达的特征症状出现之前进行,由此可防止或(可选地)延迟疾病或病症的进程。
本发明的治疗方法包括将细胞与药剂接触的步骤,所述药剂调节差异性表达的基因的基因产物的一种或多种活性。调节蛋白质活性的药剂的实例包括,但不限于核酸,蛋白质,这些蛋白质、肽、肽模拟物的天然存在的同源配体,或其它小分子。例如,适宜的药剂刺激一种或多种差异性表达低下的基因的一种或多种蛋白质活性。
针对前列腺癌进行免疫
本发明还涉及治疗或预防受试者中的PRC的方法,包括给予所述受试者核酸EphA4编码的多肽或所述多肽的免疫活性片段,或编码所述多肽或其片段的多核苷酸的步骤。疫苗也可作为核酸组合物给药,其中编码EphA4多肽或其片段的DNA或RNA被给药患者。见,例如,Wolff et.al.(1990)Science 247:1465-1468;美国专利5,580,859;5,589,466;5,804,566;5,739,118;5,736,524;5,679,647;和WO98/04720。基于DNA的递送技术的实例包括“裸露的DNA”,协助性(bupivicaine,聚合物,肽介导的)递送,阳离子脂质复合体以及粒子介导的(“基因枪”)或压力介导的递送(见,例如,美国专利5,922,687)。
本发明的多肽也可通过病毒或细菌载体表达。表达载体的实例包括减毒病毒宿主,诸如痘病毒或禽痘病毒。该方法涉及使用痘苗病毒,例如作为载体表达编码EphA4多肽或多肽片段的核苷酸序列。一旦引入宿主,重组痘苗病毒表达免疫原性肽,由此激发免疫反应。痘苗病毒以及用于免疫方案中的方法描述于例如,美国专利4,722,848。另一载体为BCG(BacilleCalmette Guerin)。BCG载体描述于Stover,et al.(1991)Nature 351:456-460。多种用于治疗性给药或免疫的其它载体例如腺病毒载体和腺伴随病毒载体,逆转录病毒载体,伤寒沙门菌(Salmonella typhi)载体,解毒的炭疽热毒素载体等是显而易见的。参见例如,Shata,et al.(2000)Mol.Med.Today6:66-71;Shedlock,et al.(2000)J.Leukoc.Biol.68:793-806;and Hipp,et al.(2000)In Vivo 14:571-85。
给予该多肽和核酸诱导受试者的抗肿瘤免疫。为了诱导抗肿瘤免疫,给予需要的患者EphA4核酸所编码多肽或所述多肽的免疫活性片段,或该多核苷酸编码的多肽或其片段。该多肽或其免疫活性片段可用作抗PRC的疫苗。有些情况下,蛋白或其片段可以以与T细胞受体(TCR)结合的形式给予或由抗原呈递细胞(APC)呈递,如巨噬细胞、树状细胞(DC)或B细胞。由于DC强烈的抗原呈递能力,利用DC是APC中最优选的。
在本发明中,抗PRC和PIN之一或二者的疫苗涉及接种给动物时具有诱导抗肿瘤免疫的功能的物质。根据本发明,EphA4核酸或其片段所编码的多肽或其片段提示是可以诱导抗表达EphA4的PRC细胞的有效和特异性免疫应答的HLA-A24或HLA-A*0201限制性的表位肽。因此,本发明也包括使用该多肽诱导抗肿瘤免疫的方法。通常,抗肿瘤免疫包括免疫反应如下:
-诱导抗肿瘤的细胞毒性淋巴细胞,
-诱导识别肿瘤的抗体,和
-诱导抗肿瘤细胞因子产生。
因此,当将某一蛋白接种给动物可诱导出这些免疫反应中任何一种时,可确定该蛋白具有抗肿瘤免疫诱导作用。蛋白诱导的抗肿瘤免疫可以通过观察在抗该蛋白宿主中的体内或体外免疫系统反应来检测。
例如,本领域熟知检测诱导细胞毒性T淋巴细胞的方法。进入活体的外来物质在抗原呈递细胞(APCs)作用下被呈递给T细胞和B细胞。对APC呈递的抗原起反应的T细胞由于受该抗原刺激,以抗原特异性方式分化成为细胞毒性T细胞(或细胞毒性T淋巴细胞;CTLs),然后增殖(这称为T细胞激活)。因此,可以通过APC将肽呈递给T细胞,并检测CTL诱导来评价某些肽诱导的CTL。此外,APC具有激活CD4+T细胞、CD8+T细胞、巨噬细胞、嗜酸性粒细胞和自然杀伤淋巴细胞的作用。由于CD4+T细胞和CD8+T细胞在抗肿瘤免疫中也很重要,因此可以使用这些细胞的激活作用作为指示剂评价肽的抗肿瘤免疫的激活作用。
本领域熟知使用树状细胞(DCs)作为APC评价CTL诱导活性的方法。DC是APCs中具有最强CTL诱导活动的代表性APC。在这个方法中,使测试多肽最初接触DC,然后这个DC接触T细胞。接触DC后检测具有抗该细胞的细胞毒性作用的T细胞证明测试多肽具有诱导细胞毒性T细胞的活性。可以检测CTL抗肿瘤活性,例如,使用51Cr标记的肿瘤细胞溶解作为指示。可供选择地,也熟知使用3H-胸腺嘧啶核苷摄取活性或LDH(乳糖脱氢酶)释放作为指示评价肿瘤细胞损害程度的方法。
除了DC,外周血单个核细胞(PBMCs)也可以用作APC。报道了通过在GM-CSF和IL-4存在下培养PBMC可以提高CTL的诱导。类似地,已经证明通过在钥孔血蓝蛋白(KLH)和IL-7存在下培养PBMC可诱导CTL。
用这些方法证实具有CTL诱导活性的测试多肽是具有DC激活作用和随后的CTL诱导活性的多肽。因此,诱导抗肿瘤细胞的CTL的多肽可有效作为抗肿瘤疫苗。此外,通过接触多肽获得诱导抗肿瘤CTL能力的APC也可用作抗肿瘤的疫苗。此外,由于APC呈递多肽抗原而获得细胞毒性的CTL也可以用作抗肿瘤疫苗。这种使用由于APC和CTL的抗肿瘤免疫治疗肿瘤的方法称作细胞免疫疗法。
通常,当使用多肽进行细胞免疫疗法时,通过具有不同结构的多个多肽组合以及它们与DC接触来增加CTL诱导的效率是已知的。因此,当用蛋白片段刺激DC时,使用多种类型片段的混合物是有利的。
可供选择地,可以通过观察诱导的抗肿瘤抗体产生来证实多肽诱导的抗肿瘤免疫。例如,当用多肽免疫的实验动物中诱导出抗多肽的抗体,以及当那些抗体抑制肿瘤细胞生长时,可以确定该多肽具有诱导抗肿瘤免疫的能力。
给予本发明的疫苗可诱导抗肿瘤免疫,抗肿瘤免疫的诱导能够治疗和预防PRC。抗癌疗法或预防癌症发生包括任何步骤,如抑制癌细胞的生长,使癌退化和抑制癌症的发生。癌症的个体死亡率降低、血液中肿瘤标志物降低、癌症伴发的可检测症状减轻等等也包括在癌症的治疗或预防中。优选这种治疗和预防效果具有统计学显著性。例如,在观察中,在5%或更低的显著性水平,其中该水平是抗细胞增殖疾病的疫苗的治疗或预防效果与没有给予疫苗的对照相比的。例如,Student′st检验、Mann-Whitney u检验或ANOVA可以用于统计分析。
上面提及的具有免疫活性的蛋白或编码该蛋白的载体可以与佐剂组合。佐剂是指当与具有免疫活性的蛋白一起(或先后)给予时,提高抗该蛋白的免疫反应的化合物。佐剂的实例包括霍乱毒素、沙门氏菌毒素、明矾等等,但不限于这些。此外,本发明的疫苗可以与药学可接受载体适当组合。这种载体的实例是无菌水、生理盐水、磷酸盐缓冲液、培养液等等。此外,根据需要,该疫苗可以含有稳定剂、悬浮剂、防腐剂、表面活性剂等等。该疫苗全身或局部给予。疫苗给药可以通过单次给予或多次给予加强进行。
当使用APC或CTL作为本发明的疫苗,例如可以用回体方法治疗或预防肿瘤。更具体地说,收集接受治疗或预防的受试者的PBMCs,该细胞回体接触多肽,随后诱导APC或CTL,该细胞可以给予受试者。通过编码该多肽的载体回体导入PBMCs也可以诱导APC。体外诱导的APC或CTL在给药前可以体外克隆。通过克隆和培养具有高活性破坏靶细胞的细胞,可以更有效地进行细胞免疫疗法。此外,以这种方式分离的APC和CTL可以用于细胞免疫疗法,不仅抗该细胞所来源的个体,而且抗来自其他个体的类似肿瘤类型。
此外,提供了包含药物有效量的本发明多肽的治疗或预防细胞增生性疾病如癌症的药物组合物。该药物组合物可以用于产生抗肿瘤免疫
抑制PRC的药物组合物
本发明中,适宜的药学配制剂包括适于经口服,经直肠,经鼻,局部(包括经颊和舌下),经阴道或胃肠外(包括经肌内,皮下和静脉内)投药,或适于经吸入或吹入投药的那些制剂。所述制剂可选包装在分散的剂量单位中。
适于经口投药的药物制剂可被合宜地制成分散单位,诸如胶囊剂、扁囊剂或片剂,其各包含预定量的活性成分;散剂或颗粒剂;或溶液、混悬剂或乳剂。活性成分还可制为大丸剂、药糖剂或糊剂,并可以是纯的形式,即无载体。用于经口投药的片剂和胶囊剂可包含常规赋形剂诸如粘合剂、填充剂、润滑剂、崩解剂或湿润剂。片剂可通过压制(compression)或模制(modeling),任选地用一种或多种配制性成分来制备。压制片剂可通过在适宜的机器中将活性成分压制成非流动形式诸如粉末或颗粒(任选与粘合剂、润滑剂、惰性稀释剂、润滑的,表面活性或分散剂混合)来制备。模制片剂可通过在适宜的机器中,将用惰性液体稀释剂湿润的粉末化合物的混合物进行模塑而制备。片剂可根据本领域众所周知的方法进行包衣。口服液体制剂的形式可以是,例如,水性或油性混悬剂、溶液、乳剂、糖浆剂或酏剂,或可以是在使用前用水或其它适宜的载体溶解的干燥产品。所述液体制剂可包含常规添加剂诸如悬浮剂、乳化剂、非水性载体(可包括食用油),或防腐剂。片剂可任选地进行制备,只要其能缓慢或有控制地释放其中的活性成分即可。药片包可含有每月一次服用的一片药物。
用于胃肠外道投药的制剂包括水性和非水性无菌注射液,其可包含抗氧化剂,缓冲液,抑菌剂和溶质,所述成份可使该制剂与目的受体的血液等张;以及包括悬浮剂和增稠剂的水性和非水性无菌混悬剂。所述制剂可被置于单位剂量或多剂量容器,例如密封安瓿和玻璃瓶中,并可以冷冻干燥(冻干)状态保存,在使用前仅需要加入无菌液体载体例如盐水、注射用水。或者,所述制剂可以是连续输注剂。临时注射剂溶液和混悬剂可用先前所述类型的无菌散剂,颗粒剂和片剂进行制备。
用于直肠投药的制剂可以是采用常用载体诸如可可脂或聚乙二醇的栓剂。用于在口中局部投药(例如经颊或舌下)的制剂包括在调味基质诸如蔗糖和阿拉伯胶或西黄蓍胶中的、包含活性成分的锭剂,以及在基质诸如明胶和甘油或蔗糖和阿拉伯胶中的、包含活性成分的芳香重剂(pastill)。对于经鼻内施用,本发明的化合物可以作为液体喷雾剂或分散性粉剂或以滴剂的形式进行使用。滴剂可用水性或非水性基质制备,所述基质中还包含一种或多种分散剂、增溶剂或悬浮剂。液体喷雾剂可适宜地从压力包中递送。
对于通过吸入的投药,化合物可适宜地通过喷雾器(insufflator)、雾化器(nebulizer)、压力包或其它适宜递送喷雾剂的方式进行递送。压力包可包含适宜的推进剂诸如二氯二氟甲烷,三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它适宜的气体。在增压气雾剂的情况下,剂量单位可通过阀瓣来递送经计量的量来确定。
或者,对于通过吸入或吹入的投药,所述化合物可采用干粉组合物的形式,例如所述化合物与适宜的粉末基质诸如乳糖或淀粉的粉末混合物。粉末组合物可以是单位剂量形式,例如,胶囊,药筒,明胶或发泡包,其中借助吸入器或吹入器来施用所述粉末。
其它配制剂包括可植入的装置和粘性贴片;其释放治疗剂。
需要时,可使用适于持续释放活性成分的上述制剂。该药物组合物还可包含其它活性成分诸如抗微生物剂、免疫抑制剂或防腐剂。
应当理解除上面具体描述的成分外,根据需要的制剂类型,本发明的制剂可包括本领域常规的其它药剂,例如,适于经口服投药的药剂可包括调味剂。
优选的单位剂量制剂是包含有效剂量的活性成分的那些制剂(如下述),或其适宜部分。
对于上述各种情况来说,组合物以约0.1-约250mg/kg/日的剂量经口服或经注射进行施用。用于成年人的剂量范围一般是约5mg-约17.5g/日,优选约5mg-约10g/日,最优选约100mg-约3g/日。分散单位剂量形式的片剂或其它单位剂型可合宜地包含有效剂量或其多剂量形式,例如,包含约5mg-约500mg,通常约100mg-约500mg的单位剂量。
