CN112225795A - 6-羟基硫酸褪黑素衍生物及其免疫原、特异性抗体的制备方法和应用 - Google Patents
6-羟基硫酸褪黑素衍生物及其免疫原、特异性抗体的制备方法和应用 Download PDFInfo
- Publication number
- CN112225795A CN112225795A CN202011096209.4A CN202011096209A CN112225795A CN 112225795 A CN112225795 A CN 112225795A CN 202011096209 A CN202011096209 A CN 202011096209A CN 112225795 A CN112225795 A CN 112225795A
- Authority
- CN
- China
- Prior art keywords
- melatonin
- hydroxy
- hydroxy sulfate
- sulfate
- buffer solution
- 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
- 239000002974 melatonin derivative Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 230000002163 immunogen Effects 0.000 title claims abstract description 31
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims abstract description 129
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims abstract description 125
- 229960003987 melatonin Drugs 0.000 claims abstract description 125
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 99
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 61
- 229940098773 bovine serum albumin Drugs 0.000 claims abstract description 42
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims abstract description 32
- 238000010171 animal model Methods 0.000 claims abstract description 15
- 239000000427 antigen Substances 0.000 claims abstract description 14
- 102000036639 antigens Human genes 0.000 claims abstract description 14
- 108091007433 antigens Proteins 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims description 67
- 239000007853 buffer solution Substances 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 31
- 239000004816 latex Substances 0.000 claims description 26
- 229920000126 latex Polymers 0.000 claims description 26
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 26
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 102100031126 6-phosphogluconolactonase Human genes 0.000 claims description 23
- 108010029731 6-phosphogluconolactonase Proteins 0.000 claims description 23
- 102000004190 Enzymes Human genes 0.000 claims description 23
- 108090000790 Enzymes Proteins 0.000 claims description 23
- 108010018962 Glucosephosphate Dehydrogenase Proteins 0.000 claims description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- OMYMRCXOJJZYKE-UHFFFAOYSA-N 6-hydroxymelatonin Chemical compound C1=C(O)C(OC)=CC2=C1NC=C2CCNC(C)=O OMYMRCXOJJZYKE-UHFFFAOYSA-N 0.000 claims description 17
- 102000014914 Carrier Proteins Human genes 0.000 claims description 17
- 108010078791 Carrier Proteins Proteins 0.000 claims description 17
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 238000003018 immunoassay Methods 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 239000012460 protein solution Substances 0.000 claims description 12
- 239000007983 Tris buffer Substances 0.000 claims description 11
- 229940126214 compound 3 Drugs 0.000 claims description 11
- 239000008055 phosphate buffer solution Substances 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 11
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 10
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 10
- 238000007865 diluting Methods 0.000 claims description 10
- 229960001484 edetic acid Drugs 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 8
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 8
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 8
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 7
- 239000012346 acetyl chloride Substances 0.000 claims description 7
- 150000001413 amino acids Chemical group 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 230000008878 coupling Effects 0.000 claims description 7
- 238000010168 coupling process Methods 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- MXJGKTHZWIGRJG-UHFFFAOYSA-N tert-butyl 2-aminooxyacetate Chemical compound CC(C)(C)OC(=O)CON MXJGKTHZWIGRJG-UHFFFAOYSA-N 0.000 claims description 7
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 6
- 239000004793 Polystyrene Substances 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 229940125904 compound 1 Drugs 0.000 claims description 6
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 6
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims description 6
- 229920002223 polystyrene Polymers 0.000 claims description 6
- 239000008057 potassium phosphate buffer Substances 0.000 claims description 6
- 239000003755 preservative agent Substances 0.000 claims description 6
- 230000002335 preservative effect Effects 0.000 claims description 6
- 238000012360 testing method Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 210000004369 blood Anatomy 0.000 claims description 5
- 239000008280 blood Substances 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- CCMKPCBRNXKTKV-UHFFFAOYSA-N 1-hydroxy-5-sulfanylidenepyrrolidin-2-one Chemical compound ON1C(=O)CCC1=S CCMKPCBRNXKTKV-UHFFFAOYSA-N 0.000 claims description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical group C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 4
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical group OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- 239000007987 MES buffer Substances 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 239000000701 coagulant Substances 0.000 claims description 4
- 239000005515 coenzyme Substances 0.000 claims description 4
- 238000000502 dialysis Methods 0.000 claims description 4
- 229950006238 nadide Drugs 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 3
- 238000007817 turbidimetric assay Methods 0.000 claims description 3
- 241000283707 Capra Species 0.000 claims description 2
- 241000700199 Cavia porcellus Species 0.000 claims description 2
- 239000008118 PEG 6000 Substances 0.000 claims description 2
- 241001494479 Pecora Species 0.000 claims description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 2
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 claims description 2
- 239000007982 barbital buffer Substances 0.000 claims description 2
- 229920003045 dextran sodium sulfate Polymers 0.000 claims description 2
- 239000003550 marker Substances 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940033663 thimerosal Drugs 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 239000008363 phosphate buffer Substances 0.000 claims 1
- 238000001514 detection method Methods 0.000 abstract description 23
- 229940088597 hormone Drugs 0.000 abstract description 12
- 239000005556 hormone Substances 0.000 abstract description 12
- 230000035945 sensitivity Effects 0.000 abstract description 7
- 238000010353 genetic engineering Methods 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000002965 ELISA Methods 0.000 description 15
- 238000003908 quality control method Methods 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 208000029560 autism spectrum disease Diseases 0.000 description 12
- 238000003556 assay Methods 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000011088 calibration curve Methods 0.000 description 10
- 108010054155 lysyllysine Proteins 0.000 description 9
- 210000002700 urine Anatomy 0.000 description 9
- 239000002207 metabolite Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 108010004073 cysteinylcysteine Proteins 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 208000019116 sleep disease Diseases 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108010047495 alanylglycine Proteins 0.000 description 3
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 3
- 238000007405 data analysis Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 108010089804 glycyl-threonine Proteins 0.000 description 3
- 108010050848 glycylleucine Proteins 0.000 description 3
- 108010015792 glycyllysine Proteins 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 108010053725 prolylvaline Proteins 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WXERCAHAIKMTKX-ZLUOBGJFSA-N Ala-Asp-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O WXERCAHAIKMTKX-ZLUOBGJFSA-N 0.000 description 2
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 2
- NXDXECQFKHXHAM-HJGDQZAQSA-N Arg-Glu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NXDXECQFKHXHAM-HJGDQZAQSA-N 0.000 description 2
- 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 2
- XDGBFDYXZCMYEX-NUMRIWBASA-N Asp-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N)O XDGBFDYXZCMYEX-NUMRIWBASA-N 0.000 description 2
- HRBYTAIBKPNZKQ-AVGNSLFASA-N Glu-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O HRBYTAIBKPNZKQ-AVGNSLFASA-N 0.000 description 2
- VEPBEGNDJYANCF-QWRGUYRKSA-N Gly-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCCN VEPBEGNDJYANCF-QWRGUYRKSA-N 0.000 description 2
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 2
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 2
- KGCLIYGPQXUNLO-IUCAKERBSA-N Leu-Gly-Glu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O KGCLIYGPQXUNLO-IUCAKERBSA-N 0.000 description 2
- KLSUAWUZBMAZCL-RHYQMDGZSA-N Leu-Thr-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(O)=O KLSUAWUZBMAZCL-RHYQMDGZSA-N 0.000 description 2
- 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 2
- HKCCVDWHHTVVPN-CIUDSAMLSA-N Lys-Asp-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O HKCCVDWHHTVVPN-CIUDSAMLSA-N 0.000 description 2
- RBEATVHTWHTHTJ-KKUMJFAQSA-N Lys-Leu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O RBEATVHTWHTHTJ-KKUMJFAQSA-N 0.000 description 2
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 2
- ATNKHRAIZCMCCN-BZSNNMDCSA-N Lys-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N ATNKHRAIZCMCCN-BZSNNMDCSA-N 0.000 description 2
- YXPJCVNIDDKGOE-MELADBBJSA-N Lys-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N)C(=O)O YXPJCVNIDDKGOE-MELADBBJSA-N 0.000 description 2
- PLDJDCJLRCYPJB-VOAKCMCISA-N Lys-Lys-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PLDJDCJLRCYPJB-VOAKCMCISA-N 0.000 description 2
- QQPSCXKFDSORFT-IHRRRGAJSA-N Lys-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN QQPSCXKFDSORFT-IHRRRGAJSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 2
