DK2004847T3 - Oligonukleotider omfattende signaleringspar og hydrofobe nukleotider, "stemless beacons", til detektion af nukleinsyrer, methyleringsstatus og mutanter af nukleinsyrer - Google Patents
Oligonukleotider omfattende signaleringspar og hydrofobe nukleotider, "stemless beacons", til detektion af nukleinsyrer, methyleringsstatus og mutanter af nukleinsyrer Download PDFInfo
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- DK2004847T3 DK2004847T3 DK07711277.9T DK07711277T DK2004847T3 DK 2004847 T3 DK2004847 T3 DK 2004847T3 DK 07711277 T DK07711277 T DK 07711277T DK 2004847 T3 DK2004847 T3 DK 2004847T3
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
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Claims (17)
1. Oligonukleotidanalog, som omfatter en konsekutiv sekvens af n nukleotider og/eller nukleotidanaloger og mindst to hydrofobe nukleotider, hvor oligonukleotidanalogen er kovalent bundet til et signaleringspar, hvor det hydrofobe nukleotid har den generelle struktur
hvor X er et nukleotid eller en nukleotidanalog eller en backbone-monomerenhed, som er i stand til at blive inkorporeret i backbone afen nukleinsyre eller nukleinsyreanalog, Q er et hydrofobt molekyle, som ikke tager del i Watson-Crick-hydrogenbinding, hvor det hydrofobe molekyle er valgt fra gruppen bestående af polyaromater og heteropoly-aromater, der eventuelt er substitueret med én eller flere valgt fra gruppen bestående af hydroxyl, brom, fluor, chlor, iod, mercapto, thio, cyano, alkylthio, heterocyklus, aryl, heteroaryl, carboxyl, carboalkoyl, alkyl, alkenyl, alkynyl, nitro, amino, alkoxyl og amido; og Y er en linkerenhed, som forbinder nukleotidet eller nukleotidanalogen eller backbone-monomerenheden og det hydrofobe molekyle; og hvor n er et helt tal på mindst 4; og hvor de mindst to hydrofobe nukleotider er anbragt højst 9 nukleotider og/eller nukleotidanaloger fra den ene ende; og hvor de mindst to hydrofobe nukleotider er anbragt i den samme afstand +/-1 nukleotid eller nukleotidanalog fra de respektive dele af signaleringsparret, og hvor signaleringsparret består af et todelt system, hvor den ene del er anbragt højst 6 nukleotider og/eller nukleotidanaloger fra 5’-enden, og den anden del er anbragt højst 6 nukleotider eller nukleotidanaloger fra 3’-enden; hvor delene af signaleringsparret ikke er identiske med det hydrofobe nukleotid, med det forbehold, at når den ene del af signaleringsparret er anbragt som en løsthængende ende ved 5’-enden, da er det første nukleotid eller nukleotidanalog ved 5’-enden ikke et hydrofobt nukleotid, og når den ene del af signaleringsparret er anbragt som en løsthængende ende ved 3’-enden, da er det første nukleotid eller nukleotidanalog ved 3’-enden ikke et hydrofobt nukleotid.
2. Oligonukleotidanalog ifølge krav 1, hvor signaleringsparret er i stand til at blive ændret i et detekterbart signal afhængigt af den fysiske afstand mellem delene af parret.
3. Oligonukleotidanalog ifølge et hvilket som helst af kravene 1 til 2, hvor den ene del af signaleringsparret er en fluorofor, og den anden del af signaleringsparret er en quencher, hvor fluoroforen og quencheren er i stand til at danne et intramolekylært FRET-kompleks.
4. Oligonukleotidanalog ifølge et hvilket som helst af kravene 1 til 3, hvor mindst to af de hydrofobe nukleotider er anbragt i modsatte halvdele af oligonukleotidanalogen.
5. Oligonukleotidanalog ifølge et hvilket som helst af kravene 1 til 4, hvor de hydrofobe molekyler af de hydrofobe nukleotider er i stand til at danne hydrofobe interaktioner med hinanden, hvorved de to dele af signaleringsparret bringes tæt på hinanden såsom inden for 40 Å.
