JP6415568B2 - A型インフルエンザrna依存性rnaポリメラーゼの低分子阻害剤 - Google Patents
A型インフルエンザrna依存性rnaポリメラーゼの低分子阻害剤 Download PDFInfo
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Description
発明の分野は、抗ウイルス性化合物および組成物である。
A型インフルエンザウイルスは、(−)−センスRNAウイルスのオルトミクソウイルス科のウイルスである。A型インフルエンザウイルスゲノムは、11のタンパク質をコードする8つの分節または染色体で構成されている1。感染の際に、ウイルスにコードされたRNA依存性RNAポリメラーゼ(RdRP)が、(−)鎖RNAを(+)鎖メッセンジャーRNA、およびゲノム複製のテンプレートとして働く一組の全長相補性ゲノムRNA(またはcRNA)に変換する。(+)鎖メッセンジャーRNAから発現されたウイルスタンパク質は、感染を確立して、感染周期を反復する最初の8つの(−)鎖染色体を含むウイルス粒子の増幅、組み立て、および放出に至るプロセスであるウイルス複製を促進するという作業に取り組む。
本発明者らは、A型インフルエンザの感染生命周期、そしておそらくウイルス複製を妨害する様々な組成物および方法を発見した。それゆえ本発明者らは、ウイルス感染(そして特にRNAウイルスへのウイルス感染)の処置のためのそのような化合物の使用、および/またはウイルス感染(そして特にRNAウイルスへのウイルス感染)を処置する薬物の製造のためのそのような化合物の使用も企図する。
RdRPを基にしたレポータシステムを用いる、新たに開発された超高感度細胞アッセイに基づいて、明白に保存されたウイルスターゲット(おそらく、ウイルス複製および/または遺伝子発現機構)に対して有意な抗ウイルス活性を有する複数の化合物(例えば、A0435およびA0439)が発見された。
細胞に基づくレポータアッセイ:RdRPの阻害剤を同定するために、本発明者らは、ウイルスの生物学に基づいてマウス細胞アッセイ系を設計した。この系を作製するために、PA、PB1、PB2、NPおよびNS1をコードするウイルス遺伝子を、遺伝子特異性オリゴヌクレオチドを用いたA/プエルトリコ/8/34型ウイルスcDNAテンプレートの逆転写酵素−ポリメラーゼ連鎖反応(またはRT−PCR)により増幅させた。得られたPCR産物を、次にRNAポリメラーゼII発現カセットを用いて哺乳動物発現ベクター(pVAX)にクローニングし、挿入物の配列をDNA配列決定により検証した。RNAポリメラーゼI依存性発現カセットを作製するために、発表された報告12と類似の手法で、マウス45S rRNA転写開始部位の上流の255bp配列から得られたRNAポリメラーゼIプロモータ配列を、多重クローニング部位に、そして続いてオーバーラップしたオリゴヌクレオチドを用いたPCRにより作製された33bpマウスRNAポリメラーゼI終結配列に連結して、pBluescriptにクローニングした。pPolIと呼ばれるこの構築物を、その後、多重クローニング部位内で消化し、5’UTR/ルシフェラーゼ/3’UTRに方向性を持ってライゲートして、pPolI−Lucを作製した。pPolI−Luc−DelUTR(即ち、欠失されたUTRを含む)およびpPolI−GFP(ルシフェラーゼの代わりに緑色蛍光タンパク質をコードするUTRを有する)構築物を、類似の方式で作製した。
1) Fields Virology 5th edition. Edited by David M Knipe and Peter M Howley, Lippincott−Raven, Philadelphia, USA, 2007.
2) Lutz A, Dyall J, Olivo PD, Pekosz A. Virus−inducible reporter genes as a tool for detecting and quantifying influenza A virus replication. J Virol Methods. 2005 Jun; 126(1−2):13−20.
3) Hale BG, Randall RE, Ortin J, Jackson D. The multifunctional NS1 protein of influenza A viruses. J Gen Virol. 2008 Oct; 89(Pt 10):2359−76.
4) Robb NC, Smith M, Vreede FT, Fodor E. NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome. J Gen Virol. 2009 Jun; 90(Pt 6):1398−407.
5) ”Update on oseltamivir resistance to influenza H1N1 (2009) viruses”. World Health Organization (WHO). December 15, 2010.
6) Kiso M, Mitamura K; Sakaitagawa Y, Shiraishi K, Kawakami C, Kimura K, Hayden F, Sugaya N, Kawaoka Y. (2004). Resistant influenza A viruses in children treated with oseltamivir: descriptive study. The Lancet 364: 759−765
7) Le M, Kiso M, Someya K, Sakai T, Nguyen H, Nguyen H, Pham D, Ngyen H, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y. Avian flu: isolation of drug−resistant H5N1 virus. Nature 2005, 437(7062): 1108
8) Dharan NJ, Infections with oseltamivir−resistant influenza A(H1N1) virus in the United States. JAMA, 2009. 301(10): p. 1034−41.
9) Gubareva LV, Matrosovich MN, Brenner MK, Bethell RC, Webster RG. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998 Nov; 178(5):1257−62.
10) http://www.cdc.gov/flu/wheekly/weeklyarchives2008−2009/wheekly35.htm
11) Sheu TG, Fry AM, Garten RJ, Deyde VM, Shwe T, Bullion L, Peebles PJ, Li Y, Klimov AI, Gubareva LV. Dual resistance to adamantanes and oseltamivir among seasonal influenza A(H1N1) viruses: 2008−2010. J Infect Dis. 2011 Jan 1; 203(1):13−7.
12) Neumann G, Zobel A, Hobom G. RNA polymerase I−mediated expression of influenza viral RNA molecules. Virology. 1994 Jul; 202(1):477−9.
Claims (8)
- 第二の抗ウイルス薬をさらに含む、請求項1または請求項2に記載の医薬組成物。
- 前記第二の抗ウイルス薬がウイルス複製を阻害する薬物であるか、または前記第二の抗ウイルス薬が、インターフェロンである、請求項3に記載の医薬組成物。
- 前記化合物を必要とする患者に投与する場合に、前記化合物が、前記患者におけるインフルエンザAウイルスのウイルス増殖を低減するのに効果的な量で前記医薬組成物中に存在する、請求項1〜6のいずれか1項に記載の医薬組成物。
- インフルエンザAウイルスによるウイルス感染の治療における使用のための請求項1に定義される式Iの化合物であって、前記化合物を必要とする患者に投与する場合に、前記化合物が、前記患者におけるインフルエンザAウイルスのウイルス増殖を低減するのに効果的な量で使用される、請求項1に定義される式Iの化合物。
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WO2021032611A1 (en) * | 2019-08-20 | 2021-02-25 | Curovir Ab | Heteroaromatic compounds useful in therapy |
KR102405727B1 (ko) | 2020-01-22 | 2022-06-07 | 한국한의학연구원 | 코로나바이러스 감염증 치료제 스크리닝 시스템 |
CN111388477B (zh) * | 2020-04-24 | 2021-06-25 | 山东师范大学 | 2-苯基吡唑[1,5-a]嘧啶类化合物作为肿瘤耐药逆转剂的应用 |
TW202348228A (zh) | 2022-02-24 | 2023-12-16 | 德商艾斯巴赫生物有限公司 | 病毒組合療法 |
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WO2013123974A1 (en) * | 2012-02-21 | 2013-08-29 | Universita' Degli Studi Di Padova | New inhibitors of influenza a and b viruses acting by disrupting pa and pb1 subunit interactions of heterotrimeric viral rna polymerase |
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AU2013407264A1 (en) | 2016-07-28 |
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JP2017500314A (ja) | 2017-01-05 |
AU2016273938B2 (en) | 2018-08-23 |
CA2939036C (en) | 2020-09-22 |
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