施用剂量要依赖多种因素,包括个体的年龄和性别,要进行治疗的具体疾病及其严重度。投药途径也可根据病症及其严重度而改变。无论如何,本领域技术人员可根据上述因素常规计算适宜和最佳剂量。
本发明的多个方面在以下实施例中描述,其并非一步限制本发明权利要求的范围。
除非另外定义,这里使用的所有专业和科学术语具有与本发明所属领域的普通技术人员通常理解的具有相同意思。尽管相似或等同于本文所描述的方法和材料可以用于实施或检测本发明,但是合适的方法和材料在下面描述。
实施本发明的最佳模式
本发明将在以下实施例中进一步描述,所述实施例不限制本发明权利要求的范围。
实施例1:
1.一般方法
患者和组织样品
在获得知情许可的条件下,自26名正在接受根治性前列腺切除术的癌症患者获得组织样品。所有手术样品均处在具有或不具有N1的T2a-T3a临床期,其Gleason得分为5-9。组织病理血诊断由一名病理学家利用LMM进行。所有样本自手术切出后立即埋于TissueTek OCT培养基(Sakura,Tokyo,Japan)中,保存在-80℃备用。在26个PRC组织中,20例癌症和10例高级PIN具有足以用于微阵列研究的RNA量和质。
激光微光束显微解剖和基于T7的RNA扩增
LMM和基于T7的RNA扩增如前所述进行。前列腺肿瘤细胞和正常前列腺导管上皮细胞利用具有脉冲的紫外窄光焦激光(pulsed ultraviolet narrowbeam-focus laser)的EZ切割系统(SL Microtest GmbH,Germany)根据生产商说明选择性分离。DNase处理之后,对总RNA进行两轮基于T7的扩增,从每种样品产生50-100μg aRNA。然后如前所述,通过利用Cy5-dCTP(肿瘤细胞)和Cy3-dCTP(正常细胞)(Amersham Biosciences,Buckinghamshire,UK)进行逆转录,标记来自PRC或PIN细胞以及正常前列腺导管上皮细胞的2.5μg等分量的aRNA(Ono et al.2000)。
cDNA微阵列分析和数据的获取
我们制作了具有选自国家生物技术信息中心(National Center forBiotechnology Information)(NCBI)的UniGene数据库(build#131)的23,040cDNA的全基因组cDNA微阵列。根据前述方法进行构建、杂交、洗涤和扫描(Ono et al.2000)。来自23,040个点的Cy3和Cy5的信号强度经定量通过取代性背景,所述分析利用ArrayVision软件(Imaging Research,Inc.,St.Catharines,Ontario,Canada)进行。随后,调节每个靶点的Cy5(肿瘤)和Cy3(对照)的荧光强度使得52种看家基因的平均Cy3/Cy5比值等于1。由于源自最低信号强度的数据较不可靠,我们确定了每个载片上的截留值(Ono etal.2000)并从进一步分析中排除Cy3和Cy5染色的信号强度低于截留值的基因。对于其它基因。我们利用每种样品的原始数据计算Cy5/Cy3比值。
鉴定从PIN到PRC的过程中发生上调或下调的基因
根据以下标准,我们鉴定了20例PRC和10例PIN中表达改变的基因:1)在超过所检查病例的50%中可获得其表达数据的基因;和2)在超过50%的可提供信息的病例中,在前列腺癌中的表达率超过3.0并且在PIN中在0,5-2.0之间(定义为上调的基因)和在癌症中的表达率超过0.33且在PIN中为0.5-2.0之间(定义为下调的基因)。
免疫组化
利用兔抗-EphA4(EphA4)多克隆抗体对福尔马林固定的和石蜡包埋的前列腺肿瘤切片中EphA4的表达进行免疫染色(Santa Cruz BiotechnologyInc.,Santa Cruz,CA)。前列腺癌组织包括异源的PRC细胞,PIN细胞和正常前列腺上皮细胞。去石蜡的组织切片置于10mM柠檬酸盐缓冲液,pH6.0中,高压灭菌加热到108℃ 15分钟用于抗原复原(antigen retrieval)。切片分别利用稀释度1∶10或1∶100的EphA4一级抗体在湿润小室中于室温保温1小时,并利用过氧化物酶标记的葡聚糖聚合物然后用二氨基联苯显色(DAKO Envision Plus System;DAKO Corporation,Carpinteria,CA)。利用伊红对切片进行复染。对于阴性对照,去除一级抗体。
2.Northern印迹分析
5’-GAAGGCGTGGTCACTAAATGTAA-3’(SEQ ID NO:3)and
5,-TTTAATTTCAGAGGGCGAAGAC-3’(SEQ ID NO:4).根据生产商的说明进行预杂交,杂交和洗涤。利用增光屏对印迹进行放射自显影,在-80℃进行7天。
3.siRNA-构建体和集落形成/MTT测定法
我们使用siRNA表达载体(psiU6BX)用于检测对靶基因的RNAi效应。U6启动子被克隆入基因特异性序列的上游(来自靶转录物的19nt序列,通过短间隔物TTCAAGAGA(SEQ ID NO:9)与相同序列的翻转互补体分离),以5个胸腺嘧啶作为终止信号,整合neo盒从而对遗传霉素(Sigma)具有抗性。EphA4的靶序列为
5’-GCAGCACCATCATCCATTG-3’(SEQ ID NO:10)(1313si),和
5’-GAAGCAGCACGACTTCTTC-3’(SEQ ID NO:11)(EGFPsi)作为阴性对照。针对EphA4完整序列长度设计靶序列。EphA4的核苷酸以及其编码的氨基酸序列分别显示为SEQ ID NO:1和SEQ ID NO:2(Genbank保藏号NM_004438)。PC3前列腺癌细胞系铺于10cm皿(5×105细胞/皿)并利用含有EGFP靶序列(EGFPsi)的psiU6BX以及含有靶序列的psiU6BX利用Lipofectamine 2000(Invitrogen)根据生产商说明进行转染。细胞利用500mg/ml遗传霉素选择一周,转染后8小时收集预备(preliminary)细胞并通过RT-PCR分析证实对EphA4的击倒效应。RT-PCR引物与上文所示的一样。这些细胞也用Giemsa溶液染色并进行MTT测定分别评价集落形成和细胞数目。
4.鉴定在从PIN到前列腺癌的恶性转化过程中上调的EphA4基因
我们的焦点在于PIN和PRC的差异表达以搜索可能参与非浸润性前体PIN向恶性癌症的转化的基因。通过比较20个PRC的表达图谱与10个PIN的表达图谱,我们鉴定了1种上调的基因,EphA4;改变的基因可能与浸润性PRC细胞中的细胞粘附和迁移力有关。EphA4是一种酪氨酸激酶受体,可能通过调节细胞形状和迁移力在神经回路发育以及血管生成中起作用并且起在PRC中的过表达可能与PRC细胞迁移力有关(Kullander et al.2002)。后者中的一些与细胞粘附以及蛋白酶活性有关,提示它们的表达改变可能PIN向PRC的转化过程中通过消除导管结构而对浸润性表型有贡献。
5.免疫组化
为了证实PIN向PRC转化中的基因表达模式,我们对在我们的数据中在PIN向PRC的转化中差异表达的基因进行免疫组化分析。通常,前列腺癌组织包括异源PRC细胞,PIN细胞以及正常前列腺上皮,并且我们比较了与同一患者的相同组织的前列腺癌发生有关的各种细胞的染色模式。如图1所示,EphA4蛋白也在PRC细胞中强表达,而来自相同患者的PIN和正常前列腺上皮中EphA4蛋白的表达很弱或不表达。结果表明该表达图谱分析高度可信。
我们的焦点在于EphA4,因为EphA4是与酪氨酸激酶活性相关的受体之一,并且是药物涉及以及抗癌抗体治疗的理想分子靶。现在多种酪氨酸激酶抑制物正在临床抗癌治疗试验中,包括EGFR(表皮生长因子受体)抑制剂,PDGFR(血小板来源的生长因子受体)抑制剂,和VEGF(血管内皮生长因子)抑制剂(Dancey and Sausville et al.,2003,Morgan et al.,2003)。此外,抗酪氨酸激酶受体ERBB2/Her2(表皮生长因子受体2)的人源化单克隆抗体trastuzumab(Herceptin)对转移性乳腺癌的HER2过表达型亚组有效(Danceyand Sausville et al.,2003)。这些酪氨酸激酶受体作为癌症的药物靶可通过小分子和抗体策略获得。
EphA4是具有酪氨酸激酶活性的受体家族之一。伴随它们的ephrin配体的功能在神经系统中得到很好的研究,其中Eph受体与ephrin分子参与后脑形成过程的规划(patterning)、轴突路径诱导以及指导神经嵴细胞的迁移(Dodelet et al.,2000,Kurai and Pasquale,2003)。这些分子也调节胚胎血管发育,并且存在一些有关Eph/ephrin与肿瘤发生的相关性的报道(Gale andYancopoulos,1999,Dodelet et al.,2000)。Eph受体家族由13个成员及其配体ephrins组成,其分成两个亚种类,A-亚类(A1-A5)和B-亚类(B1-B3)。受体基于序列相似性以及配体亲和力分成A亚类(EphA41-A8),和B亚类(EphB1-B4,B6)。A型受体通常结合大多数或全部A型配体,B型受体结合A型以及大部分B型配体(Dodelet et al.,2000,Kurai and Pasquale,2003)。在前列腺癌组织中,EphA4配体未知。Northern印迹分析显示EphA4在睾丸中很丰富,但在神经系统和其它主要器官中则不然(图2)。最近报道针对其它Eph受体家族成员的抗体,即也在几种癌症中过表达EphA42,可在体外和体内抑制乳腺癌细胞生长(Carles-Kinch et al.,2002,Coffman et al.,2003)。但是,EphA42在成人组织中遍在表达,表明抗体治疗中毒性的可能性大得多。考虑到其酪氨酸激酶活性,膜定位及其限制表达图谱,EphA4是前列腺癌最理想的分子靶之一。
6.前列腺癌细胞系中siRNA介导的生长抑制
为了研究EphA4对前列腺癌的生长或存活的影响,我们具体通过基于哺乳动物载体的RNA干扰(RNAi)技术敲除了它们的内源型表达。siRNA制备型载体的转染导致一些设计为针对EphA4的siRNA中的内源型表达降低(图3A)。siRNA对EphA4转录物的敲除效应导致集落形成试验以及MTT测定法中生长明显受抑制(图3B和3C)。这些发现证实了EphA4在前列腺癌中的过表达与癌细胞生长有关以及它们可用作前列腺癌治疗的有用分子靶。
结论是,我们鉴定了EphA4这种在前列腺癌中过表达而不在非浸润性前体PIN中过表达的酪氨酸激酶受体,其与癌细胞生长相关,证实了这种酪氨酸激酶受体是用于前列腺癌治疗的小细胞或抗体的理想分子靶。
实施例2
1.一般方法
细胞系和组织样品
人胰腺细胞系PK45 P,KLM1 and MIA-PaCa2(ATCC号:CRL-1420)获自Cell Resource Center for Biomedical Research,Institute of Development,Agingand Cancer,Tohoku University。所述细胞是公众可得的。
利用cDNA微阵列分离在PDACa细胞中过表达的基因
