AU4000900A - Beta-secretase enzyme compositions and methods - Google Patents
Beta-secretase enzyme compositions and methods Download PDFInfo
- Publication number
- AU4000900A AU4000900A AU40009/00A AU4000900A AU4000900A AU 4000900 A AU4000900 A AU 4000900A AU 40009/00 A AU40009/00 A AU 40009/00A AU 4000900 A AU4000900 A AU 4000900A AU 4000900 A AU4000900 A AU 4000900A
- Authority
- AU
- Australia
- Prior art keywords
- secretase
- seq
- protein
- sequence
- cell
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims description 170
- 239000000203 mixture Substances 0.000 title claims description 51
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 title claims description 28
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 title claims description 26
- 108090000623 proteins and genes Proteins 0.000 claims description 257
- 210000004027 cell Anatomy 0.000 claims description 248
- 102000004169 proteins and genes Human genes 0.000 claims description 225
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 147
- 102000004190 Enzymes Human genes 0.000 claims description 133
- 108090000790 Enzymes Proteins 0.000 claims description 133
- 150000001875 compounds Chemical class 0.000 claims description 98
- 230000000694 effects Effects 0.000 claims description 97
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 89
- 239000000758 substrate Substances 0.000 claims description 85
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 claims description 82
- 239000003112 inhibitor Substances 0.000 claims description 78
- 229920001184 polypeptide Polymers 0.000 claims description 72
- 150000001413 amino acids Chemical class 0.000 claims description 66
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 60
- 238000003556 assay Methods 0.000 claims description 58
- 239000012634 fragment Substances 0.000 claims description 58
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 57
- 239000013598 vector Substances 0.000 claims description 56
- 150000007523 nucleic acids Chemical class 0.000 claims description 50
- 230000014509 gene expression Effects 0.000 claims description 49
- 102000039446 nucleic acids Human genes 0.000 claims description 46
- 108020004707 nucleic acids Proteins 0.000 claims description 46
- 238000003776 cleavage reaction Methods 0.000 claims description 40
- 230000007017 scission Effects 0.000 claims description 39
- 238000012360 testing method Methods 0.000 claims description 36
- 229940121773 Secretase inhibitor Drugs 0.000 claims description 34
- 230000027455 binding Effects 0.000 claims description 33
- 239000002773 nucleotide Substances 0.000 claims description 33
- 125000003729 nucleotide group Chemical group 0.000 claims description 32
- 238000012216 screening Methods 0.000 claims description 31
- 239000013604 expression vector Substances 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 26
- 238000006467 substitution reaction Methods 0.000 claims description 26
- 208000024827 Alzheimer disease Diseases 0.000 claims description 25
- 239000011159 matrix material Substances 0.000 claims description 21
- 238000004519 manufacturing process Methods 0.000 claims description 20
- 238000001890 transfection Methods 0.000 claims description 19
- 230000002255 enzymatic effect Effects 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 15
- 239000000284 extract Substances 0.000 claims description 14
- 238000002823 phage display Methods 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 13
- 108091005804 Peptidases Proteins 0.000 claims description 11
- 230000008021 deposition Effects 0.000 claims description 11
- 238000011813 knockout mouse model Methods 0.000 claims description 11
- 239000004365 Protease Substances 0.000 claims description 10
- 230000001580 bacterial effect Effects 0.000 claims description 10
- DFVFTMTWCUHJBL-BQBZGAKWSA-N statine Chemical group CC(C)C[C@H](N)[C@@H](O)CC(O)=O DFVFTMTWCUHJBL-BQBZGAKWSA-N 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 108700019146 Transgenes Proteins 0.000 claims description 8
- 238000012217 deletion Methods 0.000 claims description 8
- 230000037430 deletion Effects 0.000 claims description 8
- 230000001939 inductive effect Effects 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 8
- 206010002022 amyloidosis Diseases 0.000 claims description 7
- 210000003527 eukaryotic cell Anatomy 0.000 claims description 7
- 239000012528 membrane Substances 0.000 claims description 7
- 241000238631 Hexapoda Species 0.000 claims description 6
- 125000000539 amino acid group Chemical group 0.000 claims description 6
- 230000000295 complement effect Effects 0.000 claims description 6
- 239000003550 marker Substances 0.000 claims description 6
- 230000002018 overexpression Effects 0.000 claims description 6
- 241000894007 species Species 0.000 claims description 6
- 229940126585 therapeutic drug Drugs 0.000 claims description 6
- 230000007170 pathology Effects 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- 230000003930 cognitive ability Effects 0.000 claims description 4
- 230000002779 inactivation Effects 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 238000011830 transgenic mouse model Methods 0.000 claims description 4
- 125000000729 N-terminal amino-acid group Chemical group 0.000 claims description 3
- 230000000903 blocking effect Effects 0.000 claims description 3
- 238000003259 recombinant expression Methods 0.000 claims description 3
- 210000005253 yeast cell Anatomy 0.000 claims description 3
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 2
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical group OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 claims description 2
- 230000007071 enzymatic hydrolysis Effects 0.000 claims description 2
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 claims description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 4
- 238000012258 culturing Methods 0.000 claims 1
- 230000017854 proteolysis Effects 0.000 claims 1
- 235000018102 proteins Nutrition 0.000 description 134
- 229940088598 enzyme Drugs 0.000 description 121
