JP2019518017A - トレースレス親和性標識を使用したタンパク質の部位選択的官能化 - Google Patents
トレースレス親和性標識を使用したタンパク質の部位選択的官能化 Download PDFInfo
- Publication number
- JP2019518017A JP2019518017A JP2018560733A JP2018560733A JP2019518017A JP 2019518017 A JP2019518017 A JP 2019518017A JP 2018560733 A JP2018560733 A JP 2018560733A JP 2018560733 A JP2018560733 A JP 2018560733A JP 2019518017 A JP2019518017 A JP 2019518017A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- group
- protein
- antibody
- formula
- 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
- 238000002372 labelling Methods 0.000 title claims abstract description 111
- 108090000623 proteins and genes Proteins 0.000 title claims description 206
- 102000004169 proteins and genes Human genes 0.000 title claims description 205
- 238000007306 functionalization reaction Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 154
- 238000000034 method Methods 0.000 claims abstract description 107
- 235000018102 proteins Nutrition 0.000 claims description 170
- -1 thiotyrosine Chemical compound 0.000 claims description 108
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 94
- 238000006243 chemical reaction Methods 0.000 claims description 61
- 229940024606 amino acid Drugs 0.000 claims description 51
- 235000001014 amino acid Nutrition 0.000 claims description 51
- 150000001540 azides Chemical class 0.000 claims description 51
- 150000001413 amino acids Chemical class 0.000 claims description 48
- 125000005647 linker group Chemical group 0.000 claims description 40
- 125000003277 amino group Chemical group 0.000 claims description 33
- 150000001345 alkine derivatives Chemical group 0.000 claims description 32
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 claims description 31
- 239000003795 chemical substances by application Substances 0.000 claims description 28
- 150000002825 nitriles Chemical class 0.000 claims description 26
- URYYVOIYTNXXBN-OWOJBTEDSA-N trans-cyclooctene Chemical compound C1CCC\C=C\CC1 URYYVOIYTNXXBN-OWOJBTEDSA-N 0.000 claims description 26
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 23
- 125000000539 amino acid group Chemical group 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 18
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 17
- 229910004013 NO 2 Inorganic materials 0.000 claims description 17
- 150000004905 tetrazines Chemical class 0.000 claims description 17
- 229910052770 Uranium Inorganic materials 0.000 claims description 16
- 235000018977 lysine Nutrition 0.000 claims description 16
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 15
- 235000018417 cysteine Nutrition 0.000 claims description 15
- 239000003446 ligand Substances 0.000 claims description 15
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 14
- 239000004472 Lysine Substances 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 14
- 239000002773 nucleotide Substances 0.000 claims description 13
- 125000003729 nucleotide group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 229940009098 aspartate Drugs 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 claims description 11
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 claims description 11
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 11
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 11
- 235000014304 histidine Nutrition 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 230000001225 therapeutic effect Effects 0.000 claims description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 10
- 229930195712 glutamate Natural products 0.000 claims description 10
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 239000000523 sample Substances 0.000 claims description 10
- 102000004190 Enzymes Human genes 0.000 claims description 9
- 108090000790 Enzymes Proteins 0.000 claims description 9
- 108010043958 Peptoids Proteins 0.000 claims description 9
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims description 9
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 8
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 8
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 229960003767 alanine Drugs 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 8
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims description 8
- 229960003104 ornithine Drugs 0.000 claims description 8
- 229910052727 yttrium Inorganic materials 0.000 claims description 8
- 238000002965 ELISA Methods 0.000 claims description 7
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 7
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 229960003136 leucine Drugs 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229920000642 polymer Polymers 0.000 claims description 7
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 7
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 6
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 claims description 6
- LLVWLCAZSOLOTF-UHFFFAOYSA-N 1-methyl-4-[1,4,4-tris(4-methylphenyl)buta-1,3-dienyl]benzene Chemical compound C1=CC(C)=CC=C1C(C=1C=CC(C)=CC=1)=CC=C(C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 LLVWLCAZSOLOTF-UHFFFAOYSA-N 0.000 claims description 6
- WTOFYLAWDLQMBZ-UHFFFAOYSA-N 2-azaniumyl-3-thiophen-2-ylpropanoate Chemical compound OC(=O)C(N)CC1=CC=CS1 WTOFYLAWDLQMBZ-UHFFFAOYSA-N 0.000 claims description 6
- RMNHPXDNGOBDOT-UHFFFAOYSA-N 4-azaniumylpyrrolidine-3-carboxylate Chemical compound NC1CNCC1C(O)=O RMNHPXDNGOBDOT-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 claims description 6
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 6
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 claims description 6
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 6
- 235000004279 alanine Nutrition 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical class COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 claims description 6
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000003384 imaging method Methods 0.000 claims description 6
- 238000010348 incorporation Methods 0.000 claims description 6
