瑞樂沙共軛衍生物對流感病毒之雙標靶治療

Zanamivir Conjugates for Dual-targeted Therapy of Influenza

柳公政(Kung-Cheng Liu)

指導教授 ： 方俊民

國立臺灣大學/理學院/化學研究所/博士(2011年)

https://doi.org/10.6342/NTU.2011.10926

摘要

流行性感冒屬於上呼吸道的感染，對於人類健康會造成很嚴重的危害，全世界各地出現的禽流感H5N1以及2009年所爆發新型流感H1N1，隨時都可能造成大規模的流行。由於目前抗流感藥物(瑞樂沙及克流感)對於H5N1流感治療效果不佳，同時感染時很容易引發無法控制的發炎反應，使得感染後具有非常高的死亡率。而對於H1N1的治療上，病毒對於克流感以及M2離子通道的抑制劑(金剛胺及金剛乙胺)產生抗藥性的問題日益嚴重，也就限制了單獨藥物使用的效果，於是目前發展服用兩種或以上的抗流感藥物；或者是同時合併使用抗流感藥物與控制宿主免疫反應的藥物，不同類型的雞尾酒式療法漸漸發展出來，以克服藥物抗藥性以及治療效果不佳的問題。
在此我們發展一種新型雙效的藥物，以瑞樂沙與抗發炎藥物(咖啡酸或是阿腸克錠)的共軛型式，希望可以同時達到抗流感以及抗發炎的功效。我們成功合成出一系列的共軛衍生物，化合物從瑞樂沙C7或者C1的位置做酯基的衍生，不僅可以作為瑞樂沙的前驅藥物，以延長藥物在生物體中的作用時間；並且藉由瑞樂沙對流感病毒上的NA辨識的能力，可以讓藥物集中分布在受病毒感染的組織周圍，以提高抗發炎藥物的選擇性，預期可以達到更甚於雞尾酒式的治療效果。
我們以鼻腔滴入的方式讓小鼠服用藥物，來對抗A/California/07/2009(H1N1)及A/Vietnam/1194/2004 (H5N1)兩種流感病毒，觀察我們所合成出來的一系列共軛化合物保護小鼠避免死亡的功效。實驗結果證實，我們所設計合成出來的瑞樂沙與咖啡酸的酯基共軛化合物50與抗流感及抗發炎藥物合併治療相較之下，明顯提高小鼠感染H5N1或H1N1後的存活率，爾後成功合成出化合物50的醯胺鍵類似物106，在小鼠實驗中也具有相當的療效。離體的細胞實驗中，一系列共軛性的化合物的確保留了抗發炎的活性，同時我們也觀察感染病毒之小鼠服用共軛化合物50後，觀察到體內細胞激素的減少。進一步的藥物動力學的實驗正在進行中，希望可以提供更多的證據來說明藥物在生物體中的作用機制。

關鍵字

流感 ； 瑞樂沙 ； 抗發炎 ； 雙標靶

並列摘要

Influenza is a respiratory infection that causes severe health problem. The worldwide spread of the H5N1 avian flu and the outbreak of the new type H1N1 human flu in 2009 have increased public awareness of the potential for global influenza pandemics. The high mortality of human infected by influenza A/H5N1 has been attributed to the poor response of virus to neuraminidase drugs (oseltamivir and zanamivir) and uncontrolled virus-induced cytokines. Monotherapy for H1N1 is limited due to the rapidly developed drug-resistance. At present, the combination therapy with two or more drugs that target different viral proteins or host immune response may overcome the problem of drug-resistance with monotherapy.
Herein we report a new type of dual-targeted conjugates of zanamivir with caffeic acid or mesalazine to inhibit both influenza virus and inflammation. A series of cleavable conjugates of zanamivir with anti-inflammatory drugs were synthesized via ester bond linkage at the C7 or C1 positions. Such prodrug not only worked as a long-acting neuraminidase inhibitor in the mice inflected with influenza virus, but also acted as a recognition unit that brought the anti-inflammatory moiety to the damaged tissue caused by the influenza virus.
The virus-infected mice were treated intranasally to demonstrate the efficiency of the dual-targeted conjugates to protect mice caused by A/California/07/2009 (H1N1) and A/Vietnam/1194/2004 (H5N1) viruses. The survival rates in the mice challenged with H1N1 or H5N1 infections were significantly improved by treatment with conjugate 50 or amide conjugate 106, in comparison with the combination treatment of zanamivir and anti-inflammatory drugs. The dual-targeted conjugates not only inactivated influenza viruses but also decreased proinflammatory cytokines as shown by the cell-based assays. Further investigation of cytokine levels in the infected mice after drug treatment and pharmacokinetic studies would give an insight into the working mechanism of conjugate 50.

並列關鍵字

Influenza ； Zanamivir ； Antiinflammation ； Dual-targeted

參考文獻

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