- 239000013615 primer Substances 0.000 description 68
- 235000001014 amino acid Nutrition 0.000 description 63
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 60
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 60
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 60
- 108091033319 polynucleotide Proteins 0.000 description 55
- 102000040430 polynucleotide Human genes 0.000 description 55
- 239000002157 polynucleotide Substances 0.000 description 55
- 239000002299 complementary DNA Substances 0.000 description 43
- 239000000047 product Substances 0.000 description 43
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 42
- 108020004414 DNA Proteins 0.000 description 36
- 210000004556 brain Anatomy 0.000 description 33
- 239000000523 sample Substances 0.000 description 32
- 238000000746 purification Methods 0.000 description 31
- 238000002425 crystallisation Methods 0.000 description 30
- 230000008025 crystallization Effects 0.000 description 30
- 238000002474 experimental method Methods 0.000 description 28
- 239000000872 buffer Substances 0.000 description 27
- 210000001519 tissue Anatomy 0.000 description 26
- 229920004890 Triton X-100 Polymers 0.000 description 25
- 239000013504 Triton X-100 Substances 0.000 description 23
- 239000013612 plasmid Substances 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000011780 sodium chloride Substances 0.000 description 21
- 108091026890 Coding region Proteins 0.000 description 20
- 241000699666 Mus <mouse, genus> Species 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 108091028043 Nucleic acid sequence Proteins 0.000 description 17
- 239000000499 gel Substances 0.000 description 17
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 15
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 14
- 238000010367 cloning Methods 0.000 description 14
- 238000012545 processing Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 241000588724 Escherichia coli Species 0.000 description 13
- 239000007983 Tris buffer Substances 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- 239000003446 ligand Substances 0.000 description 13
- 239000008188 pellet Substances 0.000 description 13
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 210000004899 c-terminal region Anatomy 0.000 description 12
- 238000009396 hybridization Methods 0.000 description 12
- 108020004999 messenger RNA Proteins 0.000 description 12
- FBKFDSUZBVDZIX-FFGDOFBPSA-N (4s)-4-[[(2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-acetamido-3-phenylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-2-methylpropanoyl]amino]-3-[4-(phosphonomethyl)phenyl]propanoyl]amino]-3-(6-chloro-1h-indol-3-yl)propanoyl]amino]-5-[[1-[[(2s)-1-amino-4-meth Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NC(C)(C)C(=O)N[C@@H](CC=1C=CC(CP(O)(O)=O)=CC=1)C(=O)N[C@@H](CC=1C2=CC=C(Cl)C=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)NC1(CC1)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(C)=O)C1=CC=CC=C1 FBKFDSUZBVDZIX-FFGDOFBPSA-N 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- 108700026244 Open Reading Frames Proteins 0.000 description 11
- 230000003321 amplification Effects 0.000 description 11
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N biotin Natural products N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 11
- 230000035772 mutation Effects 0.000 description 11
- 238000003199 nucleic acid amplification method Methods 0.000 description 11
- 238000013519 translation Methods 0.000 description 11
- 238000002965 ELISA Methods 0.000 description 10
- 108091034117 Oligonucleotide Proteins 0.000 description 10
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 10
- 239000003636 conditioned culture medium Substances 0.000 description 10
- 238000013461 design Methods 0.000 description 10
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 10
- 238000001262 western blot Methods 0.000 description 10
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 9
- -1 aspartyl Chemical group 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 230000001605 fetal effect Effects 0.000 description 9
- 108020001507 fusion proteins Proteins 0.000 description 9
- 102000037865 fusion proteins Human genes 0.000 description 9
- 239000006166 lysate Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 238000003757 reverse transcription PCR Methods 0.000 description 9
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 9
- 238000010561 standard procedure Methods 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 229920002684 Sepharose Polymers 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 238000003780 insertion Methods 0.000 description 8
- 230000037431 insertion Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 238000012163 sequencing technique Methods 0.000 description 8
- 239000001632 sodium acetate Substances 0.000 description 8
- 235000017281 sodium acetate Nutrition 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- 230000009261 transgenic effect Effects 0.000 description 8
- 108010017640 Aspartic Acid Proteases Proteins 0.000 description 7
- 102000004580 Aspartic Acid Proteases Human genes 0.000 description 7
- 238000000636 Northern blotting Methods 0.000 description 7
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 7
- 102000035195 Peptidases Human genes 0.000 description 7
- 241000700605 Viruses Species 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 229910052737 gold Inorganic materials 0.000 description 7
- 239000002751 oligonucleotide probe Substances 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 230000002441 reversible effect Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 229920000936 Agarose Polymers 0.000 description 6
- 108020004705 Codon Proteins 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 239000013592 cell lysate Substances 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 239000011536 extraction buffer Substances 0.000 description 6
- 230000013595 glycosylation Effects 0.000 description 6
- 238000006206 glycosylation reaction Methods 0.000 description 6