6. Oligonukleotidanaloger ifølge et hvilket som helst af kravene 1 til 5, hvor intet hydrofobt nukleotid er anbragt tættere på 5’-enden end en del af signaleringsparret, og intet hydrofobt nukleotid er anbragt tættere på 3’-enden end den anden del af signaleringsparret.
7. Oligonukleotidanalog ifølge et hvilket som helst af de foregående krav, hvor oligonu-kleotidet er immobiliseret på et fast underlag.
8. Fremgangsmåde til bestemmelse af hybridisering, omfattende følgende trin a) tilvejebringelse af en oligonukleotidanalog, som omfatter en konsekutiv sekvens af n nukleotider og/eller nukleotidanaloger og mindst to hydrofobe nukleotider, hvor oligonukleotidanalogen er kovalent bundet til et signaleringspar bestående af et todelt system, hvor det hydrofobe nukleotid har den generelle struktur
hvor X er et nukleotid eller en nukleotidanalog eller en backbone-monomerenhed, som er i stand til at blive inkorporeret i backbone af en nukleinsyre eller nukle-insyreanalog, Q er et hydrofobt molekyle, som ikke tager del i specifik Watson-Crick-hydrogenbinding, hvor det hydrofobe molekyle er valgt fra gruppen bestående af po-lyaromater og heteropolyaromater, der eventuelt er substitueret med én eller flere valgt fra gruppen bestående af hydroxyl, brom, fluor, chlor, iod, mercapto, thio, cyano, alkylthio, heterocyklus, aryl, heteroaryl, carboxyl, carboalkoyl, alkyl, alkenyl, alkynyl, nitro, amino, alkoxyl og amido; og Y er en linkerenhed, som forbinder nukleotidet eller nukleotidanalogen eller backbone-monomerenheden og det hydrofobe molekyle; og hvor n er et helt tal på mindst 4; og hvor de mindst to hydrofobe nukleotider er anbragt højst 9 nukleotider og/eller nukleotidanaloger fra den ene ende; og hvor de mindst to hydrofobe nukleotider er anbragt i den samme afstand +/-1 nukleotid eller nukleotidanalog fra de respektive dele af signaleringsparret, og hvor signaleringsparret består af et todelt system, hvor den ene del er anbragt højst 6 nukleotider og/eller nukleotidanalogerfra 5’-enden, og den anden del er anbragt højst 6 nukleotider eller nukleotidanaloger fra 3’-enden; hvor delene af signaleringsparret ikke er identiske med det hydrofobe nukleotid, med det forbehold, at når den ene del af signaleringsparret er anbragt som en løsthængende ende ved 5’-enden, da er det første nukleotid eller nukleotidana-log ved 5’-enden ikke et hydrofobt nukleotid, og når den ene del af signaleringsparret er anbragt som en løsthængende ende ved 3’-enden, da er det første nukleotid eller nukleotidanalog ved 3’-enden ikke et hydrofobt nukleotid; hvor de to dele af signaleringsparret er tættere på hinanden, når oligonukleotid-analogen ikke er hybridiseret til en targetsekvens, end når oligonukleotidanalo-gen er hybridiseret til en targetsekvens; og b) tilvejebringelse af en blanding af nukleinsyrer, som potentielt omfatter en targetsekvens for oligonukleotidanalogen; og c) inkubation af nukleinsyrerne og oligonukleotidanalogen under betingelser, som tillader hybridisering; og d) detektion af hybridisering ved bestemmelse af, om delene af signaleringsparret er tæt på hinanden; e) hvorved hybridisering bestemmes.
9. Fremgangsmåde ifølge krav 8, hvor oligonukleotidanalogen er en oligonukleotidana-log ifølge et hvilket som helst af kravene 1 til 7.
