JP2021521820A - 核酸−ヌクレオチド−ポリメラーゼ複合体を安定化するための方法及び組成物 - Google Patents
核酸−ヌクレオチド−ポリメラーゼ複合体を安定化するための方法及び組成物 Download PDFInfo
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Abstract
【選択図】なし
Description
本願は、2018年4月26日に出願された米国仮出願第62/662,888号に基づき、かつその権利を主張し、参照によりその全体が本明細書に組み込まれる。
ポリメラーゼ及びヌクレオチドを可溶化する水性安定化流体での三元複合体の安定化
本実施例は、4つの異なる標識ヌクレオチドのそれぞれの結合を個々に評価する方法で、ブロックされたプライムされたテンプレート核酸の検査を実証する。三元複合体を安定化することができた薬剤を含有する水溶液を使用して、(1)ポリメラーゼ、標識ヌクレオチド及びマグネシウムカチオンを含有する検査溶液を送達し、(2)非結合ポリメラーゼ及び標識ヌクレオチドとの接触から固定化三元複合体を分離し、かつ(3)画像化洗浄ステップ中に長期間にわたって三元複合体の検出を容易にした。手順で使用される異なるヌクレオチドを、同じタイプの蛍光検出可能な標識で標識し、各タイプのヌクレオチドを別々に送達及び検査した。代替的に、ヌクレオチドは、それぞれ異なる検出可能な標識を有することができ、いくつかの異なる標識ヌクレオチドタイプは、同時にブロックされたプライムされたテンプレート核酸と接触することができた。
経時的な三元複合体の安定化
本実施例では、リチウム及び/またはベタインを含有する画像化緩衝液で最大5分間洗浄することによる三元複合体の検出の改善を実証した時間滴定について説明する。
リチウム、カルシウムまたはベタインを含有する水性安定化流体での、三元複合体の安定化
本実施例は、SBB(商標)検査ステップ中の三元複合体の安定性に対するリチウム、カルシウム及びベタインの様々な組み合わせの効果を実証する。
ポリエチレンイミンでの三元複合体の安定化
SBB(商標)反応を、実施例Iに記載される12個のPCR反応からのブロックされた3’−ONH2のプライムされたテンプレートDNA上で、かつ以下の修正を伴い行った。IMG溶液は、20mMのトリシン緩衝液(pH 8.42)、50mMのKCl、0.1%Tween−80、10mMの(NH4)2SO4及び3%スクロース、ならびに以下に記載される可変の添加試薬を含んだ。検査溶液は、IMG溶液と同じ固定及び可変の試薬を含み、20U/mLのTherminator(商標)DNAポリメラーゼ(New England Biolabs,Ipswich,MA)、1mMのMgCl2、ならびにCy5−dNTP(Cy5−dATP、Cy5−dGTP及びCy5−dCTPのそれぞれについて400nM、Cy5−dTTPについて800nM)をさらに含んだ。
Claims (50)
- プライムされたテンプレート核酸を検出する方法であって、
(a)三元複合体を含む混合物を提供するステップであって、前記三元複合体が、プライムされたテンプレート核酸、ポリメラーゼ、及び前記プライムされたテンプレート核酸の次の塩基のヌクレオチド同族体を含み、
前記混合物が、前記三元複合体に存在する同じタイプの過剰なヌクレオチドをさらに含む、前記提供するステップと、
(b)前記過剰なヌクレオチドを、Li+を含む流体で置き換えるステップと、
(c)前記三元複合体がLi+を含む前記流体と接触している間に、前記三元複合体を検出するステップと、を含む、方法。 - (d)ステップ(c)の結果から、前記プライムされたテンプレート核酸分子の次の正しい塩基を同定するステップ、をさらに含む、請求項1に記載の方法。
