CN113711045A - 一种筛选用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法 - Google Patents
一种筛选用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法 Download PDFInfo
- Publication number
- CN113711045A CN113711045A CN202080020716.1A CN202080020716A CN113711045A CN 113711045 A CN113711045 A CN 113711045A CN 202080020716 A CN202080020716 A CN 202080020716A CN 113711045 A CN113711045 A CN 113711045A
- Authority
- CN
- China
- Prior art keywords
- polyq
- protein
- fragment
- compound
- length
- 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.)
- Granted
Links
- 108010040003 polyglutamine Proteins 0.000 title claims abstract description 425
- 150000001875 compounds Chemical class 0.000 title claims abstract description 350
- 238000000034 method Methods 0.000 title claims abstract description 149
- 230000004770 neurodegeneration Effects 0.000 title claims abstract description 49
- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 49
- 238000012216 screening Methods 0.000 title claims abstract description 48
- 108090000623 proteins and genes Proteins 0.000 claims description 365
- 102000004169 proteins and genes Human genes 0.000 claims description 356
- 239000012634 fragment Substances 0.000 claims description 191
- 230000003321 amplification Effects 0.000 claims description 111
- 238000003199 nucleic acid amplification method Methods 0.000 claims description 111
- 230000000694 effects Effects 0.000 claims description 90
- 230000001594 aberrant effect Effects 0.000 claims description 85
- 208000023105 Huntington disease Diseases 0.000 claims description 60
- 102000007371 Ataxin-3 Human genes 0.000 claims description 34
- 108010032947 Ataxin-3 Proteins 0.000 claims description 34
- 238000001514 detection method Methods 0.000 claims description 33
- 238000010494 dissociation reaction Methods 0.000 claims description 28
- 230000005593 dissociations Effects 0.000 claims description 28
- 102000007372 Ataxin-1 Human genes 0.000 claims description 26
- 108010032963 Ataxin-1 Proteins 0.000 claims description 26
- 238000012360 testing method Methods 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 claims description 19
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 19
- 238000011534 incubation Methods 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 238000002474 experimental method Methods 0.000 claims description 17
- 208000002569 Machado-Joseph Disease Diseases 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- 238000004458 analytical method Methods 0.000 claims description 13
- 238000000111 isothermal titration calorimetry Methods 0.000 claims description 12
- 102000007368 Ataxin-7 Human genes 0.000 claims description 11
- 108010032953 Ataxin-7 Proteins 0.000 claims description 11
- 102000007370 Ataxin2 Human genes 0.000 claims description 10
- 108010032951 Ataxin2 Proteins 0.000 claims description 10
- 102100040296 TATA-box-binding protein Human genes 0.000 claims description 10
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 claims description 10
- 239000002808 molecular sieve Substances 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 9
- 101710145783 TATA-box-binding protein Proteins 0.000 claims description 8
- 238000000338 in vitro Methods 0.000 claims description 8
- 102100020741 Atrophin-1 Human genes 0.000 claims description 7
- 238000002965 ELISA Methods 0.000 claims description 7
- 101000785083 Homo sapiens Atrophin-1 Proteins 0.000 claims description 7
- 238000000749 co-immunoprecipitation Methods 0.000 claims description 7
- 238000002875 fluorescence polarization Methods 0.000 claims description 7
- 238000002866 fluorescence resonance energy transfer Methods 0.000 claims description 7
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 claims description 7
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 238000001042 affinity chromatography Methods 0.000 claims description 4
- 238000013537 high throughput screening Methods 0.000 claims description 4
- 238000002372 labelling Methods 0.000 claims description 4
- 238000011533 pre-incubation Methods 0.000 claims description 4
- 201000003570 spinocerebellar ataxia type 17 Diseases 0.000 claims description 4
- 238000001086 yeast two-hybrid system Methods 0.000 claims description 4
- 206010003694 Atrophy Diseases 0.000 claims description 3
- 230000037444 atrophy Effects 0.000 claims description 3
- 230000003100 immobilizing effect Effects 0.000 claims description 3
- 101000915806 Homo sapiens Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform Proteins 0.000 claims description 2
- 101000891654 Homo sapiens TATA-box-binding protein Proteins 0.000 claims description 2
- 102100029014 Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform Human genes 0.000 claims description 2
- 102100032187 Androgen receptor Human genes 0.000 claims 1
- 101000775732 Homo sapiens Androgen receptor Proteins 0.000 claims 1