10. Fremgangsmåde til detektion og/eller kvantificering af hybridisering mellem en oli-gonukleotidanalog ifølge et hvilket som helst af kravene 1 til 7 og en targetsekvens under amplifikation, hvilken fremgangsmåde omfatter følgende trin: a) tilvejebringelse af en blanding af nukleinsyrer, som potentielt omfatter en tar-getsekvens; og b) tilvejebringelse af en amplifikationsbuffer omfattende et amplifikationsenzym, et sæt primere og en oligonukleotidanalog ifølge et hvilket som helst af kravene 1 til 7, hvor primerne og oligonukleotidanalogen er i stand til at hybridisere med targetsekvensen eller en sekvens, som er komplementær dertil, idet amplifikationsenzymet er i stand til at forlænge en primer på en templatedirigeret måde, og amplifikationsbufferen giver amplifikationsenzymet betingelser til at udføre en sådan forlængelse i nærværelse af primere og template; og c) inkubation af primerne og oligonukleotidanalogen med blandingen af nukleinsyrer under betingelser, der tillader hybridisering af primerne; og d) forlængelse af 3’-enden af de hybridiserede primere under anvendelse af targetsekvensen som template under anvendelse af amplifikationsenzymet; og e) inkubation af nukleinsyrerne, forlængelsesprodukterne og oligonukleotidanalogen under betingelser, der tillader hybridisering; og f) detektion af hybridisering og eventuelt kvantificering af hybridisering; og g) eventuelt gentagelse af trin c) til f).
11. Fremgangsmåde ifølge et hvilket som helst af kravene 8 til 10, hvor detektionen af hybridisering omfatter bestemmelse af smeltetemperatur og/eller affinitetstemperatur.
12. Fremgangsmåde ifølge et hvilket som helst af kravene 10 til 11, hvor nukleaseakti-vitet fjerner den mest 5’ del af signaleringsparret.
13. Fremgangsmåde ifølge et hvilket som helst af kravene 8 til 12, hvor targetsekvensen forventes at omfatte mindst ét polymorft sted, og hvor mindst to oligonukleotidana-loger ifølge et hvilket som helst af kravene 1 til 7 tilvejebringes, hvor én af disse oligo-nukleotidanaloger er komplementærtil én genotype af targetsekvensen, og den anden af oligonukleotidanalogerne er komplementærtil en anden genotype af targetsekvensen.
14. Fremgangsmåde ifølge krav 13, hvor én oligonukleotidanalog omfatter en ”C”-nukleobase ved det polymorfe sted, og den anden oligonukleotidanalog omfatter en ”A”-nukleobase ved det polymorfe sted.
15. Fremgangsmåde til bestemmelse af affinitetstemperaturen afen oligonukleotidana-log til en targetsekvens, hvilken fremgangsmåde omfatter udførelse af fremgangsmåden ifølge et hvilket som helst af kravene 8 til 14, hvor følgende trin udføres efter det sidste trin a) denaturering af blandingen og afkøling med en hurtig hastighed til en første forudbestemt temperatur over affinitetstemperaturen; og b) detektion af hybridisering ved bestemmelse af et detekterbart signal fra signaleringsparret, hvor signaleringsparret er i stand til at blive ændret i det detekterba-re signal afhængigt af den fysiske afstand mellem delene af parret; og c) denaturering af blandingen og afkøling med en hurtig hastighed til en anden forudbestemt temperatur, hvor den anden forudbestemte temperatur er lavere end den første forudbestemte temperatur, d) detektion af hybridisering ved bestemmelse af det detekterbare signal, e) gentagelse af trin 3) og 4), hvor den forudbestemte temperatur gradvist sænkes til under affinitetstemperaturen, f) og bestemmelse af affinitetstemperaturen af nukleinsyreanalogen til targetse-kvensen.
16. Fremgangsmåde ifølge et hvilket som helst af kravene 8 til 15, hvor targetsekven-sen forventes at omfatte mindst ét polymorft sted, og hvoroligonukleotidanalogen er komplementær til targetsekvensen, og det mindste ene polymorfe sted er anbragt inde i den centrale del af oligonukleotidanalogen.
