合成瑞樂沙磷衍生物來對抗流感病毒

Abstract

流行性感冒（influenza）為一種急性呼吸道疾病，由流感病毒所引起，發病快速，在歷史上爆發過的全球性疫情不勝枚舉，特別是近幾年來的H5N1 的禽流感以及H1N1的新型流感最為嚴重。瑞樂沙及克流感為治療流感最主要的兩種藥物，以病毒的神經胺酸酶作為抑制目標。神經胺酸酶在病毒的生命週期扮演很重要的角色，從演化的角度來看，不同亞型的神經胺酸酶可依照其相似程度分成兩大群：包含N1、N4、N5、N8 的group-1 以及包含N2、N3、N6、N7、N9 的 group-2，group-1 的神經胺酸酶在構型上多出了一個可結合空間，稱為150-cavity。因此我們以150-cavity 為目標，設計新型抗流感藥物。另一方面，當病人感染流感時，病毒所引發的嚴重發炎反應會產生許多嚴重併發症如肺炎，提高了病患的致死率。因此，我們設計出新型雙標靶（dual-target）藥物，結合抗流感藥物以及抗發炎藥物，希望在治療流感藥物上能有更好的成效。 之前本實驗室已經開發出瑞樂沙磷衍生物的合成方法，我們在此進一步合成中間體26，並針對不同目標來做化學結構上的修飾。我們已經成功合成出化成物34以及化合物39，期望此類新型雙標靶藥物能夠抑制發炎反應並同時具有抗病毒療效，目前生物活性測試正在進行中。 另一方面，以group-1的神經胺酸脢為抑制目標的化合物42和43目前還在和成階段，未來希望對於疫情嚴重的H5N1能夠有很有的抑制效果。

Influenza is a severe viral infection of respiratory system. The outbreaks of worldwide H5N1 avian influenza and the new type pandemic H1N1 human flu have heightened the threat of public health. Zanamivir and oseltamivir are the main anti-influenza drugs targeting the neuraminidase (NA) of influenza virus. NA plays an important role in the life cycle of influenza viruses. There are two phylogenetically distinct groups of NAs of influenza A viruses: group-1 NAs include the N1, N4, N5, and N8 subtypes, and group-2 NAs include the N2, N3, N6, N7, and N9 subtypes. The group-1 NA contains a flexible loop and a cavity, so-called “150-cavity” near the binding pocket S2. Based on this rationale, we designed new inhibitors, which targeted 150-cavity of group-1 NA for better inhibitory activity. On the other hand, the uncontrolled virus-induced cytokines could cause the high mortality of human infected by H5N1 avian influenza virus. We explored the novel dual-target bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents. Our research group has developed the zanamivir phosphonate congeners, which have better inhibitory activities. In this study I synthesized the pivotal intermediate compound 26, and further modified the C4-substituent for two specific aims. We successfully synthesized compounds 34 and 39 by conjugating the phosphono-zanamivir with anti-inflammatory agents as new dual-target drugs against influenza viruses. The bioactivity of compounds 34 and 39 is currently under investigation. We also designed the phosphono-zanamivir derivatives 42 and 43 having additional bindings to the 150-cavity of group-1 NAs. The synthetic work is in progress.