Screening for Influenza A Nucleoprotein and RNA Polymerase Inhibitors

甲形流感病毒是一種傳染病的病源體，每年有多於二十五萬人被它奪去性命。流感病毒曾引發幾次全球性大流行瘟疫，而且也在每年引發季節性流感。 ; 到目前為止， 經由美國食品藥品監督管理局批准，有五種抗流感藥物是適用於抵抗流感病毒。 但其中兩種藥物（金剛烷胺，金剛乙胺）因病毒已對其產生抗藥性而被視為無效。此外，流感病毒也對其餘三種抗流感藥物（奧司他韋，扎那米韋和帕拉米韋）產生零星的抗藥反應。因此，我們迫切需要研發新的抗病毒藥物，以防備下一次流感大爆發。 ; 我們選擇流感核糖核蛋白複合物（RNP）作為藥物篩選的標靶。RNP是由流感聚合酶複合體（PA，PB1和PB2）和核蛋白（NP）所組成的。 流感病毒必須依靠RNP才能複製及轉錄其基因組。當RNP的活性被抑制，流感病毒的增長也會因而被抑制。 ; 在我們的研究中，我們使用表面等離子共振來篩選小分子。經篩選過後，我們發現了數個針對流感核蛋白(NP)及流感聚合酶A的C端結構域（PAC）的小分子。這些初選化合物能夠抑制RNP的活性，而且能夠減低流感病毒的增長。這些發現可以幫助我們將來設計更有效的先導化合物。 ; Influenza A virus is an infectious agent which claims more than 250 000 lives annually. It was responsible for several major pandemics in the past and epidemics each year. Till now, five FDA-approved antivirals were available against influenza virus. However, two of them (Amantidine, Rimantadine) were now deemed ineffective due to drug resistance. Sporadic resistance to the remaining antivirals (Oseltamivir, Zanamivir and Peramivir) was also detected in circulating influenza virus. As a result, new antivirals were urgently needed to safeguard us from influenza outbreaks. ; We have chosen the influenza ribonucleoprotein (RNP) complex as our screening target. The RNP consists of the influenza polymerase complex (PA, PB1 and PB2) and nucleoprotein (NP). RNP is essential for the replication and transcription of viral genome. The disruption of its activity can attenuate influenza virus growth. ; In our study, we have identified several novel small molecules that target on NP and the C-terminal domain of PA (PAC) by SPR screening. These hit compounds can inhibit RNP activity and attenuate influenza virus replication. The identification of novel anti-influenza hit compounds would facilitate the design of lead inhibitors in the future. ; Lo, Chun Yeung. ; Thesis Ph.D. Chinese University of Hong Kong 2016. ; Includes bibliographical references (leaves ). ; Abstracts also in Chinese. ; Title from PDF title page (viewed on …). ; Detailed summary in vernacular field only. ; Detailed summary in vernacular field only. ; Detailed summary in vernacular field ...