- 230000001537 neural effect Effects 0.000 description 6
- 238000005457 optimization Methods 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 229910052709 silver Inorganic materials 0.000 description 6
- 239000004332 silver Substances 0.000 description 6
- 238000013518 transcription Methods 0.000 description 6
- 230000035897 transcription Effects 0.000 description 6
- 241000701161 unidentified adenovirus Species 0.000 description 6
- 230000003612 virological effect Effects 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- 108020004635 Complementary DNA Proteins 0.000 description 5
- 239000003155 DNA primer Substances 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 5
- 108700024394 Exon Proteins 0.000 description 5
- 241001529936 Murinae Species 0.000 description 5
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 5
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 5
- 108010090804 Streptavidin Proteins 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 5
- 229960002685 biotin Drugs 0.000 description 5
- 235000020958 biotin Nutrition 0.000 description 5
- 239000011616 biotin Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 210000003205 muscle Anatomy 0.000 description 5
- 235000019419 proteases Nutrition 0.000 description 5
- 238000007423 screening assay Methods 0.000 description 5
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- 208000037259 Amyloid Plaque Diseases 0.000 description 4
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 4
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 4
- 108091092195 Intron Proteins 0.000 description 4
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 4
- 108091081024 Start codon Proteins 0.000 description 4
- 108091036066 Three prime untranslated region Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000011543 agarose gel Substances 0.000 description 4
- 230000003942 amyloidogenic effect Effects 0.000 description 4
- 238000000137 annealing Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 230000004186 co-expression Effects 0.000 description 4
- 238000012761 co-transfection Methods 0.000 description 4
- 239000003599 detergent Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000002270 exclusion chromatography Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 210000000496 pancreas Anatomy 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000000816 peptidomimetic Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 108091008146 restriction endonucleases Proteins 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 238000011144 upstream manufacturing Methods 0.000 description 4
- 210000003932 urinary bladder Anatomy 0.000 description 4
- 210000004291 uterus Anatomy 0.000 description 4
- 239000012130 whole-cell lysate Substances 0.000 description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- 108010054576 Deoxyribonuclease EcoRI Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- 108010052285 Membrane Proteins Proteins 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- 108010038807 Oligopeptides Proteins 0.000 description 3
- 102000015636 Oligopeptides Human genes 0.000 description 3
- 101710182846 Polyhedrin Proteins 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 108010076504 Protein Sorting Signals Proteins 0.000 description 3
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000006180 TBST buffer Substances 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 238000005571 anion exchange chromatography Methods 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004925 denaturation Methods 0.000 description 3
- 230000036425 denaturation Effects 0.000 description 3
- 238000009795 derivation Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 3
- 239000012149 elution buffer Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- SAMYCKUDTNLASP-UHFFFAOYSA-N hexane-2,2-diol Chemical compound CCCCC(C)(O)O SAMYCKUDTNLASP-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 108010091212 pepstatin Proteins 0.000 description 3
- 229950000964 pepstatin Drugs 0.000 description 3
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- 210000002826 placenta Anatomy 0.000 description 3
- 229920002401 polyacrylamide Polymers 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 210000001236 prokaryotic cell Anatomy 0.000 description 3
- 239000012460 protein solution Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229940124598 therapeutic candidate Drugs 0.000 description 3
- 231100000027 toxicology Toxicity 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 241000201370 Autographa californica nucleopolyhedrovirus Species 0.000 description 2
- 229920002101 Chitin Polymers 0.000 description 2
- 102000004594 DNA Polymerase I Human genes 0.000 description 2
- 108010017826 DNA Polymerase I Proteins 0.000 description 2
- 108020001019 DNA Primers Proteins 0.000 description 2
- 102100031780 Endonuclease Human genes 0.000 description 2
- 102100029727 Enteropeptidase Human genes 0.000 description 2
- 108010013369 Enteropeptidase Proteins 0.000 description 2
- 102000010911 Enzyme Precursors Human genes 0.000 description 2
- 108010062466 Enzyme Precursors Proteins 0.000 description 2
- 102000005720 Glutathione transferase Human genes 0.000 description 2
- 108010070675 Glutathione transferase Proteins 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 108010033276 Peptide Fragments Proteins 0.000 description 2
- 102000007079 Peptide Fragments Human genes 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- 238000012300 Sequence Analysis Methods 0.000 description 2
- 241000256251 Spodoptera frugiperda Species 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 241000255985 Trichoplusia Species 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 229920004896 Triton X-405 Polymers 0.000 description 2
- 108091023045 Untranslated Region Proteins 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 230000007791 alzheimer disease like pathology Effects 0.000 description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 2
- 235000011130 ammonium sulphate Nutrition 0.000 description 2