- 229960000310 isoleucine Drugs 0.000 claims description 6
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 6
- OFYAYGJCPXRNBL-LBPRGKRZSA-N naphthalen-2-yl-3-alanine Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CC=CC2=C1 OFYAYGJCPXRNBL-LBPRGKRZSA-N 0.000 claims description 6
- 229920001542 oligosaccharide Polymers 0.000 claims description 6
- 150000002482 oligosaccharides Chemical class 0.000 claims description 6
- TVIDEEHSOPHZBR-AWEZNQCLSA-N para-(benzoyl)-phenylalanine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1C(=O)C1=CC=CC=C1 TVIDEEHSOPHZBR-AWEZNQCLSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 6
- 229920000233 poly(alkylene oxides) Polymers 0.000 claims description 6
- 239000004475 Arginine Substances 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 239000004471 Glycine Substances 0.000 claims description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 5
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 5
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 5
- 239000012216 imaging agent Substances 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- 102000005962 receptors Human genes 0.000 claims description 5
- 108020003175 receptors Proteins 0.000 claims description 5
- 239000004474 valine Substances 0.000 claims description 5
- 229960004295 valine Drugs 0.000 claims description 5
- RWLSBXBFZHDHHX-VIFPVBQESA-N (2s)-2-(naphthalen-2-ylamino)propanoic acid Chemical compound C1=CC=CC2=CC(N[C@@H](C)C(O)=O)=CC=C21 RWLSBXBFZHDHHX-VIFPVBQESA-N 0.000 claims description 4
- WBZIGVCQRXJYQD-YFKPBYRVSA-N (2s)-2-amino-3-(1,3-thiazol-4-yl)propanoic acid Chemical group OC(=O)[C@@H](N)CC1=CSC=N1 WBZIGVCQRXJYQD-YFKPBYRVSA-N 0.000 claims description 4
- XEGDVXZYFYKJJR-YFKPBYRVSA-N (2s)-2-amino-3-(1,3-thiazol-5-yl)propanoic acid Chemical group OC(=O)[C@@H](N)CC1=CN=CS1 XEGDVXZYFYKJJR-YFKPBYRVSA-N 0.000 claims description 4
- YYAYLSOQGBAUHK-UHFFFAOYSA-N 2-(1,3-thiazol-2-ylamino)propanoic acid Chemical compound OC(=O)C(C)NC1=NC=CS1 YYAYLSOQGBAUHK-UHFFFAOYSA-N 0.000 claims description 4
- WRFPVMFCRNYQNR-UHFFFAOYSA-N 2-hydroxyphenylalanine Chemical compound OC(=O)C(N)CC1=CC=CC=C1O WRFPVMFCRNYQNR-UHFFFAOYSA-N 0.000 claims description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 210000004899 c-terminal region Anatomy 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 229930182817 methionine Natural products 0.000 claims description 4
- 235000006109 methionine Nutrition 0.000 claims description 4
- 239000003053 toxin Substances 0.000 claims description 4
- 231100000765 toxin Toxicity 0.000 claims description 4
- XEGDVXZYFYKJJR-RXMQYKEDSA-N (2r)-2-amino-3-(1,3-thiazol-5-yl)propanoic acid Chemical group OC(=O)[C@H](N)CC1=CN=CS1 XEGDVXZYFYKJJR-RXMQYKEDSA-N 0.000 claims description 3
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 claims description 3
- 108010027164 Amanitins Proteins 0.000 claims description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 3
- 108010006654 Bleomycin Proteins 0.000 claims description 3
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 3
- 101000606465 Homo sapiens Inactive tyrosine-protein kinase 7 Proteins 0.000 claims description 3
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 3
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 3
- 102100039813 Inactive tyrosine-protein kinase 7 Human genes 0.000 claims description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 3
- 229930126263 Maytansine Natural products 0.000 claims description 3
- 108700020796 Oncogene Proteins 0.000 claims description 3
- 102000043276 Oncogene Human genes 0.000 claims description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 3
- 239000004473 Threonine Substances 0.000 claims description 3
- CIORWBWIBBPXCG-JZTFPUPKSA-N amanitin Chemical compound O=C1N[C@@H](CC(N)=O)C(=O)N2CC(O)C[C@H]2C(=O)N[C@@H](C(C)[C@@H](O)CO)C(=O)N[C@@H](C2)C(=O)NCC(=O)N[C@@H](C(C)CC)C(=O)NCC(=O)N[C@H]1CS(=O)C1=C2C2=CC=C(O)C=C2N1 CIORWBWIBBPXCG-JZTFPUPKSA-N 0.000 claims description 3
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 3
- 235000009582 asparagine Nutrition 0.000 claims description 3
- 229960001230 asparagine Drugs 0.000 claims description 3
- 108010044540 auristatin Proteins 0.000 claims description 3
- 239000000090 biomarker Substances 0.000 claims description 3
- 229960001561 bleomycin Drugs 0.000 claims description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 3
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 claims description 3
- 229930195731 calicheamicin Natural products 0.000 claims description 3
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 3
- 229940127093 camptothecin Drugs 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229960000684 cytarabine Drugs 0.000 claims description 3
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 3
- 229960005501 duocarmycin Drugs 0.000 claims description 3
- 229930184221 duocarmycin Natural products 0.000 claims description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 3
- 229960005420 etoposide Drugs 0.000 claims description 3
- 229960002949 fluorouracil Drugs 0.000 claims description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 3
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 claims description 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical class C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 claims description 3
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 claims description 3
- 230000002285 radioactive effect Effects 0.000 claims description 3
- 229960001603 tamoxifen Drugs 0.000 claims description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
- 229930184737 tubulysin Natural products 0.000 claims description 3
- 229940088594 vitamin Drugs 0.000 claims description 3
- 229930003231 vitamin Natural products 0.000 claims description 3
- 235000013343 vitamin Nutrition 0.000 claims description 3
- 239000011782 vitamin Substances 0.000 claims description 3
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N 2,4-diaminobutyric acid Chemical compound NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