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- BVWPHWLFGRCECJ-JSGCOSHPSA-N Val-Gly-Tyr Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N BVWPHWLFGRCECJ-JSGCOSHPSA-N 0.000 description 2
- QIVPZSWBBHRNBA-JYJNAYRXSA-N Val-Pro-Phe Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O QIVPZSWBBHRNBA-JYJNAYRXSA-N 0.000 description 2
- VFRROHXSMXFLSN-VANKVMQKSA-N [(2s,3s,4r,5s)-2,3,4,5-tetrahydroxy-6-oxohexyl] dihydrogen phosphate Chemical compound OP(=O)(O)OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)C=O VFRROHXSMXFLSN-VANKVMQKSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 2
- 108010041407 alanylaspartic acid Proteins 0.000 description 2
- 108010005233 alanylglutamic acid Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 108010060035 arginylproline Proteins 0.000 description 2
- 108010092854 aspartyllysine Proteins 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000027288 circadian rhythm Effects 0.000 description 2
- 238000004737 colorimetric analysis Methods 0.000 description 2
- 230000000875 corresponding effect 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
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 108010077515 glycylproline Proteins 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 108010085325 histidylproline Proteins 0.000 description 2
- 108010034529 leucyl-lysine Proteins 0.000 description 2
- 108010017391 lysylvaline Proteins 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 108010048818 seryl-histidine Proteins 0.000 description 2
- 230000008454 sleep-wake cycle Effects 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000012064 sodium phosphate buffer Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000004885 tandem mass spectrometry Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- AXFMEGAFCUULFV-BLFANLJRSA-N (2s)-2-[[(2s)-1-[(2s,3r)-2-amino-3-methylpentanoyl]pyrrolidine-2-carbonyl]amino]pentanedioic acid Chemical compound CC[C@@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AXFMEGAFCUULFV-BLFANLJRSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- QQEILXDLZRLTME-UHFFFAOYSA-N 6-sulfatoxymelatonin Chemical compound C1=C(OS(O)(=O)=O)C(OC)=CC2=C1NC=C2CCNC(C)=O QQEILXDLZRLTME-UHFFFAOYSA-N 0.000 description 1
- 208000021959 Abnormal metabolism Diseases 0.000 description 1
- IMMKUCQIKKXKNP-DCAQKATOSA-N Ala-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CCCN=C(N)N IMMKUCQIKKXKNP-DCAQKATOSA-N 0.000 description 1
- NHCPCLJZRSIDHS-ZLUOBGJFSA-N Ala-Asp-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O NHCPCLJZRSIDHS-ZLUOBGJFSA-N 0.000 description 1
- WQVYAWIMAWTGMW-ZLUOBGJFSA-N Ala-Asp-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N WQVYAWIMAWTGMW-ZLUOBGJFSA-N 0.000 description 1
- 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 1
- KIUYPHAMDKDICO-WHFBIAKZSA-N Ala-Asp-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KIUYPHAMDKDICO-WHFBIAKZSA-N 0.000 description 1
- ZIWWTZWAKYBUOB-CIUDSAMLSA-N Ala-Asp-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O ZIWWTZWAKYBUOB-CIUDSAMLSA-N 0.000 description 1
- LSLIRHLIUDVNBN-CIUDSAMLSA-N Ala-Asp-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LSLIRHLIUDVNBN-CIUDSAMLSA-N 0.000 description 1
- MKZCBYZBCINNJN-DLOVCJGASA-N Ala-Asp-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MKZCBYZBCINNJN-DLOVCJGASA-N 0.000 description 1
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 1
- FUSPCLTUKXQREV-ACZMJKKPSA-N Ala-Glu-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O FUSPCLTUKXQREV-ACZMJKKPSA-N 0.000 description 1
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 1
- XYTNPQNAZREREP-XQXXSGGOSA-N Ala-Glu-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XYTNPQNAZREREP-XQXXSGGOSA-N 0.000 description 1
- PCIFXPRIFWKWLK-YUMQZZPRSA-N Ala-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N PCIFXPRIFWKWLK-YUMQZZPRSA-N 0.000 description 1
- ZPXCNXMJEZKRLU-LSJOCFKGSA-N Ala-His-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CN=CN1 ZPXCNXMJEZKRLU-LSJOCFKGSA-N 0.000 description 1
- OKEWAFFWMHBGPT-XPUUQOCRSA-N Ala-His-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CN=CN1 OKEWAFFWMHBGPT-XPUUQOCRSA-N 0.000 description 1
- GSHKMNKPMLXSQW-KBIXCLLPSA-N Ala-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C)N GSHKMNKPMLXSQW-KBIXCLLPSA-N 0.000 description 1
- VCSABYLVNWQYQE-UHFFFAOYSA-N Ala-Lys-Lys Natural products NCCCCC(NC(=O)C(N)C)C(=O)NC(CCCCN)C(O)=O VCSABYLVNWQYQE-UHFFFAOYSA-N 0.000 description 1
- KQESEZXHYOUIIM-CQDKDKBSSA-N Ala-Lys-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KQESEZXHYOUIIM-CQDKDKBSSA-N 0.000 description 1
- DWYROCSXOOMOEU-CIUDSAMLSA-N Ala-Met-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N DWYROCSXOOMOEU-CIUDSAMLSA-N 0.000 description 1
- IHMCQESUJVZTKW-UBHSHLNASA-N Ala-Phe-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=CC=C1 IHMCQESUJVZTKW-UBHSHLNASA-N 0.000 description 1
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 1
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 1
- OEVCHROQUIVQFZ-YTLHQDLWSA-N Ala-Thr-Ala Chemical compound C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](C)C(O)=O OEVCHROQUIVQFZ-YTLHQDLWSA-N 0.000 description 1
- AETQNIIFKCMVHP-UVBJJODRSA-N Ala-Trp-Arg Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AETQNIIFKCMVHP-UVBJJODRSA-N 0.000 description 1
- IYKVSFNGSWTTNZ-GUBZILKMSA-N Ala-Val-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IYKVSFNGSWTTNZ-GUBZILKMSA-N 0.000 description 1
- BVLPIIBTWIYOML-ZKWXMUAHSA-N Ala-Val-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O BVLPIIBTWIYOML-ZKWXMUAHSA-N 0.000 description 1
- REWSWYIDQIELBE-FXQIFTODSA-N Ala-Val-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O REWSWYIDQIELBE-FXQIFTODSA-N 0.000 description 1
- UXJCMQFPDWCHKX-DCAQKATOSA-N Arg-Arg-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UXJCMQFPDWCHKX-DCAQKATOSA-N 0.000 description 1
- JGDGLDNAQJJGJI-AVGNSLFASA-N Arg-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N JGDGLDNAQJJGJI-AVGNSLFASA-N 0.000 description 1
- OVVUNXXROOFSIM-SDDRHHMPSA-N Arg-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O OVVUNXXROOFSIM-SDDRHHMPSA-N 0.000 description 1
- YSUVMPICYVWRBX-VEVYYDQMSA-N Arg-Asp-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YSUVMPICYVWRBX-VEVYYDQMSA-N 0.000 description 1
- DQNLFLGFZAUIOW-FXQIFTODSA-N Arg-Cys-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O DQNLFLGFZAUIOW-FXQIFTODSA-N 0.000 description 1
- XLWSGICNBZGYTA-CIUDSAMLSA-N Arg-Glu-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O XLWSGICNBZGYTA-CIUDSAMLSA-N 0.000 description 1
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-N 0.000 description 1
- OGUPCHKBOKJFMA-SRVKXCTJSA-N Arg-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N OGUPCHKBOKJFMA-SRVKXCTJSA-N 0.000 description 1
- YKBHOXLMMPZPHQ-GMOBBJLQSA-N Arg-Ile-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O YKBHOXLMMPZPHQ-GMOBBJLQSA-N 0.000 description 1
- OTZMRMHZCMZOJZ-SRVKXCTJSA-N Arg-Leu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O OTZMRMHZCMZOJZ-SRVKXCTJSA-N 0.000 description 1
- MNBHKGYCLBUIBC-UFYCRDLUSA-N Arg-Phe-Phe Chemical compound C([C@H](NC(=O)[C@H](CCCNC(N)=N)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MNBHKGYCLBUIBC-UFYCRDLUSA-N 0.000 description 1
- AUZAXCPWMDBWEE-HJGDQZAQSA-N Arg-Thr-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O AUZAXCPWMDBWEE-HJGDQZAQSA-N 0.000 description 1
- IZSMEUDYADKZTJ-KJEVXHAQSA-N Arg-Tyr-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IZSMEUDYADKZTJ-KJEVXHAQSA-N 0.000 description 1
- VWJFQGXPYOPXJH-ZLUOBGJFSA-N Asn-Cys-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)C(=O)N VWJFQGXPYOPXJH-ZLUOBGJFSA-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
- JLNFZLNDHONLND-GARJFASQSA-N Asn-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)N)N JLNFZLNDHONLND-GARJFASQSA-N 0.000 description 1
- ZYPWIUFLYMQZBS-SRVKXCTJSA-N Asn-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N ZYPWIUFLYMQZBS-SRVKXCTJSA-N 0.000 description 1
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 1
- FLJVGAFLZVBBNG-BPUTZDHNSA-N Asn-Trp-Arg Chemical compound N[C@@H](CC(=O)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O FLJVGAFLZVBBNG-BPUTZDHNSA-N 0.000 description 1
- JNCRAQVYJZGIOW-QSFUFRPTSA-N Asn-Val-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JNCRAQVYJZGIOW-QSFUFRPTSA-N 0.000 description 1
- CBHVAFXKOYAHOY-NHCYSSNCSA-N Asn-Val-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O CBHVAFXKOYAHOY-NHCYSSNCSA-N 0.000 description 1
- CELPEWWLSXMVPH-CIUDSAMLSA-N Asp-Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O CELPEWWLSXMVPH-CIUDSAMLSA-N 0.000 description 1
- QXHVOUSPVAWEMX-ZLUOBGJFSA-N Asp-Asp-Ser Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O QXHVOUSPVAWEMX-ZLUOBGJFSA-N 0.000 description 1
- NYQHSUGFEWDWPD-ACZMJKKPSA-N Asp-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)O)N NYQHSUGFEWDWPD-ACZMJKKPSA-N 0.000 description 1
- ZEDBMCPXPIYJLW-XHNCKOQMSA-N Asp-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N)C(=O)O ZEDBMCPXPIYJLW-XHNCKOQMSA-N 0.000 description 1
- ZSVJVIOVABDTTL-YUMQZZPRSA-N Asp-Gly-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)O)N ZSVJVIOVABDTTL-YUMQZZPRSA-N 0.000 description 1
- RQYMKRMRZWJGHC-BQBZGAKWSA-N Asp-Gly-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)O)N RQYMKRMRZWJGHC-BQBZGAKWSA-N 0.000 description 1
- LIVXPXUVXFRWNY-CIUDSAMLSA-N Asp-Lys-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O LIVXPXUVXFRWNY-CIUDSAMLSA-N 0.000 description 1
- YVHGKXAOSVBGJV-CIUDSAMLSA-N Asp-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N YVHGKXAOSVBGJV-CIUDSAMLSA-N 0.000 description 1
- GYWQGGUCMDCUJE-DLOVCJGASA-N Asp-Phe-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O GYWQGGUCMDCUJE-DLOVCJGASA-N 0.000 description 1
- PDIYGFYAMZZFCW-JIOCBJNQSA-N Asp-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N)O PDIYGFYAMZZFCW-JIOCBJNQSA-N 0.000 description 1
- ITGFVUYOLWBPQW-KKHAAJSZSA-N Asp-Thr-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O ITGFVUYOLWBPQW-KKHAAJSZSA-N 0.000 description 1
- XWKBWZXGNXTDKY-ZKWXMUAHSA-N Asp-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O XWKBWZXGNXTDKY-ZKWXMUAHSA-N 0.000 description 1