- (e)前記プライムされたテンプレート核酸のプライマーを伸長するステップ、をさらに含む、請求項2に記載の方法。
- 前記プライマーが、可逆的ターミネーター部分を含むヌクレオチドの付加によって伸長される、請求項3に記載の方法。
- 前記プライムされたテンプレートのプライマーが、可逆的ターミネーター部分を含む、請求項1に記載の方法。
- (e)前記プライマーを脱ブロックするために前記可逆的ターミネーター部分を修飾または除去するステップ、をさらに含む、請求項5に記載の方法。
- (f)前記脱ブロックされたプライマーを伸長するステップをさらに含む、請求項6に記載の方法。
- 前記脱ブロックされたプライマーが、可逆的ターミネーター部分を含むヌクレオチドの付加によって伸長される、請求項7に記載の方法。
- 前記三元複合体が、固体支持体上に固定される、請求項1〜8のいずれか1項に記載の方法。
- 前記ヌクレオチド同族体が、ステップ(c)で検出される外因性標識を含む、請求項1〜9のいずれか1項に記載の方法。
- 前記混合物が、前記テンプレート核酸に存在すると疑われる少なくとも2つの異なる塩基タイプのヌクレオチド同族体を含む、請求項10に記載の方法。
- 前記異なる塩基タイプの前記ヌクレオチド同族体が、それぞれ、異なる外因性標識を含む、請求項11に記載の方法。
- 前記ポリメラーゼが、ステップ(c)で検出される外因性標識を含む、請求項1〜12のいずれか1項に記載の方法。
- 前記混合物が、前記三元複合体に存在する同じタイプの過剰なポリメラーゼをさらに含む、請求項1〜13のいずれか1項に記載の方法。
- ステップ(c)が、前記過剰なポリメラーゼ及び前記過剰なヌクレオチドを、Li+を含む前記流体で置き換えることを含む、請求項14に記載の方法。
- 前記過剰なヌクレオチドが、前記流体に可溶性である、請求項1〜15のいずれか1項に記載の方法。
- ステップ(b)が、Li+を含み、かつ前記三元複合体に存在する前記タイプのヌクレオチドを欠く流体を、前記三元複合体に送達し、それにより前記過剰なヌクレオチドを前記流体で置き換えることを含む、請求項1〜16のいずれか1項に記載の方法。
- 前記Li+が、ステップ(c)中に1mM〜100mMの濃度で存在する、請求項1〜17のいずれか1項に記載の方法。
- 前記流体が、ベタインをさらに含む、請求項1〜18のいずれか1項に記載の方法。
- 前記流体が、ポリエチレンイミンをさらに含む、請求項1〜19のいずれか1項に記載の方法。
- 流体を含む組成物であって、前記流体が、三元複合体及びLi+を含み、前記三元複合体が、プライムされたテンプレート核酸、ポリメラーゼ、及び前記プライムされたテンプレート核酸分子の次の正しい塩基のヌクレオチド同族体を含む、組成物。
- 前記Li+が、1mM〜100mMの濃度で存在する、請求項21に記載の組成物。
- 前記流体が、ベタインをさらに含む、請求項21に記載の組成物。
- 前記流体が、ポリエチレンイミンをさらに含む、請求項21に記載の組成物。
- 前記三元複合体が、固体支持体上に固定化される、請求項21に記載の組成物。
- 前記固体支持体が、フィーチャーのアレイを含み、各フィーチャーが、前記フィーチャーにおいて、プライムされたテンプレート核酸分子、ポリメラーゼ、及び前記プライムされたテンプレート核酸分子の次の正しい塩基のヌクレオチド同族体を含む固定化三元複合体を含む、請求項25に記載の組成物。
- 前記ヌクレオチドが、外因性標識を含む、請求項21〜26のいずれか1項に記載の組成物。
- 前記流体が、前記テンプレート核酸に存在すると疑われる少なくとも4つの異なる塩基タイプのヌクレオチド同族体を含む、請求項21に記載の組成物。
- 前記異なる塩基タイプの前記ヌクレオチド同族体が、それぞれ、異なる外因性標識を含む、請求項28に記載の組成物。
- 前記ポリメラーゼが、外因性標識を含む、請求項21〜29のいずれか1項に記載の組成物。
- 前記プライムされたテンプレート核酸分子が、可逆的に終端したプライマーを含む、請求項21〜30のいずれか1項に記載の組成物。
- 前記流体が、水性である、請求項21〜31のいずれか1項に記載の組成物。
- 前記流体が、遊離ヌクレオチドを前記流体中の三元複合体の濃度よりも低い濃度でさらに含み、前記遊離ヌクレオチドが、前記三元複合体中に存在する同じタイプである、請求項21〜32のいずれか1項に記載の組成物。
- 前記流体が、遊離ポリメラーゼを前記流体中の三元複合体の濃度よりも低い濃度でさらに含み、前記遊離ポリメラーゼが、前記三元複合体中に存在する同じタイプである、請求項21〜33のいずれか1項に記載の組成物。
- プライムされたテンプレート核酸を検出する方法であって、
(a)三元複合体及びLi+を含む流体を提供するステップであって、前記三元複合体が、プライムされたテンプレート核酸、ポリメラーゼ、及び前記プライムされたテンプレート核酸分子の次の正しい塩基のヌクレオチド同族体を含む、前記提供するステップと、
(b)前記三元複合体がLi+を含む前記流体中にある間に、前記三元複合体を検出するステップと、を含む、方法。 - (c)ステップ(b)の結果から、前記プライムされたテンプレート核酸分子の前記次の正しい塩基を同定するステップ、をさらに含む、請求項35に記載の方法。
- (d)前記プライムされたテンプレート核酸のプライマーを伸長するステップ、をさらに含む、請求項36に記載の方法。
- 前記プライマーが、可逆的ターミネーター部分を含むヌクレオチドの付加によって伸長される、請求項37に記載の方法。
- 前記プライムされたテンプレートのプライマーが、可逆的ターミネーター部分を含む、請求項35に記載の方法。
- (d)前記プライマーを脱ブロックするために前記可逆的ターミネーター部分を修飾または除去するステップ、をさらに含む、請求項39に記載の方法。
- (e)可逆的ターミネーター部分を含むヌクレオチドの付加によって、前記脱ブロックされたプライマーを伸長するステップ、をさらに含む、請求項40に記載の方法。
- 前記三元複合体が、固体支持体上に固定される、請求項35〜41のいずれか1項に記載の方法。
- 前記ヌクレオチド同族体が、ステップ(b)で検出される外因性標識を含む、請求項35〜42のいずれか1項に記載の方法。
- 前記流体が、前記テンプレート核酸に存在すると疑われる少なくとも2つの異なる塩基タイプのヌクレオチド同族体を含む、請求項43に記載の方法。
- 前記異なる塩基タイプの前記ヌクレオチド同族体が、それぞれ、異なる外因性標識を含む、請求項44に記載の方法。
- 前記ポリメラーゼが、ステップ(c)で検出される外因性標識を含む、請求項35〜45のいずれか1項に記載の方法。
- 前記流体が、遊離ヌクレオチドを前記流体中の三元複合体の濃度よりも低い濃度でさらに含み、前記遊離ヌクレオチドが、前記三元複合体中に存在する同じタイプである、請求項35〜46のいずれか1項に記載の方法。
- 前記流体が、遊離ポリメラーゼを前記流体中の三元複合体の濃度よりも低い濃度でさらに含み、前記遊離ポリメラーゼが、前記三元複合体中に存在する同じタイプである、請求項35〜47のいずれか1項に記載の方法。
- 前記流体が、ベタインをさらに含む、請求項35〜48のいずれか1項に記載の方法。
- 前記流体が、ポリエチレンイミンをさらに含む、請求項35〜49のいずれか1項に記載の方法。
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US20220290216A1 (en) | 2022-09-15 |
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