- 238000005349 anion exchange Methods 0.000 description 2
- 238000002820 assay format Methods 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 210000004900 c-terminal fragment Anatomy 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000013599 cloning vector Substances 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 239000006167 equilibration buffer Substances 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 239000000413 hydrolysate Substances 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 231100000683 possible toxicity Toxicity 0.000 description 2
- 230000001323 posttranslational effect Effects 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000002110 toxicologic effect Effects 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- YMXHPSHLTSZXKH-RVBZMBCESA-N (2,5-dioxopyrrolidin-1-yl) 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoate Chemical compound C([C@H]1[C@H]2NC(=O)N[C@H]2CS1)CCCC(=O)ON1C(=O)CCC1=O YMXHPSHLTSZXKH-RVBZMBCESA-N 0.000 description 1
- BGGHCRNCRWQABU-JTQLQIEISA-N (2s)-2-amino-5-oxo-5-phenylmethoxypentanoic acid Chemical compound OC(=O)[C@@H](N)CCC(=O)OCC1=CC=CC=C1 BGGHCRNCRWQABU-JTQLQIEISA-N 0.000 description 1
- KJIQRHBVNGRPCO-UWVGGRQHSA-N (3s,4s)-3-hydroxy-6-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]heptanoic acid Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C KJIQRHBVNGRPCO-UWVGGRQHSA-N 0.000 description 1
- BCHIXGBGRHLSBE-UHFFFAOYSA-N (4-methyl-2-oxochromen-7-yl) dihydrogen phosphate Chemical compound C1=C(OP(O)(O)=O)C=CC2=C1OC(=O)C=C2C BCHIXGBGRHLSBE-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PWGJDPKCLMLPJW-UHFFFAOYSA-N 1,8-diaminooctane Chemical compound NCCCCCCCCN PWGJDPKCLMLPJW-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 101150072531 10 gene Proteins 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- QZTKDVCDBIDYMD-UHFFFAOYSA-N 2,2'-[(2-amino-2-oxoethyl)imino]diacetic acid Chemical compound NC(=O)CN(CC(O)=O)CC(O)=O QZTKDVCDBIDYMD-UHFFFAOYSA-N 0.000 description 1
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 1
- 108020005345 3' Untranslated Regions Proteins 0.000 description 1
- 101150110188 30 gene Proteins 0.000 description 1
- 108020003589 5' Untranslated Regions Proteins 0.000 description 1
- DNXDWMHPTVQBIP-ZQIUZPCESA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-[6-[(2-iodoacetyl)amino]hexyl]pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCCNC(=O)CI)SC[C@@H]21 DNXDWMHPTVQBIP-ZQIUZPCESA-N 0.000 description 1
- 230000005730 ADP ribosylation Effects 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010025188 Alcohol oxidase Proteins 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 206010002023 Amyloidoses Diseases 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 208000002109 Argyria Diseases 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 239000008000 CHES buffer Substances 0.000 description 1
- 101100436100 Caenorhabditis elegans asp-6 gene Proteins 0.000 description 1
- 101100335056 Caenorhabditis elegans flp-5 gene Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 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
- 108700010070 Codon Usage Proteins 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 241000700662 Fowlpox virus Species 0.000 description 1
- 102000002464 Galactosidases Human genes 0.000 description 1
- 108010093031 Galactosidases Proteins 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010010369 HIV Protease Proteins 0.000 description 1
- 229940122440 HIV protease inhibitor Drugs 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 101000823051 Homo sapiens Amyloid-beta precursor protein Proteins 0.000 description 1
- 101001074035 Homo sapiens Zinc finger protein GLI2 Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 108010016183 Human immunodeficiency virus 1 p16 protease Proteins 0.000 description 1
- 108010016191 Human immunodeficiency virus 2 p16 protease Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 108020005350 Initiator Codon Proteins 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- GAAKALASJNGQKD-UHFFFAOYSA-N LY-165163 Chemical compound C1=CC(N)=CC=C1CCN1CCN(C=2C=C(C=CC=2)C(F)(F)F)CC1 GAAKALASJNGQKD-UHFFFAOYSA-N 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 239000006137 Luria-Bertani broth Substances 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 102100026553 Mannose-binding protein C Human genes 0.000 description 1
- 101710110798 Mannose-binding protein C Proteins 0.000 description 1
- QTZXSYBVOSXBEJ-WDSKDSINSA-N Met-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(O)=O)CC(O)=O QTZXSYBVOSXBEJ-WDSKDSINSA-N 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- MKWKNSIESPFAQN-UHFFFAOYSA-N N-cyclohexyl-2-aminoethanesulfonic acid Chemical compound OS(=O)(=O)CCNC1CCCCC1 MKWKNSIESPFAQN-UHFFFAOYSA-N 0.000 description 1
- 108010049175 N-substituted Glycines Proteins 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 102100026459 POU domain, class 3, transcription factor 2 Human genes 0.000 description 1
- 101710133394 POU domain, class 3, transcription factor 2 Proteins 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108010003581 Ribulose-bisphosphate carboxylase Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 241000256248 Spodoptera Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- IEBGHUMBJXIXHM-AVGNSLFASA-N Val-Lys-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)O)N IEBGHUMBJXIXHM-AVGNSLFASA-N 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- IXKSXJFAGXLQOQ-XISFHERQSA-N WHWLQLKPGQPMY Chemical compound C([C@@H](C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CNC=N1 IXKSXJFAGXLQOQ-XISFHERQSA-N 0.000 description 1