- GIKOVDMXBAFXDF-NHCYSSNCSA-N Asp-Val-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GIKOVDMXBAFXDF-NHCYSSNCSA-N 0.000 description 1
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 1
- GSNRZJNHMVMOFV-ACZMJKKPSA-N Cys-Asp-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N GSNRZJNHMVMOFV-ACZMJKKPSA-N 0.000 description 1
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 1
- HYKFOHGZGLOCAY-ZLUOBGJFSA-N Cys-Cys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O HYKFOHGZGLOCAY-ZLUOBGJFSA-N 0.000 description 1
- HIPHJNWPLMUBQQ-ACZMJKKPSA-N Cys-Cys-Gln Chemical compound SC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(N)=O HIPHJNWPLMUBQQ-ACZMJKKPSA-N 0.000 description 1
- UFOBYROTHHYVGW-CIUDSAMLSA-N Cys-Cys-His Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CNC=N1)C(O)=O UFOBYROTHHYVGW-CIUDSAMLSA-N 0.000 description 1
- MUZAUPFGPMMZSS-GUBZILKMSA-N Cys-Glu-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N MUZAUPFGPMMZSS-GUBZILKMSA-N 0.000 description 1
- LYSHSHHDBVKJRN-JBDRJPRFSA-N Cys-Ile-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N LYSHSHHDBVKJRN-JBDRJPRFSA-N 0.000 description 1
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 1
- LHMSYHSAAJOEBL-CIUDSAMLSA-N Cys-Lys-Asn Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O LHMSYHSAAJOEBL-CIUDSAMLSA-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
- HSAWNMMTZCLTPY-DCAQKATOSA-N Cys-Met-Leu Chemical compound SC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(O)=O HSAWNMMTZCLTPY-DCAQKATOSA-N 0.000 description 1
- RESAHOSBQHMOKH-KKUMJFAQSA-N Cys-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CS)N RESAHOSBQHMOKH-KKUMJFAQSA-N 0.000 description 1
- CHRCKSPMGYDLIA-SRVKXCTJSA-N Cys-Phe-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O CHRCKSPMGYDLIA-SRVKXCTJSA-N 0.000 description 1
- IRKLTAKLAFUTLA-KATARQTJSA-N Cys-Thr-Lys Chemical compound C[C@@H](O)[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CCCCN)C(O)=O IRKLTAKLAFUTLA-KATARQTJSA-N 0.000 description 1
- PRBLYKYHAJEABA-SRVKXCTJSA-N Gln-Arg-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O PRBLYKYHAJEABA-SRVKXCTJSA-N 0.000 description 1
- INFBPLSHYFALDE-ACZMJKKPSA-N Gln-Asn-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O INFBPLSHYFALDE-ACZMJKKPSA-N 0.000 description 1
- AAOBFSKXAVIORT-GUBZILKMSA-N Gln-Asn-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O AAOBFSKXAVIORT-GUBZILKMSA-N 0.000 description 1
- QFTRCUPCARNIPZ-XHNCKOQMSA-N Gln-Cys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)N)N)C(=O)O QFTRCUPCARNIPZ-XHNCKOQMSA-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
- VOLVNCMGXWDDQY-LPEHRKFASA-N Gln-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N)C(=O)O VOLVNCMGXWDDQY-LPEHRKFASA-N 0.000 description 1
- MTCXQQINVAFZKW-MNXVOIDGSA-N Gln-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)N)N MTCXQQINVAFZKW-MNXVOIDGSA-N 0.000 description 1
- XFAUJGNLHIGXET-AVGNSLFASA-N Gln-Leu-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XFAUJGNLHIGXET-AVGNSLFASA-N 0.000 description 1
- FKXCBKCOSVIGCT-AVGNSLFASA-N Gln-Lys-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O FKXCBKCOSVIGCT-AVGNSLFASA-N 0.000 description 1
- JNVGVECJCOZHCN-DRZSPHRISA-N Gln-Phe-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O JNVGVECJCOZHCN-DRZSPHRISA-N 0.000 description 1
- BZULIEARJFRINC-IHRRRGAJSA-N Gln-Phe-Glu Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BZULIEARJFRINC-IHRRRGAJSA-N 0.000 description 1
- SXFPZRRVWSUYII-KBIXCLLPSA-N Gln-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N SXFPZRRVWSUYII-KBIXCLLPSA-N 0.000 description 1
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 1
- PAOHIZNRJNIXQY-XQXXSGGOSA-N Gln-Thr-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O PAOHIZNRJNIXQY-XQXXSGGOSA-N 0.000 description 1
- WIMVKDYAKRAUCG-IHRRRGAJSA-N Gln-Tyr-Glu Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O WIMVKDYAKRAUCG-IHRRRGAJSA-N 0.000 description 1
- UTKICHUQEQBDGC-ACZMJKKPSA-N Glu-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N UTKICHUQEQBDGC-ACZMJKKPSA-N 0.000 description 1
- FYBSCGZLICNOBA-XQXXSGGOSA-N Glu-Ala-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FYBSCGZLICNOBA-XQXXSGGOSA-N 0.000 description 1
- CVPXINNKRTZBMO-CIUDSAMLSA-N Glu-Arg-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)CN=C(N)N CVPXINNKRTZBMO-CIUDSAMLSA-N 0.000 description 1
- KEBACWCLVOXFNC-DCAQKATOSA-N Glu-Arg-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(O)=O KEBACWCLVOXFNC-DCAQKATOSA-N 0.000 description 1
- SBYVDRJAXWSXQL-AVGNSLFASA-N Glu-Asn-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SBYVDRJAXWSXQL-AVGNSLFASA-N 0.000 description 1
- HJIFPJUEOGZWRI-GUBZILKMSA-N Glu-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N HJIFPJUEOGZWRI-GUBZILKMSA-N 0.000 description 1
- CYHBMLHCQXXCCT-AVGNSLFASA-N Glu-Asp-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CYHBMLHCQXXCCT-AVGNSLFASA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- OPAINBJQDQTGJY-JGVFFNPUSA-N Glu-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCC(=O)O)N)C(=O)O OPAINBJQDQTGJY-JGVFFNPUSA-N 0.000 description 1
- BIHMNDPWRUROFZ-JYJNAYRXSA-N Glu-His-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O BIHMNDPWRUROFZ-JYJNAYRXSA-N 0.000 description 1
- LZMQSTPFYJLVJB-GUBZILKMSA-N Glu-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N LZMQSTPFYJLVJB-GUBZILKMSA-N 0.000 description 1
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 1
- NJCALAAIGREHDR-WDCWCFNPSA-N Glu-Leu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NJCALAAIGREHDR-WDCWCFNPSA-N 0.000 description 1
- RBXSZQRSEGYDFG-GUBZILKMSA-N Glu-Lys-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O RBXSZQRSEGYDFG-GUBZILKMSA-N 0.000 description 1
- PMSMKNYRZCKVMC-DRZSPHRISA-N Glu-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CCC(=O)O)N PMSMKNYRZCKVMC-DRZSPHRISA-N 0.000 description 1
- JDUKCSSHWNIQQZ-IHRRRGAJSA-N Glu-Phe-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JDUKCSSHWNIQQZ-IHRRRGAJSA-N 0.000 description 1
- KXTAGESXNQEZKB-DZKIICNBSA-N Glu-Phe-Val Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=CC=C1 KXTAGESXNQEZKB-DZKIICNBSA-N 0.000 description 1
- YQAQQKPWFOBSMU-WDCWCFNPSA-N Glu-Thr-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O YQAQQKPWFOBSMU-WDCWCFNPSA-N 0.000 description 1
- ZGXGVBYEJGVJMV-HJGDQZAQSA-N Glu-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O ZGXGVBYEJGVJMV-HJGDQZAQSA-N 0.000 description 1
- LZEUDRYSAZAJIO-AUTRQRHGSA-N Glu-Val-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LZEUDRYSAZAJIO-AUTRQRHGSA-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
- 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 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- PHONXOACARQMPM-BQBZGAKWSA-N Gly-Ala-Met Chemical compound [H]NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O PHONXOACARQMPM-BQBZGAKWSA-N 0.000 description 1
- JRDYDYXZKFNNRQ-XPUUQOCRSA-N Gly-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN JRDYDYXZKFNNRQ-XPUUQOCRSA-N 0.000 description 1
- RJIVPOXLQFJRTG-LURJTMIESA-N Gly-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N RJIVPOXLQFJRTG-LURJTMIESA-N 0.000 description 1
- FZQLXNIMCPJVJE-YUMQZZPRSA-N Gly-Asp-Leu Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O FZQLXNIMCPJVJE-YUMQZZPRSA-N 0.000 description 1
- ZRZILYKEJBMFHY-BQBZGAKWSA-N Gly-Asp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CN ZRZILYKEJBMFHY-BQBZGAKWSA-N 0.000 description 1
- XXGQRGQPGFYECI-WDSKDSINSA-N Gly-Cys-Glu Chemical compound NCC(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(O)=O XXGQRGQPGFYECI-WDSKDSINSA-N 0.000 description 1
- DHDOADIPGZTAHT-YUMQZZPRSA-N Gly-Glu-Arg Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DHDOADIPGZTAHT-YUMQZZPRSA-N 0.000 description 1
- 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
- FJWSJWACLMTDMI-WPRPVWTQSA-N Gly-Met-Val Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O FJWSJWACLMTDMI-WPRPVWTQSA-N 0.000 description 1
- FXLVSYVJDPCIHH-STQMWFEESA-N Gly-Phe-Arg Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FXLVSYVJDPCIHH-STQMWFEESA-N 0.000 description 1
- ZZJVYSAQQMDIRD-UWVGGRQHSA-N Gly-Pro-His Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O ZZJVYSAQQMDIRD-UWVGGRQHSA-N 0.000 description 1
- GAAHQHNCMIAYEX-UWVGGRQHSA-N Gly-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN GAAHQHNCMIAYEX-UWVGGRQHSA-N 0.000 description 1
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 1
- YDIDLLVFCYSXNY-RCOVLWMOSA-N Gly-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN YDIDLLVFCYSXNY-RCOVLWMOSA-N 0.000 description 1
- BNMRSWQOHIQTFL-JSGCOSHPSA-N Gly-Val-Phe Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 BNMRSWQOHIQTFL-JSGCOSHPSA-N 0.000 description 1
- KZTLOHBDLMIFSH-XVYDVKMFSA-N His-Ala-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O KZTLOHBDLMIFSH-XVYDVKMFSA-N 0.000 description 1
- YXBRCTXAEYSCHS-XVYDVKMFSA-N His-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N YXBRCTXAEYSCHS-XVYDVKMFSA-N 0.000 description 1
- OSZUPUINVNPCOE-SDDRHHMPSA-N His-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O OSZUPUINVNPCOE-SDDRHHMPSA-N 0.000 description 1
- HAPWZEVRQYGLSG-IUCAKERBSA-N His-Gly-Glu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O HAPWZEVRQYGLSG-IUCAKERBSA-N 0.000 description 1
- AIPUZFXMXAHZKY-QWRGUYRKSA-N His-Leu-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O AIPUZFXMXAHZKY-QWRGUYRKSA-N 0.000 description 1
- ZSKJIISDJXJQPV-BZSNNMDCSA-N His-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 ZSKJIISDJXJQPV-BZSNNMDCSA-N 0.000 description 1
- JUIOPCXACJLRJK-AVGNSLFASA-N His-Lys-Glu Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N JUIOPCXACJLRJK-AVGNSLFASA-N 0.000 description 1
- UMBKDWGQESDCTO-KKUMJFAQSA-N His-Lys-Lys Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O UMBKDWGQESDCTO-KKUMJFAQSA-N 0.000 description 1
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 1
- SVVULKPWDBIPCO-BZSNNMDCSA-N His-Phe-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O SVVULKPWDBIPCO-BZSNNMDCSA-N 0.000 description 1