- DVQHYTBCTGYNNN-UHFFFAOYSA-N azane;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound N.N.[Pt].OC(=O)C1(C(O)=O)CCC1 DVQHYTBCTGYNNN-UHFFFAOYSA-N 0.000 claims 1
- 230000027455 binding Effects 0.000 description 68
- 125000000524 functional group Chemical group 0.000 description 43
- 239000000047 product Substances 0.000 description 34
- 238000012216 screening Methods 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- 239000000306 component Substances 0.000 description 25
- 230000009257 reactivity Effects 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- 125000001151 peptidyl group Chemical group 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 239000000178 monomer Substances 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000000562 conjugate Substances 0.000 description 17
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 16
- 239000000126 substance Substances 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- 125000002252 acyl group Chemical group 0.000 description 12
- 239000011324 bead Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 150000007970 thio esters Chemical class 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 238000012546 transfer Methods 0.000 description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 9
- 239000007801 affinity label Substances 0.000 description 9
- 150000001299 aldehydes Chemical class 0.000 description 9
- 229960002685 biotin Drugs 0.000 description 9
- 239000011616 biotin Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 230000007246 mechanism Effects 0.000 description 9
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 9
- 235000020958 biotin Nutrition 0.000 description 8
- 238000013461 design Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 230000008685 targeting Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 7
- 108060003951 Immunoglobulin Proteins 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 230000010933 acylation Effects 0.000 description 7
- 238000005917 acylation reaction Methods 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 7
- 102000018358 immunoglobulin Human genes 0.000 description 7
- 238000004949 mass spectrometry Methods 0.000 description 7
- 238000011002 quantification Methods 0.000 description 7
- 241000894007 species Species 0.000 description 7
- 239000013589 supplement Substances 0.000 description 7
- BXRLWGXPSRYJDZ-UHFFFAOYSA-N 3-cyanoalanine Chemical compound OC(=O)C(N)CC#N BXRLWGXPSRYJDZ-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 6
- DGYHPLMPMRKMPD-UHFFFAOYSA-N L-propargyl glycine Natural products OC(=O)C(N)CC#C DGYHPLMPMRKMPD-UHFFFAOYSA-N 0.000 description 6
- 108010038807 Oligopeptides Proteins 0.000 description 6
- 102000015636 Oligopeptides Human genes 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000010183 spectrum analysis Methods 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 150000003573 thiols Chemical class 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 5
- 125000002947 alkylene group Chemical group 0.000 description 5
- 229940049595 antibody-drug conjugate Drugs 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 238000012650 click reaction Methods 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 229940072221 immunoglobulins Drugs 0.000 description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 5
- 229920002521 macromolecule Polymers 0.000 description 5
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- QRZUPJILJVGUFF-UHFFFAOYSA-N 2,8-dibenzylcyclooctan-1-one Chemical compound C1CCCCC(CC=2C=CC=CC=2)C(=O)C1CC1=CC=CC=C1 QRZUPJILJVGUFF-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 4
- QFLNJOIJUNDRFH-ROLXFIACSA-N [(5s)-1,5-diamino-5-carboxypentyl]-diazonioazanide Chemical compound [N-]=[N+]=NC(N)CCC[C@H](N)C(O)=O QFLNJOIJUNDRFH-ROLXFIACSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000000611 antibody drug conjugate Substances 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 4
- 150000002367 halogens Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000012038 nucleophile Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 239000011669 selenium Substances 0.000 description 4
- 229960000575 trastuzumab Drugs 0.000 description 4
- 150000003852 triazoles Chemical group 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108010090804 Streptavidin Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000011651 chromium Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000006352 cycloaddition reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 230000036964 tight binding Effects 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- VILFTWLXLYIEMV-UHFFFAOYSA-N 1,5-difluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(F)C=C1F VILFTWLXLYIEMV-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- IXSOYWMLFJYNGU-UHFFFAOYSA-N 4-(1h-indol-3-yl)butanoic acid Chemical compound C1=CC=C2C(CCCC(=O)O)=CNC2=C1.C1=CC=C2C(CCCC(=O)O)=CNC2=C1 IXSOYWMLFJYNGU-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 102000000412 Annexin Human genes 0.000 description 2
- 108050008874 Annexin Proteins 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 108010049175 N-substituted Glycines Proteins 0.000 description 2
- 108090000526 Papain Proteins 0.000 description 2
- 108010067902 Peptide Library Proteins 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000011091 antibody purification Methods 0.000 description 2
- 150000007860 aryl ester derivatives Chemical class 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 102000023732 binding proteins Human genes 0.000 description 2
- 108091008324 binding proteins Proteins 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 239000012503 blood component Substances 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 239000006274 endogenous ligand Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 2
