JP5558356B2 - 微生物細胞のための細胞透過性ペプチドおよびポリペプチド - Google Patents
微生物細胞のための細胞透過性ペプチドおよびポリペプチド Download PDFInfo
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Description
本出願は、2007年9月25日に提出した米国特許出願第60/975,104号、2007年11月22日に提出した米国特許出願第60/989,840号、および2007年11月22日に提出した米国特許出願第60/989,841号の利益を主張するものであり、これら全ての出願内容はその全体が参照によりここに取り込まれる。
定義
ここで用いられる、シグナルペプチドをコードする「変化した」核酸配列は、同じかまたは機能的に同等なペプチドをコードするポリヌクレオチドをもたらす、異なるヌクレオチドの欠失、挿入、または置換による核酸配列を含む。コードされるペプチドもまた「変化」してよく、サイレント変化を生じて機能的に同等なペプチドをもたらすアミノ酸残基の欠失、挿入、または置換を含む。意図されたアミノ酸置換が、残基の極性、電荷、溶解度、疎水性、親水性、および/または両親媒性性質の類似性に基づき、生物学的活性(例えば細胞結合もしくは細胞透過処理)またはペプチドの免疫原性活性を保持する限りにおいて行なわれてよい。例えば陰性荷電アミノ酸はアスパラギン酸およびグルタミン酸を含んでよく;陽性荷電アミノ酸はリジンおよびアルギニンを含んでよく;類似の親水性値を有する非荷電の極性頭部基をもつアミノ酸はロイシン、イソロイシン、およびバリン、グリシンおよびアラニン、アスパラギンおよびグルタミン、セリンおよびスレオニン、ならびにフェニルアラニンおよびチロシンを含んでよい。
Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Plainview, NY, および Ausubel, F. M. et al. (1989) Current Protocols in Molecular Biology, John Wiley & Sons, New York, NY. を参照のこと。低または高ストリンジェンシーのいずれかを含む多数の同等な条件は、配列(DNA、RNA、塩基組成物)の長さおよび性質、標的(DNA、RNA、塩基組成物)の性質、環境(溶液中または固体基質上での不動化)、塩およびその他の構成成分(例えばホルムアミド、硫酸デキストランおよび/またはポリエチレングリコール)の濃度、ならびに反応温度(例えば、プローブの融解温度より約5℃低い温度から、融解温度より約20℃から25℃低い温度の範囲内)のような因子に依存する。上に列挙した条件とは異なるが同等である、低または高ストリンジェンシーのいずれかの条件を作り出すため、1つ以上の因子が変化させられてよい。
メタンは反すう動物の前腸内で、反すう胃システムにおける炭素の最終還元作用を行うメタン生成菌により産生される。多段階メタン生成経路は、主に非反すう胃メタン生成菌の研究によって十分に解明されているが、反すう胃においてメタン生成菌の生育および存続を可能にするための適応はよく理解されていない。メタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)は、ニュージーランドの反すう動物における有名なメタン生成菌である。ここに述べるように、M.ルミナンチウム(M. ruminantium)のドラフトゲノム配列は、約3.0Mbのサイズおよび33.68%のGC含有量を示す。重要な発見として、M.ルミナンチウム(M. ruminantium)のゲノムは細胞の標的化および透過処理における使用のためのシグナルペプチド配列を含むことが見出された。
本発明は従って、配列番号1〜172を含むシグナルペプチド、同様にこれらのペプチドを含むポリペプチド、ならびにそれらの変化、断片、変異体、および誘導体を包含する。
vitroまたはin vivoでの発現のための構成成分を含んでよい。in vi
tro発現の構成成分は、ウサギ網状赤血球ライセート、大腸菌(E. coli)ライセート、およびコムギ胚芽抽出物のためのもの、例えばInvitrogenから市販されているExpressway(商標)またはRiPs system、iNtRON Biotechnologyから市販されているGenelator(商標)system、Novagenから市販されているEcoPro(商標)またはSTP3(商標)system、Promegaから市販されているTNT(登録商標)Quick Coupled system、およびQIAGENから市販されているEasyXpress systemを含む。培養から産生されるペプチドまたはポリペプチドは、配列および/または使用されるベクターに依存して、分泌されるかまたは細胞内に含まれてよい。当業者により理解され得るように、ペプチドまたはポリペプチドをコードする発現ベクターは、好ましくは原核または真核細胞の膜を通してペプチドの分泌を導くシグナル配列を含むように設計される。
Sciences (Maack Publishing Co., Easton, PA)の最新版に見出されるであろう。本発明で利用される医薬組成物は、経口、静脈内、筋肉内、動脈内、延髄内、包膜内、心室内、経皮、皮下、腹腔内、鼻内、経腸、外用、舌下、または直腸の手段を含むがこれらに限定されないいずれの数の経路により投与されてよい。
ゲノムサイズの推定
メタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)のM1T株(DSM1093)は、[g/l]NaCl(1)、KH2PO4(0.5)、(NH4)2SO4(0.25)、CaCL2.2H2O(0.13)、MgSO4.7H2O(0.2)、K2HPO4(1)、浄化した反すう胃液(300ml)dH2O(360ml)、NaHCO3(5)、レザズリン(0.2ml)L−システイン−HCl(0.5)、酵母抽出物(2)、ならびに、(g/l)ニトリロ三酢酸(1.5)、MgSO4.7H2O(3)、MnSO4.H2O(0.5)、NaCl(1)、FeSO4.7H2O(0.1)、CoCl2.6H2O(0.1)、CaCl2(0.1)、ZnSO4.7H2O(0.1)、CuSO4.5H2O(0.01)、AlK(SO4)2.12H2O(0.01)、H3BO3(0.01)、Na2MoO4.2H2O(0.01)、NiSO4.6H2O(0.03)、Na2SeO3(0.02)、およびNa2Wo4.2H2O(0.02)から成るBalchの微量元素溶液(10ml)(微量元素の添加;Balch et al., 1979)、から成るBY+培地(基本培地、Joblin et al., 1990)中で生育した。凍結粉砕法を用いてゲノムDNAを抽出した。細胞を遠心によって回収し、細胞ペレットを予め冷却した乳鉢内に配置し、液体窒素により凍結し、かつ予め冷却した滅菌乳鉢および乳棒を用いて穏やかに粉砕して微粉にした。ゲノムDNAの物理的せん断を減少させるため、細胞ホモジネートをアガロースプラグ上に包埋し、続く操作をプラグ内で行った。制限酵素により消化を行い、DNA断片をパルスフィールドゲル電気泳動(PFGE)を用いて分離した。
M.ルミナンチウム(M. ruminantium)ゲノムのDNAは、Agencourt Biosciences Corporation(マサチューセッツ州、米国)によりランダムショットガンクローニングアプローチ(Fleischmann et al., 1995)を用いて、およびMacrogen Corporation(ロックビル、メリーランド州、米国)によりピロシーケンスを用いて配列決定された。M.ルミナンチウム(M. ruminantium)のDNAのライブラリーを、ゲノムDNAのランダムな物理的破壊およびゲル電気泳動による断片の分離により、大腸菌(Escherichia coli)内へ構築した。40kb範囲の大きな断片をゲルから回収し、大インサートのフォスミドライブラリーを作製するために使用した。2ないし4Kb範囲のDNA断片を回収し、小インサートのプラスミドライブラリーを作製するために使用した。大および小インサートライブラリーの両方からもたらされたクローンを生育させ、それらのフォスミドまたはプラスミドDNAを回収し、ハイスループット配列決定技術を用いて配列決定した。理論的にM.ルミナンチウム(M. ruminantium)ゲノムの8倍のカバー率を生ずるために十分なクローンを配列決定した。10倍の最終理論的なカバー率を得るため、ランダムにせん断されたゲノムDNA断片についてピロシーケンスを行った。
配列の重複を見出すためにDNA配列を整列し、Paracel Genome Assembler(Paracel Inc、カリフォルニア州、米国)およびStadenパッケージ(Staden et al., 1998)を用い、標準および逆PCRの両方から得られた配列を組み合わせて、近接する(コンティグ)配列へ構築した。コンティグは翻訳領域(ORF)ファインダーGLIMMER(Gene Locator Interpolated Markov Model ER、Salzberg et al., 1998)を用いて分析し、各ORFは、National Center for Biotechnology Information(NCBI)の非重複性ヌクレオチドおよびタンパク質データベースに対するBLAST(Basic Local Alignment Search Tool(Altschul et al., 1997))により分析した。
現在までに、古細菌のシグナルペプチドモデルは存在しない。単に、特定のモデルを定めるために実験的に検証された古細菌に利用可能な分泌タンパク質は非常に少ない。この理由から翻訳領域(ORF)配列は、グラム陽性、グラム陰性、および真核細胞モデルに対して定められたSignalP バージョン3.0(Bendtsen et al., 2004)を用い、シグナルペプチドの存在について分析された。Emanuelsson at al., 2007により記載されるように、シグナルペプチドと非シグナルペプチドORFとを識別するためにSignalP-HMM(隠れマルコフモデル)が使用されたが、切断部位の予測のためにSignalP-NN(中立ネットワーク)が利用された。
コアコンセンサスペプチドはInvitrogenのカスタムペプチドサービス(Invitrogen NZ Ltd)を用いて商業的に合成した。ペプチドは少量(10〜12mg)でのFmoc化学を用いて合成し、HPLCで>95%の純度まで精製した。ペプチドのN−末端リジン(K)をフルオレセインで標識した。
標識ペプチドのM.ルミナンチウム(M. ruminantium)細胞へのエントリーに続いて蛍光アッセイを行った。10mlのBY+培地中でM.ルミナンチウム(M. ruminantium)の培養物を生育させ、10,000×gで、4℃において10分間遠心して回収した。細胞を1.5mlのポリプロピレンエッペンドルフチューブに移し、1mlのTE緩衝液(10mM Tris−HCl、1mM エチレンジアミン四酢酸、pH8)で洗浄し、13,000×gで、4℃において10分間微量遠心機で遠心して回収した。細胞(約1×108)を全量200μlのTE緩衝液に再懸濁し、20μgのフルオレセイン標識ペプチドを加えた。混合物を37℃において30分間インキュベートし、その後13,000×gで、4℃において10分間遠心した。細胞ペレット上部の液体を保持し、上清分画を構成した。細胞ペレットを200μlのTE緩衝液で、細胞を緩衝液中に繰り返し再懸濁することによって3回洗浄し、13,000×gで、4℃において10分間遠心した。
ゲノムDNAの制限酵素消化およびPFGEによる断片のサイズ決定によるM.ルミナンチウム(M. ruminantium)ゲノムのサイズ推定は、約2.5〜2.9Mbの単一染色体を示した。大および小インサートクローン(6倍ドラフトカバー率)の最初の配列決定および配列のコンティグへの構築は、ゲノムの40kb領域が、特に小インサートライブラリー内で高度に過剰表現(>20倍)されていることを示した。この大きな配列バイアスのため、さらなる配列決定(2倍の理論的ゲノムカバー率)を、サンガー配列決定法により最終の8倍のカバー率をもたらす大インサートクローンのみについて行った。8倍のドラフト段階の配列を、105のスキャフォールドを通して連結した756のコンティグへ構築した。さらなる〜10倍のカバー率に対してさらなるピロシーケンスを行い、これらの配列の構築への取り込みはコンティグの数を27に低下させた。これに続く逆および長距離PCR技術を用いるギャップ閉鎖は、コンティグの数を14に減少させた。
メタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)は、様々な食餌条件下でのその反すう胃内における有病率(培養および分子検出データに基づく)、培養物の有効性、実験室での日常的生育の快適性、ならびにこの生物に対する比較的多数の以前の研究および入手可能な背景文献により、ゲノム配列決定のために選択された。M.ルミナンチウム(M. ruminantium)内の著しく多数の配列が機能を割り当てられ、これによってこの生物の反すう胃内での生活様式の詳細な描写が可能になる。M.ルミナンチウム(M. ruminantium)の単純な基質(H2+CO2、ギ酸塩)依存性、ならびにその表面タンパク質および菌体外多糖を通した反すう胃環境との相互作用は抑制の重要な標的である。配列データはこの生物の代謝およびそれが他の微生物とどのように相互作用するかを明らかにし、かつメタン生成菌の間で保存されたシステム、および反すう胃内におけるメタン生成を阻止または減少させるために不活性化できる構成成分へと向かう。
Claims (17)
- 以下のa)を含む、単離されたポリペプチドまたはペプチド:
a)配列番号117、118または119のアミノ酸配列。 - 以下のa)〜c)のいずれかを含み、メタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)のM1 T 株(DSM1093)を透過性にする、単離されたポ
リペプチドまたはペプチド:
a)配列番号117と少なくとも90%の同一性を共有するアミノ酸配列、
b)配列番号118と少なくとも95%の同一性を共有するアミノ酸配列、
c)配列番号119と少なくとも90%の同一性を共有するアミノ酸配列。 - 以下のa)〜b)のいずれかを含み、M.ルミナンチウムのM1 T 株(DSM1093)
を透過性にする、単離されたポリペプチドまたはペプチド:
a)配列番号117または118の少なくとも15個連続するアミノ酸、
b)配列番号119の少なくとも15個連続するアミノ酸。 - 以下のa)〜e)のいずれかを含む、単離されたポリヌクレオチド:
a)配列番号117、118、および119から選択されるアミノ酸配列をコードする核酸配列、
b)配列番号117と少なくとも90%の同一性を共有するアミノ酸配列からなり、M.ルミナンチウムのM1 T 株(DSM1093)を透過性にするポリペプチドをコードする
核酸配列、
c)配列番号118と少なくとも95%の同一性を共有するアミノ酸配列からなり、M.ルミナンチウムのM1 T 株(DSM1093)を透過性にするポリペプチドをコードする
核酸配列、
d)配列番号119と少なくとも90%の同一性を共有するアミノ酸配列からなり、M.ルミナンチウムのM1 T 株(DSM1093)を透過性にするポリペプチドをコードする
核酸配列、
e)前記a)〜d)のいずれかと相補的な核酸配列。 - 以下のa)〜c)のいずれかを含む、単離されたポリヌクレオチド:
a)配列番号117または118の少なくとも15個連続するアミノ酸からなり、M.ルミナンチウムのM1 T 株(DSM1093)を透過性にするポリペプチドをコードする核
酸配列、
b)配列番号119の少なくとも15個連続するアミノ酸からなり、M.ルミナンチウムのM1 T 株(DSM1093)を透過性にするポリペプチドをコードする核酸配列、
c)前記a)〜b)のいずれかと相補的な核酸配列。 - 以下のa)を含む、単離されたポリヌクレオチド:
a)配列番号511、512および513から選択される核酸配列、又はこれに相補的な核酸配列。 - 請求項4〜6のいずれか1項に記載の単離されたポリヌクレオチドを含むベクター。
- 以下のa)〜c)のいずれかのホスト細胞:
a)請求項1〜3のいずれか1項に記載のポリペプチドまたはペプチドをコードする核酸配列を含むように遺伝的に改変されたホスト細胞、
b)請求項4〜6のいずれか1項に記載のポリヌクレオチドを含むように遺伝的に改変されたホスト細胞、
c)請求項7に記載のベクターを含むホスト細胞。 - 原核生物またはメタン生成菌である、請求項8に記載のホスト細胞。
- 大腸菌(Escherichia coli)、またはメタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)のM1T株(DSM1093)を含むメタノブレビバクター・
ルミナンチウム(Methanobrevibacter ruminantium)である、請求項9に記載のホスト細胞。 - 以下のa)またはb)を含む、抱合体分子または融合体分子:
a)請求項1〜3のいずれか1項に記載のポリペプチドまたはペプチド、
b)請求項4〜6のいずれか1項に記載のポリヌクレオチド。 - 請求項1〜3のいずれか1項に記載のポリペプチドまたはペプチドを含む抱合体分子または融合体分子であって、メタン生成化合物、抗体もしくは抗体断片、溶解酵素、ペプチド核酸、抗菌ペプチド、または抗生剤をさらに含む、抱合体分子または融合体分子。
- 微生物細胞を透過処理する方法であって、
a)請求項1〜3のいずれか1項に記載のポリペプチドまたはペプチドを提供すること、および
b)該細胞を該ポリペプチドまたはペプチドに接触させることを含む方法。 - 微生物細胞を透過処理する方法であって、
a)請求項11または12に記載の抱合体分子または融合体分子を提供すること、およびb)該細胞を該抱合体分子または融合体分子に接触させることを含む方法。 - 前記細胞がメタン生成菌である、請求項13または14に記載の方法。
- 前記細胞がメタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)である、請求項15に記載の方法。
- 前記細胞がメタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)
のM1T株(DSM1093)である、請求項16に記載の方法。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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US97510407P | 2007-09-25 | 2007-09-25 | |
US60/975,104 | 2007-09-25 | ||
US98984007P | 2007-11-22 | 2007-11-22 | |
US98984107P | 2007-11-22 | 2007-11-22 | |
US60/989,840 | 2007-11-22 | ||
US60/989,841 | 2007-11-22 | ||
PCT/NZ2008/000247 WO2009041830A2 (en) | 2007-09-25 | 2008-09-25 | Cell-permeabilising peptides and polypeptides for microbial cells |
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