- PGXZHYYGOPKYKM-IHRRRGAJSA-N His-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CN=CN2)N)C(=O)N[C@@H](CCCCN)C(=O)O PGXZHYYGOPKYKM-IHRRRGAJSA-N 0.000 description 1
- CCUSLCQWVMWTIS-IXOXFDKPSA-N His-Thr-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O CCUSLCQWVMWTIS-IXOXFDKPSA-N 0.000 description 1
- NPROWIBAWYMPAZ-GUDRVLHUSA-N Ile-Asp-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N NPROWIBAWYMPAZ-GUDRVLHUSA-N 0.000 description 1
- CTHAJJYOHOBUDY-GHCJXIJMSA-N Ile-Cys-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N CTHAJJYOHOBUDY-GHCJXIJMSA-N 0.000 description 1
- VQUCKIAECLVLAD-SVSWQMSJSA-N Ile-Cys-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N VQUCKIAECLVLAD-SVSWQMSJSA-N 0.000 description 1
- OVPYIUNCVSOVNF-ZPFDUUQYSA-N Ile-Gln-Pro Natural products CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O OVPYIUNCVSOVNF-ZPFDUUQYSA-N 0.000 description 1
- PNDMHTTXXPUQJH-RWRJDSDZSA-N Ile-Glu-Thr Chemical compound N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H]([C@H](O)C)C(=O)O PNDMHTTXXPUQJH-RWRJDSDZSA-N 0.000 description 1
- VOBYAKCXGQQFLR-LSJOCFKGSA-N Ile-Gly-Val Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O VOBYAKCXGQQFLR-LSJOCFKGSA-N 0.000 description 1
- TWYOYAKMLHWMOJ-ZPFDUUQYSA-N Ile-Leu-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O TWYOYAKMLHWMOJ-ZPFDUUQYSA-N 0.000 description 1
- PNTWNAXGBOZMBO-MNXVOIDGSA-N Ile-Lys-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N PNTWNAXGBOZMBO-MNXVOIDGSA-N 0.000 description 1
- IIWQTXMUALXGOV-PCBIJLKTSA-N Ile-Phe-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)O)C(=O)O)N IIWQTXMUALXGOV-PCBIJLKTSA-N 0.000 description 1
- PELCGFMHLZXWBQ-BJDJZHNGSA-N Ile-Ser-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)O)N PELCGFMHLZXWBQ-BJDJZHNGSA-N 0.000 description 1
- HXIDVIFHRYRXLZ-NAKRPEOUSA-N Ile-Ser-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)O)N HXIDVIFHRYRXLZ-NAKRPEOUSA-N 0.000 description 1
- CNMOKANDJMLAIF-CIQUZCHMSA-N Ile-Thr-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O CNMOKANDJMLAIF-CIQUZCHMSA-N 0.000 description 1
- YWCJXQKATPNPOE-UKJIMTQDSA-N Ile-Val-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N YWCJXQKATPNPOE-UKJIMTQDSA-N 0.000 description 1
- YHFPHRUWZMEOIX-CYDGBPFRSA-N Ile-Val-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)O)N YHFPHRUWZMEOIX-CYDGBPFRSA-N 0.000 description 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
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 1
- 241000880493 Leptailurus serval Species 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
- KWTVLKBOQATPHJ-SRVKXCTJSA-N Leu-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(C)C)N KWTVLKBOQATPHJ-SRVKXCTJSA-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
- WCTCIIAGNMFYAO-DCAQKATOSA-N Leu-Cys-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O WCTCIIAGNMFYAO-DCAQKATOSA-N 0.000 description 1
- WMTOVWLLDGQGCV-GUBZILKMSA-N Leu-Glu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N WMTOVWLLDGQGCV-GUBZILKMSA-N 0.000 description 1
- WIDZHJTYKYBLSR-DCAQKATOSA-N Leu-Glu-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WIDZHJTYKYBLSR-DCAQKATOSA-N 0.000 description 1
- KXODZBLFVFSLAI-AVGNSLFASA-N Leu-His-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CN=CN1 KXODZBLFVFSLAI-AVGNSLFASA-N 0.000 description 1
- KVOFSTUWVSQMDK-KKUMJFAQSA-N Leu-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CN=CN1 KVOFSTUWVSQMDK-KKUMJFAQSA-N 0.000 description 1
- DBSLVQBXKVKDKJ-BJDJZHNGSA-N Leu-Ile-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O DBSLVQBXKVKDKJ-BJDJZHNGSA-N 0.000 description 1
- JKSIBWITFMQTOA-XUXIUFHCSA-N Leu-Ile-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O JKSIBWITFMQTOA-XUXIUFHCSA-N 0.000 description 1
- DSFYPIUSAMSERP-IHRRRGAJSA-N Leu-Leu-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DSFYPIUSAMSERP-IHRRRGAJSA-N 0.000 description 1
- PDQDCFBVYXEFSD-SRVKXCTJSA-N Leu-Leu-Asp Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O PDQDCFBVYXEFSD-SRVKXCTJSA-N 0.000 description 1
- LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 description 1
- XVZCXCTYGHPNEM-UHFFFAOYSA-N Leu-Leu-Pro Natural products CC(C)CC(N)C(=O)NC(CC(C)C)C(=O)N1CCCC1C(O)=O XVZCXCTYGHPNEM-UHFFFAOYSA-N 0.000 description 1
- ZRHDPZAAWLXXIR-SRVKXCTJSA-N Leu-Lys-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O ZRHDPZAAWLXXIR-SRVKXCTJSA-N 0.000 description 1
- HVHRPWQEQHIQJF-AVGNSLFASA-N Leu-Lys-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HVHRPWQEQHIQJF-AVGNSLFASA-N 0.000 description 1
- KPYAOIVPJKPIOU-KKUMJFAQSA-N Leu-Lys-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O KPYAOIVPJKPIOU-KKUMJFAQSA-N 0.000 description 1
- KXCMQWMNYQOAKA-SRVKXCTJSA-N Leu-Met-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N KXCMQWMNYQOAKA-SRVKXCTJSA-N 0.000 description 1
- GCXGCIYIHXSKAY-ULQDDVLXSA-N Leu-Phe-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GCXGCIYIHXSKAY-ULQDDVLXSA-N 0.000 description 1
- KQFZKDITNUEVFJ-JYJNAYRXSA-N Leu-Phe-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CC=CC=C1 KQFZKDITNUEVFJ-JYJNAYRXSA-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
- RRVCZCNFXIFGRA-DCAQKATOSA-N Leu-Pro-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O RRVCZCNFXIFGRA-DCAQKATOSA-N 0.000 description 1
- BMVFXOQHDQZAQU-DCAQKATOSA-N Leu-Pro-Asp Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N BMVFXOQHDQZAQU-DCAQKATOSA-N 0.000 description 1
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 1
- ZJZNLRVCZWUONM-JXUBOQSCSA-N Leu-Thr-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O ZJZNLRVCZWUONM-JXUBOQSCSA-N 0.000 description 1
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 1
- ISSAURVGLGAPDK-KKUMJFAQSA-N Leu-Tyr-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O ISSAURVGLGAPDK-KKUMJFAQSA-N 0.000 description 1
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 1
- FMFNIDICDKEMOE-XUXIUFHCSA-N Leu-Val-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FMFNIDICDKEMOE-XUXIUFHCSA-N 0.000 description 1
- MPOHDJKRBLVGCT-CIUDSAMLSA-N Lys-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N MPOHDJKRBLVGCT-CIUDSAMLSA-N 0.000 description 1
- YIBOAHAOAWACDK-QEJZJMRPSA-N Lys-Ala-Phe Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 YIBOAHAOAWACDK-QEJZJMRPSA-N 0.000 description 1
- KNKHAVVBVXKOGX-JXUBOQSCSA-N Lys-Ala-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KNKHAVVBVXKOGX-JXUBOQSCSA-N 0.000 description 1
- GQUDMNDPQTXZRV-DCAQKATOSA-N Lys-Arg-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O GQUDMNDPQTXZRV-DCAQKATOSA-N 0.000 description 1
- QUYCUALODHJQLK-CIUDSAMLSA-N Lys-Asp-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O QUYCUALODHJQLK-CIUDSAMLSA-N 0.000 description 1
- GKFNXYMAMKJSKD-NHCYSSNCSA-N Lys-Asp-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O GKFNXYMAMKJSKD-NHCYSSNCSA-N 0.000 description 1
- CFVQPNSCQMKDPB-CIUDSAMLSA-N Lys-Cys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)O)N CFVQPNSCQMKDPB-CIUDSAMLSA-N 0.000 description 1
- HEWWNLVEWBJBKA-WDCWCFNPSA-N Lys-Gln-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCCN HEWWNLVEWBJBKA-WDCWCFNPSA-N 0.000 description 1
- CRNNMTHBMRFQNG-GUBZILKMSA-N Lys-Glu-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N CRNNMTHBMRFQNG-GUBZILKMSA-N 0.000 description 1
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 1
- ITWQLSZTLBKWJM-YUMQZZPRSA-N Lys-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CCCCN ITWQLSZTLBKWJM-YUMQZZPRSA-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
- JYXBNQOKPRQNQS-YTFOTSKYSA-N Lys-Ile-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JYXBNQOKPRQNQS-YTFOTSKYSA-N 0.000 description 1
- MUXNCRWTWBMNHX-SRVKXCTJSA-N Lys-Leu-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O MUXNCRWTWBMNHX-SRVKXCTJSA-N 0.000 description 1
- LJADEBULDNKJNK-IHRRRGAJSA-N Lys-Leu-Val Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O LJADEBULDNKJNK-IHRRRGAJSA-N 0.000 description 1
- XOQMURBBIXRRCR-SRVKXCTJSA-N Lys-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN XOQMURBBIXRRCR-SRVKXCTJSA-N 0.000 description 1
- YUAXTFMFMOIMAM-QWRGUYRKSA-N Lys-Lys-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O YUAXTFMFMOIMAM-QWRGUYRKSA-N 0.000 description 1
- GAHJXEMYXKLZRQ-AJNGGQMLSA-N Lys-Lys-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GAHJXEMYXKLZRQ-AJNGGQMLSA-N 0.000 description 1
- CNGOEHJCLVCJHN-SRVKXCTJSA-N Lys-Pro-Glu Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O CNGOEHJCLVCJHN-SRVKXCTJSA-N 0.000 description 1
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- BDFHWFUAQLIMJO-KXNHARMFSA-N Lys-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N)O BDFHWFUAQLIMJO-KXNHARMFSA-N 0.000 description 1
- MIMXMVDLMDMOJD-BZSNNMDCSA-N Lys-Tyr-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O MIMXMVDLMDMOJD-BZSNNMDCSA-N 0.000 description 1
- VKCPHIOZDWUFSW-ONGXEEELSA-N Lys-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN VKCPHIOZDWUFSW-ONGXEEELSA-N 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
- DJJBHQHOZLUBCN-WDSOQIARSA-N Met-Lys-Trp Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DJJBHQHOZLUBCN-WDSOQIARSA-N 0.000 description 1
- DBMLDOWSVHMQQN-XGEHTFHBSA-N Met-Ser-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DBMLDOWSVHMQQN-XGEHTFHBSA-N 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 208000029726 Neurodevelopmental disease Diseases 0.000 description 1
- WSXKXSBOJXEZDV-DLOVCJGASA-N Phe-Ala-Asn Chemical compound NC(=O)C[C@@H](C([O-])=O)NC(=O)[C@H](C)NC(=O)[C@@H]([NH3+])CC1=CC=CC=C1 WSXKXSBOJXEZDV-DLOVCJGASA-N 0.000 description 1
- CYZBFPYMSJGBRL-DRZSPHRISA-N Phe-Ala-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CYZBFPYMSJGBRL-DRZSPHRISA-N 0.000 description 1
- VHWOBXIWBDWZHK-IHRRRGAJSA-N Phe-Arg-Asp Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](CC(O)=O)C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 VHWOBXIWBDWZHK-IHRRRGAJSA-N 0.000 description 1
- JIYJYFIXQTYDNF-YDHLFZDLSA-N Phe-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N JIYJYFIXQTYDNF-YDHLFZDLSA-N 0.000 description 1
- DDYIRGBOZVKRFR-AVGNSLFASA-N Phe-Asp-Glu Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N DDYIRGBOZVKRFR-AVGNSLFASA-N 0.000 description 1