- 235000018102 proteins Nutrition 0.000 description 307
- 239000005090 green fluorescent protein Substances 0.000 description 83
- 210000004027 cell Anatomy 0.000 description 72
- 229940125904 compound 1 Drugs 0.000 description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 26
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 26
- 201000010099 disease Diseases 0.000 description 25
- 241000699666 Mus <mouse, genus> Species 0.000 description 23
- 241000699670 Mus sp. Species 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- 210000002950 fibroblast Anatomy 0.000 description 22
- 239000000523 sample Substances 0.000 description 22
- 230000002159 abnormal effect Effects 0.000 description 19
- 229940126214 compound 3 Drugs 0.000 description 19
- 230000004900 autophagic degradation Effects 0.000 description 18
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 17
- 101150043003 Htt gene Proteins 0.000 description 15
- 229940125782 compound 2 Drugs 0.000 description 15
- 210000003618 cortical neuron Anatomy 0.000 description 15
- 239000007928 intraperitoneal injection Substances 0.000 description 14
- 238000003556 assay Methods 0.000 description 13
- 210000002569 neuron Anatomy 0.000 description 13
- 208000036834 Spinocerebellar ataxia type 3 Diseases 0.000 description 12
- 239000013612 plasmid Substances 0.000 description 12
- 230000014509 gene expression Effects 0.000 description 10
- 235000004554 glutamine Nutrition 0.000 description 10
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 10
- 230000001054 cortical effect Effects 0.000 description 9
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 9
- 210000000130 stem cell Anatomy 0.000 description 9
- 239000013598 vector Substances 0.000 description 9
- 238000001262 western blot Methods 0.000 description 9
- 102100020814 Sequestosome-1 Human genes 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000007792 addition Methods 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 230000004069 differentiation Effects 0.000 description 7
- 239000013604 expression vector Substances 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 6
- 201000004562 autosomal dominant cerebellar ataxia Diseases 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 230000008045 co-localization Effects 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- -1 ATXN12 Proteins 0.000 description 5
- 102000014461 Ataxins Human genes 0.000 description 5
- 108010078286 Ataxins Proteins 0.000 description 5
- 206010008025 Cerebellar ataxia Diseases 0.000 description 5
- 208000027747 Kennedy disease Diseases 0.000 description 5
- 108010029869 Proto-Oncogene Proteins c-raf Proteins 0.000 description 5
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 5
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 241000255588 Tephritidae Species 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 230000001537 neural effect Effects 0.000 description 5
- 230000009223 neuronal apoptosis Effects 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 4
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 4
- 241000238631 Hexapoda Species 0.000 description 4
- 101001030705 Homo sapiens Huntingtin Proteins 0.000 description 4
- 101001052506 Homo sapiens Microtubule-associated proteins 1A/1B light chain 3A Proteins 0.000 description 4
- 101000644537 Homo sapiens Sequestosome-1 Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 102100024178 Microtubule-associated proteins 1A/1B light chain 3A Human genes 0.000 description 4
- 108010076818 TEV protease Proteins 0.000 description 4
- 230000004075 alteration Effects 0.000 description 4
- 239000012822 autophagy inhibitor Substances 0.000 description 4
- 230000003542 behavioural effect Effects 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- 230000007717 exclusion Effects 0.000 description 4
- 108091006047 fluorescent proteins Proteins 0.000 description 4
- 102000034287 fluorescent proteins Human genes 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 238000010379 pull-down assay Methods 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 101150074725 Atxn3 gene Proteins 0.000 description 3
- 201000008163 Dentatorubral pallidoluysian atrophy Diseases 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 101000713575 Homo sapiens Tubulin beta-3 chain Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YZDJQTHVDDOVHR-UHFFFAOYSA-N PLX-4720 Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(Cl)=CN=C3NC=2)=C1F YZDJQTHVDDOVHR-UHFFFAOYSA-N 0.000 description 3
- 229920002873 Polyethylenimine Polymers 0.000 description 3
- 102100036790 Tubulin beta-3 chain Human genes 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 210000004957 autophagosome Anatomy 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000009193 crawling Effects 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000000185 intracerebroventricular administration Methods 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- WNEILUNVMHVMPH-UHFFFAOYSA-N n-cyclopropyl-4-[6-(2,3-difluoro-4-methoxyphenoxy)-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide Chemical compound FC1=C(F)C(OC)=CC=C1OC1=NN2C(C=3C=C(C)C(C(=O)NC4CC4)=CC=3)=CN=C2C(NCCC(F)(F)F)=C1 WNEILUNVMHVMPH-UHFFFAOYSA-N 0.000 description 3