- 125000003630 glycyl group Chemical class [H]N([H])C([H])([H])C(*)=O 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 238000002898 library design Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000011572 manganese Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000002715 modification method Methods 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 229940055729 papain Drugs 0.000 description 2
- 235000019834 papain Nutrition 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000000816 peptidomimetic Substances 0.000 description 2
- 102000013415 peroxidase activity proteins Human genes 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 238000011176 pooling Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000012460 protein solution Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- HTFFMYRVHHNNBE-YFKPBYRVSA-N (2s)-2-amino-6-azidohexanoic acid Chemical compound OC(=O)[C@@H](N)CCCCN=[N+]=[N-] HTFFMYRVHHNNBE-YFKPBYRVSA-N 0.000 description 1
- UHPQFNXOFFPHJW-UHFFFAOYSA-N (4-methylphenyl)-phenylmethanamine Chemical compound C1=CC(C)=CC=C1C(N)C1=CC=CC=C1 UHPQFNXOFFPHJW-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- JTEDVYBZBROSJT-UHFFFAOYSA-N 1H-Indole-3-butanoic acid Natural products C1=CC=C2C(CCCC(=O)O)=CNC2=C1 JTEDVYBZBROSJT-UHFFFAOYSA-N 0.000 description 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- PPXUUPXQWDQNGO-UHFFFAOYSA-N 2-azidoacetic acid Chemical compound OC(=O)CN=[N+]=[N-] PPXUUPXQWDQNGO-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- LNFZAUNJFRYZLE-UHFFFAOYSA-N 2-fluoro-1h-imidazole Chemical compound FC1=NC=CN1 LNFZAUNJFRYZLE-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- RIDMSOMIFFTEJO-UHFFFAOYSA-N 2-sulfanylbenzamide Chemical compound NC(=O)C1=CC=CC=C1S RIDMSOMIFFTEJO-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- OROGUZVNAFJPHA-UHFFFAOYSA-N 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one Chemical compound CC1SC(=O)C(C)=C1O OROGUZVNAFJPHA-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- XPTMJJIPRSWBDK-UHFFFAOYSA-N 3-prop-2-ynylsulfanylprop-1-yne Chemical compound C#CCSCC#C XPTMJJIPRSWBDK-UHFFFAOYSA-N 0.000 description 1
- GIROMBRBRVMKOH-UHFFFAOYSA-N 4-(methyldisulfanyl)benzoic acid Chemical compound CSSC1=CC=C(C(O)=O)C=C1 GIROMBRBRVMKOH-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NSVXZMGWYBICRW-UHFFFAOYSA-N 9-bicyclo[6.1.0]non-4-ynylmethanol Chemical compound C1CC#CCCC2C(CO)C21 NSVXZMGWYBICRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000001692 EU approved anti-caking agent Substances 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000028180 Glycophorins Human genes 0.000 description 1
- 108091005250 Glycophorins Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 150000007649 L alpha amino acids Chemical class 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010062374 Myoglobin Proteins 0.000 description 1
- 102000036675 Myoglobin Human genes 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 108010026552 Proteome Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- PPZYBFUYKJPWBY-UHFFFAOYSA-N acetylene azide Chemical compound C#C.[N-]=[N+]=[N-] PPZYBFUYKJPWBY-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 125000005529 alkyleneoxy group Chemical group 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- OHDRQQURAXLVGJ-HLVWOLMTSA-N azane;(2e)-3-ethyl-2-[(e)-(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S/1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C\1=N/N=C1/SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-HLVWOLMTSA-N 0.000 description 1
- OHDRQQURAXLVGJ-UHFFFAOYSA-N azane;3-ethyl-2-[(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C1=NN=C1SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-UHFFFAOYSA-N 0.000 description 1
- ICCBZGUDUOMNOF-UHFFFAOYSA-N azidoamine Chemical compound NN=[N+]=[N-] ICCBZGUDUOMNOF-UHFFFAOYSA-N 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 108091006004 biotinylated proteins Proteins 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- BALGDZWGNCXXES-UHFFFAOYSA-N cyclopentane;propanoic acid Chemical compound CCC(O)=O.C1CCCC1 BALGDZWGNCXXES-UHFFFAOYSA-N 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000005070 decynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000005182 dinitrobenzenes Chemical class 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 125000005303 dithiazolyl group Chemical group S1SNC(=C1)* 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical class C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000002091 elastography Methods 0.000 description 1
- 238000002565 electrocardiography Methods 0.000 description 1
- 238000000537 electroencephalography Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 238000002594 fluoroscopy Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 229940065734 gamma-aminobutyrate Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000005179 haloacetyl group Chemical group 0.000 description 1
- 125000006277 halobenzyl group Chemical group 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 150000002411 histidines Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- OCVXZQOKBHXGRU-UHFFFAOYSA-N iodine(1+) Chemical compound [I+] OCVXZQOKBHXGRU-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 125000005438 isoindazolyl group Chemical group 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-M lactobionate Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-M 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000002582 magnetoencephalography Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000005439 maleimidyl group Chemical class C1(C=CC(N1*)=O)=O 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- LQNUZADURLCDLV-IDEBNGHGSA-N nitrobenzene Chemical group [O-][N+](=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 LQNUZADURLCDLV-IDEBNGHGSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 125000005071 nonynyl group Chemical group C(#CCCCCCCC)* 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000005702 oxyalkylene group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000002064 post-exposure prophylaxis Effects 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 108010004034 stable plasma protein solution Proteins 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 238000001931 thermography Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 150000003587 threonine derivatives Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/13—Labelling of peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