- WIVCOAKLPICYGY-KKUMJFAQSA-N Phe-Asp-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N WIVCOAKLPICYGY-KKUMJFAQSA-N 0.000 description 1
- CUMXHKAOHNWRFQ-BZSNNMDCSA-N Phe-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CUMXHKAOHNWRFQ-BZSNNMDCSA-N 0.000 description 1
- UNLYPPYNDXHGDG-IHRRRGAJSA-N Phe-Gln-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 UNLYPPYNDXHGDG-IHRRRGAJSA-N 0.000 description 1
- JJHVFCUWLSKADD-ONGXEEELSA-N Phe-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O JJHVFCUWLSKADD-ONGXEEELSA-N 0.000 description 1
- JEBWZLWTRPZQRX-QWRGUYRKSA-N Phe-Gly-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O JEBWZLWTRPZQRX-QWRGUYRKSA-N 0.000 description 1
- PMKIMKUGCSVFSV-CQDKDKBSSA-N Phe-His-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=CC=C2)N PMKIMKUGCSVFSV-CQDKDKBSSA-N 0.000 description 1
- SMFGCTXUBWEPKM-KBPBESRZSA-N Phe-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 SMFGCTXUBWEPKM-KBPBESRZSA-N 0.000 description 1
- DNAXXTQSTKOHFO-QEJZJMRPSA-N Phe-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 DNAXXTQSTKOHFO-QEJZJMRPSA-N 0.000 description 1
- OQTDZEJJWWAGJT-KKUMJFAQSA-N Phe-Lys-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O OQTDZEJJWWAGJT-KKUMJFAQSA-N 0.000 description 1
- ZVRJWDUPIDMHDN-ULQDDVLXSA-N Phe-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 ZVRJWDUPIDMHDN-ULQDDVLXSA-N 0.000 description 1
- HBXAOEBRGLCLIW-AVGNSLFASA-N Phe-Ser-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N HBXAOEBRGLCLIW-AVGNSLFASA-N 0.000 description 1
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-N 0.000 description 1
- ZVJGAXNBBKPYOE-HKUYNNGSSA-N Phe-Trp-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(O)=O)C1=CC=CC=C1 ZVJGAXNBBKPYOE-HKUYNNGSSA-N 0.000 description 1
- ZYNBEWGJFXTBDU-ACRUOGEOSA-N Phe-Tyr-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CC=CC=C2)N ZYNBEWGJFXTBDU-ACRUOGEOSA-N 0.000 description 1
- IWNOFCGBMSFTBC-CIUDSAMLSA-N Pro-Ala-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IWNOFCGBMSFTBC-CIUDSAMLSA-N 0.000 description 1
- KIZQGKLMXKGDIV-BQBZGAKWSA-N Pro-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 KIZQGKLMXKGDIV-BQBZGAKWSA-N 0.000 description 1
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 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
- KPDRZQUWJKTMBP-DCAQKATOSA-N Pro-Asp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN1 KPDRZQUWJKTMBP-DCAQKATOSA-N 0.000 description 1
- YFNOUBWUIIJQHF-LPEHRKFASA-N Pro-Asp-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O YFNOUBWUIIJQHF-LPEHRKFASA-N 0.000 description 1
- ZCXQTRXYZOSGJR-FXQIFTODSA-N Pro-Asp-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZCXQTRXYZOSGJR-FXQIFTODSA-N 0.000 description 1
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 1
- QGOZJLYCGRYYRW-KKUMJFAQSA-N Pro-Glu-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QGOZJLYCGRYYRW-KKUMJFAQSA-N 0.000 description 1
- HAAQQNHQZBOWFO-LURJTMIESA-N Pro-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H]1CCCN1 HAAQQNHQZBOWFO-LURJTMIESA-N 0.000 description 1
- ZTMLZUNPFDGPKY-VKOGCVSHSA-N Pro-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@@H]3CCCN3 ZTMLZUNPFDGPKY-VKOGCVSHSA-N 0.000 description 1
- XYSXOCIWCPFOCG-IHRRRGAJSA-N Pro-Leu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XYSXOCIWCPFOCG-IHRRRGAJSA-N 0.000 description 1
- MRYUJHGPZQNOAD-IHRRRGAJSA-N Pro-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1 MRYUJHGPZQNOAD-IHRRRGAJSA-N 0.000 description 1
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 description 1
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 1
- AJBQTGZIZQXBLT-STQMWFEESA-N Pro-Phe-Gly Chemical compound C([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H]1NCCC1)C1=CC=CC=C1 AJBQTGZIZQXBLT-STQMWFEESA-N 0.000 description 1
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 1
- VMVNCJDKFOQOHM-GUBZILKMSA-N Ser-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N VMVNCJDKFOQOHM-GUBZILKMSA-N 0.000 description 1
- YRBGKVIWMNEVCZ-WDSKDSINSA-N Ser-Glu-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O YRBGKVIWMNEVCZ-WDSKDSINSA-N 0.000 description 1
- BRGQQXQKPUCUJQ-KBIXCLLPSA-N Ser-Glu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BRGQQXQKPUCUJQ-KBIXCLLPSA-N 0.000 description 1
- FYUIFUJFNCLUIX-XVYDVKMFSA-N Ser-His-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O FYUIFUJFNCLUIX-XVYDVKMFSA-N 0.000 description 1
- CLKKNZQUQMZDGD-SRVKXCTJSA-N Ser-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CC1=CN=CN1 CLKKNZQUQMZDGD-SRVKXCTJSA-N 0.000 description 1
- CJINPXGSKSZQNE-KBIXCLLPSA-N Ser-Ile-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(O)=O CJINPXGSKSZQNE-KBIXCLLPSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 1
- UGTZYIPOBYXWRW-SRVKXCTJSA-N Ser-Phe-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O UGTZYIPOBYXWRW-SRVKXCTJSA-N 0.000 description 1
- UPLYXVPQLJVWMM-KKUMJFAQSA-N Ser-Phe-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O UPLYXVPQLJVWMM-KKUMJFAQSA-N 0.000 description 1
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 1
- 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 1
- ZSDXEKUKQAKZFE-XAVMHZPKSA-N Ser-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N)O ZSDXEKUKQAKZFE-XAVMHZPKSA-N 0.000 description 1
- STIAINRLUUKYKM-WFBYXXMGSA-N Ser-Trp-Ala Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CO)=CNC2=C1 STIAINRLUUKYKM-WFBYXXMGSA-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
- 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
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- JMQUAZXYFAEOIH-XGEHTFHBSA-N Thr-Arg-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O)N)O JMQUAZXYFAEOIH-XGEHTFHBSA-N 0.000 description 1
- YOSLMIPKOUAHKI-OLHMAJIHSA-N Thr-Asp-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O YOSLMIPKOUAHKI-OLHMAJIHSA-N 0.000 description 1
- 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 1
- HJOSVGCWOTYJFG-WDCWCFNPSA-N Thr-Glu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N)O HJOSVGCWOTYJFG-WDCWCFNPSA-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
- 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
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 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
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 1
- MXNAOGFNFNKUPD-JHYOHUSXSA-N Thr-Phe-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MXNAOGFNFNKUPD-JHYOHUSXSA-N 0.000 description 1
- NYQIZWROIMIQSL-VEVYYDQMSA-N Thr-Pro-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O NYQIZWROIMIQSL-VEVYYDQMSA-N 0.000 description 1
- GVMXJJAJLIEASL-ZJDVBMNYSA-N Thr-Pro-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O GVMXJJAJLIEASL-ZJDVBMNYSA-N 0.000 description 1
- VBMOVTMNHWPZJR-SUSMZKCASA-N Thr-Thr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VBMOVTMNHWPZJR-SUSMZKCASA-N 0.000 description 1
- LXXCHJKHJYRMIY-FQPOAREZSA-N Thr-Tyr-Ala 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](C)C(O)=O LXXCHJKHJYRMIY-FQPOAREZSA-N 0.000 description 1
- SBYQHZCMVSPQCS-RCWTZXSCSA-N Thr-Val-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O SBYQHZCMVSPQCS-RCWTZXSCSA-N 0.000 description 1
- CXUFDWZBHKUGKK-CABZTGNLSA-N Trp-Ala-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O)=CNC2=C1 CXUFDWZBHKUGKK-CABZTGNLSA-N 0.000 description 1
- DEZKIRSBKKXUEV-NYVOZVTQSA-N Trp-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)O)N DEZKIRSBKKXUEV-NYVOZVTQSA-N 0.000 description 1
- HIZDHWHVOLUGOX-BPUTZDHNSA-N Trp-Ser-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O HIZDHWHVOLUGOX-BPUTZDHNSA-N 0.000 description 1
- OOEUVMFKKZYSRX-LEWSCRJBSA-N Tyr-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N OOEUVMFKKZYSRX-LEWSCRJBSA-N 0.000 description 1
- GFHYISDTIWZUSU-QWRGUYRKSA-N Tyr-Asn-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O GFHYISDTIWZUSU-QWRGUYRKSA-N 0.000 description 1
- WAPFQMXRSDEGOE-IHRRRGAJSA-N Tyr-Glu-Gln 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](CCC(N)=O)C(O)=O WAPFQMXRSDEGOE-IHRRRGAJSA-N 0.000 description 1
- NJLQMKZSXYQRTO-FHWLQOOXSA-N Tyr-Glu-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NJLQMKZSXYQRTO-FHWLQOOXSA-N 0.000 description 1
- NOOMDULIORCDNF-IRXDYDNUSA-N Tyr-Gly-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NOOMDULIORCDNF-IRXDYDNUSA-N 0.000 description 1
- KIJLSRYAUGGZIN-CFMVVWHZSA-N Tyr-Ile-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O KIJLSRYAUGGZIN-CFMVVWHZSA-N 0.000 description 1
- NKUGCYDFQKFVOJ-JYJNAYRXSA-N Tyr-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NKUGCYDFQKFVOJ-JYJNAYRXSA-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
- RWOKVQUCENPXGE-IHRRRGAJSA-N Tyr-Ser-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RWOKVQUCENPXGE-IHRRRGAJSA-N 0.000 description 1
- LUMQYLVYUIRHHU-YJRXYDGGSA-N Tyr-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LUMQYLVYUIRHHU-YJRXYDGGSA-N 0.000 description 1
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 1
- PQPWEALFTLKSEB-DZKIICNBSA-N Tyr-Val-Glu 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](CCC(O)=O)C(O)=O PQPWEALFTLKSEB-DZKIICNBSA-N 0.000 description 1
- OBKOPLHSRDATFO-XHSDSOJGSA-N Tyr-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N OBKOPLHSRDATFO-XHSDSOJGSA-N 0.000 description 1
- IZFVRRYRMQFVGX-NRPADANISA-N Val-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N IZFVRRYRMQFVGX-NRPADANISA-N 0.000 description 1
- ZLFHAAGHGQBQQN-GUBZILKMSA-N Val-Ala-Pro Natural products CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O ZLFHAAGHGQBQQN-GUBZILKMSA-N 0.000 description 1
- NMANTMWGQZASQN-QXEWZRGKSA-N Val-Arg-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N NMANTMWGQZASQN-QXEWZRGKSA-N 0.000 description 1
- ISERLACIZUGCDX-ZKWXMUAHSA-N Val-Asp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N ISERLACIZUGCDX-ZKWXMUAHSA-N 0.000 description 1
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 1
- PTFPUAXGIKTVNN-ONGXEEELSA-N Val-His-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)NCC(=O)O)N PTFPUAXGIKTVNN-ONGXEEELSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- YMTOEGGOCHVGEH-IHRRRGAJSA-N Val-Lys-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O YMTOEGGOCHVGEH-IHRRRGAJSA-N 0.000 description 1