- 210000000653 nervous system Anatomy 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 201000003624 spinocerebellar ataxia type 1 Diseases 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- 108010032769 Autophagy-Related Protein 8 Family Proteins 0.000 description 2
- 102000007353 Autophagy-Related Protein 8 Family Human genes 0.000 description 2
- 102000003952 Caspase 3 Human genes 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- 241000255925 Diptera Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 101000941893 Felis catus Leucine-rich repeat and calponin homology domain-containing protein 1 Proteins 0.000 description 2
- 102100035695 Gamma-aminobutyric acid receptor-associated protein Human genes 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- 101001001372 Homo sapiens Gamma-aminobutyric acid receptor-associated protein Proteins 0.000 description 2
- 101001052512 Homo sapiens Microtubule-associated proteins 1A/1B light chain 3B Proteins 0.000 description 2
- QJZRFPJCWMNVAV-HHHXNRCGSA-N N-(3-aminopropyl)-N-[(1R)-1-[7-chloro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]-2-methylpropyl]-4-methylbenzamide Chemical compound NCCCN([C@H](C(C)C)C=1N(C(=O)C2=CC=C(Cl)C=C2N=1)CC=1C=CC=CC=1)C(=O)C1=CC=C(C)C=C1 QJZRFPJCWMNVAV-HHHXNRCGSA-N 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 101710156592 Putative TATA-binding protein pB263R Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 201000003622 Spinocerebellar ataxia type 2 Diseases 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 101150063416 add gene Proteins 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000004642 autophagic pathway Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000006736 behavioral deficit Effects 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 239000013613 expression plasmid Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000002795 fluorescence method Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 102000054185 human HTT Human genes 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 238000012744 immunostaining Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 229950007344 ispinesib Drugs 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 230000009465 prokaryotic expression Effects 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 201000003594 spinocerebellar ataxia type 12 Diseases 0.000 description 2
- 201000003632 spinocerebellar ataxia type 7 Diseases 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- CZIHNRWJTSTCEX-UHFFFAOYSA-N 2 Acetylaminofluorene Chemical compound C1=CC=C2C3=CC=C(NC(=O)C)C=C3CC2=C1 CZIHNRWJTSTCEX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WHMXDBPHBVLYRC-OFVILXPXSA-N 3-chloro-n-[(2s)-1-[[2-(dimethylamino)acetyl]amino]-3-[4-[8-[(1s)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl]phenyl]propan-2-yl]-4-propan-2-yloxybenzamide Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C(=O)N[C@H](CNC(=O)CN(C)C)CC1=CC=C(C=2N=C3C([C@H](C)O)=CC=CN3C=2)C=C1 WHMXDBPHBVLYRC-OFVILXPXSA-N 0.000 description 1
- HUQKUJNSVHEHIH-UHFFFAOYSA-N 5,7-dihydroxy-4-phenylchromen-2-one Chemical compound C=1C(=O)OC2=CC(O)=CC(O)=C2C=1C1=CC=CC=C1 HUQKUJNSVHEHIH-UHFFFAOYSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 102100021321 Ataxin-3 Human genes 0.000 description 1
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 208000029402 Bulbospinal muscular atrophy Diseases 0.000 description 1
- 238000011537 Coomassie blue staining Methods 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108700000266 GSK923295 Proteins 0.000 description 1
- 102100033296 Gamma-aminobutyric acid receptor-associated protein-like 1 Human genes 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
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101100164984 Homo sapiens ATXN3 gene Proteins 0.000 description 1
- 101000926844 Homo sapiens Gamma-aminobutyric acid receptor-associated protein-like 1 Proteins 0.000 description 1
- 101001024605 Homo sapiens Next to BRCA1 gene 1 protein Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 108010063296 Kinesin Proteins 0.000 description 1
- 102000010638 Kinesin Human genes 0.000 description 1
- 108010020004 Microtubule-Associated Proteins Proteins 0.000 description 1
- 102000009664 Microtubule-Associated Proteins Human genes 0.000 description 1
- 102100024177 Microtubule-associated proteins 1A/1B light chain 3B Human genes 0.000 description 1
- 101001030698 Mus musculus Huntingtin Proteins 0.000 description 1
