JP2023026528A - シアノバクテリア抽出物、その調製方法と利用方法 - Google Patents
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Abstract
Description
本出願は、その内容全体がここに参考文献として合体される2017年8月30日に出願された米国仮出願第62/552,045号の利益に関連し、それを主張するものである。
本発明は、新規なシアノバクテリア抽出物、その調製方法およびその利用法に関する。特に、前記シアノバクテリア抽出物は、エンテロウイルス(EV)、呼吸器合胞体ウイルス(RSV)、ヒトヘルペスウイルス(HHV)、エボラウイルス、ブタ流行性下痢ウイルス(PEDV)、ブタ繁殖・呼吸障害症候群ウイルス(PRRSV)等の広範囲のウイルスに対して抗ウイルス活性を示す。
シアノバクテリアは、陸地および淡水、汽水、または海水に見られる微小細菌である。シアノバクテリアは酸素生成光合成を行う。それらは光合成性であるため、水生シアノバクテリアは一般的に藍藻と呼ばれる。現在、シアノバクテリア門下には2,000以上の種が記載されている。シアノバクテリアは、抗ウイルス作用、抗菌作用、抗真菌作用、抗癌作用を持つ生物学的に活性な化合物の豊富な供給源として確認されている。シアノバクテリアから単離された化合物は、ポリケチド、アミド、アルカロイド、脂肪酸、インドール、およびリポペプチドのグループに属している。所望の治療効果を有する活性がある抽出物フラクションまたは化合物を同定するための努力がなされている。
読者に対して基本的な理解を提供するために、以下に、本開示の簡略化された概要を提示する。この要約は、本開示の広範な概要ではなく、本発明の主要/重要な要素を特定したり、本発明の範囲を画定したりするものではない。その唯一の目的は、後に提示されるより詳細な説明への前置きとして、ここに開示されるいくつかの概念を簡略化された形式で提示することにある。
添付の図面に関連して以下に提供される詳細な説明は、本例の説明として意図されており、本例が構成または利用され得る唯一の形態を表すことは意図されていない。記載は、例の機能と、例を作成および操作するための一連の工程の手順を説明している。しかしながら、同一または同等の機能およびシーケンスは、異なる例によって達成されうる。
乾燥したA.マキシマバイオマス(10 g)を、攪拌しながらd.d.水(100 ml)中に懸濁した。この懸濁液を0℃未満の冷蔵庫に少なくとも8時間置き、懸濁液を氷塊の断片へと凍結させた。次に、氷塊を0~37℃で穏やかな振動または撹拌下で解凍し、氷塊がゆっくりと溶けるようにした。凍結および解凍プロセスを少なくとも2回行い、その後、解凍した懸濁液を高速で1時間遠心分離して、固形残留物を除去した。このようにして得られた冷水AM抽出物を、FE-L-APO抽出物と呼ぶ。このFE-L-APO抽出物を凍結乾燥して、さらなる分析のためにFE-L-APO粉末を得た。
乾燥したA.マキシマバイオマス(10 g)を、攪拌しながらd.d.水(100 ml)中で懸濁させ、懸濁液を約80℃~120℃に少なくとも1時間加熱して、粗抽出物を得た。粗抽出液を3,500rpmで約20~30分間遠心分離し、これによって得られた上澄みが熱水AM抽出液(SH抽出液)である。前記水性SH抽出物を凍結乾燥して、さらなる分析のためのSH粉末を得た。
前記AM抽出物の抗ウイルス効力および細胞毒性を、それぞれ中和試験およびMTTアッセイにより調査した。結果は、特に指定のない限り、4つのウェルからの平均±SDとして表されている。
0日目に、10日齢のICRマウスに、i.P.(腹腔内)ルートでEV71/MP4(3.0×106 PFU/マウス)を接種した。接種の1時間後、マウスに0.375、0.75、1.5、または3 mg/kg/日のSHD1抽出物を腹腔内投与した。1日1回、連続して10日間、1、5、または50 mg/kg/日のSHD1抽出物を注射または経口で投与した。臨床スコアと生存率を15日間(0日から14日まで)監視した。結果を図5A(SHD1抽出物の腹腔内注射)および図5B(SHD1抽出物の経口投与)に要約した。臨床スコア「0」は健康、「1」は衰弱、「2」は片足の麻痺、「3」は両足の麻痺、「4」は死を意味する。
RSVウイルスに対する本AM抽出物の抗ウイルス活性(EC50)を、宿主細胞としてMA-104細胞を使用した一次細胞変性効果(CPE)減少アッセイを使用して調査した。ニュートラルレッド(NR)ベースのインビトロ(in vitro)毒性アッセイを使用してCC50を測定した。
本AM抽出物の抗エボラ活性(EC50)を、宿主細胞としてベロCCL81細胞を使用したプラーク減少アッセイを使用して測定した。ニュートラルレッド(NR)ベースのインビトロ(in vitro)毒性アッセイを使用してCC50を測定した。この例では、従来のFE-L-APO抽出物と抗ウイルス剤であるファビピラビルを対照として使用した。
この例では、ブタ流行性下痢ウイルス(PEDV)に対するAM抽出物の阻害活性を調査した。この例において、AM抽出物を最初にウイルスと混合した。具体的には、DMEM(50μl/ウェル)、50μlのFE-L-APO(2 mg/ml)またはSH(20 mg/ml)、および、1,000 PFU、100 PFU、10 PFUを含む100μl/ウェルのPEDVウイルス溶液を96ウェルプレートの各ウェルに順次加えた。陽性対照の場合、100μl/ウェルのDMEMを100μl/ウェルの異なるウイルス濃度と混合し、陰性対照の場合は、200μlのDMEMを使用した。次に、プレートを37℃で60分間インキュベートした。その後、各ウェルからの混合物(200μl)を、一晩培養したベロ(Vero)細胞(1×105細胞/ウェル)を含む96ウェルプレートの各ウェルに加えた。次にプレートを37℃で5日間インキュベートした。一次細胞変性効果を測定し、結果を表16に要約する。
この試験では、ブタ繁殖・呼吸障害症候群ウイルス(PRRSV)に対する本AM抽出物の阻害活性を調査した。この例では、AM抽出物を最初に宿主細胞と混合した。簡単に説明すると、ベロ細胞(1×105細胞/ウェル)を96ウェルプレートで一晩培養した。その後、50μlのFE-L-APO(2 mg/ml)およびSH(20 mg/ml)を各ウェルに加え、プレートを37℃で60分間置いた。次に、1,000 PFU、100 PFU、または、10 PFUを含むPRRSVウイルス溶液(100μl/ウェル)を各ウェルに加えた。陽性対照については、100μl/ウェルのDMEMを100μl/ウェルの異なる濃度のウイルスと混合し、他方、陰性対照については、200μlのDMEMを使用した。次にプレートを37℃で5日間インキュベートし、一次細胞変性効果を毎日測定した。
この実施例では、本AM抽出物を消化酵素で処理し、そして当該AM抽出物が経口摂取された時に抗ウイルス活性を失うかどうかを解明するためにEC50を測定した。
Claims (10)
- アルスロスピラ・マキシマ(Arthrospira maxima)抽出物(AM抽出物)であって、前記AM抽出物中少なくとも60%(重量%)の全糖を含み、かつ、前記AM抽出物中の全糖に基づいて、60%(重量%)~100%(重量%)の中性および/または正に荷電した多糖を含み、少なくとも50モル%のラムノースを含み、ここで、前記中性および/または正に 荷電した多糖はラムノースとフコースを含み、最も豊富なグリコシル結合は3-rhapであり、
前記AM抽出物は、100KDの分子量カットオフ(MWCO)を有するフィルター膜を使用して得られる高分子量フラクションに由来する、AM抽出物。 - 請求項1に記載のAM抽出物であって、
アルスロスピラ・マキシマのバイオマスを80~120℃の熱湯で抽出して、粗抽出物を得、
前記粗抽出物から固形残留物を除去して熱水抽出物を得、そして
必要に応じて、前記熱水抽出物を乾燥させて熱水抽出物粉末を得、
さらに、前記熱水抽出物または前記熱水抽出物粉末を含む溶液を、100KDの分子量カットオフ値を有するフィルター膜を使用して濾過し、高分子量フラクションを得、
必要に応じて、前記高分子量フラクションを乾燥させて高分子量抽出物粉末を得、
さらに、前記高分子量フラクションまたは前記高分子量抽出物粉末を含む溶液を、陰イオン交換カラムを用いた陰イオン交換クロマトグラフィーにかけ、
前記陰イオン交換カラムを通って流れる流出物を収集し、ここで、前記流出物は、正に荷電したおよび/または中性の多糖が豊富なAM抽出物を含み、
前記陰イオン交換カラムを塩溶液で溶出して溶出物を収集し、ここで、前記溶出物は、負に荷電した多糖が豊富なAM抽出物を含み、そして、
必要に応じて、前記流出物または前記溶出物をそれぞれ乾燥して、正に荷電したまたは中性の多糖に富む抽出物粉末と、負に荷電した多糖に富む抽出物粉末を得ることにより得られる、AM抽出物。 - 請求項1に記載のAM抽出物の調製方法であって、
アルスロスピラ・マキシマのバイオマスを80~120℃の熱湯で抽出して、粗抽出物を得る工程、
前記粗抽出物から固形残留物を除去して熱水抽出物を得る工程、そして、
必要に応じて、前記熱水抽出物を乾燥させて熱水抽出物粉末を得る工程、を有し、
さらに、前記熱水抽出物または前記熱水抽出物粉末を含む溶液を、100KDの分子量カットオフ値を有するフィルター膜を使用して濾過し、高分子量フラクションを得る工程、そして
必要に応じて、前記高分子量フラクションを乾燥させて高分子量抽出物粉末を得る工程、を有し、
さらに、前記高分子量フラクションまたは前記高分子量抽出物粉末を含む溶液を、陰イオン交換カラムを用いた陰イオン交換クロマトグラフィーにかける工程、
前記陰イオン交換カラムを通って流れる流出物を収集する工程であって、ここで、前記流出物は、正に荷電したおよび/または中性の多糖が豊富なAM抽出物を含む、工程、
前記陰イオン交換カラムを塩溶液で溶出し、溶出物を収集する工程、ここで、前記溶出物は、負に荷電した多糖が豊富なAM抽出物を含む、工程、そして、
必要に応じて、前記流出物または前記溶出物をそれぞれ乾燥して、正に荷電したまたは中性の多糖に富む抽出物粉末と、負に荷電した多糖に富む抽出物粉末を得る工程、を有する、方法。 - 前記陰イオン交換カラムは、ジエチルアミノエチル(DEAE)ベースのカラム、第四級アミノエチル(QAE)ベースのカラム、または、トリメチルアミノエタン(TMAE)ベースのカラムである、請求項3の記載の方法。
- エンテロウイルス(EV)、呼吸器合胞体ウイルス(RSV)、ヒトヘルペスウイルス(HHV)、エボラウイルス、ブタ流行性下痢ウイルス(PEDV)、または、ブタ繁殖・呼吸障害症候群ウイルス(PRRSV)によって引き起こされるウイルス感染、または、前記ウイルス感染によって引き起こされる障害の治療に使用するための薬剤の製造における請求項1または2に記載のAM抽出物の使用。
- 栄養補助食品的に許容される賦形剤と請求項1または2に記載のAM抽出物とを含む、栄養補助食品組成物。
- エンテロウイルス(EV)、呼吸器合胞体ウイルス(RSV)、ヒトヘルペスウイルス(HHV)、エボラウイルス、ブタ流行性下痢ウイルス(PEDV)、または、ブタ繁殖・呼吸障害症候群ウイルス(PRRSV)によって引き起こされるウイルス感染、または、前記ウイルス感染によって引き起こされる障害を治療するための医薬組成物であって、請求項1または2に記載のAM抽出物、および、薬学的に許容される賦形剤を含む、医薬組成物。
- 固体支持体と、前記固体支持体の片面にコーティングされた付着層とを有する生体適合性包帯(dressing)であって、前記付着層は請求項1または2に記載のAM抽出物を含む、生体適合性包帯。
- 宿主細胞におけるウイルスのウイルス複製をin vitroで阻害するための方法であって、前記ウイルスは、エンテロウイルス(EV)、呼吸器合胞体ウイルス(RSV)、ヒトヘルペスウイルス(HHV)、エボラウイルス、ブタ流行性下痢ウイルス(PEDV)、または、ブタ繁殖・呼吸障害症候群ウイルス(PRRSV)であり、請求項1または2に記載のAM抽出物の有効量に前記宿主細胞を曝露する工程を含む、方法。
- 前記宿主細胞は、哺乳動物の宿主細胞である請求項9に記載の方法。
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