- WMRWZYSRQUORHJ-YDHLFZDLSA-N Val-Phe-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)O)C(=O)O)N WMRWZYSRQUORHJ-YDHLFZDLSA-N 0.000 description 1
- CKTMJBPRVQWPHU-JSGCOSHPSA-N Val-Phe-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)O)N CKTMJBPRVQWPHU-JSGCOSHPSA-N 0.000 description 1
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 1
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 1
- UJMCYJKPDFQLHX-XGEHTFHBSA-N Val-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N)O UJMCYJKPDFQLHX-XGEHTFHBSA-N 0.000 description 1
- DLRZGNXCXUGIDG-KKHAAJSZSA-N Val-Thr-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O DLRZGNXCXUGIDG-KKHAAJSZSA-N 0.000 description 1
- PDDJTOSAVNRJRH-UNQGMJICSA-N Val-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](C(C)C)N)O PDDJTOSAVNRJRH-UNQGMJICSA-N 0.000 description 1
- 108010011164 acein 1 Proteins 0.000 description 1
- 108010069490 alanyl-glycyl-seryl-glutamic acid Proteins 0.000 description 1
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 1
- 108010011559 alanylphenylalanine Proteins 0.000 description 1
- 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 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 108010036533 arginylvaline Proteins 0.000 description 1
- 108010061502 asparagyl-alanyl-leucyl-phenylalanyl-glutamic acid Proteins 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 108010038633 aspartylglutamate Proteins 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 108010069495 cysteinyltyrosine Proteins 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- -1 diisocyanate compound Chemical class 0.000 description 1
- 150000005182 dinitrobenzenes Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 108010040856 glutamyl-cysteinyl-alanine Proteins 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- 108010040030 histidinoalanine Proteins 0.000 description 1
- 108010045383 histidyl-glycyl-glutamic acid Proteins 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 108010000761 leucylarginine Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 108010012058 leucyltyrosine Proteins 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 108010038320 lysylphenylalanine Proteins 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000030363 nerve development Effects 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 108010074082 phenylalanyl-alanyl-lysine Proteins 0.000 description 1
- 108010082795 phenylalanyl-arginyl-arginine Proteins 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 108010007513 prolyl-glycyl-prolyl-leucine Proteins 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 108010015796 prolylisoleucine Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 230000004617 sleep duration Effects 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 230000001180 sulfating effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/765—Serum albumin, e.g. HSA
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
-
- 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
- G01N33/5308—Immunoassay; Biospecific binding assay; Materials therefor for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites
-
- 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
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
-
- 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
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/581—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with enzyme label (including co-enzymes, co-factors, enzyme inhibitors or substrates)
-
- 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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6854—Immunoglobulins
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2864—Sleep disorders
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明提供了一种6‑羟基硫酸褪黑素衍生物及其免疫原、特异性抗体的制备方法和应用,本发明还提供了6‑羟基硫酸褪黑素免疫检测试剂。具体的,将结构新颖的6‑羟基硫酸褪黑素衍生物与经过基因工程改造得到的重组牛血清白蛋白偶联制得6‑羟基硫酸褪黑素人工抗原,再用6‑羟基硫酸褪黑素人工抗原免疫实验动物获得抗6‑羟基硫酸褪黑素特异性抗体,经检测表明,本发明提供的特异性抗体的特异性强、灵敏度高,与常见的30种激素无任何交叉反应;所制备的6‑羟基硫酸褪黑素免疫检测试剂,可以实现在全自动生化分析仪上对6‑羟基硫酸褪黑素的高通量、快速化检测。
Description
技术领域
本发明属于生物医学检测技术领域,具体涉及一种6-羟基硫酸褪黑素衍生物及其免疫原、特异性抗体的制备方法和应用,还涉及6-羟基硫酸褪黑素免疫检测试剂。
背景技术
孤独症谱系障碍(autism spectrum disorders,ASD)是一种起病于婴幼儿期的神经发育障碍性疾病,患病率呈逐年上升趋势,该病以社会沟通与交往障碍,局限的、重复的刻板行为,狭窄的兴趣或活动为核心症状。近年来ASD患儿所伴有的临床相关问题引起关注,特别是睡眠问题,有研究报道ASD患儿常伴睡眠-觉醒障碍问题,其中失眠最为常见,以入睡困难,睡眠持续时间短和夜醒次数多等症状为主,这可能是由于ASD患儿体内调节昼夜生物节律的下丘脑-垂体-肾上腺轴功能紊乱,引起相关神经递质代谢通路异常而导致的。研究发现ASD患儿体内对昼夜生理节律及睡眠-觉醒节律的调节发挥重要作用的褪黑激素及其代谢产物6-羟基硫酸褪黑素(6-sulfatoxymelatonin,6-SM)的水平偏低。褪黑激素是一种重要的神经内分泌激素,对机体早期神经发育、睡眠-觉醒节律、氧化应激等生理机能发挥重要作用,其合成受光周期和位于下丘脑视交叉上核生物钟的调控,呈昼夜和季节性的变化规律,褪黑激素的分泌量在凌晨两点左右达到高峰,褪黑激素的主要代谢产物6-SM随尿液排出,其化学性质十分稳定,尿液中6-SM的水平可以代表血液中褪黑激素的水平。研究发现ASD患儿晨尿中6-SM的水平明显低于健康儿童对照组。进一步研究发现ASD患儿的6-SM水平与睡眠问题的严重程度呈明显负相关,即6-SM水平越低,ASD患儿存在的睡眠问题就越严重,这表明ASD患儿睡眠问题可能与其体内褪黑激素的分泌量减少有关。因此,对ASD患儿尿液中的6-SM水平进行检测与监控,对于提高ASD患儿的治疗与康复效果具有重要的临床意义。
检测6-羟基硫酸褪黑素的实验室方法有比色法、放射免疫分析法、高效液相色谱法、液相串联质谱法、酶联免疫吸附测定法、免疫比浊法等。比色法检测的是褪黑激素与6-羟基硫酸褪黑素等物质的总和而非单一化合物水平;放射免疫分析法稳定性较差,且存在放射线辐射和污染等问题;高效液相色谱法前处理复杂,要求目标分析物在色谱上被完全分离,因此分析时间较长;液相串联质谱法检测灵敏度高,快速,但结构复杂,维护成本高,需经过专门培训的技术人员操作,不易在基层医疗机构普及;酶联免疫吸附测定法灵敏度高,特异性好,但检测时间长,准确度差,难以用于批量检测。
因此,目前市面上缺乏线性范围宽、灵敏度高、准确度高、精密度高,检测时间短,样品处理简单,仪器自动化程度高,可多样本连续检测的6-羟基硫酸褪黑素检测产品。
发明内容
为了克服现有技术的不足,本发明的第一个目的在于提供一种6-羟基硫酸褪黑素衍生物,该衍生物为新合成的化合物,自然界中不存在。
本发明的第一个目的采用以下技术方案实现:一种6-羟基硫酸褪黑素衍生物,其结构式如式Ⅰ所示:
本发明的第二个目的在于提供一种如上所述的6-羟基硫酸褪黑素衍生物的制备方法,该制备方法不同于常规制备方法,具有良好的合成效果,显著提高了6-羟基硫酸褪黑素衍生物的合成效率。
本发明的第二个目的采用以下技术方案实现:一种如结构式I所示的6-羟基硫酸褪黑素衍生物的制备方法,包括以下步骤:
(1)将化合物1与氯甲酸乙在碱性条件下酯反应,得到化合物2:
优选地,将化合物1与氯甲酸乙酯溶于合适的溶剂(如DCM)中,加入碱,N2条件下搅拌至反应完全,得到目标化合物2;优选地,化合物1与氯甲酸乙酯的摩尔投料比为1:0.5~1.5,更优选地,为1:1~1.2;
所述的碱为NaOH、KOH、Na2CO3、K2CO3,或LiOH中的一种,优选所述碱为NaOH;
优选地,反应结束之后对反应混合物进行分离纯化,例如分别采用乙酸乙酯稀释,饱和食盐水洗涤,然后干燥处理,得到目标化合物。
(2)将化合物2与乙酰氯反应,得到化合物3:
优选地,将化合物2溶于适当的溶剂(如THF)中,然后加入三氯化铝和乙酰氯,在合适的温度(如20~30℃)条件下搅拌,反应结束后,进行纯化,得到化合物3;进一步优选地,反应结束后,向反应混合物中加入水淬灭反应,用乙酸乙酯萃取,有机层浓缩后色谱柱纯化,分离得到高纯度的化合物3。
进一步优选地,化合物2、乙酰氯和三氯化铝的摩尔用量比为1:1~1.1:1~1.1;最优选地,化合物2与乙酰氯的摩尔投料比为1:1.05,化合物2与三氯化铝的摩尔投料比为1:1.05。
(3)将化合物3与2-(氨基氧基)乙酸叔丁酯在碱性条件下反应,得到化合物4:
优选的,将化合物3溶于适当的溶剂(如DMF)中,然后加入2-(氨基氧基)乙酸叔丁酯和碱,于60~90℃下搅拌,反应结束后,对反应物进行纯化,优选地,向反应混合物中加入水,然后用乙酸乙酯萃取,有机层浓缩并用快速色谱法纯化,得到化合物4;
其中优选地,化合物3与2-(氨基氧基)乙酸叔丁酯的摩尔投料比为1:0.8~1.2;其中所述2-(氨基氧基)乙酸叔丁酯具有如下结构:
所述碱为NaOH、KOH、Na2CO3、K2CO3,或LiOH中的一种,优选所述碱为K2CO3。
(4)将化合物4通过水解反应,脱去叔丁基,得到6-羟基硫酸褪黑素衍生物:
优选地,将化合物4溶于合适的溶剂(如THF)中,然后向化合物4的THF溶液中加入酸,进行水解反应,得到式Ⅰ所示的目标化合物,进一步优选地,所述酸为HCl与甲醇的混合溶液,其中HCl与MeOH体积比为1:5~10,HCl的浓度为6mol/L~8mol/L。
本发明的第三个目的在于提供一种6-羟基硫酸褪黑素免疫原。
本发明的第三个目的采用以下技术方案实现:一种6-羟基硫酸褪黑素免疫原,所述6-羟基硫酸褪黑素免疫原由上述结构式Ⅰ所示的6-羟基硫酸褪黑素衍生物与载体蛋白连接而成,其结构式如式Ⅱ所示:
其中,载体蛋白为重组牛血清白蛋白,优选地,所述重组牛血清白蛋白的氨基酸序列为SEQ ID NO:1。
其中SEQ ID NO:1的序列如下所示:
MKWVTFISLLLLFSSAYSRGVFRRDTHKKSEIAHRFKDLGEEHFKGLVLIAFSQYLQQCPFDEHVKKLVNELTEFAKKTCVADESHAGCEKSLHTLFGDELCKKVASLRETYGDMADCCEKQEPERNECFLSHKDDSPDLPKLKPDPNTLCDEFKADEKKFWGKYLYEIARRHPYFYAPELLYYANKKYNGVFQECCQAEDKGACLLPKKIETMREKVLTSSARQRLRCASIQKKFGERALKAWSVARLSQKFPKAEFVEVTKKLVTDLTKVHKECCHGDLLECADDRADLAKYICDNQDTISSKLKKECCDKPLLEKSHCIAEVEKDAIPENLPPLTADFAEDKKDVCKNYQEAKDAFLGSFLYEYSRRHPEYAVSVLLRLAKKEYEATLEECCAKDDPHACYSTVFDKLKKHLVDEPQNLIKQNCDQFEKLGEYGFQNALIVRYTRKKVPQVSTPTLVEVSRSLGKVGTRCCTKKPESERMPCTEDYLSLILNRLCVLHEKTPVSEKKVTKCCTESLVNRRPCFSALTPDETYVPKAFDEKLFTFHADICTLPDTEKKQIKKQTALVELLKHKPKATEEQLKKTVMENFVAFVDKCCAADDKEACFAVEGPKKLVVSTQTALA
本发明第四个目的在于提供一种上述式II所示的6-羟基硫酸褪黑素免疫原的制备方法。
本发明的第四个目的采用以下技术方案实现:一种上述式II所示的6-羟基硫酸褪黑素免疫原的制备方法,包括以下步骤:
(B1)载体蛋白溶液的制备:将重组牛血清白蛋白溶解于磷酸盐缓冲液中,得到载体蛋白溶液;
(B2)6-羟基硫酸褪黑素衍生物溶液的制备:将上述结构式Ⅰ所示的6-羟基硫酸褪黑素衍生物与二甲基甲酰胺、乙醇、磷酸钾缓冲液、1-乙基-3-(-3-二甲氨丙基)碳二亚胺和N-羟基硫代琥珀酰亚胺混合,搅拌溶解,得到结构式Ⅰ所示的6-羟基硫酸褪黑素衍生物溶液;
(B3)式II所示的6-羟基硫酸褪黑素免疫原的合成:将步骤(B2)得到的6-羟基硫酸褪黑素衍生物溶液加入到步骤(B1)得到的载体蛋白溶液中,搅拌反应,经透析纯化,得到式II所示的6-羟基硫酸褪黑素免疫原。
进一步优选地,(B1)所述重组牛血清白蛋白氨基酸序列为SEQ ID NO:1。
在本发明的一个优选实施方式中,提供了一种式II所示的述6-羟基硫酸褪黑素免疫原的制备方法,包括以下步骤:
(b1)载体蛋白溶液的制备:将载体蛋白溶解于0.2M的磷酸钾缓冲液(pH=8.5)中,载体蛋白的终浓度为3-5mg/mL,得到载体蛋白溶液;
(b2)6-羟基硫酸褪黑素衍生物溶液的制备:将100-300mg上述的6-羟基硫酸褪黑素衍生物、2-6mL二甲基甲酰胺、2-6mL乙醇、3-10mL的磷酸钾缓冲液(10mM,pH=5.0)、100-300mg1-乙基-3-(-3-二甲氨丙基)碳二亚胺、20-80mg N-羟基硫代琥珀酰亚胺混合,搅拌溶解反应30-120min,得到6-羟基硫酸褪黑素衍生物溶液;
(b3)6-羟基硫酸褪黑素免疫原的合成:将步骤(b2)得到的6-羟基硫酸褪黑素衍生物溶液加入到步骤(b1)得到的载体蛋白溶液中,并在0-8℃下搅拌过夜,经透析纯化,得到式II所示的6-羟基硫酸褪黑素免疫原。
本发明的第五个目的在于提供一种抗6-羟基硫酸褪黑素特异性抗体。
本发明的第五个目的采用以下技术方案实现:一种抗6-羟基硫酸褪黑素特异性抗体,所述抗6-羟基硫酸褪黑素特异性抗体为使用式II所示的6-羟基硫酸褪黑素免疫原对实验动物进行注射后所得到的特异性抗体,所述的实验动物为兔子、山羊、绵羊、小鼠、大鼠、豚鼠或马中的一种。
本发明的第六个目的在于提供一种如上所述的抗6-羟基硫酸褪黑素特异性抗体的制备方法。
本发明的第六个目的采用以下技术方案实现:一种抗6-羟基硫酸褪黑素特异性抗体的制备方法,包含以下步骤:
(C1)将式II所示的6-羟基硫酸褪黑素免疫原用磷酸盐缓冲液稀释,得到6-羟基硫酸褪黑素人工抗原溶液,然后将6-羟基硫酸褪黑素人工抗原溶液与等量弗氏完全佐剂混合,对上述的实验动物进行多点注射;
(C2)3-6周后,再用相同的6-羟基硫酸褪黑素人工抗原溶液与等量弗氏不完全佐剂混合,对步骤(C1)所述的实验动物进行多点注射,之后每隔3-6周注射一次,共计注射3-10次;
(C3)对步骤(C2)中完成注射的实验动物取血,分离纯化,得到抗6-羟基硫酸褪黑素特异性抗体。
在本发明的一个优选实施方式中,提供了一种所述抗6-羟基硫酸褪黑素特异性抗体的制备方法,包含以下步骤:
(c1)将上述的6-羟基硫酸褪黑素免疫原用0.01M磷酸钠缓冲液(pH=6.0)稀释至终浓度为1.0-3.0mg/mL,得到人工抗原溶液,然后将人工抗原溶液与等量弗氏完全佐剂混合,对实验动物兔子进行多点注射;
(c2)4周后,再用相同的人工抗原溶液与等量弗氏不完全佐剂对步骤(c1)所述的实验动物兔子进行多点注射,之后每隔4周注射一次,共计注射5-8次;
(c3)对步骤(c2)完成注射的实验动物兔子取血,分离纯化,得到抗6-羟基硫酸褪黑素特异性抗体。
本发明的第七个目的在于提供一种6-羟基硫酸褪黑素均相酶免疫检测试剂。
本发明的第七个目的采用以下技术方案实现:一种6-羟基硫酸褪黑素均相酶免疫检测试剂,由R1试剂与R2试剂组成,其中,所述R1试剂包含前述的抗6-羟基硫酸褪黑素特异性抗体与R1缓冲液;所述R2试剂包含6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物与R2缓冲液;
所述的R1缓冲液含有酶底物、辅酶、牛血清白蛋白及Tris缓冲液,所述的酶底物为葡萄糖-6-磷酸,所述的辅酶为氧化型烟酰胺腺嘌呤二核苷酸;
所述的6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物由上述结构式Ⅰ所示的6-羟基硫酸褪黑素衍生物与重组葡萄糖-6-磷酸脱氢酶偶联而成;其结构式如式Ⅲ所示:
所述的R2缓冲液为含有牛血清白蛋白的Tris缓冲液。
进一步地,优选所述重组葡萄糖-6-磷酸脱氢酶的氨基酸序列为SEQ ID NO:2。
其中,SEQ ID NO:2的序列如下所示:
MSTTPNTPTSASHEPSCKKVSAGPHEGPSSPAGKRPAPPCTLVIFGAGGDLTKKRLLVPALYNLAVDGLLDDGMKIIGVNHGERETSVWREDLHKKSLQQFAADKASTFHAGKLDDKAWDWVAQRLEYMAGEFETDDTFTKKLKQKLDQAPGGNVIFYLAVSSRFFKKPIVEHLGKAGLLKEADGGSGGFRRIVVEKKPFGTDLATARDLNAHILSYANESQVYRIDHFLGKKDTVQSILAVRFANALFEPIWRREYIDSVQITAAETIGVEGRGKKFYEQTGAFRDMLPNHLFQLLGMVAMEPPNSFDKAEAVRDKKAEIFDAIQPLTADDVVFGQYEKKGPAGVGYREEPDVAPDSTTETYAAARVYVENWRWAGVPFYLRTGKKRLAARRTEISVQLKKPVPFRLFRDTPVDALTPNVLTLRIDPAHGTSFDFNVKKTPGPLMQIGAVQSSFDYADFFAEKKANVGYETLLYDCMLGDETLFQRADSIETSWAAVDDVLHPKKSGGAMPVHGYPAGSEGPAEADALLARDGHAWRPLKKRDAVEKK
具体的,所述6-羟基硫酸褪黑素均相酶免疫检测试剂的制备方法,包含以下步骤:
(D1)将0.25%牛血清白蛋白、50mmol/L葡萄糖-6-磷酸及50mmol/L氧化型烟酰胺腺嘌呤二核苷酸依次加入50mmol/L Tris缓冲液中搅拌溶解制成R1缓冲液,再将抗6-羟基硫酸褪黑素特异性抗体1以1∶500-1∶5000的体积比加入到上述R1缓冲液中混匀,再用6mol/L的盐酸调节pH至8.0,制成R1试剂;
(D2)将0.25%牛血清白蛋白加入100mmol/L Tris缓冲液中搅拌溶解制成R2缓冲液,再将6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物以1:1000~1:8000的体积比加入到上述R2缓冲液中混匀,再用6mol/L的盐酸调节pH至7.6,制成R2试剂;
所述的6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物的制备方法,包含以下步骤:
(E1)称取15mg活力单位为100KU的重组葡萄糖-6-磷酸脱氢酶,在室温条件下溶解于30mL磷酸钠(pH=8.0)缓冲液中,然后加入225mg还原态的烟酰胺腺嘌呤二核苷酸、135mg葡萄糖-6-磷酸以及0.75mL卡必醇,再逐滴加入2mL二甲基亚砜,得到重组葡萄糖-6-磷酸脱氢酶溶液;
(E2)在无水状态下称取10mg上述结构式Ⅰ所示的6-羟基硫酸褪黑素衍生物,溶解于600μL二甲基甲酰胺中,将上述溶液温度降到-2~-8℃后加入3μL三丁胺、1.5μL氯甲酸异丁酯、1.5μL N,N′-二环己基碳二亚胺,-2~-8℃下搅拌30分钟,得到6-羟基硫酸褪黑素衍生物激活液;
(E3)将6-羟基硫酸褪黑素衍生物激活液逐滴加入到重组葡萄糖-6-磷酸脱氢酶溶液中,2-8℃搅拌反应12小时,反应结束后经G-25凝胶层析柱纯化得到结构式如式III所示的6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物。
本发明的第八个目的在于提供一种6-羟基硫酸褪黑素胶乳增强免疫比浊检测试剂。
本发明的第八个目的采用以下技术方案实现:一种6-羟基硫酸褪黑素胶乳增强免疫比浊检测试剂,由L1试剂与L2试剂组成;
其中,所述L1试剂由前述的抗6-羟基硫酸褪黑素特异性抗体、pH=8.0的缓冲液、牛血清白蛋白、氯化钠、吐温-20、丙三醇、乙二胺四乙酸、促凝剂以及防腐剂组成;
所述L2试剂由6-羟基硫酸褪黑素-牛血清白蛋白复合体包被的聚苯乙烯胶乳颗粒、pH=8.0的缓冲液、牛血清白蛋白、氯化钠、吐温-20、丙三醇、乙二胺四乙酸以及防腐剂组成;
所述的6-羟基硫酸褪黑素-牛血清白蛋白复合体由前述结构式Ⅰ所示的6-羟基硫酸褪黑素衍生物与牛血清白蛋白偶联而成,其结构式如式Ⅳ所示:
所述的聚苯乙烯胶乳颗粒直径范围为50-250nm;
所述的缓冲液为磷酸盐缓冲液、甘氨酸缓冲液、MES缓冲液、硼酸盐缓冲液、Tris-HCl缓冲液或巴比妥缓冲液中的一种;
所述促凝剂为PEG-4000、PEG-6000、PEG-8000或硫酸葡聚糖钠中的一种;
所述防腐剂为叠氮钠、硫柳汞、苯酚或乙基汞硫代硫酸钠中的一种;
具体的,所述6-羟基硫酸褪黑素胶乳增强免疫比浊检测试剂的制备方法,包含以下步骤:
(F1)将0.5mg/mL的抗6-羟基硫酸褪黑素特异性抗体溶解于50mmol/L pH=8.0的磷酸盐缓冲液中,然后添加质量分数为0.5%-2.5%的牛血清白蛋白、0.25%-1.0%的氯化钠、0.1%-0.5%的吐温-20、1.0%-5.0%的丙三醇、0.1%-1.0%的乙二胺四乙酸、0.5%-2.5%的PEG-4000以及0.01%-0.1%的叠氮钠,搅拌均匀,调节pH=7.5,制成L1试剂;
(F2)将0.5mg表面带有羧基的直径为150nm的聚苯乙烯胶乳颗粒加入4.5mL0.05mol/L pH=6.2的MES缓冲液中,然后加入5mg碳二亚胺,在37℃下反应1小时,制成胶乳颗粒溶液,再将0.5mg6-羟基硫酸褪黑素-牛血清白蛋白复合体用4.5mL 0.05mol/L pH=9.2的硼酸盐缓冲液稀释后,立即加入到上述胶乳颗粒溶液中,在37℃下反应12小时,然后加入1mL 0.1mol/L pH=8.5的甘氨酸缓冲液搅拌2小时,反应终止后离心去除上清液,再将沉淀物用10mL 50mmol/L pH=8.0的Tris-HCl缓冲液洗涤3次,再用25mL 50mmol/L pH=8.5的甘氨酸缓冲液稀释成胶乳悬浊液,最后加入质量分数为0.5%-2.5%的牛血清白蛋白、0.25%-1.0%的氯化钠、0.1%-0.5%的吐温-20、1.0%-5.0%的丙三醇、0.1%-1.0%的乙二胺四乙酸以及0.01%-0.1%的叠氮钠,搅拌均匀,制成L2试剂;
所述的6-羟基硫酸褪黑素-牛血清白蛋白复合体的制备方法,包含以下步骤:
将10mg牛血清白蛋白用5mL 0.1mol/L pH=7.8的磷酸盐缓冲液稀释,然后加入100mg上述结构式Ⅰ所示的6-羟基硫酸褪黑素衍生物,再加入50mg的偶联活化剂,在4℃下反应12小时,再用0.1mol/L pH=7.8的磷酸盐缓冲液在4℃下透析18小时,得到6-羟基硫酸褪黑素-牛血清白蛋白复合体;
所述的偶联活化剂为1-乙基-3-(3-二甲基氨基丙基)碳二亚胺、N,N′-二环己基碳二亚胺、N-羟基琥珀酰亚胺、三丁胺、戊二醛、二异氰酸化合物或二卤化二硝基苯中的一种。
相比现有技术,本发明的有益效果在于:
1.本发明设计的结构式I所示的6-羟基硫酸褪黑素衍生物及其合成方法均为针对性的新设计与研究,在现有技术中并不存在;
2.本发明以结构式I所示的6-羟基硫酸褪黑素衍生物制备出的抗6-羟基硫酸褪黑素特异性抗体的特异性强、灵敏度高,并且与常见的32种激素及激素代谢物无任何交叉反应,因此能够用于制备具有较高的准确性、精密度、灵敏度和特异性的6-羟基硫酸褪黑素检测试剂;
3.本发明使用经过基因工程改造得到的重组牛血清白蛋白与6-羟基硫酸褪黑素衍生物偶联得到6-羟基硫酸褪黑素免疫原,以及使用经过基因工程改造得到的重组葡萄糖-6-磷酸脱氢酶与6-羟基硫酸褪黑素衍生物偶联得到6-羟基硫酸褪黑素酶标偶联物,偶联效率高,显著提高免疫原的免疫原性与酶标偶联物的稳定性。
4.本发明的两种6-羟基硫酸褪黑素检测试剂可以实现在全自动生化分析仪上对6-羟基硫酸褪黑素高通量、快速化的检测,能同时测定多个样品,具有操作简便、灵敏度高、特异性强、结果准确等优点,还能有效降低6-羟基硫酸褪黑素检测成本,有利于临床推广使用。
附图说明
图1为实施例4所述6-羟基硫酸褪黑素的ELISA检测标准曲线;
图2为实施例8所述6-羟基硫酸褪黑素均相酶免疫检测试剂校准曲线;
图3为实施例10所述6-羟基硫酸褪黑素胶乳增强免疫比浊检测试剂校准曲线。
具体实施方式
下面结合附图以及具体实施方式,对本发明做进一步描述,这些附图均为简化的示意图,仅以阐释说明本发明的有益效果。除非特别指明,以下实施例中所用的试剂、仪器、设备、耗材均可从正规渠道商购买获得。
实施例1:6-羟基硫酸褪黑素衍生物的合成
(1)化合物2的合成:
将化合物1(50g,0.2mol)与氯甲酸乙酯(22g,0.2mol)溶解于DCM(250ml)中,然后向混合物中加入NaOH(8g,0.2mol),N2条件下搅拌过夜,然后将混合物用乙酸乙酯稀释,盐水洗涤,硫酸钠干燥,旋转蒸干,得到26g固体化合物,即为化合物2。
(2)化合物3的合成:
将化合物2(26g,85mmol)溶解于200mL四氢呋喃中,然后在溶液中加入三氯化铝(12g,90mmol)和乙酰氯(7g,90mmol),然后室温搅拌0.5h;然后用水淬灭反应,用乙酸乙酯萃取,有机层浓缩并用色谱柱纯化,得到化合物3共14g。
(3)化合物4的合成:
将化合物3(2g,5.8mmol)溶解于DMF(20ml)中,然后加入2-(氨基氧基)乙酸叔丁酯(10g,5.8mmol)和碳酸钾(11g),然后80℃搅拌过夜;反应结束后,向反应混合物中加入水,然后用乙酸乙酯萃取,有机层浓缩并用快速色谱法纯化,得到棕色固体1.2g,即为化合物4。
(4)式I所示6-羟基硫酸褪黑素衍生物的合成:
将化合物4(1.1g)溶解于THF(50ml)中,然后在溶液中加入10ml HCl与MeOH的混合溶液(HCl与MeOH体积比为1:5,HCl浓度为6mol/L),室温搅拌过夜,反应结束后,将反应混合物浓缩,快速色谱柱纯化,得到0.6g式I所示的6-羟基硫酸褪黑素衍生物。
实施例2:6-羟基硫酸褪黑素免疫原的制备
6-羟基硫酸褪黑素免疫原的制备方法具体步骤如下:
(1)载体蛋白溶液的制备:将重组牛血清白蛋白(氨基酸序列为SEQ ID NO:1)溶解于0.2M的磷酸钾缓冲液(pH=8.5)中,载体蛋白的终浓度为3-5mg/mL,得到载体蛋白溶液;
(2)6-羟基硫酸褪黑素衍生物溶液的制备:将100-300mg上述的6-羟基硫酸褪黑素衍生物、2-6mL二甲基甲酰胺、2-6mL乙醇、3-10mL的磷酸钾缓冲液(10mM,pH=5.0)、100-300mg1-乙基-3-(-3-二甲氨丙基)碳二亚胺、20-80mg N-羟基硫代琥珀酰亚胺混合,搅拌溶解反应30-120min,得到6-羟基硫酸褪黑素衍生物溶液;
(3)6-羟基硫酸褪黑素免疫原的合成:将步骤(2)得到的6-羟基硫酸褪黑素衍生物溶液加入到步骤(1)得到的载体蛋白溶液中,并在0-8℃下搅拌过夜,经透析纯化,得到6-羟基硫酸褪黑素免疫原,结构式如式II所示:
实施例3:抗6-羟基硫酸褪黑素特异性抗体的制备
抗6-羟基硫酸褪黑素特异性抗体的制备方法具体步骤如下:
(1)将实施例2制备的6-羟基硫酸褪黑素免疫原用0.01M磷酸钠缓冲液(pH=6.0)稀释至终浓度为1.0-3.0mg/mL,得到人工抗原溶液,然后将人工抗原溶液与等量弗氏完全佐剂混合,对实验动物兔子进行多点注射;
(2)4周后,再用相同的人工抗原溶液与等量弗氏不完全佐剂对步骤(1)中实验动物兔子进行多点注射,之后每隔4周注射一次,共计注射5-8次;
(3)对步骤(2)完成注射的实验动物兔子取血,分离纯化,得到抗6-羟基硫酸褪黑素特异性抗体。
实施例4:ELISA法检验抗6-羟基硫酸褪黑素特异性抗体的性能
1、6-羟基硫酸褪黑素的ELISA检测标准曲线的建立:
(1)ELISA标准品的制备:
将6-羟基硫酸褪黑素粉末(购于Sigma公司)溶解于甲醇溶液,制备成1mg/mL的储存液。用ELISA缓冲液将储存液依次稀释为0.00ng/mL、10.00ng/mL、20.00ng/mL、40.00ng/mL、80.00ng/mL、160.00ng/mL的标准溶液。其中,ELISA缓冲液含有50mM Tris,145mM NaCl和体积百分比0.25%的BSA。
(2)利用6-羟基硫酸褪黑素的ELISA检验方法制备标准曲线:
用PBS将实施例3中所制备的抗6-羟基硫酸褪黑素抗体稀释成1:10000的终浓度溶液,100μL/孔包被在96孔酶联板上,4℃放置12-24h;用PBS将上述包被有抗6-羟基硫酸褪黑素抗体的96孔酶联板洗涤3次后,加入200μL/孔的体积百分比0.5%的BSA溶液,4℃封闭放置8-16h。然后用PBS洗涤3次,加入20μL/孔的标准品。再加入100μL/孔工作浓度的HRP-6-羟基硫酸褪黑素偶联物;室温下孵育30min后PBS洗板5次;然后每孔加入100μL TMB底物,室温孵育30min。再每孔加入100μL终止液(2M硫酸)。测定450nm的吸光值。根据各标准品所对应的450nm的吸光值定标,制作标准曲线,结果如图1所示。
2、待测样品中6-羟基硫酸褪黑素含量的检测:
(1)制作待测样品:
制备方法:将6-羟基硫酸褪黑素粉末(购于Sigma公司)溶解于甲醇溶液制成1mg/mL的储存液,并将此储存液稀释于空白尿液中,至终浓度分别为0.00ng/mL、30.00ng/mL、120.00ng/mL,分别形成空白、低值、高值浓度的尿液样本。空白尿液为不含6-羟基硫酸褪黑素的健康人尿液。
(2)测试方法:
利用上述6-羟基硫酸褪黑素的ELISA检验方法,将上述空白、低值、高值浓度的尿液样本代替标准品,测试上述空白、低值、高值浓度的尿液样本在450nm的吸光值。
(3)测试结果:
对照图1中所示的6-羟基硫酸褪黑素的ELISA检验的标准曲线,计算每个样本中6-羟基硫酸褪黑素含量,并对每个样本进行3个复孔测定,根据上述样本中6-羟基硫酸褪黑素的实际含量计算回收率,结果如表1所示。
表1:6-羟基硫酸褪黑素的ELISA检测结果
由表1中结果可知:采用本发明提供的6-羟基硫酸褪黑素的ELISA检测试剂测定不同浓度样品中的6-羟基硫酸褪黑素回收率都较高,均在99%-101%之间,说明本发明所述的抗6-羟基硫酸褪黑素特异性抗体可以用于样本中6-羟基硫酸褪黑素的检测,并且结果准确度高。
实施例5:34种常见激素及激素代谢物干扰试验
选取34种常见激素及激素代谢物进行干扰检测,调整浓度至1mg/L,采用实施例4的ELISA检验方法对相应干扰物质的浓度进行测定,34种常见激素及激素代谢物名称以及测定结果详见表2。
表2:常见干扰物名称及测定结果
测定结果显示:上述34种常见激素及激素代谢物等价于6-羟基硫酸褪黑素的浓度均为0.00ng/mL。由此可见,本发明的抗体是抗6-羟基硫酸褪黑素的特异性抗体,与常见干扰物无交叉反应。
实施例6:6-羟基硫酸褪黑素均相酶免疫检测试剂的制备
6-羟基硫酸褪黑素均相酶免疫检测试剂的制备方法,具体步骤如下:
(1)将0.25%牛血清白蛋白、50mmol/L葡萄糖-6-磷酸及50mmol/L氧化型烟酰胺腺嘌呤二核苷酸依次加入50mmol/L Tris缓冲液中搅拌溶解制成R1缓冲液,再将抗6-羟基硫酸褪黑素特异性抗体1以1∶1500的体积比加入到上述R1缓冲液中混匀,再用6mol/L的盐酸调节pH至8.0,制成R1试剂;
(2)将0.25%牛血清白蛋白加入100mmol/L Tris缓冲液中搅拌溶解制成R2缓冲液,再将6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物以1∶3000的体积比加入到上述R2缓冲液中混匀,再用6mol/L的盐酸调节pH至7.6,制成R2试剂。
所述的6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物的制备方法,包含以下步骤:
(1)称取15mg活力单位为100KU的重组葡萄糖-6-磷酸脱氢酶(其氨基酸序列为SEQID NO:2),在室温条件下溶解于30mL磷酸钠(pH=8.0)缓冲液中,然后加入225mg还原态的烟酰胺腺嘌呤二核苷酸、135mg葡萄糖-6-磷酸以及0.75mL卡必醇,再逐滴加入2mL二甲基亚砜,得到重组葡萄糖-6-磷酸脱氢酶溶液;
(2)在无水状态下称取10mg实施例1合成的6-羟基硫酸褪黑素衍生物,溶解于600μL二甲基甲酰胺中,将上述溶液温度降到-2~-8℃后加入3μL三丁胺、1.5μL氯甲酸异丁酯、1.5μL N,N′-二环己基碳二亚胺,-2~-8℃下搅拌30分钟,得到6-羟基硫酸褪黑素衍生物激活液;
(3)将6-羟基硫酸褪黑素衍生物激活液逐滴加入到重组葡萄糖-6-磷酸脱氢酶溶液中,2-8℃搅拌反应12小时,反应结束后经G-25凝胶层析柱纯化得到6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物,结构式如式III所示:
实施例7:6-羟基硫酸褪黑素校准品、质控品的制备
(1)校准品制备:将6-羟基硫酸褪黑素纯品粉末分别加入6份浓度为50mmol/L pH=7.2的Tris-HCl缓冲液中,搅拌溶解,至终浓度分别为0.00ng/mL、10.00ng/mL、20.00ng/mL、40.00ng/mL、80.00ng/mL、160.00ng/mL,然后在每份溶液中分别加入质量分数为0.5%的氯化钠、1.0%的牛血清白蛋白、0.75%的乙二胺四乙酸、0.05%的叠氮钠,搅拌均匀,即为6-羟基硫酸褪黑素校准品(6个浓度)。
(2)质控品制备:将6-羟基硫酸褪黑素纯品粉末分别加入3份浓度为50mmol/L pH=7.2的Tris-HCl缓冲液中,搅拌溶解,至终浓度分别为0.00ng/mL、30.00ng/mL、120.00ng/mL,然后在每份溶液中分别加入质量分数为0.5%的氯化钠、1.0%的牛血清白蛋白、0.75%的乙二胺四乙酸、0.05%的叠氮钠,搅拌均匀,即为6-羟基硫酸褪黑素质控品(3个浓度)。
实施例8:6-羟基硫酸褪黑素均相酶免疫检测试剂校准曲线制作及质控实验
1、制作均相酶免疫检测校准曲线:
在迈瑞BS480全自动生化分析仪中放入R1试剂、R2试剂及校准品,然后对生化分析仪进行反应参数设置,具体参数详见表3;实际操作过程中需不断调整R1试剂和R2试剂的体积比例,同时调整测光点,最后由生化分析仪自动得出均相酶免疫检测校准曲线,如图2所示。
表3:迈瑞BS480全自动生化分析仪反应参数
2、质控实验:
利用上述的6-羟基硫酸褪黑素均相酶免疫检测方法,对质控品进行测定,并根据步骤1中制作的均相酶免疫检测校准曲线,计算每个质控品中6-羟基硫酸褪黑素的含量,每个质控品重复测定10次,检测结果及数据分析详见表4。
表4:6-羟基硫酸褪黑素均相酶免疫检验试剂检测结果及数据分析
实验结果表明:测定不同浓度质控品中6-羟基硫酸褪黑素含量的CV值均低于3%,回收率均在98%-102%之间,说明本发明的6-羟基硫酸褪黑素均相酶免疫检测试剂测定生物样本中6-羟基硫酸褪黑素含量的精密度较高,结果准确。
实施例9:6-羟基硫酸褪黑素胶乳增强免疫比浊检测试剂的制备
6-羟基硫酸褪黑素胶乳增强免疫比浊检测试剂的制备方法,包含以下步骤:
(1)将0.5mg/mL的抗6-羟基硫酸褪黑素特异性抗体溶解于50mmol/L pH=8.0的磷酸盐缓冲液中,然后添加质量分数为1.25%的牛血清白蛋白、0.75%的氯化钠、0.25%的吐温-20、2.75%的丙三醇、0.5%的乙二胺四乙酸、1.25%的PEG-4000以及0.03%的叠氮钠,搅拌均匀,调节pH=7.5,制成L1试剂;
(2)将0.5mg表面带有羧基的直径为150nm的聚苯乙烯胶乳颗粒加入4.5mL0.05mol/L pH=6.2的MES缓冲液中,然后加入5mg碳二亚胺,在37℃下反应1小时,制成胶乳颗粒溶液,再将0.5mg6-羟基硫酸褪黑素-牛血清白蛋白复合体用4.5mL 0.05mol/L pH=9.2的硼酸盐缓冲液稀释后,立即加入到上述胶乳颗粒溶液中,在37℃下反应12小时,然后加入1mL 0.1mol/L pH=8.5的甘氨酸缓冲液搅拌2小时,反应终止后离心去除上清液,再将沉淀物用10mL 50mmol/L pH=8.0的Tris-HCl缓冲液洗涤3次,再用25mL 50mmol/L pH=8.5的甘氨酸缓冲液稀释成胶乳悬浊液,最后加入质量分数为1.25%的牛血清白蛋白、0.55%的氯化钠、0.25%的吐温-20、3.0%的丙三醇、0.45%的乙二胺四乙酸以及0.03%的叠氮钠,搅拌均匀,制成L2试剂;
所述的6-羟基硫酸褪黑素-牛血清白蛋白复合体的制备方法,包含以下步骤:
将10mg牛血清白蛋白用5mL 0.1mol/L pH=7.8的磷酸盐缓冲液稀释,然后加入100mg上述的6-羟基硫酸褪黑素衍生物,再加入50mg的N-羟基琥珀酰亚胺,在4℃下反应12小时,再用0.1mol/L pH=7.8的磷酸盐缓冲液在4℃下透析18小时,得到6-羟基硫酸褪黑素-牛血清白蛋白复合体,结构式如式IV所示:
实施例10:6-羟基硫酸褪黑素胶乳增强免疫比浊检测试剂校准曲线制作及质控实验
1.、制作胶乳增强免疫比浊检测试剂校准曲线:
在奥林巴斯AU480全自动生化分析仪中放入L1试剂、L2试剂及校准品,然后对生化分析仪进行反应参数设置,具体参数详见表5;实际操作过程中需不断调整L1试剂和L2试剂的体积比例,同时调整测光点,最后由生化分析仪自动得出胶乳增强免疫比浊检测校准曲线,如图3所示。
表5:奥林巴斯AU480全自动生化分析仪反应参数
2、质控实验:
利用上述的胶乳增强免疫比浊检测方法,对质控品进行测定,并根据步骤1中制作的胶乳增强免疫比浊检测校准曲线,计算每个质控品中6-羟基硫酸褪黑素的含量,每个质控品重复测定10次,检测结果及数据分析详见表6。
表6:6-羟基硫酸褪黑素胶乳增强免疫比浊试剂检测结果及数据分析
实验结果表明:测定不同浓度质控品中6-羟基硫酸褪黑素含量的CV值均低于3%,回收率均在98%-102%之间,说明本发明的6-羟基硫酸褪黑素胶乳增强免疫比浊检测试剂测定生物样本中6-羟基硫酸褪黑素含量的精密度较高,结果准确。
对于本领域的技术人员来说,可根据以上描述的技术方案以及构思做出其它各种相应的变更以及修改,而所有的这些变更以及修改都应该属于本发明权利要求的保护范围之内。
序列表
<110> 湖南苏阳医疗科技有限公司
<120> 6-羟基硫酸褪黑素衍生物及其免疫原、特异性抗体的制备方法和应用
<130> ZT2010837A
<141> 2020-10-14
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 625
<212> PRT
<213> Artificial Sequence
<400> 1
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Leu Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Thr His Lys Lys Ser Glu Ile
20 25 30
Ala His Arg Phe Lys Asp Leu Gly Glu Glu His Phe Lys Gly Leu Val
35 40 45
Leu Ile Ala Phe Ser Gln Tyr Leu Gln Gln Cys Pro Phe Asp Glu His
50 55 60
Val Lys Lys Leu Val Asn Glu Leu Thr Glu Phe Ala Lys Lys Thr Cys
65 70 75 80
Val Ala Asp Glu Ser His Ala Gly Cys Glu Lys Ser Leu His Thr Leu
85 90 95
Phe Gly Asp Glu Leu Cys Lys Lys Val Ala Ser Leu Arg Glu Thr Tyr
100 105 110
Gly Asp Met Ala Asp Cys Cys Glu Lys Gln Glu Pro Glu Arg Asn Glu
115 120 125
Cys Phe Leu Ser His Lys Asp Asp Ser Pro Asp Leu Pro Lys Leu Lys
130 135 140
Pro Asp Pro Asn Thr Leu Cys Asp Glu Phe Lys Ala Asp Glu Lys Lys
145 150 155 160
Phe Trp Gly Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe
165 170 175
Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Asn Lys Lys Tyr Asn Gly Val
180 185 190
Phe Gln Glu Cys Cys Gln Ala Glu Asp Lys Gly Ala Cys Leu Leu Pro
195 200 205
Lys Lys Ile Glu Thr Met Arg Glu Lys Val Leu Thr Ser Ser Ala Arg
210 215 220
Gln Arg Leu Arg Cys Ala Ser Ile Gln Lys Lys Phe Gly Glu Arg Ala
225 230 235 240
Leu Lys Ala Trp Ser Val Ala Arg Leu Ser Gln Lys Phe Pro Lys Ala
245 250 255
Glu Phe Val Glu Val Thr Lys Lys Leu Val Thr Asp Leu Thr Lys Val
260 265 270
His Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg
275 280 285
Ala Asp Leu Ala Lys Tyr Ile Cys Asp Asn Gln Asp Thr Ile Ser Ser
290 295 300
Lys Leu Lys Lys Glu Cys Cys Asp Lys Pro Leu Leu Glu Lys Ser His
305 310 315 320
Cys Ile Ala Glu Val Glu Lys Asp Ala Ile Pro Glu Asn Leu Pro Pro
325 330 335
Leu Thr Ala Asp Phe Ala Glu Asp Lys Lys Asp Val Cys Lys Asn Tyr
340 345 350
Gln Glu Ala Lys Asp Ala Phe Leu Gly Ser Phe Leu Tyr Glu Tyr Ser
355 360 365
Arg Arg His Pro Glu Tyr Ala Val Ser Val Leu Leu Arg Leu Ala Lys
370 375 380
Lys Glu Tyr Glu Ala Thr Leu Glu Glu Cys Cys Ala Lys Asp Asp Pro
385 390 395 400
His Ala Cys Tyr Ser Thr Val Phe Asp Lys Leu Lys Lys His Leu Val
405 410 415
Asp Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Asp Gln Phe Glu Lys
420 425 430
Leu Gly Glu Tyr Gly Phe Gln Asn Ala Leu Ile Val Arg Tyr Thr Arg
435 440 445
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
450 455 460
Ser Leu Gly Lys Val Gly Thr Arg Cys Cys Thr Lys Lys Pro Glu Ser
465 470 475 480
Glu Arg Met Pro Cys Thr Glu Asp Tyr Leu Ser Leu Ile Leu Asn Arg
485 490 495
Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Lys Lys Val Thr
500 505 510
Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala
515 520 525
Leu Thr Pro Asp Glu Thr Tyr Val Pro Lys Ala Phe Asp Glu Lys Leu
530 535 540
Phe Thr Phe His Ala Asp Ile Cys Thr Leu Pro Asp Thr Glu Lys Lys
545 550 555 560
Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Leu Lys His Lys Pro
565 570 575
Lys Ala Thr Glu Glu Gln Leu Lys Lys Thr Val Met Glu Asn Phe Val
580 585 590
Ala Phe Val Asp Lys Cys Cys Ala Ala Asp Asp Lys Glu Ala Cys Phe
595 600 605
Ala Val Glu Gly Pro Lys Lys Leu Val Val Ser Thr Gln Thr Ala Leu
610 615 620
Ala
625
<210> 2
<211> 549
<212> PRT
<213> Artificial Sequence
<400> 2
Met Ser Thr Thr Pro Asn Thr Pro Thr Ser Ala Ser His Glu Pro Ser
1 5 10 15
Cys Lys Lys Val Ser Ala Gly Pro His Glu Gly Pro Ser Ser Pro Ala
20 25 30
Gly Lys Arg Pro Ala Pro Pro Cys Thr Leu Val Ile Phe Gly Ala Gly
35 40 45
Gly Asp Leu Thr Lys Lys Arg Leu Leu Val Pro Ala Leu Tyr Asn Leu
50 55 60
Ala Val Asp Gly Leu Leu Asp Asp Gly Met Lys Ile Ile Gly Val Asn
65 70 75 80
His Gly Glu Arg Glu Thr Ser Val Trp Arg Glu Asp Leu His Lys Lys
85 90 95
Ser Leu Gln Gln Phe Ala Ala Asp Lys Ala Ser Thr Phe His Ala Gly
100 105 110
Lys Leu Asp Asp Lys Ala Trp Asp Trp Val Ala Gln Arg Leu Glu Tyr
115 120 125
Met Ala Gly Glu Phe Glu Thr Asp Asp Thr Phe Thr Lys Lys Leu Lys
130 135 140
Gln Lys Leu Asp Gln Ala Pro Gly Gly Asn Val Ile Phe Tyr Leu Ala
145 150 155 160
Val Ser Ser Arg Phe Phe Lys Lys Pro Ile Val Glu His Leu Gly Lys
165 170 175
Ala Gly Leu Leu Lys Glu Ala Asp Gly Gly Ser Gly Gly Phe Arg Arg
180 185 190
Ile Val Val Glu Lys Lys Pro Phe Gly Thr Asp Leu Ala Thr Ala Arg
195 200 205
Asp Leu Asn Ala His Ile Leu Ser Tyr Ala Asn Glu Ser Gln Val Tyr
210 215 220
Arg Ile Asp His Phe Leu Gly Lys Lys Asp Thr Val Gln Ser Ile Leu
225 230 235 240
Ala Val Arg Phe Ala Asn Ala Leu Phe Glu Pro Ile Trp Arg Arg Glu
245 250 255
Tyr Ile Asp Ser Val Gln Ile Thr Ala Ala Glu Thr Ile Gly Val Glu
260 265 270
Gly Arg Gly Lys Lys Phe Tyr Glu Gln Thr Gly Ala Phe Arg Asp Met
275 280 285
Leu Pro Asn His Leu Phe Gln Leu Leu Gly Met Val Ala Met Glu Pro
290 295 300
Pro Asn Ser Phe Asp Lys Ala Glu Ala Val Arg Asp Lys Lys Ala Glu
305 310 315 320
Ile Phe Asp Ala Ile Gln Pro Leu Thr Ala Asp Asp Val Val Phe Gly
325 330 335
Gln Tyr Glu Lys Lys Gly Pro Ala Gly Val Gly Tyr Arg Glu Glu Pro
340 345 350
Asp Val Ala Pro Asp Ser Thr Thr Glu Thr Tyr Ala Ala Ala Arg Val
355 360 365
Tyr Val Glu Asn Trp Arg Trp Ala Gly Val Pro Phe Tyr Leu Arg Thr
370 375 380
Gly Lys Lys Arg Leu Ala Ala Arg Arg Thr Glu Ile Ser Val Gln Leu
385 390 395 400
Lys Lys Pro Val Pro Phe Arg Leu Phe Arg Asp Thr Pro Val Asp Ala
405 410 415
Leu Thr Pro Asn Val Leu Thr Leu Arg Ile Asp Pro Ala His Gly Thr
420 425 430
Ser Phe Asp Phe Asn Val Lys Lys Thr Pro Gly Pro Leu Met Gln Ile
435 440 445
Gly Ala Val Gln Ser Ser Phe Asp Tyr Ala Asp Phe Phe Ala Glu Lys
450 455 460
Lys Ala Asn Val Gly Tyr Glu Thr Leu Leu Tyr Asp Cys Met Leu Gly
465 470 475 480
Asp Glu Thr Leu Phe Gln Arg Ala Asp Ser Ile Glu Thr Ser Trp Ala
485 490 495
Ala Val Asp Asp Val Leu His Pro Lys Lys Ser Gly Gly Ala Met Pro
500 505 510
Val His Gly Tyr Pro Ala Gly Ser Glu Gly Pro Ala Glu Ala Asp Ala
515 520 525
Leu Leu Ala Arg Asp Gly His Ala Trp Arg Pro Leu Lys Lys Arg Asp
530 535 540
Ala Val Glu Lys Lys
545
Claims (10)
2.一种结构式如式I所示的6-羟基硫酸褪黑素衍生物的制备方法,其特征在于,包括以下步骤:
(1)将化合物1与氯甲酸乙酯在碱性条件下反应,得到化合物2:
(2)将化合物2与乙酰氯反应,得到化合物3:
(3)将化合物3与2-(氨基氧基)乙酸叔丁酯在碱性条件下反应,得到化合物4:
其中,所述2-(氨基氧基)乙酸叔丁酯具有如下结构:
(4)将化合物4通过水解反应,得到式I所示的6-羟基硫酸褪黑素衍生物:
优选地,步骤(1)中化合物1与氯甲酸乙酯的摩尔投料比为1:0.5~1.5,更优选地,为1:1~1.2;所述的碱为NaOH、KOH、Na2CO3、K2CO3或LiOH中的一种,优选所述碱为NaOH;
进一步优选地,步骤(2)反应中加入三氯化铝作为催化剂,其中化合物2、乙酰氯和三氯化铝的摩尔用量比为1:1~1.1:1~1.1;
进一步优选地,步骤(3)中化合物3与2-(氨基氧基)乙酸叔丁酯的摩尔用量比为1:0.8~1.2;所述碱为NaOH、KOH、Na2CO3、K2CO3,或LiOH中的一种,优选所述碱为K2CO3;
进一步优选地,步骤(4)中所述水解反应是向反应液中加入酸,进行水解反应,所述酸为HCl与甲醇的混合溶液,其中HCl与MeOH的体积比为1:5~10,HCl的浓度为6mol/L~8mol/L。
4.根据权利要求3所述的6-羟基硫酸褪黑素免疫原,其特征在于,所述重组牛血清白蛋白的氨基酸序列为SEQ ID NO:1。
5.一种如权利要求3-4任一项所述的6-羟基硫酸褪黑素免疫原的制备方法,其特征在于,包括以下步骤:
(B1)载体蛋白溶液的制备:将权利要求3-4任一项中所述的重组牛血清白蛋白溶解于磷酸盐缓冲液中,得到载体蛋白溶液;
(B2)6-羟基硫酸褪黑素衍生物溶液的制备:将式I所示的6-羟基硫酸褪黑素衍生物与二甲基甲酰胺、乙醇、磷酸钾缓冲液、1-乙基-3-(-3-二甲氨丙基)碳二亚胺和N-羟基硫代琥珀酰亚胺混合,搅拌溶解,得到6-羟基硫酸褪黑素衍生物溶液;
(B3)6-羟基硫酸褪黑素免疫原的合成:将步骤(B2)得到的6-羟基硫酸褪黑素衍生物溶液加入到步骤(B1)得到的载体蛋白溶液中,搅拌反应,经透析纯化,得到6-羟基硫酸褪黑素免疫原。
6.一种抗6-羟基硫酸褪黑素特异性抗体,其特征在于,所述抗6-羟基硫酸褪黑素特异性抗体是使用权利要求3-4任一项所述的6-羟基硫酸褪黑素免疫原对实验动物进行注射后所得到的特异性抗体,所述的实验动物为兔子、山羊、绵羊、小鼠、大鼠、豚鼠或马中的一种。
7.一种权利要求6所述的抗6-羟基硫酸褪黑素特异性抗体的制备方法,其特征在于,包含以下步骤:
(C1)将权利要求3-4任一项所述的6-羟基硫酸褪黑素免疫原用磷酸盐缓冲液稀释,得到6-羟基硫酸褪黑素人工抗原溶液,然后将6-羟基硫酸褪黑素人工抗原溶液与等量弗氏完全佐剂混合,对实验动物进行多点注射;
(C2)3-6周后,再用相同的6-羟基硫酸褪黑素人工抗原溶液与等量弗氏不完全佐剂混合,对步骤(C1)所述的实验动物进行多点注射,之后每隔3-6周注射一次,共计注射3-10次;
(C3)对步骤(C2)中完成注射的实验动物取血,分离纯化,得到抗6-羟基硫酸褪黑素特异性抗体。
8.一种6-羟基硫酸褪黑素均相酶免疫检测试剂,其特征在于,由R1试剂与R2试剂组成;
其中,所述R1试剂包含权利要求6-7任一项所述的抗6-羟基硫酸褪黑素特异性抗体与R1缓冲液;
所述R2试剂包含6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物与R2缓冲液;
所述的R1缓冲液含有酶底物、辅酶、牛血清白蛋白及Tris缓冲液,所述的酶底物为葡萄糖-6-磷酸,所述的辅酶为氧化型烟酰胺腺嘌呤二核苷酸;
所述的6-羟基硫酸褪黑素重组葡萄糖-6-磷酸脱氢酶标记偶联物由式I所示的6-羟基硫酸褪黑素衍生物与重组葡萄糖-6-磷酸脱氢酶偶联而成;其结构式如式Ⅲ所示:
所述的R2缓冲液为含有牛血清白蛋白的Tris缓冲液。
9.根据权利要求8所述的6-羟基硫酸褪黑素均相酶免疫检测试剂,其特征在于,所述重组葡萄糖-6-磷酸脱氢酶的氨基酸序列为SEQ ID NO:2。
10.一种6-羟基硫酸褪黑素胶乳增强免疫比浊检测试剂,其特征在于,由L1试剂与L2试剂组成;
其中,所述L1试剂由权利要求6-7任一项所述的抗6-羟基硫酸褪黑素特异性抗体、pH=8.0的缓冲液、牛血清白蛋白、氯化钠、吐温-20、丙三醇、乙二胺四乙酸、促凝剂以及防腐剂组成;
所述L2试剂由6-羟基硫酸褪黑素-牛血清白蛋白复合体包被的聚苯乙烯胶乳颗粒、pH=8.0的缓冲液、牛血清白蛋白、氯化钠、吐温-20、丙三醇、乙二胺四乙酸以及防腐剂组成;
所述的6-羟基硫酸褪黑素-牛血清白蛋白复合体由式I所示的6-羟基硫酸褪黑素衍生物与牛血清白蛋白偶联而成,其结构式如式Ⅳ所示:
所述的聚苯乙烯胶乳颗粒直径范围为50-250nm;
所述的缓冲液为磷酸盐缓冲液、甘氨酸缓冲液、MES缓冲液、硼酸盐缓冲液、Tris-HCl缓冲液或巴比妥缓冲液中的一种;
所述促凝剂为PEG-4000、PEG-6000、PEG-8000或硫酸葡聚糖钠中的一种;
所述防腐剂为叠氮钠、硫柳汞、苯酚或乙基汞硫代硫酸钠中的一种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011096209.4A CN112225795A (zh) | 2020-10-14 | 2020-10-14 | 6-羟基硫酸褪黑素衍生物及其免疫原、特异性抗体的制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011096209.4A CN112225795A (zh) | 2020-10-14 | 2020-10-14 | 6-羟基硫酸褪黑素衍生物及其免疫原、特异性抗体的制备方法和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112225795A true CN112225795A (zh) | 2021-01-15 |
Family
ID=74112590
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011096209.4A Pending CN112225795A (zh) | 2020-10-14 | 2020-10-14 | 6-羟基硫酸褪黑素衍生物及其免疫原、特异性抗体的制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112225795A (zh) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103524435A (zh) * | 2013-10-22 | 2014-01-22 | 华南农业大学 | 一种乙酰甲喹残留标示物脱二氧乙酰甲喹的半抗原和完全抗原及其制备方法 |
CN103601662A (zh) * | 2013-11-21 | 2014-02-26 | 深圳市药品检验所 | 一种褪黑素半抗原、褪黑素完全抗原及其制备方法和应用 |
CN103969454A (zh) * | 2013-12-18 | 2014-08-06 | 深圳市药品检验所 | 褪黑素快速检测方法及其检测卡和制备方法 |
CN104530222A (zh) * | 2014-12-20 | 2015-04-22 | 苏州博源医疗科技有限公司 | 紫杉醇免疫原、抗紫杉醇特异性抗体和紫杉醇检测试剂 |
CN111018924A (zh) * | 2019-12-19 | 2020-04-17 | 苏州博源医疗科技有限公司 | 一种柔红霉素衍生物及其制备方法与柔红霉素检测试剂 |
CN111487206A (zh) * | 2019-01-09 | 2020-08-04 | 北京九强生物技术股份有限公司 | 6-磷酸葡萄糖脱氢酶突变体及其在制备万古霉素检测试剂中的用途 |
-
2020
- 2020-10-14 CN CN202011096209.4A patent/CN112225795A/zh active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103524435A (zh) * | 2013-10-22 | 2014-01-22 | 华南农业大学 | 一种乙酰甲喹残留标示物脱二氧乙酰甲喹的半抗原和完全抗原及其制备方法 |
CN103601662A (zh) * | 2013-11-21 | 2014-02-26 | 深圳市药品检验所 | 一种褪黑素半抗原、褪黑素完全抗原及其制备方法和应用 |
CN103969454A (zh) * | 2013-12-18 | 2014-08-06 | 深圳市药品检验所 | 褪黑素快速检测方法及其检测卡和制备方法 |
CN104530222A (zh) * | 2014-12-20 | 2015-04-22 | 苏州博源医疗科技有限公司 | 紫杉醇免疫原、抗紫杉醇特异性抗体和紫杉醇检测试剂 |
CN111487206A (zh) * | 2019-01-09 | 2020-08-04 | 北京九强生物技术股份有限公司 | 6-磷酸葡萄糖脱氢酶突变体及其在制备万古霉素检测试剂中的用途 |
CN111018924A (zh) * | 2019-12-19 | 2020-04-17 | 苏州博源医疗科技有限公司 | 一种柔红霉素衍生物及其制备方法与柔红霉素检测试剂 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TR201809424T4 (tr) | Risperidon ve paliperidon haptenleri. | |
CN110950820B (zh) | 一种氯丙嗪衍生物及其制备方法与氯丙嗪检测试剂 | |
CN106645692B (zh) | 雌三醇均相酶免疫检测试剂、制备方法及检测方法 | |
CN104447984B (zh) | 多西紫杉醇免疫原、抗多西紫杉醇特异性抗体和多西紫杉醇检测试剂 | |
CN104788560B (zh) | 环孢霉素a免疫原、抗环孢霉素a特异性抗体和环孢霉素a检测试剂 | |
CN110003300B (zh) | 一种17-羟类固醇的衍生物、检测试剂及制备方法 | |
CN110981861A (zh) | 一种氯氮平衍生物及其制备方法与氯氮平检测试剂 | |
CN107973836B (zh) | 醛固酮衍生物及其制备方法、醛固酮均相酶免疫检测试剂 | |
Jiang et al. | A gold-based immunochromatographic strip for the specific detection of tacrolimus in whole blood | |
CN106596917B (zh) | 高香草酸均相酶免疫检测试剂、制备方法及检测方法 | |
CN107132349A (zh) | 一种同型半胱氨酸自动化检测试剂、制备方法及检测方法 | |
CN116338163A (zh) | 一步法定量检测cd3/gprc5d双特异性抗体的方法 | |
CN112225795A (zh) | 6-羟基硫酸褪黑素衍生物及其免疫原、特异性抗体的制备方法和应用 | |
CN111620931B (zh) | 万古霉素衍生物及其制备方法和应用 | |
CN108490195A (zh) | 一种维生素b12免疫法测定方法及其试剂 | |
CN112611876B (zh) | 一种核酸适配体-四链体的尿液氨基酸检测试剂盒及方法 | |
CN114671809A (zh) | 一种奥卡西平衍生物、免疫原、抗奥卡西平特异性抗体及其制备方法与应用 | |
CN110967481B (zh) | 一种拉莫三嗪衍生物、其制备方法及其在均相酶免疫检测试剂中的应用 | |
CN108205064B (zh) | 25ohd3检测试剂、试剂盒及其检测方法 | |
CN114685409B (zh) | 一种艾司西酞普兰衍生物、免疫原、抗艾司西酞普兰特异性抗体及其制备方法与应用 | |
CN114685342B (zh) | 一种左乙拉西坦衍生物、免疫原、抗左乙拉西坦特异性抗体及其制备方法与应用 | |
US20060099654A1 (en) | Methods and kits for the determination of sirolimus in a sample | |
CN112225672B (zh) | 甲氧基去甲肾上腺素衍生物、免疫原、特异性抗体及其制备方法与应用 | |
CN114685400B (zh) | 一种阿立哌唑关键基团衍生物、免疫原、抗阿立哌唑特异性抗体及其制备方法与应用 | |
CN112266330B (zh) | 一种甲氧基肾上腺素衍生物、免疫原、抗甲氧基肾上腺素特异性抗体及其制备方法与应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210115 |
|
RJ01 | Rejection of invention patent application after publication |