已经描述了cDNA微阵列玻片的制作(Ono K,Tanaka T,Tsunoda T,Kitahara O,Kihara C,Okamoto A,Ochiai K,Takagi T,and Nakamura Y.CancerRes.,60:5007-5011,2000)。对于表达图谱的每次分析,制备一式两份含有大约27000个DNA点的cDNA微阵列玻片。简言之,自PDACa细胞纯化总RNA,正常胰管上皮自18份胰腺癌组织通过显微解剖获得。基于进行T7的RNA扩增获得适合微阵列试验的RNA。自PDACa细胞和正常细胞上皮扩增的RNA的等分试样通过反转录分别利用Cy5-dCTP和Cy3-dCTP(Amersham Biosciences)标记。如前所述进行杂交,洗涤和检测(OnoK,Tanaka T,Tsunoda T,Kitahara O,Kihara C,Okamoto A,Ochiai K,Takagi T,and Nakamura Y.Cancer Res.,60:5007-5011,2000)。随后,在上调的基因中,焦点集中在四种基因上,包括EphA4,这是由于根据我们以前获自29个政查过那人组织中的基因表达数据,其表达率在超过50%的信息性癌症中超过5.0并且其表达水平在正常主要生命器官中相对较低(Saito-Hisaminato A,Katagiri T,Kakiuchi S,Nakamura T,Tsunoda T,Nakamura Y.Genome-wideprofiling of gene expression in 29 normal human tissues with a cDNA microarray.DNA Res.,9:35-45,2002)。
EphA4的半定量RT-PCR
来自显微解剖的PDACa细胞以及正常胰管上皮细胞经过两轮通过基于T7的体外转录进行的扩增(Epicentre Technologies)并被合成为单链cDNA。制备稀释度合适的每种单链cDNA用于通过监测β-肌动蛋白(ACTB)和β2-MG作为定量对照进行随后的PCR扩增。本发明人使用的引物序列为:
5’-GAAGGCGTGGTCACTAAATGTAA-3’(SEQ ID NO:3)和
5’-TTTAATTTCAGAGGGCGAAGAC-3’(SEQ ID NO:4)用于EphA4,
5’-CATCCACGAAACTACCTTCAACT-3’(SEQ.ID.NO.5)和
5’-TCTCCTTAGAGAGAAGTGGGGTG-3’(SEQ.ID.NO.6)用于ACTB,
5’-CACCCCCACTGAAAAAGAGA-3’(SEQ ID NO:7)和
5’-TACCTGTGGAGCAAGGTGC-3’(SEQ ID NO:8)用于β2-MG。
所有反应包括在94℃初始变性2min,然后在GeneAmp PCR系统9700(PE Applied Biosystems)上,于94℃、30s,58℃、30s,和72℃、1min循环21次(对于ACTB和β2-MG)或28-32次(对于EphA4)。
免疫组化
利用兔抗-EphA4(EphA4)多克隆抗体对用福尔马林固定并用石蜡包埋的前列腺肿瘤切片中EphA4的表达进行免疫染色(Santa CruzBiotechnology Inc.,Santa Cruz,CA)。前列腺癌组织包括异源的PRC细胞,PIN细胞和正常前列腺上皮细胞。去石蜡的组织切片置于10mM柠檬酸盐缓冲液,pH6.0中,加热到108℃ 15分钟用于抗原复原(antigen retrieval)。切片分别利用稀释度1∶10或1∶100的EphA4一级抗体在湿润小室中于室温保温1小时,并利用过氧化物酶标记的葡聚糖聚合物然后用二氨基联苯显色(DAKO Envision Plus System;DAKO Corporation,Carpinteria,CA)。利用伊红对切片进行复染。对于阴性对照,去除一级抗体。
2.Northern印迹分析
人多组织Northern印迹(Clontech,Palo Alto,CA)与EphA4的
dCTP-标记的PCR产物杂交,所述产物利用前述引物扩增。根据生产商的说明进行预杂交,杂交和洗涤。利用增光屏对印迹进行放射自显影,在-80℃进行7天。
构建psiU6BX质粒
编码siRNA的DNA片段被插入GAP的核苷酸85-490,所述核苷酸如下面的质粒序列(SEQ ID No:15)中(-)所示:
GACGGATCGGGAGATCTCCCGATCCCCTATGGTGCACTCTCAGTACAATCTGCTCTGGATCCACTAGTAACGGCCGCCAGTGTGCTGGAATTCGGCTTGGGGATCAGCGTTTGAGTAAGAGCCCGCGTCTGAACCCTCCGCGCCGCCCCGGCCCCAGTGGAAAGACGCGCAGGCAAAACGCACCACGTGACGGAGCGTGACCGCGCGCCGAGCGCGCGCCAAGGTCGGGCAGGAAGAGGGCCTATTTCCCATGATTCCTTCATATTTGCATATACGATACAAGGCTGTTAGAGAGATAATTAGAATTAATTTGACTGTAAACACAAAGATATTAGTACAAAATACGTGACGTAGAAAGTA |
ATAATTTCTTGGGTAGTTTGCAGTTTTAAAATTATGTTTTAAAATGGACTATCATATGCTTACCGTAACTTGAAAGTATTTCGATTTCTTGGCTTTATATATCTTGTGGAAAGGACGAAACACC------TTTTTACATCAGGTTGTTTTTCTGTTTGGTTTTTTTTTTACACCACGTTTATACGCCGGTGCACGGTTTACCACTGAAAACACCTTTCATCTACAGGTGATATCTTTTAACACAAATAAAATGTAGTAGTCCTAGGAGACGGAATAGAAGGAGGTGGGGCCTAAAGCCGAATTCTGCAGATATCCATCACACTGGCGGCCGCTCGAGTGAGGCGGAAAGAACCAGCTGGGGCTCTAGGGGGTATCCCCACGCGCCCTGTAGCGGCGCATTAAGCGCGGCGGGTGTGGTGGTTACGCGCAGCGTGACCGCTACACTTGCCAGCGCCCTAGCGCCCGCTCCTTTCGCTTTCTTCCCTTCCTTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGCTCTAAATCGGGGGCTCCCTTTAGGGTTCCGATTTAGTGCTTTACGGCACCTCGACCCCAAAAAACTTGATTAGGGTGATGGTTCACGTAGTGGGCCATCGCCCTGATAGACGGTTTTTCGCCCTTTGACGTTGGAGTCCACGTTCTTTAATAGTGGACTCTTGTTCCAAACTGGAACAACACTCAACCCTATCTCGGTCTATTCTTTTGATTTATAAGGGATTTTGCCGATTTCGGCCTATTGGTTAAAAAATGAGCTGATTTAACAAAAATTTAACGCGAATTAATTCTGTGGAATGTGTGTCAGTTAGGGTGTGGAAAGTCCCCAGGCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCAATTAGTCAGCAACCAGGTGTGGAAAGTCCCCAGGCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCTGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTCCCGGGAGCTTGTATATCCATTTTCGGATCTGATCAAGAGACAGGATGAGGATCGTTTCGCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGC |
GGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGCGGGACTCTGGGGTTCGAAATGACCGACCAAGCGACGCCCAACCTGCCATCACGAGATTTCGATTCCACCGCCGCCTTCTATGAAAGGTTGGGCTTCGGAATCGTTTTCCGGGACGCCGGCTGGATGATCCTCCAGCGCGGGGATCTCATGCTGGAGTTCTTCGCCCACCCCAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTTATCATGTCTGTATACCGTCGACCTCTAGCTAGAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGA |
AGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTC |
snRNAU6基因用RNA聚合酶III转录,产生3’末端具有尿嘧啶的短转录物。snRNAU6基因含有启动子区的基因组片段通过PCR利用以下引物组扩增,
5’-GGGGATCAGCGTTTGAGTAA-3’(SEQ ID No:16),和
5’-TAGGCCCCACCTCCTTCTAT-3’(SEQ ID No:17),其中利用人胎盘DNA作为模板。产物经纯化利用TA克隆试剂盒根据生产商的方案(Invitrogen)克隆入pCR质粒载体。含有snRNAU6基因的BamHI,XhoI片段经纯化克隆入pcDNA3.1(+)质粒的核苷酸1257-56片段,其通过PCR利用以下引物组扩增:
5’-TGCGGATCCAGAGCAGATTGTACTGAGAGT-3’(SEQ ID No:18)和
5’-CTCTATCTCGAGTGAGGCGGAAAGAACCA-3’(SEQ ID No:19)。连接的DNA用作利用以下引物进行PCR的模板,
5’-TTTAAGCTTGAAGACTATTTTTACATCAGGTTGTTTTTCT-3’(SEQID No:20)和
5’-TTTAAGCTTGAAGACACGGTGTTTCGTCCTTTCCACA-3’(SEQ IDNo:21)。产物用HindIII消化,随后自我连接产生psiU6BX载体质粒。为了对照,通过将下示双链核苷酸克隆入psiU6BX载体的BbsI位点来制备psiU6BX-EGFP:
5’-CACCGAAGCAGCACGACTTCTTCTTCAAGAGAGAAGAAGTCGTGCTGCTTC-3’(SEQ ID No:22)和
5’-AAAAGAAGCAGCACGACTTCTTCTCTCTTGAAGAAGAAGTCGTGCTGCTTC-3’(SEQ ID No:23)。
siRNA表达型构建体
siRNA的核苷酸序列利用siRNA设计计算机程序进行设计,所述程序可得自Ambion网站(
http://www.ambion.com/techlib/misc/siRNA finder.html)。简言之,用于siRNA合成的核苷酸序列利用以下方案选择:
siRNA靶部位的选择:
1.从目标转录物的起始密码子AUG开始,扫描下游的AA二核苷酸序列。记录每个AA的存在和3′邻近的19个核苷酸作为潜在的siRNA靶部位。Tuschl等推荐反对设计siRNA接近5′和3′非翻译区(UTRs)和接近起始密码子的区域(75个碱基内),因为这些可能富含调节蛋白结合部位。UTR结合蛋白和/或翻译起始复合物可能妨碍siINA核酸内切酶复合体的结合。
2.将潜在的靶部位和适宜的基因组数据库(人,小鼠,大鼠等)进行比较,并排除考虑与其它编码序列具有显著同源性的任何靶序列。
3.选择用于合成的合格靶序列。沿着基因长度可以选择几个靶序列用于评估。
用于EphA4的siRNA的寡核苷酸显示如下。每种寡核苷酸是靶序列的有义核苷酸序列和反义核苷酸序列的组合。发夹环结构以及靶序列的核苷酸序列分别显示为SEQ ID NO:14和SEQ ID NO:10(内切酶识别位点从每个发夹环结构序列删除).