- 102100035558 Zinc finger protein GLI2 Human genes 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 231100000230 acceptable toxicity Toxicity 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 210000004727 amygdala Anatomy 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000005844 autocatalytic reaction Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000002459 blastocyst Anatomy 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- KTVIXTQDYHMGHF-UHFFFAOYSA-L cobalt(2+) sulfate Chemical compound [Co+2].[O-]S([O-])(=O)=O KTVIXTQDYHMGHF-UHFFFAOYSA-L 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 210000000877 corpus callosum Anatomy 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 229940079919 digestives enzyme preparation Drugs 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- NLEBIOOXCVAHBD-QKMCSOCLSA-N dodecyl beta-D-maltoside Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 NLEBIOOXCVAHBD-QKMCSOCLSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001400 expression cloning Methods 0.000 description 1
- 208000015756 familial Alzheimer disease Diseases 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229960004198 guanidine Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 1
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000004030 hiv protease inhibitor Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000011539 homogenization buffer Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000046783 human APP Human genes 0.000 description 1
- 210000000688 human artificial chromosome Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 108091006086 inhibitor proteins Proteins 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007852 inverse PCR Methods 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- DVCSNHXRZUVYAM-BQBZGAKWSA-N leu-asp Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC(O)=O DVCSNHXRZUVYAM-BQBZGAKWSA-N 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 238000000670 ligand binding assay Methods 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 238000001690 micro-dialysis Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 108091005601 modified peptides Proteins 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 210000004898 n-terminal fragment Anatomy 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 108700010839 phage proteins Proteins 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 229940067631 phospholipid Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 210000004896 polypeptide structure Anatomy 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000013823 prenylation Effects 0.000 description 1
- 239000002987 primer (paints) Substances 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 210000004777 protein coat Anatomy 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000030788 protein refolding Effects 0.000 description 1
- 208000009305 pseudorabies Diseases 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 229940124788 therapeutic inhibitor Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000012090 tissue culture technique Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 239000011686 zinc sulphate Substances 0.000 description 1
- 235000009529 zinc sulphate Nutrition 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6478—Aspartic endopeptidases (3.4.23)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Wood Science & Technology (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Peptides Or Proteins (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2004203403A AU2004203403A1 (en) | 1999-02-10 | 2004-07-26 | Beta-secretase enzyme compositions and methods |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11957199P | 1999-02-10 | 1999-02-10 | |
| US60119571 | 1999-02-10 | ||
| US13917299P | 1999-06-15 | 1999-06-15 | |
| US60139172 | 1999-06-15 | ||
| PCT/US2000/003819 WO2000047618A2 (en) | 1999-02-10 | 2000-02-10 | HUMAN β-SECRETASE ENZYME, INHIBITORS AND THEIR COMPOSITIONS AND USES |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2004203403A Division AU2004203403A1 (en) | 1999-02-10 | 2004-07-26 | Beta-secretase enzyme compositions and methods |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU4000900A true AU4000900A (en) | 2000-08-29 |
Family
ID=26817477
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU40009/00A Abandoned AU4000900A (en) | 1999-02-10 | 2000-02-10 | Beta-secretase enzyme compositions and methods |
Country Status (10)
| Country | Link |
|---|---|
| US (3) | US6627739B1 (https=) |
| EP (1) | EP1165609A2 (https=) |
| JP (1) | JP4653318B2 (https=) |
| CN (1) | CN1390232A (https=) |
| AU (1) | AU4000900A (https=) |
| CA (1) | CA2359785A1 (https=) |
| GB (1) | GB2364059B (https=) |
| HK (2) | HK1044545A1 (https=) |
| NZ (1) | NZ534876A (https=) |
| WO (1) | WO2000047618A2 (https=) |
Families Citing this family (71)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9701684D0 (en) | 1997-01-28 | 1997-03-19 | Smithkline Beecham Plc | Novel compounds |
| US6699671B1 (en) | 1998-09-24 | 2004-03-02 | Pharmacia & Upjohn Company | Alzheimer's disease secretase, APP substrates therefor, and uses therefor |
| EP1939297A1 (en) * | 1998-09-24 | 2008-07-02 | Pharmacia & Upjohn Company LLC | Alzheimer's disease secretase |
| PL205294B1 (pl) | 1998-09-24 | 2010-03-31 | Upjohn Co | Izolowany lub oczyszczony polipeptyd, oczyszczony lub izolowany polinukleotyd, wektor, wektor ekspresyjny, komórka gospodarza, sposób wytwarzania polipeptydu, sposoby identyfikowania czynnika obniżającego, modulującego lub hamującego aktywność, zastosowanie takiego czynnika, izolowany kwas nukleinowy, obejmujący go wektor i ich zastosowanie, sposoby zmniejszania komórkowego wytwarzania beta amyloidu i zastosowanie antysensownego reagenta |
| US20040234976A1 (en) * | 1998-09-24 | 2004-11-25 | Gurney Mark E. | Alzheimer's disease secretase, app substrates therefor, and uses therefor |
| US6844148B1 (en) | 1998-09-24 | 2005-01-18 | Pharmacia & Upjohn Company | Alzheimer's disease secretase, APP substrates therefor, and uses therefor |
| US7115410B1 (en) | 1999-02-10 | 2006-10-03 | Elan Pharmaceuticals, Inc. | β-secretase enzyme compositions and methods |
| US7456007B1 (en) | 1998-12-31 | 2008-11-25 | Elan Pharmaceuticals, Inc. | β-secretase enzyme compositions and methods |
| GB2364059B (en) | 1999-02-10 | 2004-01-14 | Elan Pharm Inc | Beta-Secretase enzyme compositions and methods |
| WO2000058479A1 (en) * | 1999-03-26 | 2000-10-05 | Amgen Inc. | Beta secretase genes and polypeptides |
| US7087399B1 (en) * | 1999-05-13 | 2006-08-08 | Scios, Inc. | β-secretase and modulation of β-secretase activity |
| US7169759B1 (en) * | 1999-06-15 | 2007-01-30 | Elan Pharmaceuticals, Inc. | Tetrapeptide inhibitors of β-secretase |
| CA2374610A1 (en) * | 1999-06-28 | 2001-01-04 | Jordan J. N. Tang | Catalytically active recombinant memapsin and methods of use thereof |
| EP1496124A1 (en) * | 1999-06-28 | 2005-01-12 | Oklahoma Medical Research Foundation | Catalytically active recombinant memapsin and methods of use thereof |
| US20090162883A1 (en) * | 1999-09-23 | 2009-06-25 | Pharmacia & Upjohn Company | Alzheimer's Disease Secretase, APP Substrates Thereof, and Uses Thereof |
| US7514408B1 (en) | 1999-12-02 | 2009-04-07 | Elan Pharmaceuticals, Inc. | β-secretase enzyme compositions and methods |
| DE60124080T2 (de) | 2000-03-23 | 2007-03-01 | Elan Pharmaceuticals, Inc., San Francisco | Verbindungen und verfahren zur behandlung der alzheimerschen krankheit |
| US6878363B2 (en) * | 2000-05-17 | 2005-04-12 | Bristol-Myers Squibb Pharma Company | Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging |
| KR100436924B1 (ko) * | 2000-06-28 | 2004-06-23 | (주) 디지탈바이오텍 | 베타 시크리테아제의 제조 방법 |
| PE20020276A1 (es) | 2000-06-30 | 2002-04-06 | Elan Pharm Inc | COMPUESTOS DE AMINA SUSTITUIDA COMO INHIBIDORES DE ß-SECRETASA PARA EL TRATAMIENTO DE ALZHEIMER |
| EP1666452A2 (en) | 2000-06-30 | 2006-06-07 | Elan Pharmaceuticals, Inc. | Compounds to treat Alzheimer's disease |
| US6846813B2 (en) | 2000-06-30 | 2005-01-25 | Pharmacia & Upjohn Company | Compounds to treat alzheimer's disease |
| JP2004502664A (ja) | 2000-06-30 | 2004-01-29 | イーラン ファーマスーティカルズ、インコーポレイテッド | アルツハイマー病処置用化合物 |
| CA2410898A1 (en) | 2000-07-19 | 2002-01-24 | Pharmacia & Upjohn Company | Substrates and assays for .beta.-secretase activity |
| US7806980B2 (en) * | 2000-12-23 | 2010-10-05 | Elan Pharmaceuticals, Inc. | Method for crystallizing human beta secretase in complex with an inhibitor |
| WO2002053594A2 (en) * | 2000-12-28 | 2002-07-11 | Oklahoma Medical Research Foundation | Inhibitors of memapsin 2 and use thereof |
| JP2004524843A (ja) | 2001-02-23 | 2004-08-19 | イーラン ファーマスーティカルズ、インコーポレイテッド | Ｂａｃｅ−１のトランスジェニックノックアウト |
| US7384773B1 (en) * | 2001-05-10 | 2008-06-10 | Pfizer Inc | Crystal of HIV protease-cleaved human beta secretase and method for crystallization thereof |
| US7524668B1 (en) * | 2001-05-10 | 2009-04-28 | Elan Pharmaceuticals, Inc. | Crystal of human beta secretase having monoclinic space group symmetry C2 and methods for crystallization thereof |
| EP1390497A2 (en) | 2001-05-25 | 2004-02-25 | Genset | Human cdnas and proteins and uses thereof |
| MXPA03011046A (es) | 2001-06-01 | 2004-06-25 | Elan Pharm Inc | Hidroxialquilaminas. |
| US6906104B2 (en) | 2001-06-13 | 2005-06-14 | Pharmacia & Upjohn Company | Aminediols for the treatment of Alzheimer's disease |
| BR0210721A (pt) | 2001-06-27 | 2004-07-20 | Elan Pharm Inc | Composto, sal ou éster farmaceuticamente aceitável, método para fabricar um composto, e, método para tratar um paciente que tem, ou para evitar que o paciente adquira uma doença ou condição |
| BR0211121A (pt) | 2001-07-10 | 2004-10-26 | Elan Pharm Inc | Composto, métodos para o tratamento ou prevenção de doenças e para fabricar um composto, intermediário, e, uso de um composto ou sal |
| MXPA04000338A (es) | 2001-07-10 | 2004-07-23 | Upjohn Co | Diamindioles para tratamiento de enfermedad de alzheimer. |
| EP1285578B1 (en) * | 2001-08-21 | 2007-10-31 | Smithkline Beecham Plc | Transgenic animal model of Alzheimer's disease |
| US7186539B1 (en) | 2001-08-31 | 2007-03-06 | Pharmacia & Upjohn Company | Method for refolding enzymes |
| EP1432674A2 (en) | 2001-10-04 | 2004-06-30 | Elan Pharmaceuticals, Inc. | Hydroxypropylamines |
| JP4547152B2 (ja) | 2001-10-23 | 2010-09-22 | オクラホマ メディカル リサーチ ファウンデーション | β−セクレターゼ阻害剤および使用方法 |
| AU2002359376B2 (en) | 2001-11-08 | 2008-01-10 | Elan Pharmaceuticals, Inc. | N, N'-substituted-1,3-diamino-2-hydroxypropane derivatives |
| AU2002360508A1 (en) | 2001-12-06 | 2003-06-23 | Elan Pharmaceuticals, Inc. | Substituted hydroxyethylamines |
| CH698246B1 (de) * | 2001-12-20 | 2009-06-30 | Hoffmann La Roche | Test zur Identifizierung von Inhibitoren von Beta-Sekretasen. |
| US7273743B2 (en) | 2002-02-21 | 2007-09-25 | Elan Pharmaceuticals, Inc. | Modified BACE |
| WO2003076455A2 (en) | 2002-03-05 | 2003-09-18 | Ramot At Tel-Aviv University Ltd. | Immunizing composition and method for inducing an immune response against the ss-secretase cleavage site of amyloid precursor protein |
| WO2004058686A1 (en) | 2002-04-30 | 2004-07-15 | Elan Pharmaceuticals, Inc. | Hydroxypropyl amides for the treatment of alzheimer’s disease |
| US7442537B1 (en) | 2002-05-10 | 2008-10-28 | Elan Pharmaceuticals, Inc. | Crystals of unliganded beta secretase and/or beta secretase-like proteins and the use thereof |
| CA2507484A1 (en) | 2002-11-27 | 2004-06-17 | Elan Pharmaceuticals, Inc. | Substituted ureas and carbamates |
| US7521481B2 (en) | 2003-02-27 | 2009-04-21 | Mclaurin Joanne | Methods of preventing, treating and diagnosing disorders of protein aggregation |
| TW200512195A (en) | 2003-04-21 | 2005-04-01 | Elan Pharm Inc | Benzamide 2-hydroxy-3-diaminoalkanes |
| JP4739192B2 (ja) | 2003-05-02 | 2011-08-03 | イーラン ファーマスーティカルズ、インコーポレイテッド | Ｂａｃｅのグリコシル化変異体 |
| US20050014160A1 (en) * | 2003-07-18 | 2005-01-20 | Sriram Kumaraswamy | Assays for protease enzyme activity |
| JP2007528400A (ja) | 2004-03-09 | 2007-10-11 | エラン ファーマシューティカルズ，インコーポレイテッド | 置換ヒドロキシエチルアミン系のアスパラギン酸プロテアーゼ阻害薬 |
| WO2006010095A2 (en) | 2004-07-09 | 2006-01-26 | Elan Pharmaceuticals Inc. | Oxime derivative substituted hydroxyethylamine aspartyl protease inhibitors |
| WO2006040153A2 (en) * | 2004-10-13 | 2006-04-20 | Ablynx N.V. | Single domain camelide anti -amyloid beta antibodies and polypeptides comprising the same for the treatment and diagnosis of degenarative neural diseases such as alzheimer's disease |
| US7906625B2 (en) | 2005-01-24 | 2011-03-15 | Amgen Inc. | Humanized anti-amyloid antibody |
| US20060223849A1 (en) * | 2005-03-14 | 2006-10-05 | Mjalli Adnan M | Benzazole derivatives, compositions, and methods of use as beta-secretase inhibitors |
| CA2618508A1 (en) * | 2005-08-10 | 2007-02-22 | Oklahoma Medical Research Foundation | Truncated memapsin 2 for use for treating alzheimer's disease |
| WO2007047305A1 (en) | 2005-10-12 | 2007-04-26 | Elan Pharmaceuticals, Inc. | Methods of treating amyloidosis using cyclopropyl derivative aspartyl protease inhibitors |
| WO2007056401A1 (en) * | 2005-11-09 | 2007-05-18 | Merck & Co., Inc. | Method for identifying modulators of osbp useful for treating alzheimer's disease |
| JP4590638B2 (ja) * | 2006-03-20 | 2010-12-01 | 国立大学法人鳥取大学 | 家族性筋萎縮性側索硬化症（ｆａｌｓ）発症するトランスジェニックマウス |
| US20070292895A1 (en) * | 2006-05-19 | 2007-12-20 | Xiao-Ping Shi | Assays and methods to detect beta-secretase and its activity in body fluids and tissue extracts |
| TW200815349A (en) | 2006-06-22 | 2008-04-01 | Astrazeneca Ab | New compounds |
| KR20090027877A (ko) * | 2007-09-13 | 2009-03-18 | 한국생명공학연구원 | Ｂｅｔａ－ｓｉｔｅ ＡＰＰ ｃｌｅａｖｉｎ ｇｅｎｚｙｍｅ（ＢＡＣＥ）를 발현하는 형질전환 식물체 |
| CN101270359B (zh) * | 2008-04-30 | 2012-05-23 | 江苏省原子医学研究所 | 一种重组人淀粉样蛋白Aβ42的制备方法及应用 |
| TW201020244A (en) | 2008-11-14 | 2010-06-01 | Astrazeneca Ab | New compounds |
| EP2281824A1 (en) | 2009-08-07 | 2011-02-09 | Noscira, S.A. | Furan-imidazolone derivatives, for the treatment of cognitive, neurodegenerative or neuronal diseases or disorders |
| WO2012064836A1 (en) | 2010-11-10 | 2012-05-18 | Genentech, Inc. | Methods and compositions for neural disease immunotherapy |
| EP2643299B1 (en) | 2010-11-22 | 2016-06-22 | Noscira, S.A. | Bipyridine sulfonamide derivatives for the treatment of neurodegenerative diseases or conditions |
| JP6134725B2 (ja) * | 2011-10-14 | 2017-05-24 | ジェネンテック， インコーポレイテッド | Ｂａｃｅ１のペプチド阻害剤 |
| WO2016081640A1 (en) | 2014-11-19 | 2016-05-26 | Genentech, Inc. | Anti-transferrin receptor / anti-bace1 multispecific antibodies and methods of use |
| JP6859259B2 (ja) | 2014-11-19 | 2021-04-14 | ジェネンテック， インコーポレイテッド | ＢＡＣＥｌに対する抗体及び神経疾患免疫療法のためのその使用 |
Family Cites Families (52)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5200339A (en) | 1990-08-17 | 1993-04-06 | Abraham Carmela R | Proteases causing abnormal degradation of amyloid β-protein precursor |
| US5292652A (en) | 1990-10-05 | 1994-03-08 | Athena Neurosciences, Inc. | Amyloidin protease and uses thereof |
| ES2236682T5 (es) | 1991-01-21 | 2011-03-31 | Elan Pharmaceuticals, Inc. | Ensayo y modelo para la enfermedad de alzheimer. |
| WO1993018159A2 (en) | 1992-03-09 | 1993-09-16 | Chiron Corporation | Compositions and methods for pace 4 and 4.1 gene and polypeptides in cells |
| IL105793A0 (en) | 1992-05-28 | 1993-09-22 | Lilly Co Eli | Protease and related dna compounds |
| US5455169A (en) | 1992-06-04 | 1995-10-03 | Alzheimer's Institute Of America, Inc. | Nucleic acids for diagnosing and modeling Alzheimer's disease |
| US5837672A (en) | 1992-07-10 | 1998-11-17 | Athena Neurosciences, Inc. | Methods and compositions for the detection of soluble β-amyloid peptide |
| US5766846A (en) | 1992-07-10 | 1998-06-16 | Athena Neurosciences | Methods of screening for compounds which inhibit soluble β-amyloid peptide production |
| ATE239797T1 (de) | 1993-01-25 | 2003-05-15 | Takeda Chemical Industries Ltd | Antikörper gegen beta-amyloid oder derivative davon und seine verwendung |
| AU702293B2 (en) | 1993-10-27 | 1999-02-18 | Athena Neurosciences, Inc. | Transgenic animals harboring APP allele having Swedish mutation |
| WO1996006927A1 (en) | 1994-09-01 | 1996-03-07 | Merck & Co., Inc. | Transgenic animal expressing a familial form of human amyloid precursor protein |
| US5863902A (en) * | 1995-01-06 | 1999-01-26 | Sibia Neurosciences, Inc. | Methods of treating neurodegenerative disorders using protease inhibitors |
| EP0818951A4 (en) | 1995-04-04 | 2002-10-16 | Lilly Co Eli | Amyloid precursor protein PROTEASE |
| JPH11507538A (ja) | 1995-06-07 | 1999-07-06 | アテナ ニューロサイエンシズ インコーポレイティド | β−セクレターゼ、β−セクレターゼに対する抗体、及びβ−セクレターゼ阻害を検出するためのアッセイ |
| US6329163B1 (en) * | 1995-06-07 | 2001-12-11 | Elan Pharmaceuticals, Inc. | Assays for detecting β-secretase inhibition |
| US5744346A (en) | 1995-06-07 | 1998-04-28 | Athena Neurosciences, Inc. | β-secretase |
| US6221645B1 (en) | 1995-06-07 | 2001-04-24 | Elan Pharmaceuticals, Inc. | β-secretase antibody |
| AU735015B2 (en) * | 1996-06-10 | 2001-06-28 | Scripps Research Institute, The | Use of substrate subtraction libraries to distinguish enzyme specificities |
| GB9618966D0 (en) | 1996-09-11 | 1996-10-23 | Smithkline Beecham Plc | Novel compounds |
| DE19641180A1 (de) | 1996-09-24 | 1998-03-26 | Schering Ag | Verfahren zur Darstellung von APP-Sekretase Modulation und deren Verwendung als Mittel zur Behandlung der Alzheimer'schen Erkrankung |
| WO1998021589A1 (en) | 1996-11-15 | 1998-05-22 | The Trustees Of The University Of Pennsylvania | Screening for modulators of amyloid processing |
| WO1998022597A2 (en) | 1996-11-20 | 1998-05-28 | Oklahoma Medical Research Foundation | Cloning and characterization of napsin, an aspartic protease |
| JPH10155487A (ja) | 1996-11-28 | 1998-06-16 | Kagaku Gijutsu Shinko Jigyodan | アミノ酸配列と、このアミノ酸配列を有する 蛋白が結合するｄｎａ配列 |
| AU1684097A (en) * | 1996-12-11 | 1998-07-03 | Athena Neurosciences, Inc. | Beta-secretase isolated from human 293 cells |
| EP0848062A3 (en) | 1996-12-14 | 2000-07-05 | Smithkline Beecham Corporation | Aspartic protease ASP1 |
| GB9626022D0 (en) | 1996-12-14 | 1997-01-29 | Smithkline Beecham Plc | Novel compounds |
| GB9701684D0 (en) * | 1997-01-28 | 1997-03-19 | Smithkline Beecham Plc | Novel compounds |
| US6037137A (en) | 1997-02-20 | 2000-03-14 | Oncoimmunin, Inc. | Fluorogenic peptides for the detection of protease activity |
| GB9721094D0 (en) | 1997-10-03 | 1997-12-03 | Unilever Plc | Autophobic hairspray compositions |
| ATE440951T1 (de) | 1997-12-17 | 2009-09-15 | Serono Genetics Inst Sa | Verlängerte cdns, die für sekretierte proteine kodieren |