- 101800000135 N-terminal protein Proteins 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 102100037001 Next to BRCA1 gene 1 protein Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 101800001452 P1 proteinase Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000033063 Progressive myoclonic epilepsy Diseases 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 241000235070 Saccharomyces Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003627 allelochemical Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 238000003016 alphascreen Methods 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 230000005033 autophagosome formation Effects 0.000 description 1
- 238000003705 background correction Methods 0.000 description 1
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012496 blank sample Substances 0.000 description 1
- 229950004398 broxuridine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000005257 cortical tissue Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002309 glutamines Chemical class 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 238000002017 high-resolution X-ray diffraction Methods 0.000 description 1
- 108091008147 housekeeping proteins Proteins 0.000 description 1
- 102000048929 human MAP1LC3B Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000003007 myelin sheath Anatomy 0.000 description 1
- 210000004898 n-terminal fragment Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000006764 neuronal dysfunction Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000155 polyglutamine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000007319 proteasomal degradation pathway Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000012857 radioactive material Substances 0.000 description 1
- 238000003739 radiometry method Methods 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000015629 regulation of autophagy Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229950003647 semaxanib Drugs 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000013605 shuttle vector Substances 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 229960000487 sorafenib tosylate Drugs 0.000 description 1
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004960 subcellular localization Effects 0.000 description 1
- 108091005946 superfolder green fluorescent proteins Proteins 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 238000011870 unpaired t-test Methods 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/02—Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Biotechnology (AREA)
- Food Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Psychology (AREA)
- Peptides Or Proteins (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种筛选或鉴定用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法以及由该方法获得的化合物和用途。
Description
PCT国内申请，说明书已公开。
Claims (19)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910180717.1A CN111679082A (zh) | 2019-03-11 | 2019-03-11 | 一种筛选用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法 |
| CN2019101807171 | 2019-03-11 | ||
| CN2019110004158 | 2019-10-21 | ||
| CN201911000415.8A CN112763718A (zh) | 2019-10-21 | 2019-10-21 | 一种筛选用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法 |
| PCT/CN2020/078775 WO2020182143A1 (zh) | 2019-03-11 | 2020-03-11 | 一种筛选用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113711045A true CN113711045A (zh) | 2021-11-26 |
| CN113711045B CN113711045B (zh) | 2024-08-27 |
Family
ID=72427122
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202080020716.1A Active CN113711045B (zh) | 2019-03-11 | 2020-03-11 | 一种筛选用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20220170930A1 (zh) |
| EP (1) | EP3940384A4 (zh) |
| JP (1) | JP2022525325A (zh) |
| CN (1) | CN113711045B (zh) |
| WO (1) | WO2020182143A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022140246A1 (en) | 2020-12-21 | 2022-06-30 | Hangzhou Jijing Pharmaceutical Technology Limited | Methods and compounds for targeted autophagy |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004064733A2 (en) * | 2003-01-15 | 2004-08-05 | Board Of Regents, University Of Texas System | The use of c-raf inhibitors for the treatment of neurodegenerative diseases |
| WO2008021210A2 (en) * | 2006-08-11 | 2008-02-21 | Combinatorx, Incorporated | Methods and compositions for the treatment of neurodegenerative disorders |
| WO2010011964A2 (en) * | 2008-07-24 | 2010-01-28 | Siemens Medical Solutions Usa, Inc. | Imaging agents useful for identifying ad pathology |
| WO2014062621A1 (en) * | 2012-10-15 | 2014-04-24 | Stc.Unm | Treatment of autophagy-based disorders and related pharmaceutical compositions, diagnostic and screening assays and kits |
| WO2016114655A1 (en) * | 2015-01-12 | 2016-07-21 | Ry Pharma B.V. | Treating neuromuscular or neurologic disease through reducing gabaergic and/or glycinergic inhibitory neurotransmitter overstimulation |