- C07K1/062—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha- or omega-carboxy functions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
- C07K1/084—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- 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
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
Abstract
Description
本出願は、2016年2月9日出願の米国仮特許出願第62/388,862号、2016年2月18日出願の米国仮特許出願第62/389,137号、2016年4月4日出願の米国仮特許出願第62/390,624号、及び2016年8月8日出願の米国仮特許出願第62/494,420号に基づく優先権を主張するものであり、これらの内容全体が参照により本明細書に組み込まれる。
i. ペプチド(W)と、
ii. 第1の直交反応性部分(R)と、
iii. 求電子性部分を含む、WとRとの間の共有結合と
を含む化合物であって、求電子性部分が、タンパク質のアミノ基と反応することができ、それによってWとRとの間の共有結合が切断される、化合物を提供する。
Eは、ハロゲン、-CN、-NO2、-SO2、-SO2NHW4、-S(O)C1〜C6アルキル、-S(O)アリール、及び-OC1〜C6アルキルからなる群から選択される部分であり、
Xは、O、S又はSeであり、
Yは、アルキル、ポリアルキレンオキシド、ペプチド、ペプトイド、及びそれらの組合せからなる群から選択されるリンカーであり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択され、
R'は、-C(O)W1、-SO2W1、-CH2W2、-C(O)W3、-SO2W3、-C(O)W4又は-SO2W4であり、ここで、
W1は、N末端においてC(O)又はSO2に結合されている、1〜25個のアミノ酸残基の直鎖状ペプチドを含み、
W2は、O-チロシン又はS-チオチロシン残基においてCH2に結合されている、1〜25個のアミノ酸残基のペプチドを含み、
W3は、2,P-ジアミノ-n-アルカン酸残基のP-アミノ基においてC(O)又はSO2に結合されている、1〜25個のアミノ酸残基のペプチドを含み、ここで、Pは、3、4、5、6、7又は8であり、
W4は、N末端においてC(O)又はSO2に連結されている、25個までの残基のペプチドを含み、
qは、0、1、2、3又は4である)の構造を有する、化合物に関する。
Xは-OHであり(化合物1a)、
Xは-NH2であり(化合物1b)、
Xは、
Xは、
Eは、ハロゲン、-CN、-NO2、-SO2、-SO2NHW4、-S(O)C1〜C6アルキル、-S(O)アリール、及び-OC1〜C6アルキルからなる群から選択される部分であり、
Xは、O、S又はSeであり、
Yは、アルキル、ポリアルキレンオキシド、及びそれらの組合せからなる群から選択されるリンカーであり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択され、
R'は、-C(O)W1、-SO2W1、-CH2W2、-C(O)W3、-SO2W3、-C(O)W4又は-SO2W4であり、ここで、
W1は、N末端においてC(O)又はSO2に結合されている、1〜25個のアミノ酸残基の直鎖状ペプチドを含み、
W2は、O-チロシン又はS-チオチロシン残基においてCH2に結合されている、1〜25個のアミノ酸残基のペプチドを含み、
W3は、2,P-ジアミノ-n-アルカン酸残基のP-アミノ基においてC(O)又はSO2に結合されている、1〜25個のアミノ酸残基のペプチドを含み、ここで、Pは、3、4、5、6、7又は8であり、
W4は、N末端においてC(O)又はSO2に連結している、25個までの残基のペプチドを含み、
qは、0、1、2、3又は4である)の構造を有する、化合物に関する。
Eは、
R1、R2、R3、R4、及びR5は独立して、H、F、Cl、NO2、CN及びLから選択され(ただし、R1、R2、R3、R4、及びR5の1つのみがLであることを条件とする)、
Lは、R-(CH2CH2O)q(CH2)r-C(O)-X-又はR-(CH2CH2O)q(CH2)r-X-SO2-であり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択され、
Xは、O又はSであり、
X1、X2、X3、X4、X5、X6、X7及びX8は独立して、天然アミノ酸及び2,3-ジアミノプロピオン酸、チオチロシン、4-ベンゾイルフェニルアラニン、2-チアゾール-アラニン、ノルバリン、1-ナフチルアラニン、2-ナフチルアラニン、3-ナフチルアラニン、N-ε-カルバミル-リジン、2-チエニルアラニン、3-アミノピロリジン-4-カルボン酸、2',4'-フェニルアラニン、2',5'-フェニルアラニン、2',6'-フェニルアラニン、3',4'-フェニルアラニン、-OH、-O-(C1〜C6)アルキル、-O-アリール、アミノ、-(C1〜C6)アルキルアミノ、ジ-(C1〜C6)アルキルアミノの残基から選択され、又は存在せず(ただし、X1、X2、X3、X4、X5、X6、X7及びX8の少なくとも1つが存在することを条件とする)、
Qは電子求引性置換基(例えば、ハロアルキル、-F、-NO2又は-CN)であり、
gは0〜8であり、mは0又は1であり、nは0〜8であり、pは1〜8であり、rは1〜20であり、qは0〜100である)の構造を有する、化合物に関する。
タンパク質を本明細書に開示される化合物のいずれか1つと接触させる工程と、
タンパク質のアミノ基と化合物の第1の直交反応性部分との間に共有結合を形成する工程と、
第1の直交反応性部分とペプチドとの間の共有結合を切断する工程と
を含む、方法に関する。
部位選択的に官能化されたタンパク質を、第2の直交反応性部分を含むペイロード化合物と接触させる工程と、
第1の直交反応性部分と第2の直交反応性部分との間に1つ又は複数の共有結合を形成する工程と
を更に含む。
複数の同一タンパク質を用意する工程であって、各タンパク質が2個以上のアミノ(-NH2)基を含む工程と、
複数のタンパク質を、本開示による化合物から独立して選択される複数の標識用化合物と接触させる工程と、
1つ又は複数のタンパク質の1個若しくは複数の求核基と1つ又は複数の化合物の第1の直交反応性部分との間に共有結合を形成して、1つ又は複数の標識タンパク質を得る工程と、
最高の選択性で標識されたタンパク質を同定する工程と、
対応する部位選択的標識用化合物を同定する工程と
を含む、方法を提供する。
(a)抗体を式(XI):
X1、X2、X3及びX4は独立して、天然アミノ酸及び2,3-ジアミノプロピオン酸、チオチロシン、4-ベンゾイルフェニルアラニン、2-チアゾール-アラニン、ノルバリン、1-ナフチルアラニン、2-ナフチルアラニン、3-ナフチルアラニン、N-ε-カルバミル-リジン、2-チエニルアラニン、3-アミノピロリジン-4-カルボン酸、2',4'-フェニルアラニン、2',5'-フェニルアラニン、2',6'-フェニルアラニン、3',4'-フェニルアラニンの残基から選択される残基であり、又は存在せず(ただし、X1、X2、X3、及びX4の少なくとも1つが存在することを条件とする)、
Qは、H又は電子求引性置換基(例えば、ハロアルキル、-F、-NO2又は-CN)であり、
n=0〜10であり、
p=0〜10である)の化合物と接触させる工程と、
(b)工程(a)の生成物を、独立して、n=0〜20であり、m=1〜40である式(XII):
Zは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択される部分であり、
Mは1〜40であり、
nは0〜20である)の化合物と接触させる
工程とを含む、方法に関する。
抗体を式(XIII):
Xは、ヒスチジン、3-(4-チアゾリル)-L-アラニン、(R)-又は(S)-2-アミノ-3-(チアゾール-5-イル)プロパン酸)であり、
Y=O、S又はSeであり、
Zは、アルキニル若しくはシクロアルキニル、アジド、ホルミル、アセチル、1,3-ジエン、ニトリルオキシド、ニトロン、trans-シクロオクテン又はテトラジンであり、
m=0〜30であり、
n=1〜20であり、
p=1〜20であり、
q=1〜2であり、
u=0〜5であり、
フェニル環は、F、NO2、又はCNで場合によって置換されており、
Yとベンズアミドカルボニルは、オルト、メタ又はパラの関係でありうる)の化合物と接触させる工程を含む、方法に関する。
抗体を式(XIV):
U及びU'は独立して、システイン、アスパルタート、グルタマート、2,3-ジアミノプロピオン酸、リジン、又はオルニチンであり、
Xは、
Zは、アルキニル若しくはシクロアルキニル、アジド、ホルミル、アセチル、1,3-ジエン、ニトリルオキシド、ニトロン、trans-シクロオクテン又はテトラジンであり、
mは0〜15であり、
nは1〜25である)の化合物と接触させる工程を含む、方法に関する。
抗体を式(XV):
U及びU'は独立して、システイン、アスパルタート、グルタマート、2,3-ジアミノプロピオン酸、リジン、又はオルニチンであり、
Xは、
WはHであり、かつYはFであり、又は
WはFであり、かつYはHであり、
mは0〜15であり、
nは1〜25であり、
pは0〜1である)の化合物と接触させる工程を含む、方法に関する。
抗体を式(XVI):
U及びU'は独立して、システイン、アスパルタート、グルタマート、2,3-ジアミノプロピオン酸、2,4-ジアミノ酪酸、リジン、又はオルニチンであり、
Xは、
Y=O、S又はSeであり、
Zは、アルキニル若しくはシクロアルキニル、アジド、ホルミル、アセチル、1,3-ジエン、ニトリルオキシド、ニトロン、trans-シクロオクテン又はテトラジンであり、
m=0〜30であり、
n=1〜20であり、
p=1〜20であり、
フェニル環は、F、NO2、又はCNで場合によって置換されており、Yとベンズアミドカルボニルは、オルト、メタ又はパラの関係でありうる)の化合物と接触させる工程を含む、方法に関する。
Pはタンパク質であり、
Lysはリジン残基であり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択される部分であり、mは0〜40であり、nは1〜20である)の化合物を提供する。
Pはタンパク質であり、
Lysはリジン残基であり、
Gはペイロード化合物を含む部分であり、
mは0〜40であり、
nは1〜20である)の化合物を提供する。
結合コンビナトリアルライブラリーのスクリーンは、平衡状態にある成分間の親和性にのみ依存するが、稀な事象として特異的部位への密接な結合分子を提供する。必ず、更に何回かのスクリーニングが、親和性を最適化するのに必要とされる。予想されるのは、三要素試剤の密接な結合と近位の反応性タンパク質アミノ基の捕獲との両方が部位特異的標識化に必要とされることを考えれば、結合ライブラリー(bonding libraries)のスクリーンがあれば、同様に稀な事象として速い標識ライブラリーメンバーが明らかになるということである。
Y-SPhZ-W(式中、Yは、1個若しくは複数の炭素又はアルキレンオキシド単位によって優先的にアシル官能基に連結している直交反応性基を含有し、SPhZは、しばしばm-若しくはp-チオ-ベンゾイル又はチオ-チロシル基、或いはそれらのフェノール類縁体であり、Wは、典型的に少なくとも1個のアミノ酸を含む部分である)を有する場合が多い。アルキルチオエステル等を反応性基として含有するライブラリーは、図9においてみられるように環状チオエステルを使用して、リンカー部Xを三要素試剤前駆体に導入して、SPPSにより調製することができる。
前述の説明は、主に親和性要素がオリゴマー官能基のみを含有するライブラリーに基づき、標的タンパク質に対するリガンドについての情報は本質的に存在していない。そのようなライブラリーは、アミノ酸をいくつかの可変性位置のうちでランダム化することによって構築され、タンパク質の不偏な第一選択スクリーンを表すという点で「ユニバーサル」動的標識用ライブラリーである。特異的部位への結合決定因子が利用可能であるとき、ライブラリーにおいてそのような公知の親和性(ペプチジル又は非ペプチジル)要素を取り込み又は組み立てることが好都合である。それらを可変性(例えば、ペプチジル)要素と組み合わせて、親和性基の不変的な特徴とすることによって、ライブラリーは、標的タンパク質部位を本質的に標的にし、それらに偏向している。このシナリオでは、コンビナトリアルライブラリーの全体の複雑性を低減することができ、一方ではライブラリーメンバーのタンパク質標的に対する親和性が増強する。