17. Fremgangsmåde ifølge et hvilket som helst af kravene 15 til 16, hvor der anvendes to eller flere oligonukleotidanaloger ifølge et hvilket som helst af kravene 1 til 7 i det samme lukkede reagensglas.
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| DKPA200600379 | 2006-03-16 | ||
| PCT/DK2007/000134 WO2007104318A2 (en) | 2006-03-16 | 2007-03-16 | Oligonucleotides comprising signalling pairs and hydrophobic nucleotides, stemless beacons, for detection of nucleic acids, methylation status and mutants of nucleic acids |
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| BRPI0820738A2 (pt) | 2007-12-14 | 2015-06-16 | Minitube America Inc | Separação específica do gênero de células de esperma e embriões |
| US20110053226A1 (en) * | 2008-06-13 | 2011-03-03 | Riboxx Gmbh | Method for enzymatic synthesis of chemically modified rna |
| DE102010012421B4 (de) | 2009-03-23 | 2023-04-20 | Vermicon Ag | Verfahren zum spezifischen Nachweis von Mikroorganismen |
| WO2011032034A2 (en) | 2009-09-10 | 2011-03-17 | University Of Idaho | Nucleobase-functionalized conformationally restricted nucleotides and oligonucleotides for targeting nucleic acids |
| JP5717169B2 (ja) * | 2010-09-14 | 2015-05-13 | 国立大学法人名古屋大学 | オリゴヌクレオチド及びその利用 |
| CN103958519A (zh) | 2011-07-19 | 2014-07-30 | 爱达荷州大学 | 用于靶向核酸的探针和方法的实施方式 |
| EP2820157B1 (en) | 2012-03-02 | 2019-05-01 | Winthrop-University Hospital | Method for using probe based pcr detection to measure the levels of circulating demethylated beta cell derived dna as a measure of beta cell loss in diabetes |
| CN102911111B (zh) * | 2012-11-08 | 2014-06-11 | 齐鲁工业大学 | 一种咔唑苯甲醛缩对苯二胺双席夫碱及其制备方法 |
| EP3350347B1 (en) | 2015-09-14 | 2021-01-20 | Pentabase APS | Methods and materials for detection of mutations |
| CN108827935B (zh) * | 2018-06-08 | 2021-09-07 | 南京师范大学 | 一种基于金纳米孔阵列的dna甲基化表面增强拉曼散射光谱检测方法及其应用 |
| SG11202110814QA (en) * | 2019-05-13 | 2021-11-29 | Pentabase Aps | Melting temperature methods, kits and reporter oligo for detecting variant nucleic acids |
| CN110261964B (zh) * | 2019-07-01 | 2021-06-04 | 国检中心深圳珠宝检验实验室有限公司 | 一种用于光纤光谱仪的光纤头 |
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| US5466578A (en) | 1992-04-09 | 1995-11-14 | The United States Of America As Represented By The Secretary Of The Navy | Surfactant-enhanced light emission- or absorbance-based binding assays for polynucleic acids |
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| EP0892808B1 (en) | 1996-04-12 | 2008-05-14 | PHRI Properties, Inc. | Detection probes, kits and assays |
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| US20100068704A1 (en) | 2010-03-18 |
| CA2645136C (en) | 2017-09-19 |
| EP2004847A2 (en) | 2008-12-24 |
| WO2007104318A2 (en) | 2007-09-20 |
| US8133984B2 (en) | 2012-03-13 |
| WO2007104318A3 (en) | 2008-03-20 |
| EP2004847B1 (en) | 2017-05-03 |
| CN101448957A (zh) | 2009-06-03 |
| JP5284112B2 (ja) | 2013-09-11 |
| JP2009529337A (ja) | 2009-08-20 |
| AU2007224843A1 (en) | 2007-09-20 |
| CA2645136A1 (en) | 2007-09-20 |
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