JP6857365B2 - 抗肝腫瘍ウイルス剤 - Google Patents
抗肝腫瘍ウイルス剤 Download PDFInfo
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- JP6857365B2 JP6857365B2 JP2018504607A JP2018504607A JP6857365B2 JP 6857365 B2 JP6857365 B2 JP 6857365B2 JP 2018504607 A JP2018504607 A JP 2018504607A JP 2018504607 A JP2018504607 A JP 2018504607A JP 6857365 B2 JP6857365 B2 JP 6857365B2
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/14—Antivirals for RNA viruses
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
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Description
1)感染
感染のステップではウイルスは受容体と接触して細胞内に侵入する。現在、HCVの受容体として、CD81、SR-B1、Claudin1及びOccludin等が知られている。
宿主のタンパク質のほとんどが、翻訳に際してmRNAの5'末端にあるCap構造を必要とする。一方、HCVではCap構造を必要としない。HCVの5'側に存在するInternal Ribosomal Entry Site(IRES)と呼ばれる領域の2次構造にRibosomeが直接結合して、Cap非依存的な翻訳によりウイルスの前駆タンパク質(約3000アミノ酸)が翻訳される。前駆タンパク質から10種類のウイルスタンパク質が宿主のタンパク質分解酵素とウイルス自身のタンパク質分解酵素(NS3-4A)により産生される。
HCVの複製は非構造タンパク質から成る複製複合体により行なわれる。初めに、ウイルスのプラス鎖を鋳型にしてRNA依存性RNAポリメラーゼ(NS5B)の働きにより複製中間体であるマイナス鎖RNAが合成される。次に、マイナス鎖RNAを鋳型にしてNS5Bによりプラス鎖RNAのウイルスゲノムが複製される。
ウイルス粒子の形成はEndoplasmic ReticulumとLipid Dropletを足場として、構造タンパク質であるCore、E1、E2とウイルスゲノムが集合することで完成する。この際、NS5Aが重要な役割を果すことがわかっている。
ウイルス粒子は細胞外に放出されるが、このときapolipoproteinが必要であることがわかっている。
で示される化合物又はその薬学的に許容される塩を有効成分として含有するものである。本発明に係る抗肝腫瘍ウイルス剤によれば、肝腫瘍ウイルス(HBV及び/又はHCV)感染症を予防又は治療することができる。
1)HCVとHBVの感染者が対象となる
本願では、Clofarabineが抗HBV活性と抗HCV活性を有することを見出した。従来の抗HBV剤はHCVに対しては無効なため、薬剤の対象はHBV感染者(世界で約3.5億人)となる。また、従来の抗HCV剤はHBVに対しては無効なため、薬剤の対象はHCV感染者(世界で約2億人)となる。これに対して、ClofarabineはHCVとHBVの両ウイルスに対して有効なため、対象は世界で計約5.5億人と拡大する。薬剤の開発には莫大な開発費がかかるが、1つの薬剤で2つの感染症をカバーできるため、開発費を軽減する効果が期待できる。さらに、Clofarabineは現在、臨床で白血病に使用されている薬剤であるため、開発費の軽減効果が期待できる。
Clofarabineは現在、臨床で白血病に使用されている薬剤であるために、安全性に対する評価が保証されている。さらに、Clofarabineは白血病に対する血中有効濃度(約2μM)の100分の1の濃度(約20nM)で抗HBV活性を示すので、肝炎に対して使用する際は白血病の治療に対するよりも大幅な副作用の軽減が期待できる。
生理活性物質以外では、Clofarabineは生活環の異なるDNAウイルスとRNAウイルスに有効な初めての抗ウイルス剤である。このことは、Clofarabineが広域のスペクトラムを有する抗ウイルス剤であることを示唆している。現在、ウイルス感染症に対して抗ウイルス剤が開発されているものは非常に少なく、現状では、ほとんどのウイルスに対して抗ウイルス剤は存在しない。Clofarabineは抗ウイルス剤が存在しない病原ウイルスに対しても使用できることが期待できる。また、Clofarabineは初めてのmDAAであるため、人類にとって脅威となる未知のウイルスのアウトブレークに有効な抗ウイルス剤となる潜在能力を有しているものと考えられる。非常に病原性の高いウイルスが出現して、新規の抗ウイルス剤を開発する時間的余裕のない状況下では、mDAAの存在は人類の存続にとって非常に重要となることが予想される。また、テロの脅威に晒されている現在、未知のウイルスを使用したバイオテロに対してもmDAAは有用と考えられる。
Clofarabineの抗HBV活性及び抗HCV活性、並びにCladribineの抗HCV活性
1.材料及び方法
1−1.抗HBV活性の測定
抗HBV活性の評価は、ヒト肝癌細胞株HepG2にHBVゲノムの2倍長の遺伝子を導入したHBV産生細胞であるHepG2.2.15細胞株を用いて、薬剤添加後7日目の細胞内HBV DNA量あるいは培養上清中のHBV DNA量を定量的PCR法にて評価した。HBV DNAのPCRではForward primer(HBV-S190F; 5'-GCT CGT GTT ACA GGC GGG-3’:配列番号1)とReverse primer (HBV-S703R; 5'-GAA CCA CTG AAC AAA TGG CAC TAG TA-3':配列番号2)を用いた。PCRは95℃10sec to 62℃ 10sec to 72℃30secを1反応として35 Cycle実施した。
抗HCV活性の評価はヒト肝癌細胞株HuH-7由来のOR6細胞とヒト肝癌細胞株Li23由来のORL8細胞を用いて実施した。OR6細胞及びORL8細胞では、遺伝子型1b型のO株のゲノムにRenilla Luciferase遺伝子を組み込んでいるため、HCV RNA複製のレベルをRenilla Luciferase活性を測定することで簡便且つ正確に評価することができる。OR6細胞あるいはORL8細胞に薬剤を添加して3日目に細胞を回収し、Renilla Luciferase活性を測定した。
OR6細胞は3x103 cell/well、HepG2 NTCP-myc細胞は2x104 cell/wellになるように播種した。24時間後に薬剤を添加し、OR6細胞は3日間、HepG2 NTCP-myc細胞は7日間培養した。培養後、Premix WST-1 Cell Proliferation Assay System (TaKaRa)を10μl添加して37℃2時間培養後、450nmでマイクロプレートリーダーを用いて吸光度を測定した。
抗HBV剤のスクリーニングには、ヒト癌細胞株であるHepG2細胞にHBV遺伝子を導入したHepG2.2.15細胞株を使用した(Production of hepatitis B virus particles in HepG2 cells transfected with cloned hepatitis B virus DNA. Sells MA, Chen ML, and Acs G., Proc. Natl. Acad. Sci. USA 84: 1005-1009 (1987))。抗HCV剤のスクリーニングには、世界標準のヒト肝癌細胞株であるHuH-7細胞にHCV遺伝子を導入したOR6細胞を使用した(Efficient replication of a full-length hepatitis C virus genome, strain O, in cell culture, and development of a luciferase reporter system. Ikeda M, Abe K, Dansako H, Nakamura T, Naka K, Kato N., Biochem. Biophys. Res. Commun., 329(4):1350-9 (2005))。また、これ以外に本発明者らがこれまでに独自に開発したヒト肝癌細胞株Li23細胞にHCV遺伝子を導入したORL8細胞株も使用する(Efficient replication systems for hepatitis C virus using a new human hepatoma cell line. Kato N, Mori K, Abe K, Dansako H, Kuroki M, Ariumi Y, Wakita T, Ikeda M., Virus Res., 146(1-2):41-50 (2009))。本発明者を除くと、抗HCV剤のスクリーニングは世界的にもHuH-7細胞株のみを用いて実施されている。HuH-7細胞とLi23細胞では細胞内環境が異なるために、Li23細胞を用いることでHuH-7細胞だけを用いて行ったスクリーニングでは見落とされてしまう薬剤を救済することができる。
Claims (10)
- 肝腫瘍ウイルスがB型肝炎ウイルス及び/又はC型肝炎ウイルスである、請求項1記載の抗肝腫瘍ウイルス剤。
- 肝腫瘍ウイルスがB型肝炎ウイルス又はC型肝炎ウイルスである、請求項1記載の抗肝腫瘍ウイルス剤。
- 肝腫瘍ウイルスがB型肝炎ウイルスである、請求項1記載の抗肝腫瘍ウイルス剤。
- 肝腫瘍ウイルスがC型肝炎ウイルスである、請求項1記載の抗肝腫瘍ウイルス剤。
- 請求項1記載の抗肝腫瘍ウイルス剤を含有する肝腫瘍ウイルス関連疾患予防又は治療剤であって、前記関連疾患が慢性肝炎、肝硬変及び肝癌から成る群より選択される、前記予防又は治療剤。
- 肝腫瘍ウイルス関連疾患がB型肝炎ウイルス及び/又はC型肝炎ウイルス関連疾患である、請求項6記載の予防又は治療剤。
- 肝腫瘍ウイルス関連疾患がB型肝炎ウイルス又はC型肝炎ウイルス関連疾患である、請求項6記載の予防又は治療剤。
- 肝腫瘍ウイルス関連疾患がB型肝炎ウイルス関連疾患である、請求項6記載の予防又は治療剤。
- 肝腫瘍ウイルス関連疾患がC型肝炎ウイルス関連疾患である、請求項6記載の予防又は治療剤。
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