EphA4的siRNA插入序列
1313si:
5’-CACCGCAGCACCATCATCCATTGTTCAAGAGACAATGGATGATGGTGCTGC-3’(SEQ ID NO:12)和
5’-AAAAGCAGCACCATCATCCATTGTCTCTTGAACAATGGATGATGGTGCTGC-3’(SEQ ID NO:13)
用于对照的siRNA的插入序列
EGFPsi:(对照)
5’-CACCGAAGCAGCACGACTTCTTCTTCAAGAGAGAAGAAGTCGTGCTGCTTC-3’(SEQ ID NO:22)和
5’-AAAAGAAGCAGCACGACTTCTTCTCTCTTGAAGAAGAAGTCGTGCTGCTTC-3’(SEQ ID NO:23)
每种序列的SEQ ID NO列于表1
基因 | siRNA | 效应 | 插入seq SEQ ID NO | 发夹siRNA | 靶SEQ IDNO | 位置 | |
EphA4 | 1313si | + | 12 | 13 | 14 | 10 | 1357-1375 |
对照 | EGFPsi | - | 22 | 23 | 11 |
集落形成/MTT测定法
人PDACa细胞系诸如PK45P,KLM1 and MIA-PaCa2铺于10-cm皿(5×105细胞/皿),并利用Lipofectamine 2000(Invitrogen)或FuGENE6(Roche),根据生产商的说明,用含有EGFP靶序列(EGFP)的psiU6BX和含有靶序列的psiU6BX进行转染。细胞利用500mg/ml遗传霉素选择一周细胞利用500mg/ml遗传霉素选择一周,转染后8小时收集预备细胞并通过RT-PCR分析证实对EphA4的击倒效应。RT-PCR引物与上文所示的一样。这些细胞也用Giemsa溶液染色并进行MTT测定分别评价集落形成和细胞数目。
2.siRNA对基因EphA4的表达的降低以及对癌细胞的生长抑制
在以前的研究中,通过组合激光显微解剖和具有点样的27,000基因的全基因组cNDA微阵列产生了PDACa的精确表达图谱。研究人鉴定了超过200种基因作为与被认为是PDACa来源的正常胰管上皮中的表达图谱相比在PDACa细胞中上调的基因(Nakamura T, Furukawa Y,Nakagawa H,TsunodaT,Ohigashi H,Murata K,Ishikawa O,Ohgaki,Kashimura N,Miyamoto M,Hirano S,Kondo S,Katoh H,Nakamura Y,and Katagiri T.Genome-wide cDNAmicroarray analysis of gene-expression profiles in pancreatic cancers usingpopulations of tumor cells and normal ductal epithelium cells selected for purityby laser microdissection.Oncogene,2004 Feb 9,Epub ahead of print)。基于PDACa细胞的这些表达图谱,本发明人选择了一种过表达型基因EphA4并通过免疫组化证实了在PDACa中的过表达(图1B)。它们的产物是细胞膜蛋白,是抗癌药物涉及和抗体治疗的理想分子靶。临床试验证实抗酪氨酸激酶受体ERBB2/Her2(表皮生长因子受体2)的人源化单克隆抗体trastuzumab(Herceptin)对于转移性乳腺癌的HER2过表达型亚组有效,介导必要的细胞功能和保持恶性表型所需的信号途径的细胞表面分子是目前最有希望的癌症治疗靶(Pegram M,and Slamon DJ.Biological rationale for Her2/neu as atarget for monoclonal antibody therapy.Semin.Oncology,27(suppl 9):13-19,2000)。靶向这些膜分子的药物涉及可通过阻断生长促进型信号和/或利用Trastuzumab在相同的途径中调节ADCC活性来实现。
EphA4(Genbank保藏号NM_004438;SEQ ID No.1,2)
本发明人通过RT-PCR和免疫组化证实了PDACa中EphA4的过表达(图1B),但在胰腺癌组织中,EphA4配体未知。Northern印迹分析(图2)显示EphA4在睾丸中富含,但在中枢神经系统以及其它主要器官中不然。最近靶向另一Eph受体家族成员EphA42(其在几种癌症中过表达)的抗体据报道在体外和体内抑制乳腺癌细胞(Carles-Kinch K,Kilpatrick KE,Stewart JC,Kinch MS.Antibody targeting of the EphA42 tyrosine kinase inhibits malignantcell behavior.Cancer Res.,62:2840-2847,2002)。但是,EphA42在成人组织中遍在表达,表明抗体疗法中毒性的可能性大得多。为了研究EphA4对PDACa细胞的生长或存活的影响,本发明人具体通过siRNA击倒了EphA4在PDACa细胞系中的内源性表达。siRNA诱导型载体的转染明显导致一种针对EphA4设计的siRNA即1313si的内源表达的降低(图3A)。siRNA对EphA4mRNA的击倒效应导致集落形成试验(图3B)和MTT测定法(图3C)中明显的生长抑制。考虑到其酪氨酸激酶活性,膜定位以及其特异性表达模式,EphA4是胰腺癌的最为理想的分子靶之一。
结论是,本发明人鉴定了在PDACa细胞中过表达的四种膜型分子,所有这些分子可能于癌细胞生长相关,提示这些膜型分子是致死性胰腺癌的治疗的理想分子靶,并且这些膜分子的抗体可用于治疗方法中。
工业实用性
本发明所述的方法可用于鉴定用于预防和治疗PRC和PADCa的其它分子靶。本发明的数据有利于全面理解PRC,促进新的诊断策略的开发,并提供治疗药物和预防药剂的分子靶。所述信息有利于更加深入了解前列腺癌发生,并提供开发诊断、治疗和最终预防PRC的新的策略。
本发明还显示细胞生长特异性靶向EphA4基因的小干扰RNA(siRNA)的抑制。因此,siRNA可用于开发抗癌药物。例如,阻断EphA4表达或预防其活性的药剂可用作抗癌剂用于治疗,具体是用于治疗前列腺癌或胰腺癌诸如胰管腺癌(PDACa)的抗癌剂。
本文所引用的全部专利,专利申请,和出版物均为全文引入作为参考。此外,虽然已对照本发明的具体实施方案对本发明进行了详细描述,对本领域技术人员来说,在不背离本发明的精神和范围的情况下可对其进行多种改变和修饰是显而易见的。
对比文件
Abate-Shen,C.,and Shen,M.M. Molecular genetics of prostate cancer.Genes&Dev.,14:2410-2434,2000.
Bostwick,D.G. Prostatic intraepithelial neoplasia.Curr.Urol.Rep.,1:65-70,2000.
DeMarzo,A.M.,Nelson,W.G.,Isaacs,W.B.,and Epstein,J.I.Pathological andmolecular aspects of prostate cancer. Lancet,361:955-964,2003.
Gronberg,H.Prostate cancer epidemiology. Lancet,361:859-64,2003.
Kullander,K.,and Klein,R. Mechanisms and functions of Eph and ephrin signalling.Nat.Rev.Mol.Cell.Biol.,3:75-486,2002.
McNeal,J.E.,and Bostwick,D.G.Intraductal dysplasia:a premalignant lesion of theprostate.Hum.Pathol.,17:64-71,1986.
Montironi R,Mazzucchelli R,Scarpelli M.Precancerous lesions and conditions of the prostate:from morphological and biological characterization to chemoprevention.Ann.N.Y.Acad.Sci.,963:169-184,2002.
Nelson,G.N.,and Wilding,G.Prostate cancer prevention agent:criteria and pipeline forcandidate chemoprevention agents.Urology,57,56-63,2001.
Ono,K.,Tanaka,T.,Tsunoda,T.,Kitahara,O.,Kihara,C.,Okamoto,A.,Ochiai,K.,Takagi,T.,and Nakamura,Y.Alterations of gene expression during colorectal carcinogenesisrevealed by cDNA microarrays after laser-capture microdissection of tumor tissues and normalepithelia. Cancer Res.,60:5007-5011,2000.
Steiner,M.S.High grade prostatic intraepithelial neoplasia is a disease.Curr.Urol.Rep.,2:195-198,2001.
van der Kwast,T.H.,Lopes,C.,Santonja,C.,Pihl,C.G.,Neetens,I.,Martikainen,P.,DiLollo,S.,Bubendorf,L.,Hoedemaeker,R.F.;Members of the pathology committee of theEuropean Randomised Study of Screening for Prostate Cancer. Guidelines for processing andreporting of prostatic needle biopsies.J Clin.Pathol.,56:336-40,2003.
Emmert-Buck,M.R.,Bonner,R.F.,Smith,P.D.,Chuaqui,R.F.,Zhuang,Z.,Goldstein,S.R.,Weiss,R.A.,and Liotta,L.A.Laser capture microdissection.Science,274:998-1001.,1996.
Carles-Kinch K,Kilpatrick KE,Stewart JC,Kinch MS. Antibody targeting of theEphA42 tyrosine kinase inhibits malignant cell behavior. Cancer Res.,62:2840-2847,2002.
Coffman KT,Hu M,Carles-Kinch K,Tice D,Donacki N,Munyon K,Kifle G,Woods R,Langermann S,Kiener PA,Kinch MS.Differential EphA42 epitope display on normal versusmalignant cells.Cancer Res.63:7907-7912,2003.
Dancey J and Sausville EA.Issue and progress with protein kinase inhibitor sfor cancertreatment.Nat.Rev.Drug Discovery 2:296-313,2003.
Dodelet VC,Pasquale EB.Eph receptors and ephrin lignads:embryogenesis totumorigenesis.Oncogene,19:5614-5619,2000.
Gale NW and Yancopoulos GD.Growth factors acting via endothelial cell-specificreceptor tyrosine kinases:VEGFs,angiopoietins,and ephrins in vascular development.GeneDev.,13:1055-1066,1999.
Han M,Partin AW,Piantadosi S,Epstein JI,Walsh PC.J Urol,166:16-419,2001.
Kurai KK,Pasquale EB.‘Eph7ective signaling:forward,reverse and crosstal k.J.CellSci.,116:2823-2832,2003.
Morgan B,Thomas AL,Drevs J,Hennig J,Buchert M,Jivan A,Horsfield MA,Mross K,Ball HA,Lee L,Mietlowski W,Fuxuis S,Unger C,O′Byrne K,Henry A,Cherryman GR,Laurent D,Dugan M,Marme D,Steward WP.Dynamic contrast-enhanced magnetic resonanceimaging as a biomarker for the pharmacological response of PTK787/ZK 222584,an inhibitorof the vascular endothelial growth factor receptor tyrosine kinases,in patients with advancedcolorectal cancer and liver metastases:results from two phase I studies.J.Clin.Oncol.,21:3955-3964,2003.
Sharp PA.RNAi and double-strand RNA.Genes Dev.1999 Jan 15;13(2):139-41..
Hammond SM,Bemstein E,Beach D,Hannon GJ.An RNA-directed nuclease mediatespost-transcriptional gene silencing in Drosophila cells.Nature.2000 Mar 16;404(6775):293-6.Hannon GJ.RNA interference.Nature.2002 Jul 11;418(6894):244-51.
Elbashir SM,Harborth J,Lendeckel W,Yalcin A,Weber K,Tuschl T.Duplexes of21-nueleotide RNAs mediate RNA interference in cultured mammalian cells.Nature.2001May 24;411(6836):494-8.
Miyagishi M,Taira K.U6 promoter-driven siRNAs with four uridine 3′overhangsefficiently suppress targeted gene expression in mammalian cells.Nat Biotechnol.2002May;20(5):497-500
Brunmelkamp TR,Bernards R,Agami R.A System for Stable Expression of ShortInterfering RNAs in Mammalian Cells Science.296(5567):550-553,April 19,2002.
序列表
<110>肿瘤疗法科学股份有限公司(ONCOTHERAPY SCIENCE,INC.)
THE UNIVERSITY OF TOKYO
<120>EphA4作为PRC和PDACa的治疗靶
<130>ONC-AO413P
<150>US60/548,335
<151>2004-02-27
<150>US60/555,809
<151>2004-03-24
<160>23
<170>PatentIn version 3.1
<210>1
<211>3468
<212>DNA
<213>人(Homo sapiens)
<220>
<221>CDS
<222>(43)..(3003)
<223>
<400>1
ctgggataga agcggcagga gcagcgttgg caccggcgaa cc atg gct ggg att 54
Met Ala Gly Ile
1
ttc tat ttc gcc cta ttt tcg tgt ctc ttc ggg att tgc gac gct gtc 102
Phe Tyr Phe Ala Leu Phe Ser Cys Leu Phe Gly Ile Cys Asp Ala Val
5 10 15 20
aca ggt tcc agg gta tac ccc gcg aat gaa gtt acc tta ttg gat tcc 150
Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr Leu Leu Asp Ser
25 30 35
aga tct gtt cag gga gaa ctt ggg tgg ata gca agc cct ctg gaa gga 198
Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser Pro Leu Glu Gly
40 45 50
ggg tgg gag gaa gtg agt atc atg gat gaa aaa aat aca cca atc cga 246
Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn Thr Pro Ile Arg
55 60 65
acc tac caa gtg tgc aat gtg atg gaa ccc agc cag aat aac tgg cta 294
Thr Tyr Gln Val Cys Asn Val Met Glu Pro Ser Gln Asn Asn Trp Leu
70 75 80
cga act gat tgg atc acc cga gaa ggg gct cag agg gtg tat att gag 342
Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg Val Tyr Ile Glu
85 90 95 100
att aaa ttc acc ttg agg gac tgc aat agt ctt ccg ggc gtc atg ggg 390
Ile Lys Phe Thr Leu Arg Asp Cys Ash Ser Leu Pro Gly Val Met Gly
105 110 115
act tgc aag gag acg ttt aac ctg tac tac tat gaa tca gac aac gac 438
Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu Ser Asp Asn Asp
120 125 130
aaa gag cgt ttc atc aga gag aac cag ttt gtc aaa att gac acc att 486
Lys Glu Arg Phe Ile Arg Glu Asn Gln Phe Val Lys Ile Asp Thr Ile
135 140 145
gct gct gat gag agc ttc acc caa gtg gac att ggt gac aga atc atg 534
Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly Asp Arg Ile Met
150 155 160
aag ctg aac acc gag atc cgg gat gta ggg cca tta agc aaa aag ggg 582
Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu Ser Lys Lys Gly
165 170 175 180
ttt tac ctg gct ttt cag gat gtg ggg gcc tgc atc gcc ctg gta tca 630
Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile Ala Leu Val Ser
185 190 195
gtc cgt gtg ttc tat aaa aag tgt cca ctc aca gtc cgc aat ctg gcc 678
Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val Arg Asn Leu Ala
200 205 210
cag ttt cct gac acc atc aca ggg gct gat acg tct tcc ctg gtg gaa 726
Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser Ser Leu Val Glu
215 220 225
gtt cga ggc tcc tgt gtc aac aac tca gaa gag aaa gat gtg cca aaa 774
Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys Asp Val Pro Lys
230 235 240
atg tac tgt ggg gca gat ggt gaa tgg ctg gta ccc att ggc aac tgc 822
Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro Ile Gly Asn Cys
245 250 255 260
cta tgc aac gct ggg cat gag gag cgg agc gga gaa tgc caa gct tgc 870
Leu Cys Asn Ala Gly His Glu Glu Arg Ser Gly Glu Cys Gln Ala Cys
265 270 275
aaa att gga tat tac aag gct ctc tcc acg gat gcc acc tgt gcc aag 918
Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala Thr Cys Ala Lys
280 285 290
tgc cca ccc cac agc tac tct gtc tgg gaa gga gcc acc tcg tgc acc 966
Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala Thr Ser Cys Thr
295 300 305
tgt gac cga ggc ttt ttc aga gct gac aac gat gct gcc tct atg ccc 1014
Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala Ala Ser Met Pro
310 315 320
tgc acc cgt cca cca tct gct ccc ctg aac ttg att tca aat gtc aac 1062
Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile Ser Asn Val Asn
325 330 335 340
gag aca tct gtg aac ttg gaa tgg agt agc cct cag aat aca ggt ggc 1110
Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln Asn Thr Gly Gly
345 350 355
cgc cag gac att tcc tat aat gtg gta tgc aag aaa tgt gga gct ggt 1158
Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys Cys Gly Ala Gly
360 365 370
gac ccc agc aag tgc cga ccc tgt gga agt ggg gtc cac tac acc cca 1206
Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val His Tyr Thr Pro
375 380 385
cag cag aat ggc ttg aag acc acc aaa gtc tcc atc act gac ctc cta 1254
Gln Gln Asn Gly Leu Lys Thr Thr Lys Val Ser Ile Thr Asp Leu Leu
390 395 400
gct cat acc aat tac acc ttt gaa atc tgg gct gtg aat gga gtg tcc 1302
Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val Asn Gly Val Ser
405 410 415 420
aaa tat aac cct aac cca gac caa tca gtt tct gtc act gtg acc acc 1350
Lys Tyr Asn Pro Asn Pro Asp Gln Ser Val Ser Val Thr Val Thr Thr
425 430 435
aac caa gca gca cca tca tcc att gct ttg gtc cag gct aaa gaa gtc 1398
Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln Ala Lys Glu Val
440 445 450
aca aga tac agt gtg gca ctg gct tgg ctg gaa cca gat cgg ccc aat 1446
Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro Asp Arg Pro Asn
455 460 465
ggg gta atc ctg gaa tat gaa gtc aag tat tat gag aag gat cag aat 1494
Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu Lys Asp Gln Asn
470 475 480
gag cga agc tat cgt ata gtt cgg aca gct gcc agg aac aca gat atc 1542
Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg Asn Thr Asp Ile
485 490 495 500
aaa ggc ctg aac cct ctc act tcc tat gtt ttc cac gtg cga gcc agg 1590
Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His Val Arg Ala Arg
505 510 515
aca gca gct ggc tat gga gac ttc agt gag ccc ttg gag gtt aca acc 1638
Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu Glu Val Thr Thr
520 525 530
aac aca gtg cct tcc cgg atc att gga gat ggg gct aac tcc aca gtc 1686
Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala Asn Ser Thr Val
535 540 545
ctt ctg gtc tct gtc tcg ggc agt gtg gtg ctg gtg gta att ctc att 1734
Leu Leu Val Ser Val Ser Gly Ser Val Val Leu Val Val Ile Leu Ile
550 555 560
gca gct ttt gtc atc agc cgg aga cgg agt aaa tac agt aaa gcc aaa 1782
Ala Ala Phe Val Ile Ser Arg Arg Arg Ser Lys Tyr Ser Lys Ala Lys
565 570 575 580
caa gaa gcg gat gaa gag aaa cat ttg aat caa ggt gta aga aca tat 1830
Gln Glu Ala Asp Glu Glu Lys His Leu Asn Gln Gly Val Arg Thr Tyr
585 590 595
gtg gac ccc ttt acg tac gaa gat ccc aac caa gca gtg cga gag ttt 1878
Val Asp Pro Phe Thr Tyr Glu Asp Pro Asn Gln Ala Val Arg Glu Phe
600 605 610
gcc aaa gaa att gac gca tcc tgc att aag att gaa aaa gtt ata gga 1926
Ala Lys Glu Ile Asp Ala Ser Cys Ile Lys Ile Glu Lys Val Ile Gly
615 620 625
gtt ggt gaa ttt ggt gag gta tgc agt ggg cgt ctc aaa gtg cct ggc 1974
Val Gly Glu Phe Gly Glu Val Cys Ser Gly Arg Leu Lys Val Pro Gly
630 635 640
aag aga gag atc tgt gtg gct atc aag act ctg aaa gct ggt tat aca 2022
Lys Arg Glu Ile Cys Val Ala Ile Lys Thr Leu Lys Ala Gly Tyr Thr
645 650 655 660
gac aaa cag agg aga gac ttc ctg agt gag gcc agc atc atg gga cag 2070
Asp Lys Gln Arg Arg Asp Phe Leu Ser Glu Ala Ser Ile Met Gly Gln
665 670 675
ttt gac cat ccg aac atc att cac ttg gaa ggc gtg gtc act aaa tgt 2118
Phe Asp His Pro Asn Ile Ile His Leu Glu Gly Val Val Thr Lys Cys
680 685 690
aaa cca gta atg atc ata aca gag tac atg gag aat ggc tcc ttg gat 2166
Lys Pro Val Met Ile Ile Thr Glu Tyr Met Glu Asn Gly Ser Leu Asp
695 700 705
gca ttc ctc agg aaa aat gat ggc aga ttt aca gtc att cag ctg gtg 2214
Ala Phe Leu Arg Lys Asn Asp Gly Arg Phe Thr Val Ile Gln Leu Val
710 715 720
ggc atg ctt cgt ggc att ggg tct ggg atg aag tat tta tct gat atg 2262
Gly Met Leu Arg Gly Ile Gly Ser Gly Met Lys Tyr Leu Ser Asp Met
725 730 735 740
agc tat gtg cat cgt gat ctg gcc gca cgg aac atc ctg gtg aac agc 2310
Ser Tyr Val His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Asn Ser
745 750 755
aac ttg gtc tgc aaa gtg tct gat ttt ggc atg tcc cga gtg ctt gag 2358
Asn Leu Val Cys Lys Val Ser Asp Phe Gly Met Ser Arg Val Leu Glu
760 765 770
gat gat ccg gaa gca gct tac acc acc agg ggt ggc aag att cct atc 2406
Asp Asp Pro Glu Ala Ala Tyr Thr Thr Arg Gly Gly Lys Ile Pro Ile
775 780 785
cgg tgg act gcg cca gaa gca att gcc tat cgt aaa ttc aca tca gca 2454
Arg Trp Thr Ala Pro Glu Ala Ile Ala Tyr Arg Lys Phe Thr Ser Ala
790 795 800
agt gat gta tgg agc tat gga atc gtt atg tgg gaa gtg atg tcg tac 2502
Ser Asp Val Trp Ser Tyr Gly Ile Val Met Trp Glu Val Met Ser Tyr
805 810 815 820
ggg gag agg ccc tat tgg gat atg tcc aat caa gat gtg att aaa gcc 2550
Gly Glu Arg Pro Tyr Trp Asp Met Ser Asn Gln Asp Val Ile Lys Ala
825 830 835
att gag gaa ggc tat cgg tta ccc cct cca atg gac tgc ccc att gcg 2598
Ile Glu Glu Gly Tyr Arg Leu Pro Pro Pro Met Asp Cys Pro Ile Ala
840 845 850
ctc cac cag ctg atg cta gac tgc tgg cag aag gag agg agc gac agg 2646
Leu His Gln Leu Met Leu Asp Cys Trp Gln Lys Glu Arg Ser Asp Arg
855 860 865
cct aaa ttt ggg cag att gtc aac atg ttg gac aaa ctc atc cgc aac 2694
Pro Lys Phe Gly Gln Ile Val Asn Met Leu Asp Lys Leu Ile Arg Asn
870 875 880
ccc aac agc ttg aag agg aca ggg acg gag agc tcc aga cct aac act 2742
Pro Asn Ser Leu Lys Arg Thr Gly Thr Glu Ser Ser Arg Pro Asn Thr
885 890 895 900
gcc ttg ttg gat cca agc tcc cct gaa ttc tct gct gtg gta tca gtg 2790
Ala Leu Leu Asp Pro Ser Ser Pro Glu Phe Ser Ala Val Val Ser Val
905 910 915
ggc gat tgg ctc cag gcc att aaa atg gac cgg tat aag gat aac ttc 2838
Gly Asp Trp Leu Gln Ala Ile Lys Met Asp Arg Tyr Lys Asp Asn Phe
920 925 930
aca gct gct ggt tat acc aca cta gag gct gtg gtg cac gtg aac cag 2886
Thr Ala Ala Gly Tyr Thr Thr Leu Glu Ala Val Val His Val Asn Gln
935 940 945
gag gac ctg gca aga att ggt atc aca gcc atc acg cac cag aat aag 2934
Glu Asp Leu Ala Arg Ile Gly Ile Thr Ala Ile Thr His Gln Asn Lys
950 955 960
att ttg agc agt gtc cag gca atg cga acc caa atg cag cag atg cac 2982
Ile Leu Ser Ser Val Gln Ala Met Arg Thr Gln Met Gln Gln Met His
965 970 975 980
ggc aga atg gtt ccc gtc tga gccagtactg aataaactca aaactcttga 3033
Gly Arg Met Val Pro Val
985
aattagttta cctcatccat gcactttaat tgaagaactg cacttttttt acttcgtctt 3093
cgccctctga aattaaagaa atgaaaaaaa aaaacaatat ctgcagcgtt gcttggtgca 3153
cagattgctg aaactgtggg gcttacagaa atgactgccg gtcatttgaa tgagacctgg 3213
aacaaatcgt ttctcagaag tacttttctg ttcatcacca gtctgtaaaa tacatgtacc 3273
tatagaaata gaacactgcc tctgagtttt gatgctgtat ttgctgccag acactgagct 3333
tctgagacat ccctgattct ctctccattt ggaattacaa ccattgtatt ttgtttgtgg 3393
cataaattac agtcatctgt ctttcactgg aatgaagacc atgcctagga acatttttta 3453
aggactcagc tgtgg 3468
<210>2
<211>986
<212>PRT
<213>人(Homo sapiens)
<400>2
Met Ala Gly Ile Phe Tyr Phe Ala Leu Phe Ser Cys Leu Phe Gly Ile
1 5 10 15
Cys Asp Ala Val Thr Gly Ser Arg Val Tyr Pro Ala Asn Glu Val Thr
20 25 30
Leu Leu Asp Ser Arg Ser Val Gln Gly Glu Leu Gly Trp Ile Ala Ser
35 40 45
Pro Leu Glu Gly Gly Trp Glu Glu Val Ser Ile Met Asp Glu Lys Asn
50 55 60
Thr Pro Ile Arg Thr Tyr Gln Val Cys Asn Val Met Glu Pro Ser Gln
65 70 75 80
Asn Asn Trp Leu Arg Thr Asp Trp Ile Thr Arg Glu Gly Ala Gln Arg
85 90 95
Val Tyr Ile Glu Ile Lys Phe Thr Leu Arg Asp Cys Asn Ser Leu Pro
100 105 110
Gly Val Met Gly Thr Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Tyr Glu
115 120 125
Ser Asp Asn Asp Lys Glu Arg Phe Ile Arg Glu Asn Gln Phe Val Lys
130 135 140
Ile Asp Thr Ile Ala Ala Asp Glu Ser Phe Thr Gln Val Asp Ile Gly
145 150 155 160
Asp Arg Ile Met Lys Leu Asn Thr Glu Ile Arg Asp Val Gly Pro Leu
165 170 175
Ser Lys Lys Gly Phe Tyr Leu Ala Phe Gln Asp Val Gly Ala Cys Ile
180 185 190
Ala Leu Val Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Leu Thr Val
195 200 205
Arg Asn Leu Ala Gln Phe Pro Asp Thr Ile Thr Gly Ala Asp Thr Ser
210 215 220
Ser Leu Val Glu Val Arg Gly Ser Cys Val Asn Asn Ser Glu Glu Lys
225 230 235 240
Asp Val Pro Lys Met Tyr Cys Gly Ala Asp Gly Glu Trp Leu Val Pro
245 250 255
Ile Gly Asn Cys Leu Cys Asn Ala Gly His Glu Glu Arg Ser Gly Glu
260 265 270
Cys Gln Ala Cys Lys Ile Gly Tyr Tyr Lys Ala Leu Ser Thr Asp Ala
275 280 285
Thr Cys Ala Lys Cys Pro Pro His Ser Tyr Ser Val Trp Glu Gly Ala
290 295 300
Thr Ser Cys Thr Cys Asp Arg Gly Phe Phe Arg Ala Asp Asn Asp Ala
305 310 315 320
Ala Ser Met Pro Cys Thr Arg Pro Pro Ser Ala Pro Leu Asn Leu Ile
325 330 335
Ser Asn Val Asn Glu Thr Ser Val Asn Leu Glu Trp Ser Ser Pro Gln
340 345 350
Asn Thr Gly Gly Arg Gln Asp Ile Ser Tyr Asn Val Val Cys Lys Lys
355 360 365
Cys Gly Ala Gly Asp Pro Ser Lys Cys Arg Pro Cys Gly Ser Gly Val
370 375 380
His Tyr Thr Pro Gln Gln Asn Gly Leu Lys Thr Thr Lys Val Ser Ile
385 390 395 400
Thr Asp Leu Leu Ala His Thr Asn Tyr Thr Phe Glu Ile Trp Ala Val
405 410 415
Asn Gly Val Ser Lys Tyr Asn Pro Asn Pro Asp Gln Ser Val Ser Val
420 425 430
Thr Val Thr Thr Asn Gln Ala Ala Pro Ser Ser Ile Ala Leu Val Gln
435 440 445
Ala Lys Glu Val Thr Arg Tyr Ser Val Ala Leu Ala Trp Leu Glu Pro
450 455 460
Asp Arg Pro Asn Gly Val Ile Leu Glu Tyr Glu Val Lys Tyr Tyr Glu
465 470 475 480
Lys Asp Gln Asn Glu Arg Ser Tyr Arg Ile Val Arg Thr Ala Ala Arg
485 490 495
Asn Thr Asp Ile Lys Gly Leu Asn Pro Leu Thr Ser Tyr Val Phe His
500 505 510
Val Arg Ala Arg Thr Ala Ala Gly Tyr Gly Asp Phe Ser Glu Pro Leu
515 520 525
Glu Val Thr Thr Asn Thr Val Pro Ser Arg Ile Ile Gly Asp Gly Ala
530 535 540
Asn Ser Thr Val Leu Leu Val Ser Val Ser Gly Ser Val Val Leu Val
545 550 555 560
Val Ile Leu Ile Ala Ala Phe Val Ile Ser Arg Arg Arg Ser Lys Tyr
565 570 575
Ser Lys Ala Lys Gln Glu Ala Asp Glu Glu Lys His Leu Asn Gln Gly
580 585 590
Val Arg Thr Tyr Val Asp Pro Phe Thr Tyr Glu Asp Pro Asn Gln Ala
595 600 605
Val Arg Glu Phe Ala Lys Glu Ile Asp Ala Ser Cys Ile Lys Ile Glu
610 615 620
Lys Val Ile Gly Val Gly Glu Phe Gly Glu Val Cys Ser Gly Arg Leu
625 630 635 640
Lys Val Pro Gly Lys Arg Glu Ile Cys Val Ala Ile Lys Thr Leu Lys
645 650 655
Ala Gly Tyr Thr Asp Lys Gln Arg Arg Asp Phe Leu Ser Glu Ala Ser
660 665 670
Ile Met Gly Gln Phe Asp His Pro Asn Ile Ile His Leu Glu Gly Val
675 680 685
Val Thr Lys Cys Lys Pro Val Met Ile Ile Thr Glu Tyr Met Glu Asn
690 695 700
Gly Ser Leu Asp Ala Phe Leu Arg Lys Asn Asp Gly Arg Phe Thr Val
705 710 715 720
Ile Gln Leu Val Gly Met Leu Arg Gly Ile Gly Ser Gly Met Lys Tyr
725 730 735
Leu Ser Asp Met Ser Tyr Val His Arg Asp Leu Ala Ala Arg Asn Ile
740 745 750
Leu Val Asn Ser Asn Leu Val Cys Lys Val Ser Asp Phe Gly Met Ser
755 760 765
Arg Val Leu Glu Asp Asp Pro Glu Ala Ala Tyr Thr Thr Arg Gly Gly
770 775 780
Lys Ile Pro Ile Arg Trp Thr Ala Pro Glu Ala Ile Ala Tyr Arg Lys
785 790 795 800
Phe Thr Ser Ala Ser Asp Val Trp Ser Tyr Gly Ile Val Met Trp Glu
805 810 815
Val Met Ser Tyr Gly Glu Arg Pro Tyr Trp Asp Met Ser Asn Gln Asp
820 825 830
Val Ile Lys Ala Ile Glu Glu Gly Tyr Arg Leu Pro Pro Pro Met Asp
835 840 845
Cys Pro Ile Ala Leu His Gln Leu Met Leu Asp Cys Trp Gln Lys Glu
850 855 860
Arg Ser Asp Arg Pro Lys Phe Gly Gln Ile Val Asn Met Leu Asp Lys
865 870 875 880
Leu Ile Arg Asn Pro Asn Ser Leu Lys Arg Thr Gly Thr Glu Ser Ser
885 890 895
Arg Pro Asn Thr Ala Leu Leu Asp Pro Ser Ser Pro Glu Phe Ser Ala
900 905 910
Val Val Ser Val Gly Asp Trp Leu Gln Ala Ile Lys Met Asp Arg Tyr
915 920 925
Lys Asp Asn Phe Thr Ala Ala Gly Tyr Thr Thr Leu Glu Ala Val Val
930 935 940
His Val Asn Gln Glu Asp Leu Ala Arg Ile Gly Ile Thr Ala Ile Thr
945 950 955 960
His Gln Asn Lys Ile Leu Ser Ser Val Gln Ala Met Arg Thr Gln Met
965 970 975
Gln Gln Met His Gly Arg Met Val Pro Val
980 985
<210>3
<211>23
<212>DNA
<213>人工的
<220>
<223>用于RT-PCR的人工合成的引物序列
<400>3
gaaggcgtgg tcactaaatg taa 23
<210>4
<211>22
<212>DNA
<213>人工的
<220>
<223>用于RT-PCR的人工合成的引物序列
<400>4
tttaatttca gagggcgaag ac 22
<210>5
<211>23
<212>DNA
<213>人工的
<220>
<223>用于RT-PCR的人工合成的引物序列
<400>5
catccacgaa actaccttca act 23
<210>6
<211>23
<212>DNA
<213>人工的
<220>
<223>用于RT-PCR的人工合成的引物序列
<400>6
tctccttaga gagaagtggg gtg 23
<210>7
<211>20
<212>DNA
<213>人工的
<220>
<223>用于RT-PCR的人工合成的引物序列
<400>7
cacccccact gaaaaagaga 20
<210>8
<211>19
<212>DNA
<213>人工的
<220>
<223>用于RT-PCR的人工合成的引物序列
<400>8
tacctgtgga gcaaggtgc 19
<210>9
<211>9
<212>DNA
<213>人工的
<220>
<223>siRNA的人工合成的spcer序列
<400>9
ttcaagaga 9
<210>10
<211>19
<212>DNA
<213>人工的
<220>
<223>siRNA的人工合成的靶序列
<400>10
gcagcaccat catccattg 19
<210>11
<211>19
<212>DNA
<213>人工的
<220>
<223>siRNA的人工合成的靶序列
<400>11
gaagcagcac gacttcttc 19
<210>12
<211>51
<212>DNA
<213>人工的
<220>
<223>siRNA的人工合成的序列
<400>12
caccgcagca ccatcatcca ttgttcaaga gacaatggat gatggtgctg c 51
<210>13
<211>51
<212>DNA
<213>人工的
<220>
<223>siRNA的人工合成的序列
<400>13
aaaagcagca ccatcatcca ttgtctcttg aacaatggat gatggtgctg c 51
<210>14
<211>47
<212>DNA
<213>人工的
<220>
<223>siRNA发夹设计
<400>14
gcagcaccat catccattgt tcaagagaca atggatgatg gtgctgc 47
<210>15
<211>4863
<212>DNA
<213>人工的
<220>
<223>siRNA表达载体的人工构建的质粒序列
<400>15
gacggatcgg gagatctccc gatcccctat ggtgcactct cagtacaatc tgctctggat 60
ccactagtaa cggccgccag tgtgctggaa ttcggcttgg ggatcagcgt ttgagtaaga 120
gcccgcgtct gaaccctccg cgccgccccg gccccagtgg aaagacgcgc aggcaaaacg 180
caccacgtga cggagcgtga ccgcgcgccg agcgcgcgcc aaggtcgggc aggaagaggg 240
cctatttccc atgattcctt catatttgca tatacgatac aaggctgtta gagagataat 300
tagaattaat ttgactgtaa acacaaagat attagtacaa aatacgtgac gtagaaagta 360
ataatttctt gggtagtttg cagttttaaa attatgtttt aaaatggact atcatatgct 420
taccgtaact tgaaagtatt tcgatttctt ggctttatat atcttgtgga aaggacgaaa 480
caccttttta catcaggttg tttttctgtt tggttttttt tttacaccac gtttatacgc 540
cggtgcacgg tttaccactg aaaacacctt tcatctacag gtgatatctt ttaacacaaa 600
taaaatgtag tagtcctagg agacggaata gaaggaggtg gggcctaaag ccgaattctg 660
cagatatcca tcacactggc ggccgctcga gtgaggcgga aagaaccagc tggggctcta 720
gggggtatcc ccacgcgccc tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc 780
gcagcgtgac cgctacactt gccagcgccc tagcgcccgc tcctttcgct ttcttccctt 840
cctttctcgc cacgttcgcc ggctttcccc gtcaagctct aaatcggggg ctccctttag 900
ggttccgatt tagtgcttta cggcacctcg accccaaaaa acttgattag ggtgatggtt 960
cacgtagtgg gccatcgccc tgatagacgg tttttcgccc tttgacgttg gagtccacgt 1020
tctttaatag tggactcttg ttccaaactg gaacaacact caaccctatc tcggtctatt 1080
cttttgattt ataagggatt ttgccgattt cggcctattg gttaaaaaat gagctgattt 1140
aacaaaaatt taacgcgaat taattctgtg gaatgtgtgt cagttagggt gtggaaagtc 1200
cccaggctcc ccagcaggca gaagtatgca aagcatgcat ctcaattagt cagcaaccag 1260
gtgtggaaag tccccaggct ccccagcagg cagaagtatg caaagcatgc atctcaatta 1320
gtcagcaacc atagtcccgc ccctaactcc gcccatcccg cccctaactc cgcccagttc 1380
cgcccattct ccgccccatg gctgactaat tttttttatt tatgcagagg ccgaggccgc 1440
ctctgcctct gagctattcc agaagtagtg aggaggcttt tttggaggcc taggcttttg 1500
caaaaagctc ccgggagctt gtatatccat tttcggatct gatcaagaga caggatgagg 1560
atcgtttcgc atgattgaac aagatggatt gcacgcaggt tctccggccg cttgggtgga 1620
gaggctattc ggctatgact gggcacaaca gacaatcggc tgctctgatg ccgccgtgtt 1680
ccggctgtca gcgcaggggc gcccggttct ttttgtcaag accgacctgt ccggtgccct 1740
gaatgaactg caggacgagg cagcgcggct atcgtggctg gccacgacgg gcgttccttg 1800
cgcagctgtg ctcgacgttg tcactgaagc gggaagggac tggctgctat tgggcgaagt 1860
gccggggcag gatctcctgt catctcacct tgctcctgcc gagaaagtat ccatcatggc 1920
tgatgcaatg cggcggctgc atacgcttga tccggctacc tgcccattcg accaccaagc 1980
gaaacatcgc atcgagcgag cacgtactcg gatggaagcc ggtcttgtcg atcaggatga 2040
tctggacgaa gagcatcagg ggctcgcgcc agccgaactg ttcgccaggc tcaaggcgcg 2100
catgcccgac ggcgaggatc tcgtcgtgac ccatggcgat gcctgcttgc cgaatatcat 2160
ggtggaaaat ggccgctttt ctggattcat cgactgtggc cggctgggtg tggcggaccg 2220
ctatcaggac atagcgttgg ctacccgtga tattgctgaa gagcttggcg gcgaatgggc 2280
tgaccgcttc ctcgtgcttt acggtatcgc cgctcccgat tcgcagcgca tcgccttcta 2340
tcgccttctt gacgagttct tctgagcggg actctggggt tcgaaatgac cgaccaagcg 2400
acgcccaacc tgccatcacg agatttcgat tccaccgccg ccttctatga aaggttgggc 2460
ttcggaatcg ttttccggga cgccggctgg atgatcctcc agcgcgggga tctcatgctg 2520
gagttcttcg cccaccccaa cttgtttatt gcagcttata atggttacaa ataaagcaat 2580
agcatcacaa atttcacaaa taaagcattt ttttcactgc attctagttg tggtttgtcc 2640
aaactcatca atgtatctta tcatgtctgt ataccgtcga cctctagcta gagcttggcg 2700
taatcatggt catagctgtt tcctgtgtga aattgttatc cgctcacaat tccacacaac 2760
atacgagccg gaagcataaa gtgtaaagcc tggggtgcct aatgagtgag ctaactcaca 2820
ttaattgcgt tgcgctcact gcccgctttc cagtcgggaa acctgtcgtg ccagctgcat 2880
taatgaatcg gccaacgcgc ggggagaggc ggtttgcgta ttgggcgctc ttccgcttcc 2940
tcgctcactg actcgctgcg ctcggtcgtt cggctgcggc gagcggtatc agctcactca 3000
aaggcggtaa tacggttatc cacagaatca ggggataacg caggaaagaa catgtgagca 3060
aaaggccagc aaaaggccag gaaccgtaaa aaggccgcgt tgctggcgtt tttccatagg 3120
ctccgccccc ctgacgagca tcacaaaaat cgacgctcaa gtcagaggtg gcgaaacccg 3180
acaggactat aaagatacca ggcgtttccc cctggaagct ccctcgtgcg ctctcctgtt 3240
ccgaccctgc cgcttaccgg atacctgtcc gcctttctcc cttcgggaag cgtggcgctt 3300
tctcatagct cacgctgtag gtatctcagt tcggtgtagg tcgttcgctc caagctgggc 3360
tgtgtgcacg aaccccccgt tcagcccgac cgctgcgcct tatccggtaa ctatcgtctt 3420
gagtccaacc cggtaagaca cgacttatcg ccactggcag cagccactgg taacaggatt 3480
agcagagcga ggtatgtagg cggtgctaca gagttcttga agtggtggcc taactacggc 3540
tacactagaa gaacagtatt tggtatctgc gctctgctga agccagttac cttcggaaaa 3600
agagttggta gctcttgatc cggcaaacaa accaccgctg gtagcggttt ttttgtttgc 3660
aagcagcaga ttacgcgcag aaaaaaagga tctcaagaag atcctttgat cttttctacg 3720
gggtctgacg ctcagtggaa cgaaaactca cgttaaggga ttttggtcat gagattatca 3780
aaaaggatct tcacctagat ccttttaaat taaaaatgaa gttttaaatc aatctaaagt 3840
atatatgagt aaacttggtc tgacagttac caatgcttaa tcagtgaggc acctatctca 3900
gcgatctgtc tatttcgttc atccatagtt gcctgactcc ccgtcgtgta gataactacg 3960
atacgggagg gcttaccatc tggccccagt gctgcaatga taccgcgaga cccacgctca 4020
ccggctccag atttatcagc aataaaccag ccagccggaa gggccgagcg cagaagtggt 4080
cctgcaactt tatccgcctc catccagtct attaattgtt gccgggaagc tagagtaagt 4140
agttcgccag ttaatagttt gcgcaacgtt gttgccattg ctacaggcat cgtggtgtca 4200
cgctcgtcgt ttggtatggc ttcattcagc tccggttccc aacgatcaag gcgagttaca 4260
tgatccccca tgttgtgcaa aaaagcggtt agctccttcg gtcctccgat cgttgtcaga 4320
agtaagttgg ccgcagtgtt atcactcatg gttatggcag cactgcataa ttctcttact 4380
gtcatgccat ccgtaagatg cttttctgtg actggtgagt actcaaccaa gtcattctga 4440
gaatagtgta tgcggcgacc gagttgctct tgcccggcgt caatacggga taataccgcg 4500
ccacatagca gaactttaaa agtgctcatc attggaaaac gttcttcggg gcgaaaactc 4560
tcaaggatct taccgctgtt gagatccagt tcgatgtaac ccactcgtgc acccaactga 4620
tcttcagcat cttttacttt caccagcgtt tctgggtgag caaaaacagg aaggcaaaat 4680
gccgcaaaa agggaataag ggcgacacgg aaatgttgaa tactcatact cttccttttt 4740
caatattatt gaagcattta tcagggttat tgtctcatga gcggatacat atttgaatgt 4800
atttagaaaa ataaacaaat aggggttccg cgcacatttc cccgaaaagt gccacctgac 4860
gtc 4863
<210>16
<211>20
<212>DNA
<213>人工的
<220>
<223>人工合成的引物序列
<400>16
ggggatcagc gtttgagtaa 20
<210>17
<211>20
<212>DNA
<213>人工的
<220>
<223>人工合成的引物序列
<400>17
taggccccac ctccttctat 20
<210>18
<211>30
<212>DNA
<213>人工的
<220>
<223>人工合成的引物序列
<400>18
tgcggatcca gagcagattg tactgagagt 30
<210>19
<211>29
<212>DNA
<213>人工的
<220>
<223>人工合成的引物序列
<400>19
ctctatctcg agtgaggcgg aaagaacca 29
<210>20
<211>40
<212>DNA
<213>人工的
<220>
<223>人工合成的引物序列
<400>20
tttaagcttg aagactattt ttacatcagg ttgtttttct 40
<210>21
<211>37
<212>DNA
<213>人工的
<220>
<223>人工合成的引物序列
<400>21
tttaagcttg aagacacggt gtttcgtcct ttccaca 37
<210>22
<211>51
<212>DNA
<213>人工的
<220>
<223>siRNA的人工合成的序列
<400>22
caccgaagca gcacgacttc ttcttcaaga gagaagaagt cgtgctgctt c 51
<210>23
<211>51
<212>DNA
<213>人工的
<220>
<223>siRNA的人工合成的序列
<400>23
aaaagaagca gcacgacttc ttctctcttg aagaagaagt cgtgctgctt c 51
Claims (50)
1.诊断受试者中的PRC或患PRC的倾向性的方法,包括测定源自患者的生物样品中EphA4的表达水平,其中所述水平与所述基因的正常对照水平相比增加表明所述受试者患有或可能患PRC。
2.权利要求的方法1,其中所述增加是超过所述正常对照水平至少10%。
3.权利要求的方法1,其中所述表达水平通过任何一种选自下组的方法测定:
(a)检测EphA4的mRNA,
(b)检测EphA4编码的蛋白质,和
(c)检测EphA4编码的蛋白质的生物活性。
4.权利要求的方法1,其中所述表达水平通过检测EphA4探针与所述患者来源的生物样品的基因转录物的杂交来测定。
5.权利要求的方法4,其中所述杂交步骤在DNA阵列上进行。
6.权利要求的方法1,其中所述生物样品包含上皮细胞。
7.权利要求的方法1,其中所述生物样品包含PRC细胞。
8.权利要求的方法7,其中所述生物样品包含来自PRC的上皮细胞。
9.筛选用于治疗或预防PRC的化合物的方法,所述方法包括以下步骤:
a)使受试化合物与EphA4编码的多肽接触;
b)检测所述多肽与受试化合物之间的结合活性;和
c)选择与所述多肽结合的化合物。
10.筛选用于治疗或预防PRC的化合物的方法,所述方法包括以下步骤:
a)使候选化合物与表达EphA4的细胞接触;和
b)选择降低EphA4表达水平的化合物。
11.权利要求10的方法,其中所述细胞包含前列腺癌细胞。
12.筛选用于治疗或预防PRC的化合物的方法,所述方法包括以下步骤:
a)使受试化合物与EphA4编码的多肽接触;
b)检测步骤(a)的多肽的生物活性;和
c)选择与不存在受试化合物时检测到的生物活性相比抑制多肽的生物活性的化合物。
13.权利要求12的方法,其中所述生物活性是酪氨酸激酶活性。
14.筛选用于治疗或预防PRC的化合物的方法,所述方法包括以下步骤:
a)使受试化合物与其中导入了载体的细胞接触,所述载体包含EphA4基因的转录调节区以及在所述转录调节区的控制下表达的报道基因,
b)测定所述报道基因的表达或活性;和
c)选择与不存在受试化合物时的水平相比降低所述报道基因的表达或活性水平的化合物。
15.治疗或预防受试者中的PRC的方法,包括给药所述受试者反义组合物,所述组合物包含与EphA4编码序列互补的核苷酸序列。
16.治疗或预防受试者中的PRC的方法,包括给药所述受试者siRNA组合物,其中所述组合物降低EphA4的表达。
17.权利要求16的方法,其中所述siRNA包含EphA4的有义核酸和反义核酸。
18.权利要求17的方法,其中所述siRNA包含对应序列SEQ ID NO:10的核糖核苷酸序列作为靶序列。
19.权利要求18的方法,所述siRNA的通式为5’-[A]-[B]-[A’]-3’,其中[A]是与SEQ ID NO:10的核苷酸组成的序列对应的核糖核苷酸序列,
[B]是大约3至大约23个核苷酸组成的核糖核苷酸序列,和
[A’]是[A]的互补序列组成的核糖核苷酸序列。
20.权利要求16的方法,其中所述组合物包含转染增强剂。
21.治疗或预防受试者中的PRC的方法,包括给药所述受试者药物有效量的抗体或其片段,所述抗体或其片段与EphA4编码的蛋白质结合。
22.治疗或预防受试者中的PRC的方法,包括给药所述受试者疫苗,所述疫苗包含EphA4编码的多肽或所述多肽的免疫活性片段,或编码所述多肽的多核苷酸。
23.治疗或预防受试者中的PRC的方法,包括给药通过权利要求9-14之一的方法获得的化合物的步骤。
24.用于治疗或预防PRC的组合物,所述组合物包含药物有效量的针对EphA4的反义多核苷酸或siRNA作为活性成分,并包含可药用的载体。
25.权利要求24的组合物,其中所述siRNA包含SEQ ID NO:10组成的核苷酸序列作为靶序列。
26.用于治疗或预防PRC的组合物,所述组合物包含药物有效量的抗体或其片段作为活性成分,所述抗体或其片段与EphA4编码的蛋白质结合,并包含可药用的载体。
27.用于治疗或预防PRC的组合物,所述组合物包含药物有效量的通过权利要求9-14之一的方法选出的化合物作为活性成分,并包含可药用的载体。
28.治疗或预防受试者中的胰腺癌的方法,包括给药所述受试者包含EphA4的siRNA的组合物。
29.权利要求28的方法,其中所述siRNA包含EphA4的有义核酸和反义核酸。
30.权利要求28的方法,其中胰腺癌是胰管腺癌(PDACa)。
31.权利要求29的方法,其中所述siRNA包含对应SEQ ID NO:10组成的序列的核糖核苷酸序列作为靶序列。
32.权利要求31的方法,所述siRNA的通式为5’-[A]-[B]-[A’]-3’,其中[A]是与SEQ ID NO:10的核苷酸组成的序列相对应的核糖核苷酸序列,
[B]是大约3至大约23个核苷酸组成的核糖核苷酸序列,和
[A’]是[A]的互补序列组成的核糖核苷酸序列。
33.权利要求的方法28,其中所述组合物包含转染增强剂。
34.双链分子,其包含有义链和反义链,其中有义链包含对应SEQ IDNO:10组成的靶序列的核糖核苷酸序列,反义链包含与所述有义链互补的核糖核苷酸序列,其中所述有义链和反义链相互杂交形成所述双链分子,并且其中所述双链分子被引入表达EphA4基因的细胞时抑制所述基因的表达。
35.权利要求34的双链分子,其中所述靶序列包含来自SEQ ID NO:1组成的核苷酸序列的至少约10个连续核苷酸。
36.权利要求35的双链分子,其中所述靶序列包含来自SEQ ID NO:1组成的核苷酸序列的约19到约25个连续核苷酸。
37.权利要求36的双链分子,其中所述双链分子是包含经由单链核糖核苷酸序列连接的有义链和反义链的单一(single)核糖核苷酸转录物。
38.权利要求35的双链分子,其中所述双链分子是长度小于大约100个核苷酸的寡核苷酸。
39.权利要求38的双链分子,其中所述双链分子是长度小于大约75个核苷酸的寡核苷酸。
40.权利要求39的双链分子,所述双链分子是长度小于大约50个核苷酸的寡核苷酸。
41.权利要求40的双链分子,所述双链分子是长度小于大约25个核苷酸的寡核苷酸。
42.权利要求41的双链寡核苷酸,其中所述双链分子是长度为大约19个至大约25个核苷酸的寡核苷酸。
43.编码权利要求35的双链分子的载体。
44.权利要求43的载体,其中所述载体编码具有二级结构并包含有义链和反义链的转录物。
45.权利要求44的载体,其中所述转录物还包含连接所述有义链和所述反义链的单链核糖核苷酸序列。
46.包含含有有义核酸链与反义核酸链的组合的多核苷酸的载体,其中所述有义核酸包含SEQ ID NO:10组成的核苷酸序列,并且所述反义链核酸由与有义链互补的序列组成。
47.权利要求的载体46,其中所述多核苷酸的通式为
5’-[A]-[B]-[A’]-3’
其中[A]是SEQ ID NO:10组成的核苷酸序列,[B]是大约3至大约23个核苷酸组成的核苷酸序列,和[A’]是[A]的互补序列组成的核苷酸序列。
48 用于治疗或预防胰腺癌的药物组合物,包含药物有效量的EphA4的小干扰RNA(siRNA)作为活性成分,并包含可药用的载体。
49.权利要求48的药物组合物,其中所述siRNA包含SEQ ID NO:10组成的核苷酸序列作为靶序列。
50.权利要求49的组合物,其中所述siRNA的通式为
5’-[A]-[B]-[A’]-3’
其中[A]是与SEQ ID NO:10组成的核苷酸序列相对应的核糖核苷酸序列,[B]是3至23个核苷酸组成的核糖核苷酸序列,[A’]是与[A]互补的核糖核苷酸序列。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US54833504P | 2004-02-27 | 2004-02-27 | |
US60/548,335 | 2004-02-27 | ||
US60/555,809 | 2004-03-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1973040A true CN1973040A (zh) | 2007-05-30 |
Family
ID=34910997
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2005800135582A Pending CN1973040A (zh) | 2004-02-27 | 2005-02-18 | EphA4作为PRC和PDACa的治疗靶 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20080063640A1 (zh) |
EP (1) | EP1733047A2 (zh) |
JP (1) | JP2007525220A (zh) |
CN (1) | CN1973040A (zh) |
TW (1) | TW200538555A (zh) |
WO (1) | WO2005083118A2 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106999578A (zh) * | 2014-07-31 | 2017-08-01 | 美国政府(由卫生和人类服务部的部长所代表) | 针对epha4的人类单克隆抗体和其用途 |
CN111320693A (zh) * | 2015-09-08 | 2020-06-23 | 卫材R&D管理有限公司 | 抗EphA4抗体 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008102906A1 (en) * | 2007-02-20 | 2008-08-28 | Oncotherapy Science, Inc. | Hspc-hrpc transition genes |
EP2195425A4 (en) * | 2007-08-24 | 2011-01-19 | Oncotherapy Science Inc | PKIB AND NAALADL2 FOR TARGET GENES OF THERAPY AND DIAGNOSIS OF PROSTATE CANCER |
WO2012024255A2 (en) * | 2010-08-16 | 2012-02-23 | Duke University | Camkk-beta as a target for treating cancer |
EP3683311A4 (en) | 2017-09-11 | 2021-06-02 | National University Corporation Hokkaido University | MEDICINE FOR THE TREATMENT OF CANCER |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002031209A2 (en) * | 2000-10-13 | 2002-04-18 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Genes related to development of refractory prostate cancer |
US20030190640A1 (en) * | 2001-05-31 | 2003-10-09 | Mary Faris | Genes expressed in prostate cancer |
US7622260B2 (en) * | 2001-09-05 | 2009-11-24 | The Brigham And Women's Hospital, Inc. | Diagnostic and prognostic tests |
US20030144188A1 (en) * | 2002-01-15 | 2003-07-31 | Biaoyang Lin | Androgen regulated nucleic acid molecules and encoded proteins |
AU2003217421A1 (en) * | 2002-02-19 | 2003-09-09 | Idec Pharmaceuticals Corporation | Prostate specific genes and the use thereof in design or therapeutics |
TW200418988A (en) * | 2002-09-30 | 2004-10-01 | Oncotherapy Science Inc | Method for diagnosing prostate cancer |
US20040121413A1 (en) * | 2002-12-20 | 2004-06-24 | Aebersold Rudolf H. | Androgen-regulated genes and uses for diagnosis, prognosis and treatment of prostate neoplastic conditions |
-
2005
- 2005-02-04 US US10/598,296 patent/US20080063640A1/en not_active Abandoned
- 2005-02-04 JP JP2007500403A patent/JP2007525220A/ja active Pending
- 2005-02-04 WO PCT/JP2005/002090 patent/WO2005083118A2/en not_active Application Discontinuation
- 2005-02-04 EP EP05710142A patent/EP1733047A2/en not_active Withdrawn
- 2005-02-18 CN CNA2005800135582A patent/CN1973040A/zh active Pending
- 2005-02-18 TW TW094104772A patent/TW200538555A/zh unknown
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106999578A (zh) * | 2014-07-31 | 2017-08-01 | 美国政府(由卫生和人类服务部的部长所代表) | 针对epha4的人类单克隆抗体和其用途 |
US10934360B2 (en) | 2014-07-31 | 2021-03-02 | The Hong Kong University Of Science And Technology | Human monoclonal antibodies against EPHA4 and their use |
CN106999578B (zh) * | 2014-07-31 | 2022-03-04 | 美国政府(由卫生和人类服务部的部长所代表) | 针对epha4的人类单克隆抗体和其用途 |
US12037404B2 (en) | 2014-07-31 | 2024-07-16 | The Hong Kong University Of Science And Technology | Human monoclonal antibodies against EphA4 and their use |
CN111320693A (zh) * | 2015-09-08 | 2020-06-23 | 卫材R&D管理有限公司 | 抗EphA4抗体 |
CN111320693B (zh) * | 2015-09-08 | 2023-04-07 | 卫材R&D管理有限公司 | 抗EphA4抗体 |
Also Published As
Publication number | Publication date |
---|---|
US20080063640A1 (en) | 2008-03-13 |
WO2005083118A3 (en) | 2006-04-13 |
WO2005083118A2 (en) | 2005-09-09 |
TW200538555A (en) | 2005-12-01 |
EP1733047A2 (en) | 2006-12-20 |
JP2007525220A (ja) | 2007-09-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1890381B (zh) | 诊断乳腺癌的方法 | |
JP2007506425A (ja) | 肝細胞癌を診断する方法 | |
TW200538739A (en) | EphA4 as therapeutic target of PRC and PDACa | |
JP2009502112A (ja) | 腎細胞癌を診断および処置するための方法 | |
JP2006500946A (ja) | 精巣精上皮腫の診断方法 | |
JP4851451B2 (ja) | 乳癌関連遺伝子znfn3a1 | |
CN1973040A (zh) | EphA4作为PRC和PDACa的治疗靶 | |
JP2007530431A (ja) | 膵臓癌を治療するための組成物および方法 | |
JP4614952B2 (ja) | 腎細胞癌(rcc)の潜在的な新規治療標的としての低酸素誘導タンパク質2(hig2) | |
US8828964B2 (en) | Cancer cell identification marker and cancer cell proliferation inhibitor | |
JP2021195364A (ja) | Rnaを含有する抗腫瘍剤、免疫細胞の活性化方法、腫瘍細胞の転移の抑制方法、免疫賦活剤、抗腫瘍剤の抗腫瘍効果の増強剤、及び医薬組成物 | |
CN106554962B (zh) | 过表达gpr160的癌症的预防、诊断和治疗 | |
Zhou et al. | Knockdown of the long non‑coding RNA CACNA1G‑AS1 enhances cytotoxicity and apoptosis of human diffuse large B cell lymphoma by regulating miR‑3160‑5p | |
WO2019039439A1 (ja) | Dctn1タンパク質とretタンパク質との融合タンパク質 | |
US20110110896A1 (en) | Modulating levels of RNA-binding proteins for the treatment of breast cancer | |
JP6425942B2 (ja) | 前立腺癌の判定、治療選択方法、予防又は治療剤 | |
CN1984925A (zh) | 前列腺癌相关的基因和多肽 | |
US8182997B2 (en) | Prostate cancer related gene STYK1 | |
KR20230075710A (ko) | 상피세포성장인자수용체(egfr) 변이를 갖는 암 치료용 조성물 | |
Mak et al. | KDM4A promotes NEPC progression through regulation of MYC expression | |
Cui et al. | Identification of CDKL3 as a Critical Promoter in Development of Glioma Through Regulation of RRM2 and JNK Signaling Pathway | |
JP6403260B2 (ja) | 前立腺癌の判定、治療選択方法、予防又は治療剤 | |
JP2007522791A (ja) | 結腸直腸癌を診断する方法 | |
JP2022505047A (ja) | 抗がん療法のための標的 |
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 |