| US20160296630A1 (en) * | 2012-11-30 | 2016-10-13 | Endocyte, Inc. | Methods for treating cancer using combination therapies |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101224207A (zh) * | 2007-10-12 | 2008-07-23 | 中国科学院上海有机化学研究所 | 具有诱导自吞噬治疗错误折叠蛋白聚集所致疾病的药物及其筛选方法 |
| US20100016221A1 (en) * | 2008-07-17 | 2010-01-21 | Riken | Method of degrading protein by chaperone-mediated autophagy |
| JP6550333B2 (ja) * | 2012-09-27 | 2019-07-24 | ザ ユニヴァーシティ オヴ ブリティッシュ コロンビア | ペプチドに誘導されたタンパク質ノックダウン |
-
2020
- 2020-03-11 WO PCT/CN2020/078775 patent/WO2020182143A1/zh unknown
- 2020-03-11 JP JP2021555238A patent/JP2022525325A/ja active Pending
- 2020-03-11 US US17/437,968 patent/US20220170930A1/en active Pending
- 2020-03-11 CN CN202080020716.1A patent/CN113711045B/zh active Active
- 2020-03-11 EP EP20769239.3A patent/EP3940384A4/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004064733A2 (en) * | 2003-01-15 | 2004-08-05 | Board Of Regents, University Of Texas System | The use of c-raf inhibitors for the treatment of neurodegenerative diseases |
| WO2008021210A2 (en) * | 2006-08-11 | 2008-02-21 | Combinatorx, Incorporated | Methods and compositions for the treatment of neurodegenerative disorders |
| WO2010011964A2 (en) * | 2008-07-24 | 2010-01-28 | Siemens Medical Solutions Usa, Inc. | Imaging agents useful for identifying ad pathology |
| WO2014062621A1 (en) * | 2012-10-15 | 2014-04-24 | Stc.Unm | Treatment of autophagy-based disorders and related pharmaceutical compositions, diagnostic and screening assays and kits |
| US20160296630A1 (en) * | 2012-11-30 | 2016-10-13 | Endocyte, Inc. | Methods for treating cancer using combination therapies |
| WO2016114655A1 (en) * | 2015-01-12 | 2016-07-21 | Ry Pharma B.V. | Treating neuromuscular or neurologic disease through reducing gabaergic and/or glycinergic inhibitory neurotransmitter overstimulation |
Non-Patent Citations (2)
| Title |
|---|
| NICOLE C MCKNIGHT: "Genome-wide siRNA screen reveals amino acid starvation-induced autophagy requires SCOC and WAC", EMBO J, vol. 31, no. 8, pages 1 - 8 * |
| 宋修云: "10种香豆素衍生物神经保护作用筛选及机制初探", 药学学报, vol. 50, no. 6, pages 699 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3940384A4 (en) | 2022-12-21 |
| JP2022525325A (ja) | 2022-05-12 |
| EP3940384A1 (en) | 2022-01-19 |
| WO2020182143A1 (zh) | 2020-09-17 |
| CN113711045B (zh) | 2024-08-27 |
| US20220170930A1 (en) | 2022-06-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Chou et al. | GSK3beta-mediated Drp1 phosphorylation induced elongated mitochondrial morphology against oxidative stress | |
| EP2039367B1 (en) | Prophylactic/therapeutic agent for neurodegenerative disease | |
| WO2008091799A2 (en) | Cell-based methods for identifying inhibitors of parkinson's disease-associated lrrk2 mutants | |
| Ding et al. | ADP/ATP translocase 1 protects against an α-synuclein-associated neuronal cell damage in Parkinson’s disease model | |
| JP2008513462A (ja) | ｐ５３−依存性および非依存性ガン抑制の調節因子としてのＡＲＦ−ＢＰ１、およびその使用 | |
| CN113711045B (zh) | 一种筛选用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法 | |
| AU2001290179B2 (en) | Mechanism of conditional regulation of the hypoxia-inducible factor-1 by the von hippel-lindau tumor suppressor protein | |
| Tomashevski et al. | Constitutive Wee1 activity in adult brain neurons with M phase-type alterations in Alzheimer neurodegeneration | |
| CN112763718A (zh) | 一种筛选用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法 | |
| US7491501B2 (en) | Methods for identifying modulators of intracellular aggregate formation | |
| AU2001290179A1 (en) | Mechanism of conditional regulation of the hypoxia-inducible factor-1 by the von hippel-lindau tumor suppressor protein | |
| Shinoda et al. | Interaction of 14‐3‐3 with Bid during seizure‐induced neuronal death | |
| CN111679082A (zh) | 一种筛选用于治疗或预防polyQ相关的神经退行性疾病的化合物的方法 | |
| King et al. | Mitophagy | |
| Leung et al. | Drosophila tweety facilitates autophagy to regulate mitochondrial homeostasis and bioenergetics in Glia | |
| WO2023284782A1 (zh) | 筛选用于治疗或预防mHTT相关的神经退行性疾病的化合物的方法，靶蛋白，以及化合物 | |
| US20050142630A1 (en) | Interaction of NMDA receptor with the protein tyrosine phosphatase step in psychotic disorders | |
| WO1999027088A2 (en) | Novel gene and protein expressed in neural and pancreatic tissues | |
| US20050221411A1 (en) | Interaction of NMDA receptor with the protein tyrosine phosphatase step in psychotic disorders | |
| Khan et al. | AAA+ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex | |
| Hu | TRIP-Br1 mediates degradation of multiple adenylyl cyclase isoforms by XIAP E3 ligase | |
| CN117186199A (zh) | β2-微球蛋白封闭肽、其药物组合物及用途 | |
| Zhang | The Role of Mitofusin (Mfn) in the Pathogenesis of Parkinson's Disease and Myopathy/frontotemporal Dementia | |
| McCray | Structural, biochemical, and cell biological characterization of RAB7 mutants that cause peripheral neuropathy | |
| US20040072275A1 (en) | Interaction of NMDA receptor with protein tyrosine phosphatase |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |