JP6678103B2 - 生体触媒組成物 - Google Patents
生体触媒組成物 Download PDFInfo
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- JP6678103B2 JP6678103B2 JP2016530514A JP2016530514A JP6678103B2 JP 6678103 B2 JP6678103 B2 JP 6678103B2 JP 2016530514 A JP2016530514 A JP 2016530514A JP 2016530514 A JP2016530514 A JP 2016530514A JP 6678103 B2 JP6678103 B2 JP 6678103B2
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- protein
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Description
a)最適に及ばないpH、及び/又は
b)化学的ストレス、及び/又は
c)生物学的ストレス、及び/又は
d)溶媒、及び/又は
e)物理的ストレス。
a)遊離の保護されていない酵素と比較したときストレス条件下で活性の増加、及び/又は
b)遊離の保護されていない酵素と比較したとき連続操作で使用するための回収可能性の増加
を有する。
a)前記対象から試料を得る工程と、
b)陰性コントロール基準として健常対象から試料を得る工程と、
c)陽性コントロール基準としてこの疾患に罹患している対象から試料を得る工程と、
d)工程a)−c)で得られた試料のそれぞれに存在する特定の分子の量を測定する工程と、
e)工程d)で得られた試料のそれぞれに存在する前記分子の量を比較する工程と
を含み得る。
シリカナノ粒子(SNP)などの固体担体物質へのラクターゼ/β−ガラクトシダーゼ(EC3.2.1.23)の固定化及び保護には、以下の通りである4つの主要な工程を必要とする。
i. 酵素とのさらなる化学結合のためのアンカーポイント(すなわち、アミン)を導入するためのSNPの表面修飾
ii. 導入されたアミン部分と二官能性架橋剤(例えば、グルタルアルデヒド)との化学反応
iii. 二官能性架橋剤の自由活性官能基を介するSNPの表面における酵素の結合
iv. 保護層を得るための固定化酵素及びSNPの自由表面の両方の周囲のシラン構築ブロックの重縮合
ii)保護されるべき酵素のさらなる固定を可能にするアミン官能基をSNPの表面に導入するために、それらをアミノシランと反応させた。保護層のさらなる結合のためのシラノール基を残すように、この修飾は部分的にのみであるべきであることに注意することが重要である。
より詳細には、水中に懸濁したSNP(18mL;3.2mg/ml)をAPTES(3−アミノプロピルトリエトキシシラン、11mg)とともに20℃で90分間インキュベートした。水での2回の洗浄工程の後、得られたアミノ修飾SNPを1g/Lの最終濃度の二官能性架橋剤(酵素のさらなる固定化を可能にするための)グルタルアルデヒドと30分間反応させた。
iii)水での2回の洗浄工程の後、得られたSNPをMES(2−(N−モルホリノ)エタンスルホン酸)緩衝液(pH6.2、1mM、5mM MgCl2)に再懸濁し、400rpmでの磁気撹拌下でラクターゼ酵素(100μg/ml)とともに20℃で1時間インキュベートした。
iv)SNP上に固定化された酵素の保護は、製造された酵素固定化SNPを酵素の周囲に自己集合したシラン構築ブロックの混合物とともにインキュベートし、酵素の周囲の保護層を形成した重縮合反応を行わせることによって行った。対象のタンパク質又はタンパク質型化合物及び表面上のそのアミノ酸残基に無関係に適切な構築ブロックを選択しなければならない。自己集合構築ブロックの好ましい選択の例を表1に示す。表に想定される保護層構築ブロックのリスト及び保護タンパク質のタンパク質表面のアミノ酸残基と自己集合構築ブロックとの間の相互作用の主な力を示す。SNPの表面におけるこの層の結合を可能にするSNPの裸の表面における重縮合反応も起こった。そのために、酵素固定化SNP(18mL;3.2mg/mL)を最初に400rpmでの撹拌下で36μlのTEOSと20℃で反応させた。2時間の反応の後に、18μlのAPTESを加え、4℃で保護層を徐々に成長させた。SNPの試料を2時間ごとに採取し、20時間後にMES緩衝液での2回の洗浄工程により反応を停止させた。種々の時点における保護シラン層の厚さを上述のように測定し、図2B及び図3に報告する。これらの結果から、有機シラン層は、それぞれ4、6及び20時間の反応の後に厚さが2、10及び25nmであることがわかった。これらの結果から、酵素固定化SNPの表面における有機シリカ層の成長を制御することが可能であることが確認された。
本明細書で述べた方法により保護された酵素の耐熱性を、実施例1で述べたように製造した20nmの保護層を有するラクターゼ修飾粒子を用いて試験した。触媒活性は、実施例1においても述べたONPG比色法を用いて測定した。
本明細書で述べた方法により保護した酵素の抵抗性及びそれらのpH活性範囲の拡大を、実施例1で述べたように製造した20nmの保護層を有するラクターゼ修飾粒子を用いて試験した。触媒活性は、実施例1においても述べたONPG比色法を用いて測定した。
本明細書で述べた方法により保護した酵素のプロテアーゼに対する抵抗性を、実施例1で述べたように製造した20nmの保護層を有するラクターゼ修飾粒子を用いて試験した。遊離及び保護酵素を0.1M Tris−HCl(pH7.4)中でプロテイナーゼK及びトリプシン(1mg/mL)とともに37℃で60分間インキュベートした。遊離酵素の活性はゼロに低下したが、保護酵素の活性は変化しないままであった。
SNPへの酸性ホスファターゼ(EC3.1.3.2)の固定化及び有機シランの層を成長させることによる保護を実施例1で述べたように実施した。保護層の厚さを増加させながら、保護触媒を製造し、人工基質としてのリン酸パラニトロフェニル(pNPP)を用いてアッセイした。405nmでの生成物p−ニトロフェニル(pNP)の出現を分光光度法で追跡したところ、アルカリ条件で示された。
SNPへのラクターゼ/β−ガラクトシダーゼ(EC3.2.1.23)の固定化は、実施例1で述べたように実施した。SNPに固定化された酵素の保護は、製造した酵素固定化SNPを酵素の周囲に自己集合したシラン構築ブロックの混合物とともにインキュベートし、酵素の周囲に保護層を形成した重縮合反応にかけることによって行った。用いたシランは、APTES、TEOS、ベンジルトリエトキシシラン(BTES)、プロピルトリエトキシシラン(PTES)及びヒドロキシメチルトリエトキシシラン(HMTES)である。より詳細には、酵素固定化SNP(18mL;3.2mg/ml)を最初に400rpmでの撹拌下で36μlのTEOSと20℃で反応させた。1時間の反応後に、18μlのAPTES、18μlのBTES、18μlのPTES及び36μlのHMTESを加え、保護層を20℃で成長させた。SNPの試料を漸増反応時間で採取し、20時間後にMES緩衝液での2回の洗浄工程により反応を停止させた。種々の時点における、保護シラン層の厚さを前述のように測定した。図10に示すように、有機シラン層は、4、6、10、17及び20時間の反応後にそれぞれ2、8、12及び16nmの厚さであった。
a)少なくとも1つのタンパク質又はタンパク質型化合物の最適pHと異なり、該pH値が最適pHと+/−5、+/−4、+/−3、+/−2、+/−1、+/−0.5pH単位異なる、pH、及び/又は
b)化学的ストレス、及び/又は
c)生物学的ストレス、及び/又は
d)溶媒、及び/又は
e)物理的ストレス、及び/又は
f)保護されていないタンパク質又はタンパク質型化合物の最適温度を60℃、特に50℃、特に40℃より高い、特に30℃、特に20℃、特に10℃、特に5℃超える、高温、及び/又は
g)保護されていないタンパク質又はタンパク質型化合物の最適温度から60℃、特に50℃、特に40℃より高い、特に30℃、特に20℃、特に10℃、特に5℃逸脱する、低温。
a)遊離の保護されていない酵素と比較したときストレス条件下で活性の増加、及び/又は
b)遊離の保護されていない酵素と比較して連続操作で使用するための回収可能性の増加。
a)固体担体を得る工程と、
b)対象の少なくとも1つのタンパク質又はタンパク質型化合物、特に少なくとも1つの酵素又は酵素型化合物を、及び任意選択的に、少なくとも1つの任意選択の分子を担体の表面に固定化する工程と、
c)固体担体の表面に結合した少なくとも1つのタンパク質又はタンパク質型化合物及び任意選択の分子を自己集合構築ブロックとともにインキュベートして、固体担体の自由表面並びに固体担体の表面に結合した少なくとも1つのタンパク質又はタンパク質型化合物及び任意選択の分子の周囲の多孔性ナノ環境を生じさせる工程と、
d)特定の時点に保護物質の自己集合反応を停止させて、所望の厚さを有する好ましい保護層を得る工程。
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Claims (29)
- 少なくとも
ナノ粒子である固体担体、
タンパク質
及び
タンパク質型化合物
から選択される
機能性成分であって、タンパク質及びタンパク質型化合物から選択される機能性成分が 酵素又は酵素型化合物である機能性成分
並びに
機能性成分を少なくとも部分的に埋め込むことにより、
機能性成分を保護するための保護層
並びに
酵素又は酵素型化合物を固体担体の表面に結合させるための少なくとも1つの二官能性 架橋剤
を含む
組成物を製造する方法であって、
最初に
少なくとも1つの機能性成分を固体担体の表面上に固定化し、
次いで、
機能性成分を
少なくとも部分的に
埋め込むこと
により
機能性成分を保護するための
保護層を、
その少なくとも一部が
相互に
及び
固定化機能性成分
と相互作用すること
ができるモノマーである
構築ブロックを用いて
構築する
工程を含み、構築ブロックが、水性条件下でのシリカ前駆体の重縮合による保護層を構築し、シリカ前駆体がトリアルコキシシラン及びテトラアルコキシシランであり、該方法が、所望の厚さを有する好ましい保護層を得るために、構築ブロックを用いて保護層を構築するための保護物質の自己集合反応を、特定の反応時間間隔の後に停止する工程をさらに含み、
保護層の厚さが1nm−25nmの範囲にあり、少なくとも1つの機能性成分の長軸の 長さの50%−150%である
方法。 - 用いるモノマーが固体担体の表面とさらに相互作用することができる、請求項1に記載の方法。
- 機能性成分を
固体担体の表面上に
固定化する前に、
固体担体を修飾して
表面上の
機能性成分の固定化を改善する、
請求項1又は2に記載の方法。 - 機能性成分の固定化を改善するために表面領域の一部のみが修飾されるが、他の部分が修飾されていないままであり、モノマーが担体表面の修飾されていない部分と結合相互作用することができる、請求項3に記載の方法。
- 機能性成分が担体表面上にランダム配向で固定化される、請求項3又は4に記載の方法。
- 組成物が
アダプター分子、
アンカー分子、
足場分子
及び/又は
受容体分子
の群から選択される少なくとも1種の機能性分子をさらに含む、請求項1から5の何れか一項に記載の方法。 - 機能性成分を保護するための保護層が少なくとも1種の機能性分子をも埋め込んでいるように
アダプター分子、
アンカー分子、
足場分子
及び/又は
受容体分子
の群から選択される少なくとも1種の機能性分子とさらに相互作用することができるようなモノマー構築ブロックが選択される、請求項6に記載の方法。 - 層が多孔性層として構築される、請求項1から7の何れか一項に記載の方法。
- 有機シランモノマーを、機能性成分を少なくとも部分的に埋め込む保護層を構築するための構築ブロックとして用いる、請求項1から8の何れか一項に記載の方法。
- アルコール、
アミン、
カルボキシレート
芳香族官能基、
チオール、
チオエーテル、
グアニジニウム、
イミダゾール、
脂肪族鎖、
アミド
及び/又はフェノール
から選択される
固定化機能性成分と相互作用する
少なくとも1つの官能基、
特に
弱い力の相互作用により
タンパク質又はタンパク質型化合物の
表面に存在するアミノ酸の
1つ又は複数のアミノ酸側鎖と
相互作用する
官能基
を有する
有機シランモノマー、
特に
テトラオルトシリケート、
からなる群から選択され、
そして特に
ベンジルトリエトキシシラン、
プロピルトリエトキシシラン、
イソブチルトリエトキシシラン、
n−オクチルトリエトキシシラン、
ヒドロキシメチルトリエトキシシラン、
ビス(2−ヒドロキシエチル)−3−アミノプロピルトリエトキシシラン、
アミノプロピルトリエトキシシラン、
ウレイドプロピルトリエトキシシラン、
(N−アセチルグリシル)−3−アミノプロピルトリエトキシシラン
から選択され、
及び/又は
ベンジルトリメトキシシラン、
プロピルトリメトキシシラン、
イソブチルトリメトキシシラン、
n−オクチルトリメトキシシラン、
ヒドロキシメチルトリメトキシシラン、
ビス(2−ヒドロキシエチル)−3−アミノプロピルトリメトキシシラン、
アミノプロピルトリメトキシシラン、
ウレイドプロピルトリメトキシシラン
(N−アセチルグリシル)−3−アミノプロピルトリメトキシシラン
から選択され、
及び/又は
ベンジルトリヒドロキシエトキシシラン、
プロピルトリヒドロキシエトキシシラン、
イソブチルトリヒドロキシエトキシシラン、
n−オクチルトリヒドロキシエトキシシラン、
ヒドロキシメチルトリヒドロキシエトキシシラン、
ビス(2−ヒドロキシエチル)−3−アミノプロピルトリヒドロキシエトキシシラン、
アミノプロピルトリヒドロキシエトキシシラン、
ウレイドプロピルトリヒドロキシエトキシシラン
(N−アセチルグリシル)−3−アミノプロピルトリヒドロキシメトキシシラン
から選択される
有機シランモノマーが用いられる、
請求項9に記載の方法。 - 複数の異なる有機シランモノマーが用いられる、請求項10に記載の方法。
- 少なくとも1つの機能性成分について、
Phe、Tyr、Trp、Gly、Ala、Leu、Ile、Val、
Pro、Ser、Thr、Asp、Asn、Gln、Asp、Glu、
Lys、Arg、His
からなる群から選択される
少なくとも数種の
表面アミノ酸
のそれぞれの量が
決定され、
決定に従って
複数の異なる有機シランモノマーが用いられる、
請求項11に記載の方法。 - ナノ粒子である固体担体、
タンパク質
及び
タンパク質型化合物
から選択される
機能性成分であって、タンパク質及びタンパク質型化合物から選択される機能性成分 が酵素又は酵素型化合物である少なくとも1つの機能性成分、
酵素又は酵素型化合物を固体担体の表面に結合させるための少なくとも1つの二官能性 架橋剤、を含み、
酵素又は酵素型化合物が固体担体の表面に固定化され、
並びに
機能性成分を少なくとも部分的に埋め込むことにより
機能性成分を保護するための保護層
を含む組成物であって、
機能性成分を保護するための保護層が
構築ブロック
により構築された
層であり、
そのモノマーが
相互に
及び
固定化機能性成分
と相互作用することができ、構築ブロックが、水性条件下でのシリカ前駆体の重縮合による保護層を構築し、シリカ前駆体がトリアルコキシシラン及びテトラアルコキシシランであり、
保護層の厚さが1nm−25nmの範囲にあり、少なくとも1つの機能性成分の長軸の 長さの50%−150%である
組成物。 - 固体担体がナノ粒子、
特に、
有機ナノ粒子、
無機ナノ粒子、
有機−無機複合ナノ粒子、
自己集合有機ナノ粒子、
メソ多孔性シリカナノ粒子(SNP)、
金ナノ粒子、
チタンナノ粒子
の群から選択されるナノ粒子である、請求項13に記載の組成物。 - 担体が
特に、最大100μm、好ましくは
20−1000nm、
特に200−500nm、
特に300−400nmの範囲の
粒径を有する粒子状担体である、請求項13又は14に記載の組成物。 - 保護層の厚さが
1−100nm、
1nm−50nm、
1nm−30nm、
1nm−25nm、
1nm−20nm、
1nm−15nm、
好ましくは5nm−15nmの
範囲にある、請求項13から15の何れか一項に記載の組成物。 - 保護層の厚さが
長軸の長さの少なくとも30%であり、層が多孔性である、
請求項13から16の何れか一項に記載の組成物。 - 細孔径が
1nm−10nm、
特に2nm−9nm、
特に3nm−8nm、
特に4nm−7nm、
特に4nm−6nm、
特に4nm−5nmである、
請求項13から17の何れか一項に記載の組成物。 - 組成物の使用中にそれとの相互作用のために機能性成分への分子の拡散を可能にするように細孔径が寸法化されている、
請求項13から18の何れか一項に記載の組成物。 - 固体担体の表面への
少なくとも1つの機能性成分の
固定化結合
が共有結合である、
請求項13から19の何れか一項に記載の組成物。 - 少なくとも1つの機能性成分を結合させるための
少なくとも1つの
二官能性架橋剤が、
アミンをスルフヒドリル(チオール)官能基に架橋結合させるための架橋剤
及び/又は
スルフヒドリルをスルフヒドリル(チオール)官能基に架橋結合させるための架橋剤、
及び/又は
グルタルアルデヒド、
酒石酸ジスクシンイミジル、
スベリン酸ビス[スルホスクシンイミジル]、
エチレングリコールビス(コハク酸スルホスクシンイミジル)、
アジプイミド酸ジメチル、
ピメルイミド酸ジメチル、
アミノ安息香酸スルホスクシンイミジル(4−ヨードアセチル)、
1,5−ジフルオロ−2,4−ジニトロベンゼン、
活性化スルフヒドリル(スルフヒドリル反応性2−ピリジルジチオ)、
BSOCOES(ビス[2−(スクシンイミドオキシカルボニルオキシ)エチル]スルホン)、
DSP(ジチオビス[プロピオン酸スクシンイミジル])、
DTSSP(3,3’−ジチオビス[プロピオン酸スルホスクシンイミジル])、
DTBP(ジメチル3,3’−ジチオビスプロピオンイミデート・2HCl)、
DST(酒石酸ジスクシンイミジル)、
スルホ−LC−SMPT(4−スルホスクシンイミジル−6−メチル−a−(2−ピリジルジチオ)トルアミド)ヘキサノエート))、
SPDP(3−(2−ピリジルジチオ)−プロピオン酸N−スクシンイミジル)、
LC−SPDP(スクシンイミジル6−(3−[2−ピリジルジチオ]−プロピオンアミド)ヘキサノエート)、
SMPT(4−スクシンイミジルオキシカルボニル−メチル−a−[2−ピリジルジチオ]トルエン)、
DPDPB(1,4−ジ−[3’−(2’−ピリジルジチオ)−プロピオンアミド]ブタン)、
DTME(ジチオ−ビスマレイミドエタン)、
BMDB(1,4ビスマレイミジル−2,3−ジヒドロオキシブタン)
からなる群から選択される二官能性架橋剤である、
請求項13から20の何れか一項に記載の組成物。 - 保護層のモノマー構築ブロック
と
固定化機能性成分と
の間の相互作用が
特に、弱い力の相互作用に基づいて
タンパク質又はタンパク質型化合物のアミノ酸側鎖間で生じる、
請求項13から21の何れか一項に記載の組成物。 - 異なる構築ブロックが異なる機能性部分及び/又は異なるアミノ酸側鎖と相互作用するように複数の異なる構築ブロックが供給される、
請求項22に記載の組成物。 - 固定化された少なくとも1つのタンパク質又はタンパク質型化合物と相互作用する
保護物質の官能基が
アルコール、
アミン、
カルボキシレート、
芳香族官能基、
チオール、
チオエーテル、
グアニジニウム、
イミダゾール、
脂肪族鎖、
アミド
及び/又はフェノール
のうちの1つである、
請求項13から23の何れか一項に記載の組成物。 - 有機シランモノマーが機能性成分を少なくとも部分的に埋め込む保護層を構築するための構築ブロックとして用いられる、請求項13から24の何れか一項に記載の組成物。
- タンパク質
及び
タンパク質型化合物
から選択される
前記機能性成分
が
オキシドレダクターゼ、
トランスフェラーゼ、
ヒドロラーゼ、
リアーゼ、
イソメラーゼ
及び/又はリガーゼ
からなる群から選択される
酵素又は酵素型化合物である、
請求項13から25の何れか一項に記載の組成物。 - 触媒工程における請求項13から26の何れか一項に記載の組成物の使用。
- 工程中、組成物が
特にpH値が機能性成分に最適なpHと少なくとも+/−0.5pH単位及び/又は最大+/−5pH単位異なるような機能性成分の最適pHと異なる少なくとも1つのpHに、
並びに/あるいは
化学的ストレスに、及び/又は
生物学的ストレスに、及び/又は
溶媒に、及び/又は
物理的ストレスに、及び/又は
機能性成分の
最適温度を
少なくとも5℃、及び/又は最大60℃、
特に50℃、
特に40℃より高い、
特に30℃、
特に20℃、
特に10℃
超える
高温に、及び/又は
機能性成分の
最適温度から
少なくとも5℃、及び/又は最大60℃
逸脱している
低温に、
さらされる、
触媒工程における請求項13から26の何れか一項に記載の組成物の使用。 - 治療、特に
スフィンゴミエリナーゼ欠乏(ASMD)症候群、
ニーマン−ピック病(NPD)、
リソソーム蓄積症、
ゴーシェ病、
ファブリー病、
MPSI、
MPSII、
MPSVI
糖原病II型、
癌、
アレルギー性疾患、
代謝疾患、
心血管疾患、
自己免疫疾患、
神経系疾患、
リンパ系疾患
及びウイルス性疾患
の1つの治療に用いるための、請求項13から26の何れか一項に記載の組成物。
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EP13178504 | 2013-07-30 | ||
PCT/EP2014/066365 WO2015014888A1 (en) | 2013-07-30 | 2014-07-30 | Biocatalytical composition |
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US (2) | US20160168559A1 (ja) |
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US11541105B2 (en) | 2018-06-01 | 2023-01-03 | The Research Foundation For The State University Of New York | Compositions and methods for disrupting biofilm formation and maintenance |
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JP3312364B2 (ja) * | 1991-10-07 | 2002-08-05 | ジェネンコア インターナショナル インコーポレーテッド | 被覆した酵素含有顆粒 |
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HRP20191194T1 (hr) | 2019-10-04 |
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PT3027750T (pt) | 2019-06-28 |
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