動的標識用ライブラリーの特有の特徴は、標的タンパク質にコンジュゲートしている単位がトレースレスリンカー(又は、代替的にトレースレス親和性標識)に由来することである。この特徴は、コンジュゲートされたタンパク質には現れない非常に多様な結合決定因子が親和性標識に存在することが可能になるという点で、標識化にとって最も重要なものである。この設計要素は、極めて複雑であり、機能的役割も望ましい特性ももたない外来要素と等しい場合が多い結合決定因子の保持につながる手法に比べて大きな利点をもたらす。
Eは、ハロゲン、-CN、-NO2、-SO2、-SO2NHW4、-S(O)C1〜C6アルキル、-S(O)アリール、及び-OC1〜C6アルキルからなる群から選択される部分であり、
Xは、O、S又はSeであり、
Yは、アルキル、ポリアルキレンオキシド、ペプチド、ペプトイド、及びそれらの組合せからなる群から選択されるリンカーであり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択され、
R'は、存在しない、又は-C(O)OH、-C(O)OC1〜C6アルキル、-C(O)NH2、-C(O)NHC1〜C6アルキル、-C(O)N(C1〜C6アルキル)2、-SO2NH2、-SO2NHC1〜C6アルキル、若しくは-SO2N(C1〜C6アルキル)2であり、
W4は、N末端においてC(O)又はSO2に連結されている、25個までの残基のペプチドを含み、
qは、0、1、2、3又は4である)の化合物を提供する。
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択され、
R1は、水素又はC1〜C6-アルキルであり、
R2は、水素又はC1〜C6-アルキルであり、
R3は、電子求引性基(例えば、ハロアルキル、-F、-NO2又は-CN)であり、
qは0〜100であり、rは1〜20であり、mは0〜1であり、nは0〜4である)の構造を有する。
有機合成のルーチン技法を使用して、市販の出発材料から化合物を調製した(Advanced Organic Chemistry: Reactions, Mechanisms and Structure、第4版; March, Jerry; 2006を参照のこと)。
化合物(1a)、(1b)、(2)及び(3)を調製し、質量スペクトル分析によって特性評価を行った。
化合物(1a): M計算値=551.2 [M+H]+;実測値 551.09(図35を参照のこと)。
化合物(1b): M計算値=550.2 [M+H]+;実測値 572.2 [M+Na]+(図36を参照のこと)
化合物(2): M計算値=752.3 [M+H]+;実測値 752.02(図25を参照のこと)。
化合物(1a):Xは-OHであり、
化合物(1b):Xは-NH2であり、
化合物(2):Xは
化合物(3);(以下の実施例2を参照のこと):Xは
Rは
以下の化合物を合成し、質量スペクトル分析によって構造的特性評価を行った。M計算値=1395.6;実測値=1396.39(図30を参照のこと)。
以下の化合物を合成し、質量スペクトル分析によって構造的特性評価を行った。M計算値=1381.6;実測値=1382.4。図31を参照のこと。
以下の化合物を合成し、質量スペクトル分析によって構造的特性評価を行った。M計算値=1367.6;実測値=1368.3。図32を参照のこと。
以下の化合物を合成し、質量スペクトル分析によって構造的特性評価を行った。M計算値=2033.8;実測値=2034.3。図33を参照のこと。
以下の化合物を合成し、HNMR及び質量スペクトル分析によって構造的特性評価を行った。M計算値=794.3;実測値=795.04。図34A及び図34Bを参照のこと。
Claims (50)
- i. ペプチド(W)と、
ii. 第1の直交反応性部分(R)と、
iii. 求電子性部分を含む、WとRとの間の共有結合と
を含む化合物であって、求電子性部分が、タンパク質のアミノ基と反応することができ、それによってWとRとの間の共有結合が切断される、化合物。 - Wが、1〜25個、4〜15個、6〜10個又は4〜8個のアミノ酸残基のペプチドである、請求項1に記載の化合物。
- WとRとの間の共有結合が、-C(O)O-、-C(O)S-、-C(O)Se-、-SO2O-、-SO2S-及び-SO2Se-から選択される求電子性部分を含む、請求項1に記載の化合物。
- ペプチドの4つ以下の位置が、3位とC末端位との間においてW、F、Y、I、又はLで固定される、請求項2に記載の化合物。
- Rが、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択される部分を含む、請求項1に記載の化合物。
- 式(II):
Eは、ハロゲン、-CN、-NO2、-SO2、-SO2NHW4、-S(O)C1〜C6アルキル、-S(O)アリール、及び-OC1〜C6アルキルからなる群から選択される部分であり、
Xは、O、S又はSeであり、
Yは、アルキル、ポリアルキレンオキシド、及びそれらの組合せからなる群から選択されるリンカーであり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニルからなる群から選択され、
R'は、-C(O)W1、-SO2W1、-CH2W2、-C(O)W3、-SO2W3、-C(O)W4又は-SO2W4であり、ここで、
W1は、N末端においてC(O)又はSO2に結合されている、1〜25個のアミノ酸残基の直鎖状ペプチドを含み、
W2は、O-チロシン又はS-チオチロシン残基においてCH2に結合されている、1〜25個のアミノ酸残基のペプチドを含み、
W3は、2,P-ジアミノ-n-アルカン酸残基のP-アミノ基においてC(O)又はSO2に結合されている、1〜25個のアミノ酸残基のペプチドを含み、ここで、Pは、3、4、5、6、7又は8であり、
W4は、N末端においてC(O)又はSO2に連結されている、25個までの残基のペプチドを含み、
qは、0、1、2、3又は4である)の構造を有する、請求項1に記載の化合物。 - Yが、次式:
-(CH2CH2O)m(CH2)n-
(式中、mは0〜30であり、nは1〜20である)を有する、請求項6に記載の化合物。 - W1、W2、W3及びW4が独立して、4〜8個又は6〜10個のアミノ酸残基のペプチドを含む、請求項6に記載の化合物。
- 式(III):
Eは、ハロゲン、-CN、-NO2、-SO2、-SO2NHW4、-S(O)C1〜C6アルキル、-S(O)アリール、及び-OC1〜C6アルキルからなる群から選択される部分であり、
Xは、O、S又はSeであり、
Yは、アルキル、ポリアルキレンオキシド、及びそれらの組合せからなる群から選択されるリンカーであり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニルからなる群から選択され、
R'は、-C(O)W1、-SO2W1、-CH2W2、-C(O)W3、-SO2W3、-C(O)W4又は-SO2W4であり、ここで、
W1は、N末端においてC(O)又はSO2に結合されている、1〜25個のアミノ酸残基の直鎖状ペプチドを含み、
W2は、O-チロシン又はS-チオチロシン残基においてCH2に結合されている、1〜25個のアミノ酸残基のペプチドを含み、
W3は、2,P-ジアミノ-n-アルカン酸残基のP-アミノ基においてC(O)又はSO2に結合されている、1〜25個のアミノ酸残基のペプチドを含み、ここで、Pは、3、4、5、6、7又は8であり、
W4は、N末端においてC(O)又はSO2に連結されている、25個までの残基のペプチドを含み、
qは、0、1、2、3又は4である)の構造を有する、請求項1に記載の化合物。 - Yが、次式:
-(CH2CH2O)m(CH2)n-
(式中、mは0〜30であり、nは1〜20である)を有する、請求項9に記載の化合物。 - W1、W2、W3及びW4が独立して、4〜8個又は6〜10個のアミノ酸残基のペプチドを含む、請求項9に記載の化合物。
- 式(IV):
Eは、
R1、R2、R3、R4、及びR5は独立して、H、F、Cl、NO2、CN及びLから選択され(ただし、R1、R2、R3、R4、及びR5の1つのみがLであることを条件とする)、
Lは、R-(CH2CH2O)q(CH2)r-C(O)-X-又はR-(CH2CH2O)q(CH2)r-X-SO2-であり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択され、
Xは、O又はSであり、
X1、X2、X3、X4、X5、X6、X7及びX8は独立して、天然アミノ酸及び2,3-ジアミノプロピオン酸、チオチロシン、4-ベンゾイルフェニルアラニン、2-チアゾール-アラニン、ノルバリン、1-ナフチルアラニン、2-ナフチルアラニン、3-ナフチルアラニン、N-ε-カルバミル-リジン、2-チエニルアラニン、3-アミノピロリジン-4-カルボン酸、2',4'-フェニルアラニン、2',5'-フェニルアラニン、2',6'-フェニルアラニン、3',4'-フェニルアラニン、-OH、-O-(C1〜C6)アルキル、-O-アリール、アミノ、-(C1〜C6)アルキルアミノ、ジ-(C1〜C6)アルキルアミノの残基から選択され、又は存在せず(ただし、X1、X2、X3、X4、X5、X6、X7及びX8の少なくとも1つが存在することを条件とする)、
Qは電子求引性置換基(例えば、ハロアルキル、-F、-NO2又は-CN)であり、
gは0〜8であり、
mは、0又は1であり、
nは0〜8であり、
pは1〜8であり、
rは1〜20であり、
qは0〜100である)の構造を有する、請求項1に記載の化合物。 - X1、X2、X3、X4、X5、X6、X7及びX8が独立して、グルタミン酸、グルタミン、アスパラギン酸、アスパラギン、アルギニン、メチオニン、セリン、チロシン、ロイシン、イソロイシン、アラニン、グリシン、トレオニン、バリン、プロリン、フェニルアラニン、トリプトファン、2,3-ジアミノプロピオン酸、チオチロシン、4-ベンゾイルフェニルアラニン、2-チアゾール-アラニン、ノルバリン、1-ナフチルアラニン、2-ナフチルアラニン、3-ナフチルアラニン、N-ε-カルバミル-リジン、2-チエニルアラニン、3-アミノピロリジン-4-カルボン酸、2',4'-フェニルアラニン、2',5'-フェニルアラニン、2',6'-フェニルアラニン、3',4'-フェニルアラニン、-OH、-O-(C1〜C6)アルキル、-O-アリール、アミノ、-(C1〜C6)アルキルアミノ、ジ-(C1〜C6)アルキルアミノの群から選択されるアミノ酸残基であり、又は存在しない(ただし、X1、X2、X3、X4、X5、X6、X7及びX8の少なくとも1つが存在することを条件とする)、請求項12に記載の化合物。
- X1、X2、X3、X4、X5、X6、X7及びX8の少なくとも2つ、少なくとも3つ、少なくとも4つ、少なくとも5つ、少なくとも6つ、少なくとも7つ、又は8つが存在する、請求項12に記載の化合物。
- X1、X2、X3、X4、X5、X6、X7及びX8の少なくとも4つが独立して、芳香族環を含有するアミノ酸、ロイシン、バリン又はイソロイシンである、請求項12に記載の化合物。
- タンパク質のアミノ基を部位選択的に官能化して、部位選択的に官能化されたタンパク質を得る方法であって、
タンパク質を請求項1から15のいずれか一項に記載の化合物と接触させる工程と、
タンパク質のアミノ基と化合物の第1の直交反応性部分との間に共有結合を形成する工程と、
第1の直交反応性部分とペプチドとの間の共有結合を切断する工程と
を含む、方法。 - 第1の直交反応性部分がアジドを含む、請求項15に記載の方法。
- タンパク質が抗体であり、アミノ基が抗体のFab領域に位置する、請求項15に記載の方法。
- 抗体が、癌又は自己免疫疾患の処置に有用な治療用抗体である、請求項18に記載の方法。
- 化合物が、タンパク質の保存領域への親和性を有する、請求項15に記載の方法。
- 親和性が10μM以下のKdで表される、請求項20に記載の方法。
- 部位選択的に官能化されたタンパク質を、第2の直交反応性部分を含むペイロード化合物と接触させる工程と、
第1の直交反応性部分と第2の直交反応性部分との間に1つ又は複数の共有結合を形成する工程と
を更に含む、請求項15に記載の方法。 - 第1の直交反応性部分がアジドを含み、第2の直交反応性部分がアルキンを含む、請求項22に記載の方法。
- ペイロード化合物が、イメージング部分、抗体、抗体フラグメント、タンパク質、光学剤、ビタミン、酵素、ペプチド、ペプトイド、毒素、薬物、プロドラッグ、バイオマーカーに対するリガンド、又はエフェロサイトーシスの刺激物質である、請求項22に記載の方法。
- ペイロード化合物が、ホラート、EGFR、ALK、MET、PTK7及びKRAS又はいずれかの癌遺伝子産物からなる群から選択される受容体を標的とする、請求項22に記載の方法。
- ペイロード化合物が、アントラサイクリン、タキソール、アウリスタチン、アマニチン、カンプトテシン、ブレオマイシン、カルボプラチナ、シタラビン、5-フルオロウラシル、タモキシフェン、カリケアマイシン、メイタンシン、ツブリシン、エトポシド、デュオカルマイシン誘導体、例えばCC-1065、類縁体、デュオカルマイシン及びエスペラマイシン、ホラート、ピロロベンゾジアゼピン、並びにRGD連結部分の群から選択される、請求項22に記載の方法。
- ペイロード化合物が、放射性標識、分子イメージング剤、光プローブ、ヌクレオチド、オリゴ糖、及びポリマーからなる群から選択される、請求項22に記載の方法。
- 第1の直交反応性部分と第2の直交反応性部分との間における1つ又は複数の共有結合の形成工程が、生理的温度及びpHにおいて行われる、請求項22に記載の方法。
- 生理的温度が10〜45℃であり、生理的pHが5〜9である、請求項27に記載の方法。
- 部位選択的標識用化合物を同定する方法であって、
複数の同一タンパク質を用意する工程であって、各タンパク質が2個以上のアミノ(-NH2)基を含む工程と、
複数のタンパク質を、請求項1から15のいずれか一項に記載の化合物から独立して選択される複数の標識用化合物と接触させる工程と、
1つ又は複数のタンパク質の1個若しくは複数のアミノ基と1つ又は複数の化合物の第1の直交反応性部分との間に共有結合を形成して、1つ又は複数の標識タンパク質を得る工程と、
最高の選択性で標識されたタンパク質を同定する工程と、
対応する部位選択的標識用化合物を同定する工程と
を含む、方法。 - 最高の選択性及び最高の収率で標識されたタンパク質を同定する工程を更に含む、請求項30に記載の方法。
- 部位選択的標識用化合物が、クリックケミストリー反応をELISA技術と併せて使用して、標的タンパク質における第1の直交反応性部分の取り込みの程度をモニタリングして同定される、請求項30に記載の方法。
- タンパク質が抗体である、請求項30に記載の方法。
- 抗体が、癌又は自己免疫疾患の処置に有用な治療用抗体である、請求項33に記載の方法。
- アミノ基が抗体のFab領域に位置する、請求項33に記載の方法。
- 標識用化合物が、タンパク質の保存領域への親和性を有する、請求項33に記載の方法。
- 親和性が10μM以下のKdで表される、請求項36に記載の方法。
- 式(V):
Pはタンパク質であり、
Lysはリジン残基であり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニルからなる群から選択される部分であり、
mは0〜40であり、
nは1〜20である)の
化合物。 - Pが抗体である、請求項38に記載の化合物。
- 式(V):
Pはタンパク質であり、
Lysはリジン残基であり、
Gはペイロード化合物を含む部分であり、
mは0〜40であり、
nは1〜20である)の
化合物。 - Gが、トリアゾール部分を更に含む、請求項40に記載の化合物。
- 請求項38に記載の化合物及び1つ又は複数の薬学的に許容される担体又は賦形剤を含む、医薬組成物。
- 患者における癌を処置する方法であって、その処置を必要とする患者に有効量の請求項38に記載の化合物を投与する工程を含む、方法。
- 抗体を標識する方法であって、
(a)抗体を式(XI):
X1、X2、X3及びX4は独立して、天然アミノ酸及び2,3-ジアミノプロピオン酸、チオチロシン、4-ベンゾイルフェニルアラニン、2-チアゾール-アラニン、ノルバリン、1-ナフチルアラニン、2-ナフチルアラニン、3-ナフチルアラニン、N-ε-カルバミル-リジン、2-チエニルアラニン、3-アミノピロリジン-4-カルボン酸、2',4'-フェニルアラニン、2',5'-フェニルアラニン、2',6'-フェニルアラニン、3',4'-フェニルアラニンの残基から選択される残基であり、又は存在せず(ただし、X1、X2、X3、及びX4の少なくとも1つが存在することを条件とする)、
Qは、H又は電子求引性置換基であり、
n=0〜10であり、
p=0〜10である)の化合物と接触させる工程と、
(b)工程(a)の生成物を、独立して、n=0〜20であり、m=1〜40である式(XII):
Zは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニル(例えば、アルデヒド)からなる群から選択される部分であり、
Mは1〜40であり、
nは0〜20である)の化合物と接触させる
工程とを含む、方法。 - 抗体のFcフラグメントを部位選択的に標識する方法であって、
抗体を式(XIII):
Xは、ヒスチジン、3-(4-チアゾリル)-L-アラニン、(R)-又は(S)-2-アミノ-3-(チアゾール-5-イル)プロパン酸)であり、
Y=O、S又はSeであり、
Zは、アルキニル若しくはシクロアルキニル、アジド、ホルミル、アセチル、1,3-ジエン、ニトリルオキシド、ニトロン、trans-シクロオクテン又はテトラジンであり、
m=0〜30であり、
n=1〜20であり、
p=1〜20であり、
q=1〜2であり、
u=0〜5であり、
フェニル環は、F、NO2、又はCNで場合によって置換されており、
Yとベンズアミドカルボニルは、オルト、メタ又はパラの関係でありうる)の化合物と接触させる工程を含む、方法。 - 抗体のFcフラグメントを部位選択的に標識する方法であって、
抗体を式(XIV):
U及びU'は独立して、システイン、アスパルタート、グルタマート、2,3-ジアミノプロピオン酸、リジン、又はオルニチンであり、
Xは、
Zは、アルキニル若しくはシクロアルキニル、アジド、ホルミル、アセチル、1,3-ジエン、ニトリルオキシド、ニトロン、trans-シクロオクテン又はテトラジンであり、
mは0〜15であり、
nは1〜25である)の化合物と接触させる工程を含む、方法。 - 抗体のFcフラグメントを部位選択的に標識する方法であって、
抗体を式(XV):
U及びU'は独立して、システイン、アスパルタート、グルタマート、2,3-ジアミノプロピオン酸、リジン、又はオルニチンであり、
Xは、
WはHであり、かつYはFであり、又は
WはFであり、かつYはHであり、
mは0〜15であり、
nは1〜25であり、
pは0〜1である)の化合物と接触させる工程を含む、方法。 - 抗体のFcフラグメントを部位選択的に標識する方法であって、
抗体を式(XVI):
U及びU'は独立して、システイン、アスパルタート、グルタマート、2,3-ジアミノプロピオン酸、2,4-ジアミノ酪酸、リジン、又はオルニチンであり、
Xは、
Y=O、S又はSeであり、
Zは、アルキニル若しくはシクロアルキニル、アジド、ホルミル、アセチル、1,3-ジエン、ニトリルオキシド、ニトロン、trans-シクロオクテン又はテトラジンであり、
m=0〜30であり、
n=1〜20であり、
p=1〜20であり、
フェニル環は、F、NO2、又はCNで場合によって置換されており、Yとベンズアミドカルボニルは、オルト、メタ又はパラの関係でありうる)の化合物と接触させる工程を含む、方法。 - 式(XVII):
Eは、ハロゲン、-CN、-NO2、-SO2、-SO2NHW4、-S(O)C1〜C6アルキル、-S(O)アリール、及び-OC1〜C6アルキルからなる群から選択される部分であり、
Xは、O、S又はSeであり、
Yは、アルキル、ポリアルキレンオキシド、ペプチド、ペプトイド、及びそれらの組合せからなる群から選択されるリンカーであり、
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニルからなる群から選択され、
R'は、存在しない、又は-C(O)OH、-C(O)OC1〜C6アルキル、-C(O)NH2、-C(O)NHC1〜C6アルキル、-C(O)N(C1〜C6アルキル)2、-SO2NH2、-SO2NHC1〜C6アルキル、若しくは-SO2N(C1〜C6アルキル)2であり、
W4は、N末端においてC(O)又はSO2に連結されている、25個までの残基のペプチドを含み、
qは、0、1、2、3又は4である)の化合物。 - 式(XVIII):
Rは、アルキン、シクロアルキン、アジド、1,3-ジエン、ニトリルオキシド、ニトロン、テトラジン、trans-シクロオクテン、及びカルボニルからなる群から選択され、
R1は、水素又はC1〜C6-アルキルであり、
R2は、水素又はC1〜C6-アルキルであり、
R3は、電子求引性基であり、
qは0〜100であり、rは1〜20であり、mは0〜1であり、nは0〜4である)の構造を有する、請求項49に記載の化合物。
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662388862P | 2016-02-09 | 2016-02-09 | |
US62/388,862 | 2016-02-09 | ||
US201662389137P | 2016-02-18 | 2016-02-18 | |
US62/389,137 | 2016-02-18 | ||
US201662390624P | 2016-04-04 | 2016-04-04 | |
US62/390,624 | 2016-04-04 | ||
US201662494420P | 2016-08-08 | 2016-08-08 | |
US62/494,420 | 2016-08-08 | ||
PCT/US2017/016932 WO2017139329A1 (en) | 2016-02-09 | 2017-02-08 | Site-selective functionalization of proteins using traceless affinity lables |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2019518017A true JP2019518017A (ja) | 2019-06-27 |
Family
ID=59563485
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018560733A Pending JP2019518017A (ja) | 2016-02-09 | 2017-02-08 | トレースレス親和性標識を使用したタンパク質の部位選択的官能化 |
Country Status (5)
Country | Link |
---|---|
US (2) | US10329321B2 (ja) |
EP (1) | EP3413921A4 (ja) |
JP (1) | JP2019518017A (ja) |
CA (1) | CA3013829A1 (ja) |
WO (1) | WO2017139329A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3703676A4 (en) | 2017-11-04 | 2021-12-15 | Advanced Proteome Therapeutics, Inc. | COMPOSITION AND PROCESS FOR MODIFYING POLYPEPTIDES |
WO2020086311A1 (en) * | 2018-10-23 | 2020-04-30 | The Regents Of The University Of California | Thiophosphorodichloridate reagents for chemoselective histidine bioconjugation |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050037974A1 (en) * | 1997-11-07 | 2005-02-17 | Conjuchem, Inc. | Affinity markers for human serum albumin |
US20130165382A1 (en) * | 2010-06-01 | 2013-06-27 | Advanced Proteome Therapeutics Inc. | Crosslinking of proteins and other entities via conjugates of alpha-haloacetophenones, benzyl halides, quinones, and their derivatives |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ215865A (en) | 1985-04-22 | 1988-10-28 | Commw Serum Lab Commission | Method of determining the active site of a receptor-binding analogue |
US5010175A (en) | 1988-05-02 | 1991-04-23 | The Regents Of The University Of California | General method for producing and selecting peptides with specific properties |
US5182366A (en) | 1990-05-15 | 1993-01-26 | Huebner Verena D | Controlled synthesis of peptide mixtures using mixed resins |
US5650489A (en) | 1990-07-02 | 1997-07-22 | The Arizona Board Of Regents | Random bio-oligomer library, a method of synthesis thereof, and a method of use thereof |
US5612034A (en) | 1990-10-03 | 1997-03-18 | Redcell, Inc. | Super-globuling for in vivo extended lifetimes |
ATE176239T1 (de) | 1990-11-21 | 1999-02-15 | Iterex Pharma Lp | Synthese äquimolarer mischungen vielzähliger oligomere, speziell oligopeptidmischungen |
DE69217497T2 (de) | 1991-09-18 | 1997-06-12 | Affymax Tech Nv | Verfahren zur synthese der verschiedenen sammlungen von oligomeren |
US5270170A (en) | 1991-10-16 | 1993-12-14 | Affymax Technologies N.V. | Peptide library and screening method |
US5573905A (en) | 1992-03-30 | 1996-11-12 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
US5288514A (en) | 1992-09-14 | 1994-02-22 | The Regents Of The University Of California | Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support |
NZ256952A (en) | 1992-09-24 | 1997-07-27 | Chiron Corp | Synthesis of n-substituted polyamides and pharmaceutical compositions |
US5565324A (en) | 1992-10-01 | 1996-10-15 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
CA2526907C (en) * | 2003-01-17 | 2012-11-13 | Advanced Proteome Therapeutics, Inc. | Tandem analyses of noncovalently driven effectors for modulatory mapping of activities of protein sites |
SG186451A1 (en) | 2010-07-12 | 2013-01-30 | Covx Technologies Ireland Ltd | Multifunctional antibody conjugates |
PE20151140A1 (es) * | 2012-08-16 | 2015-08-07 | Janssen Pharmaceutica Nv | Pirazoles sustituidos como bloqueadores del canal de calcio tipo n |
HRP20221233T1 (hr) * | 2014-03-14 | 2022-12-09 | Biomolecular Holdings Llc | Spojevi korisni u pripravi hibridnog imunoglobina koji sadrži nepeptidilnu vezu |
-
2017
- 2017-02-08 JP JP2018560733A patent/JP2019518017A/ja active Pending
- 2017-02-08 US US15/427,678 patent/US10329321B2/en active Active
- 2017-02-08 EP EP17750665.6A patent/EP3413921A4/en not_active Withdrawn
- 2017-02-08 WO PCT/US2017/016932 patent/WO2017139329A1/en active Application Filing
- 2017-02-08 CA CA3013829A patent/CA3013829A1/en active Pending
-
2019
- 2019-05-06 US US16/403,971 patent/US20200095275A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050037974A1 (en) * | 1997-11-07 | 2005-02-17 | Conjuchem, Inc. | Affinity markers for human serum albumin |
US20130165382A1 (en) * | 2010-06-01 | 2013-06-27 | Advanced Proteome Therapeutics Inc. | Crosslinking of proteins and other entities via conjugates of alpha-haloacetophenones, benzyl halides, quinones, and their derivatives |
Non-Patent Citations (4)
Title |
---|
CHEM. COMMUN., JPN6022025645, 1998, pages 815 - 816, ISSN: 0004802182 * |
J. CHEM. SOC., CHEM. COMMUN., JPN6022025647, 1988, pages 270 - 272, ISSN: 0004802184 * |
KRANTZ, A. ET AL.: ""Site-specific Labeling of a Protein Lysine Residue By Novel Kinetic Labeling Combinatorial Librarie", COMPUT. STRUCT. BIOTECHNOL. J., vol. Vol. 9; e201403001, JPN6021008023, 2014, pages 1 - 11, ISSN: 0004458483 * |
TETRAHEDRON LETTERS, vol. 34, JPN6022025646, 1993, pages 4671 - 4674, ISSN: 0004802183 * |
Also Published As
Publication number | Publication date |
---|---|
WO2017139329A1 (en) | 2017-08-17 |
US20170275331A1 (en) | 2017-09-28 |
EP3413921A1 (en) | 2018-12-19 |
US20200095275A1 (en) | 2020-03-26 |
CA3013829A1 (en) | 2017-08-17 |
US10329321B2 (en) | 2019-06-25 |
EP3413921A4 (en) | 2019-08-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kee et al. | 18F-Trifluoromethanesulfinate enables direct C–H 18F-trifluoromethylation of native aromatic residues in peptides | |
Dirksen et al. | Rapid oxime and hydrazone ligations with aromatic aldehydes for biomolecular labeling | |
US9688663B2 (en) | Crosslinking reagents, methods, and compositions for studying protein-protein interactions | |
US20230295092A1 (en) | 18f - tagged inhibitors of prostate specific membrane antigen (psma) and their use as imaging agents for prostate cancer | |
EA021001B1 (ru) | Биосинтетический пирролинкарбоксилизин и сайт-специфичные модификации белка за счет химической модификации остатков пирролинкарбоксилизина и пирролизина | |
US10960089B2 (en) | Radiolabeled drug | |
Wang et al. | A Disulfide Intercalator Toolbox for the Site‐Directed Modification of Polypeptides | |
US20230044430A1 (en) | Composition and method for modifying polypeptides | |
US20110270151A1 (en) | Image-guided energy deposition for targeted drug delivery | |
Wängler et al. | DOTA derivatives for site-specific biomolecule-modification via click chemistry: synthesis and comparison of reaction characteristics | |
US8951499B2 (en) | Trifunctional reagent for conjugation to a biomolecule | |
Quigley et al. | Click‐chemistry (CuAAC) Trimerization of an αvβ6 integrin targeting Ga‐68‐peptide: enhanced contrast for in‐vivo PET imaging of human lung adenocarcinoma xenografts | |
US20200095275A1 (en) | Site-selective functionalization of proteins using traceless affinity labels | |
CN105579434A (zh) | 基于乙烯基砜的18f标记组合物和方法及其用途 | |
US20220107327A1 (en) | Multi-target crosslinkers and uses thereof | |
JP5115988B2 (ja) | 分析試料調製方法および分析試料ならびに糖鎖捕捉物質 | |
Zhu et al. | A novel and simplified route to the synthesis of N3S chelators for 99mTc labeling | |
JPH04506343A (ja) | ターゲッティング薬剤 | |
Rajagopalan et al. | Chemistry of bifunctional photoprobes. 6. Synthesis and characterization of high specific activity metalated photochemical probes: development of novel rhenium photoconjugates of human serum albumin and Fab fragments | |
Mihala et al. | Amino acid and peptide bioconjugates | |
WO2024043249A1 (ja) | 環状ペプチドまたはその塩、およびmdmx阻害剤 | |
US20220403443A1 (en) | High-throughput enzyme assay for screening activity of acyltransferases | |
CA3228449A1 (en) | Human transferrin receptor binding peptide | |
TW202334179A (zh) | 胜肽 | |
Son | Structural Investigation into Chemically Synthesized Peptides using Modern Biophysical Techniques |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200207 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210308 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210607 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210908 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20220124 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220524 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20220524 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20220531 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20220606 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20220624 |
|
C211 | Notice of termination of reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C211 Effective date: 20220704 |