| AU1726199A (en) | 1997-12-31 | 1999-07-19 | Chiron Corporation | Metastatic cancer regulated gene |
| ES2312205T3 (es) | 1998-03-10 | 2009-02-16 | Genentech, Inc. | Nuevo polipeptido y acidos nucleicos que lo codifican. |
| CA2330242A1 (fr) | 1998-06-05 | 1999-12-16 | Aventis Pharma S.A. | Polypeptides possedant une activite de type beta-secretase |
| US6844148B1 (en) | 1998-09-24 | 2005-01-18 | Pharmacia & Upjohn Company | Alzheimer's disease secretase, APP substrates therefor, and uses therefor |
| US6699671B1 (en) | 1998-09-24 | 2004-03-02 | Pharmacia & Upjohn Company | Alzheimer's disease secretase, APP substrates therefor, and uses therefor |
| US20040234976A1 (en) | 1998-09-24 | 2004-11-25 | Gurney Mark E. | Alzheimer's disease secretase, app substrates therefor, and uses therefor |
| PL205294B1 (pl) | 1998-09-24 | 2010-03-31 | Upjohn Co | Izolowany lub oczyszczony polipeptyd, oczyszczony lub izolowany polinukleotyd, wektor, wektor ekspresyjny, komórka gospodarza, sposób wytwarzania polipeptydu, sposoby identyfikowania czynnika obniżającego, modulującego lub hamującego aktywność, zastosowanie takiego czynnika, izolowany kwas nukleinowy, obejmujący go wektor i ich zastosowanie, sposoby zmniejszania komórkowego wytwarzania beta amyloidu i zastosowanie antysensownego reagenta |
| US6313268B1 (en) | 1998-10-16 | 2001-11-06 | Vivian Y. H. Hook | Secretases related to Alzheimer's dementia |
| US6245884B1 (en) | 1998-10-16 | 2001-06-12 | Vivian Y. H. Hook | Secretases related to alzheimer's dementia |
| GB2364059B (en) | 1999-02-10 | 2004-01-14 | Elan Pharm Inc | Beta-Secretase enzyme compositions and methods |
| GB2389113B (en) | 1999-02-10 | 2004-02-04 | Elan Pharm Inc | B-secretase inhibitor |
| EP1445263A1 (en) | 1999-02-10 | 2004-08-11 | Elan Pharmaceuticals, Inc. | Human beta-secretase enzyme, inhibitors and their compositions and uses |
| DE19910108C2 (de) | 1999-03-08 | 2001-02-22 | Falk Fahrenholz | Zellen, die ein Amyloidvorläuferprotein und eine alpha-Sekretase coexprimieren, ein Testverfahren zur Identifikation alpha-Sekretase-aktiver Substanzen sowie eines zur Identifikation weiterer Sekretasen, ein Testverfahren zur Bestimmung der Anfälligkeit gegenüber Morbus Alzheimer und Verwendung von Nukleinsäuren, die für eine alpha-Sekretase codieren, für die Gentherapie |
| WO2000058479A1 (en) | 1999-03-26 | 2000-10-05 | Amgen Inc. | Beta secretase genes and polypeptides |
| WO2000068266A1 (en) | 1999-05-11 | 2000-11-16 | Eli Lilly And Company | Amyloid precursor protein protease and related nucleic acid compounds |
| US7087399B1 (en) | 1999-05-13 | 2006-08-08 | Scios, Inc. | β-secretase and modulation of β-secretase activity |
| CA2374610A1 (en) | 1999-06-28 | 2001-01-04 | Jordan J. N. Tang | Catalytically active recombinant memapsin and methods of use thereof |
| WO2001023533A2 (en) | 1999-09-23 | 2001-04-05 | Pharmacia & Upjohn Company | Alzheimer's disease secretase, app substrates therefor, and uses therefor |
| GB9924957D0 (en) | 1999-10-21 | 1999-12-22 | Smithkline Beecham Plc | Novel treatment |
| GB9925136D0 (en) | 1999-10-22 | 1999-12-22 | Smithkline Beecham Plc | Novel treatment |
| US6361975B1 (en) | 1999-11-16 | 2002-03-26 | Smithkline Beecham Corporation | Mouse aspartic secretase-2(mASP-2) |
| US6291223B1 (en) | 1999-11-23 | 2001-09-18 | Smithkline Beecham Corporation | Mouse aspartic secretase-1 (mASP1) |
-
2000
- 2000-02-10 GB GB0121314A patent/GB2364059B/en not_active Expired - Fee Related
- 2000-02-10 EP EP00919298A patent/EP1165609A2/en not_active Ceased
- 2000-02-10 CA CA002359785A patent/CA2359785A1/en not_active Abandoned
- 2000-02-10 HK HK02104538.9A patent/HK1044545A1/zh unknown
- 2000-02-10 AU AU40009/00A patent/AU4000900A/en not_active Abandoned
- 2000-02-10 CN CN00806471A patent/CN1390232A/zh active Pending
- 2000-02-10 NZ NZ534876A patent/NZ534876A/en not_active IP Right Cessation
- 2000-02-10 WO PCT/US2000/003819 patent/WO2000047618A2/en not_active Ceased
- 2000-02-10 JP JP2000598533A patent/JP4653318B2/ja not_active Expired - Fee Related
- 2000-02-10 HK HK02104530.7A patent/HK1044543B/zh not_active IP Right Cessation
- 2000-11-28 US US09/724,566 patent/US6627739B1/en not_active Expired - Fee Related
- 2000-11-28 US US09/724,569 patent/US7109017B1/en not_active Expired - Fee Related
- 2000-11-28 US US09/724,571 patent/US7067271B1/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP4653318B2 (ja) | 2011-03-16 |
| HK1044543A1 (en) | 2002-10-25 |
| WO2000047618A9 (en) | 2001-10-25 |
| NZ534876A (en) | 2006-02-24 |
| GB0121314D0 (en) | 2001-10-24 |
| GB2364059B (en) | 2004-01-14 |
| US7067271B1 (en) | 2006-06-27 |
| EP1165609A2 (en) | 2002-01-02 |
| WO2000047618A2 (en) | 2000-08-17 |
| HK1044543B (zh) | 2004-12-03 |
| CA2359785A1 (en) | 2000-08-17 |
| HK1044545A1 (zh) | 2002-10-25 |
| JP2003524393A (ja) | 2003-08-19 |
| GB2364059A (en) | 2002-01-16 |
| WO2000047618A3 (en) | 2001-09-07 |
| US6627739B1 (en) | 2003-09-30 |
| US7109017B1 (en) | 2006-09-19 |
| CN1390232A (zh) | 2003-01-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7067271B1 (en) | β-secretase enzyme compositions and methods | |
| US20110281752A1 (en) | Beta-secretase enzyme compositions and methods | |
| US7199227B2 (en) | Polynucleotides encoding human histone deacetylase HDAC9c | |
| US7718413B2 (en) | Glycosylation variants of BACE | |
| US20080139476A1 (en) | Caspase-8 interacting proteins | |
| US7456007B1 (en) | β-secretase enzyme compositions and methods | |
| US7514408B1 (en) | β-secretase enzyme compositions and methods | |
| GB2389182A (en) | Method of purifying b-secretase | |
| EP1445263A1 (en) | Human beta-secretase enzyme, inhibitors and their compositions and uses | |
| AU2004203403A1 (en) | Beta-secretase enzyme compositions and methods | |
| MXPA01008063A (en) | &bgr;-SECRETASE ENZYME COMPOSITIONS AND METHODS | |
| US7052893B2 (en) | Isolated human sulfatase-like polypeptides | |
| US7198911B2 (en) | Identification and cloning of a novel human gene, RET16, involved in the intracellular signaling cascade |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted |