JP2017160173A - 抗hcv活性を有する薬剤 - Google Patents
抗hcv活性を有する薬剤 Download PDFInfo
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- JP2017160173A JP2017160173A JP2016048508A JP2016048508A JP2017160173A JP 2017160173 A JP2017160173 A JP 2017160173A JP 2016048508 A JP2016048508 A JP 2016048508A JP 2016048508 A JP2016048508 A JP 2016048508A JP 2017160173 A JP2017160173 A JP 2017160173A
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- Prior art keywords
- hcv
- guanfacine
- cells
- agent
- hepatitis
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Abstract
Description
[1]グアンファシン又はその塩を含む、抗HCV剤。
[2]グアンファシンの塩が、グアンファシン塩酸塩である、[1]に記載の抗HCV剤。
[3]HCVが、遺伝子型1bのHCVである、[1]又は[2]に記載の抗HCV剤。
[4][1]〜[3]のいずれかに記載の抗HCV剤を単離された細胞又は組織に投与することを含む、HCVの複製をin vitroで抑制する方法。
[5]グアンファシン若しくはその塩、又は[1]〜[3]のいずれかに記載の抗HCV剤を含む、C型肝炎の治療又は予防用組成物。
[6][5]に記載のC型肝炎の治療又は予防用組成物を含む、C型肝炎の治療又は予防用キット。
1. 抗HCV剤
本発明は、抗HCV活性を有する、抗HCV剤を提供する。一般に、抗HCV活性は、HCVの感染、複製、粒子形成、放出及び再感染のいずれかを抑制する活性を意味する。本明細書において「抗HCV活性」は、HCVの複製の抑制活性、特にHCV RNAの複製抑制活性及び/又はHCVタンパク質の発現抑制活性を含む。本明細書においてHCVに対する「抑制」とは、本発明に係る抗HCV剤を使用しない場合と比較して、HCVの複製量又はHCVタンパク質の発現量を低下させることを意味する。
「グアンファシン(guanfacine)」(N-アミジノ-2-(2,6-ジクロロフェニル)アセトアミド)は、以下の式で示される。
in vivoでの方法については、後述の「2. 組成物及び治療/予防方法」の項に記載する。
本発明はまた、上述のグアンファシン若しくはその塩、又は本発明に係る抗HCV剤を含む、C型肝炎の治療又は予防用組成物を提供する。組成物は、医薬組成物であってもよい。C型肝炎は、例えば、C型急性肝炎、C型慢性肝炎及びC型劇症肝炎を含み得る。
本発明はまた、上述の本発明に係るC型肝炎の治療又は予防用組成物を含む、C型肝炎の治療又は予防用キットを提供する。本発明に係るキットは、別の薬剤、例えば、上述したインターフェロンなどの他の抗HCV剤を含んでいてもよい。本発明に係るキットは、希釈剤、溶媒、洗浄液若しくはその他の試薬を含む容器、使用説明書、又はC型肝炎治療法若しくは予防法に適用するために必要な器具をさらに含んでいてもよい。キットに含まれる複数の成分は、それぞれ別の容器に入れられていてもよいし、混合して1つの容器に入れられていてもよい。
抗HCV活性の評価
抗HCV活性は、本発明者らがヒト肝癌細胞株Li23から開発したORL8細胞を用いて評価した(国際公開第WO2010/026965号; Kato N, et al., Virus Res., 146(1-2): 41-50 (2009))。ORL8細胞は、平成20年7月31日(原寄託日)付で独立行政法人製品評価技術基盤機構、特許生物寄託センター(NITE-IPOD)(千葉県木更津市かずさ鎌足2-5-8 120号室)に受託番号FERM BP-11157でブダペスト条約に基づき国際寄託されている。なお、本寄託株は、平成21年7月30日に国内寄託(原寄託)からブダペスト条約に基づく国際寄託に移管された。ORL8細胞には、レポーター遺伝子としてレニラルシフェラーゼ遺伝子が組み込まれた、遺伝子型1bのHCV(O株)のゲノム(全長HCV RNA)が導入されている。ORL8細胞に導入されているHCVゲノムは、約3000アミノ酸残基からなるHCV前駆体タンパク質のアミノ酸配列においてQ1112R、K1609E及びS2200R、又はQ1112R、P1115L及びS2200Rのアミノ酸置換を有するアミノ酸配列をコードする塩基配列を含む。ORL8細胞について検出されるレニラルシフェラーゼ活性は、細胞内のHCV RNA複製レベルと非常によく相関する。そのため、ORL8細胞のレニラルシフェラーゼ活性を測定することによって、HCV RNA複製レベルを簡便かつ正確に評価することができる。したがって、薬剤の抗HCV活性を、ORL8細胞のレニラルシフェラーゼ活性を指標として評価することができ、レニラルシフェラーゼ活性の低下はその薬剤が抗HCV活性を有することを示す。
HCVコアタンパク質発現量への影響の解析
ORL8細胞を、6ウェルプレートにウェル1つあたり細胞6×104個になるように播種した。培養24時間後に、溶媒としてDMSOに溶解させたグアンファシン塩酸塩を、培地中で625、1250、2500、5000又は10000nMの濃度になるように細胞に添加した。一方、対照として溶媒のみを細胞に添加した。3日間培養した後、細胞を回収し、ウエスタンブロット法にてコアタンパク質及びβ-アクチンタンパク質の発現量を解析した。ウエスタンブロット法は、サンプルをSDS-PAGE電気泳動に供し、常法に従って、抗HCVコアタンパク質抗体(株式会社特殊免疫研究所、東京、日本)及び抗β-アクチン抗体(Sigma-Aldrich社、米国)を用いて行った。
細胞毒性の評価
ORL8細胞を、24ウェルプレートにウェル1つあたり細胞2×104個になるように播種した。培養24時間後に、溶媒としてDMSOに溶解させたグアンファシン塩酸塩を、培地中で0.12、0.24、0.49、0.98、1.95、3.91、7.81、15.6、31.3、62.5、125、250又は500μMの濃度になるように細胞に添加した。一方、対照として溶媒のみを細胞に添加した。3日間培養した後、Premix WST-1 Cell Proliferation Assay System (タカラバイオ株式会社、滋賀、日本) 10μlを培地に添加して、37℃で2時間培養後、マイクロプレートリーダーを用いて450nmの吸光度を測定した。実験は独立した3ウェルで行った。得られた吸光度の、対照(グアンファシン塩酸塩添加無し)における吸光度の平均値に対する比率を算出し、細胞生存率(%)を得た。グアンファシン塩酸塩の各濃度における細胞生存率(%)の平均値及び標準偏差を算出した。
Claims (6)
- グアンファシン又はその塩を含む、抗HCV剤。
- グアンファシンの塩が、グアンファシン塩酸塩である、請求項1に記載の抗HCV剤。
- HCVが、遺伝子型1bのHCVである、請求項1又は2に記載の抗HCV剤。
- 請求項1〜3のいずれか一項に記載の抗HCV剤を単離された細胞又は組織に投与することを含む、HCVの複製をin vitroで抑制する方法。
- グアンファシン若しくはその塩、又は請求項1〜3のいずれか一項に記載の抗HCV剤を含む、C型肝炎の治療又は予防用組成物。
- 請求項5に記載のC型肝炎の治療又は予防用組成物を含む、C型肝炎の治療又は予防用キット。
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JP2011510096A (ja) * | 2008-04-18 | 2011-03-31 | ウォーソー・オーソペディック・インコーポレーテッド | 疼痛および/または炎症の治療のためのαアドレナリン作動性受容体アゴニスト |
JP2013079204A (ja) * | 2011-10-03 | 2013-05-02 | Okayama Univ | 新規抗hcv剤 |
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JP2011510096A (ja) * | 2008-04-18 | 2011-03-31 | ウォーソー・オーソペディック・インコーポレーテッド | 疼痛および/または炎症の治療のためのαアドレナリン作動性受容体アゴニスト |
JP2013079204A (ja) * | 2011-10-03 | 2013-05-02 | Okayama Univ | 新規抗hcv剤 |
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