JP6842779B2 - 二本鎖核酸分子、およびその用途 - Google Patents
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- 229960000984 tocofersolan Drugs 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
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- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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- C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
本発明の一側面は、所定の塩基配列を含む第1ポリヌクレオチド鎖、および当該第1ポリヌクレオチド鎖と相補的な塩基配列を含む第2ポリヌクレオチド鎖を含む、二本鎖核酸分子(以下、「本発明に係る核酸分子」とも称する)に関する。
本発明において、第1ポリヌクレオチド鎖は、下記化学式(1)(配列番号1)で表される塩基配列を含むものである。
これらのうち、第1ポリヌクレオチド鎖に対して上記(a)の化学的修飾(3’末端への化学修飾基の付加)が施されたものは、化学式(1)においてkが1である場合に相当する。この場合、具体的には、第1ポリヌクレオチド鎖の3’末端のヌクレオチドの塩基に結合した3’末端側のホスホジエステル結合の酸素原子に、「−L−M」で表される構造を有する基が結合している。化学式(1)においてkが1であるとき、Lは、下記化学式(2a)〜(2g):
第1ポリヌクレオチド鎖に対して上記(b)の化学的修飾(構成塩基の修飾糖部分を含む塩基による置換)が施される場合、第1ポリヌクレオチド鎖を構成する各ヌクレオチドは、それぞれ独立して、2’−O−メチル、2’−メトキシエトキシ、2’−フルオロ、2’−アリル、2’−O−[2(メチルアミノ)−2−オキソエチル]、4’−チオ、4’−(CH2)2−O−2’−架橋、2’−ロックド核酸または2’−O−(N−メチルカルバメート)からなる群から選択される修飾糖部分を含む塩基で置換されうる。なかでも、修飾糖部分は、2’−O−メチルまたは2’−フルオロ修飾を含むことが好ましい。
第1ポリヌクレオチド鎖に対して上記(c)の化学的修飾(ホスホジエステル結合のリン原子修飾結合による置換)が施される場合、第1ポリヌクレオチド鎖を構成するホスホジエステル結合は、それぞれ独立して、下記化学式(4):
本発明に係る核酸分子の第2ポリヌクレオチド鎖は、配列番号1と完全に相補的なヌクレオチド配列を含むDNA鎖、RNA鎖またはDNA/RNAキメラ鎖である。抗腫瘍活性の観点から、第2ポリヌクレオチド鎖のうち、第1ポリヌクレオチド鎖の相補性領域とハイブリダイズする領域(以下、単に「ハイブリダイズ領域」とも称する。)はRNA鎖であることが好ましい。すなわち、好ましい一実施形態では、第2ポリヌクレオチド鎖が、下記化学式(5)(配列番号2)で表される塩基配列を含む。
本発明に係る核酸分子は、その塩基配列に基づき、従来公知の手法(核酸自動合成機を用いたホスホロアミダイト法による合成)により、化学的に合成することができる。また、このようにして製造された第1ポリヌクレオチド鎖および第2ポリヌクレオチド鎖の一方または双方の3’末端に上述した「−L−M」で表される修飾構造を導入する手法についても、従来公知の知見(例えば、国際公開第2007/094135号パンフレットや特開2011−251912号公報など)が適宜参照されうる。さらに、特定箇所のホスホジエステル結合を上記化学式(3)で表されるリン原子修飾構造とする手法についても、従来公知の知見が適宜参照されうる。例えば、ホスホロアミダイト法による核酸合成の最終段階における3価のリンの5価への酸化を、酸化剤溶液に代えて硫化剤溶液を用いて行うことで、ホスホジエステル結合に代えてホスホロチオエート結合を導入することが可能である。
・Syn−1
以下の配列番号3で表される第1ポリヌクレオチド鎖と、配列番号4で表される第2ポリヌクレオチド鎖とを有する二本鎖核酸分子(Syn−1)を準備し、膀胱がん細胞(JB−V235細胞)の増殖抑制活性を評価した。なお、以下の配列番号3において、3’末端側の2残基(GG)が3’末端付加配列であり、それ以外の部分が相補性領域に相当する。また、以下の配列番号4において、3’末端側の2残基(GG)が3’末端付加配列であり、それ以外の部分がハイブリダイズ領域に相当する。
上記と同様の手法により、Syn−1またはA−miR−145(いずれも終濃度5nM)をJB−V235細胞にトランスフェクションした。トランスフェクションから72時間後に細胞を回収し、細胞をセルスクレイパーで回収し、以下のウェスタンブロッティングによりがん関連分子(c−MycおよびFascin)の発現量を解析した。
・Syn−2
上記の配列番号3で表される第1ポリヌクレオチド鎖と、以下の配列番号5で表される第2ポリヌクレオチド鎖とを有する二本鎖核酸分子(Syn−2)を準備した。なお、以下の配列番号5において、3’末端側の2残基(TT)が3’末端付加配列であり、それ以外の部分がハイブリダイズ領域に相当する。
以下の配列番号6で表される第1ポリヌクレオチド鎖と、上記の配列番号4で表される第2ポリヌクレオチド鎖とを有する二本鎖核酸分子(Syn−3)を準備した。なお、以下の配列番号6において、3’末端側の2残基(TT)が3’末端付加配列であり、それ以外の部分が相補性領域に相当する。
上記のSyn−1、Syn−2、およびSyn−3を用いて、大腸がん細胞(DLD−1細胞)の増殖抑制活性を評価した。
Syn−1およびA−miR−145を用いて、終濃度が5nM、10nMまたは15nMとなるようにT−24細胞にトランスフェクションした。トランスフェクションから72時間後、試験例1と同様に生存細胞数を計測した。その結果を図6に示す。
・Syn−4
上記の配列番号3で表される第1ポリヌクレオチド鎖と、以下の配列番号9で表される第2ポリヌクレオチド鎖とを有する二本鎖核酸分子(Syn−4)を準備した。なお、以下の配列番号9において、3’末端側の2残基(TT)が3’末端付加配列であり、それ以外の部分がハイブリダイズ領域に相当する。また、配列番号9において「^」の符号で示される4箇所のホスホジエステル結合はホスホロチオエート結合で置換されたものである。さらに、配列番号9において下線が付された塩基は2’−フルオロの修飾糖部分を含むものであり、二重下線が付された塩基は2’−O−メチルの修飾糖部分を含むものである。
以下の配列番号10で表される第1ポリヌクレオチド鎖と、上記の配列番号4で表される第2ポリヌクレオチド鎖とを有する二本鎖核酸分子(Syn−5)を準備した。なお、以下の配列番号10において、3’末端側の2残基(TT)が3’末端付加配列であり、それ以外の部分が相補性領域に相当する。また、配列番号10において「^」の符号で示される4箇所のホスホジエステル結合はホスホロチオエート結合で置換されたものである。さらに、配列番号10において下線が付された塩基は2’−フルオロの修飾糖部分を含むものであり、二重下線が付された塩基は2’−O−メチルの修飾糖部分を含むものである。
上記の配列番号3で表される第1ポリヌクレオチド鎖と、以下の配列番号11で表される第2ポリヌクレオチド鎖とを有する二本鎖核酸分子(Syn−6)を準備した。なお、以下の配列番号11において、3’末端側の2残基(TT)が3’末端付加配列であり、それ以外の部分がハイブリダイズ領域に相当する。また、配列番号11において「^」の符号で示される4箇所のホスホジエステル結合はホスホロチオエート結合で置換されたものである。さらに、配列番号11において下線が付された塩基は2’−フルオロの修飾糖部分を含むものであり、二重下線が付された塩基は2’−O−メチルの修飾糖部分を含むものである。
以下の配列番号12で表される第1ポリヌクレオチド鎖と、上記の配列番号4で表される第2ポリヌクレオチド鎖とを有する二本鎖核酸分子(Syn−7)を準備した。なお、以下の配列番号12において、3’末端側の2残基(TT)が3’末端付加配列であり、それ以外の部分が相補性領域に相当する。また、配列番号12において「^」の符号で示される4箇所のホスホジエステル結合はホスホロチオエート結合で置換されたものである。さらに、配列番号12において下線が付された塩基は2’−フルオロの修飾糖部分を含むものであり、二重下線が付された塩基は2’−O−メチルの修飾糖部分を含むものである。
・Syn−8
以下の配列番号13で表される第1ポリヌクレオチド鎖と、上記の配列番号4で表される第2ポリヌクレオチド鎖とを有する二本鎖核酸分子(Syn−8)を準備した。なお、以下の配列番号13においては、3’末端側に3’末端付加配列が存在しない。
以下の配列番号14で表される第1ポリヌクレオチド鎖と、配列番号15で表される第2ポリヌクレオチド鎖とを有する二本鎖核酸分子(Syn−9)を準備した。なお、配列番号14で表される第1ポリヌクレオチドの構造は、配列番号13で表されるポリヌクレオチドの3’末端に上記化学式(3)で表される構造(*2には水素原子が結合;ベンゼンピリジン(BP)構造)が付加された構造に相当する。また、配列番号15で表される第2ポリヌクレオチドの構造は、配列番号4で表されるポリヌクレオチドの3’末端付加配列(GG)が上記化学式(3)で表される構造(*2には水素原子が結合;ベンゼンピリジン(BP)構造)で置換された構造に相当する。
上記の配列番号3で表される第1ポリヌクレオチド鎖(3’末端付加配列(GG)を有する)と、上記の配列番号15で表される第2ポリヌクレオチド鎖(3’末端にBP構造を有する)とを有する二本鎖核酸分子(Syn−10)を準備した。
上記の配列番号13で表される第1ポリヌクレオチド鎖(3’末端付加配列を有さない)と、上記の配列番号15で表される第2ポリヌクレオチド鎖(3’末端にBP構造を有する)とを有する二本鎖核酸分子(Syn−11)を準備した。
以下の配列番号16で表される第1ポリヌクレオチド鎖と、上記の配列番号8で表される第2ポリヌクレオチド鎖(hsa−miR−145−5p)とを有する二本鎖核酸分子(Syn−12)を準備した。なお、以下の配列番号16において、3’末端側の2残基(UU)が3’末端付加配列であり、それ以外の部分が相補性領域に相当する。また、配列番号16において「^」の符号で示される4箇所のホスホジエステル結合はホスホロチオエート結合で置換されたものである。さらに、配列番号16において下線が付された塩基は2’−フルオロの修飾糖部分を含むものであり、二重下線が付された塩基は2’−O−メチルの修飾糖部分を含むものである。
・ユニット構造(unitPIC)型医薬組成物の調製
国際公開第2013/162041号パンフレットの実施例の記載に準じて、ブロックコポリマーを調製した。具体的には、親水性ポリマー鎖セグメントが2本のPEG(分子量はそれぞれ10kDa)から構成されており、カチオン性ポリアミノ酸セグメントが20個のオルニチン残基で構成されている構造を有するブロックコポリマーを調製した。
Claims (5)
- 以下のいずれかの二本鎖核酸分子:
下記の配列番号3で表される塩基配列からなる第1ポリヌクレオチド鎖、および下記の配列番号4で表される塩基配列からなる第2ポリヌクレオチド鎖を含む、二本鎖核酸分子;
下記の配列番号13で表される塩基配列からなる第1ポリヌクレオチド鎖、および下記の配列番号4で表される塩基配列からなる第2ポリヌクレオチド鎖を含む、二本鎖核酸分子;
下記の配列番号14で表される塩基配列からなる第1ポリヌクレオチド鎖、および下記の配列番号15で表される塩基配列からなる第2ポリヌクレオチド鎖を含む、二本鎖核酸分子:
のいずれかで表される置換または非置換の環式化合物含有基を表すか、または、2以上の前記環式化合物含有基がそれぞれホスホジエステル結合を介して連結してなる2価の基を表し;Mは、水素原子またはヒドロキシル保護基を表す。 - 以下のいずれかの二本鎖核酸分子:
下記の配列番号3で表される塩基配列からなる第1ポリヌクレオチド鎖、および下記の配列番号4で表される塩基配列からなる第2ポリヌクレオチド鎖を含む、二本鎖核酸分子;
下記の配列番号13で表される塩基配列からなる第1ポリヌクレオチド鎖、および下記の配列番号4で表される塩基配列からなる第2ポリヌクレオチド鎖を含む、二本鎖核酸分子;
下記の配列番号14で表される塩基配列からなる第1ポリヌクレオチド鎖、および下記の配列番号15で表される塩基配列からなる第2ポリヌクレオチド鎖を含む、二本鎖核酸分子:
- 請求項1または2に記載の二本鎖核酸分子をコードする塩基配列を含む、ベクター。
- 請求項1または2に記載の二本鎖核酸分子、または請求項3に記載のベクターを有効成分として含む、抗腫瘍剤。
- 膀胱がん、大腸がん、乳がん、白血病、卵巣がん、前立腺がん、肝細胞がん(Hepatocarcinoma)、肺がん、胃がん、食道がん、膵臓がん、神経膠腫、咽頭がん、鼻咽腔がん、口腔がん、および下垂体腫瘍からなる群から選択される腫瘍の予防および/または治療のための、請求項4に記載の抗腫瘍剤。
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