抗流感病毒新药--神经氨酸酶抑制剂

流感病毒神经氨酸酶抑制剂是继金刚烷胺/金刚乙胺和病毒疫苗之后的一类全新作用机制的流感预防与治疗药物。本文从药理学，药效学及临床应用等方面对目前各国已经上市及正在开发中的神经氨酸酶抑制剂类药物进行了简述。     

流感病毒神经氨酸酶抑制剂的合成筛选

总结流感病毒神经氨酸酶抑制剂有效的结构特点及其结晶结构，对神经氨酸酶抑制剂进行了合成探索和构效关系研究，共设计合成6个未见报道的新化合物，其中3个为目标物，3个为中间体，通过MS，^1H-NMR证明其结构，并测定了它们的抑酶活性，结果所有化合物对神经氨酸酶都显示一定活性，同时还测定了这几个化合物抗流感病毒株粤防72-243的活性及体外抗HIV-1整合酶活性。     

流感病毒神经氨酸酶抑制剂

流感病毒神经氨酸酶促进流感病毒从感染细胞释放并有利于病毒在呼吸道内的播散。现已开发出一些强效、特异性神经氨酸酶抑制剂。成为一类新的抗流感病毒药物,其中的2种即扎那米韦（zanamivir)和oseltamivir在一些西方国家已批准上市,RWJ－270201也已进入临床实验阶段。该类药物可以抑制A和B型流感病毒的复制。扎那米韦由于口服生物利用底,采用吸入给药。oseltamivir可口服给药。两种药物都可以有效预防流感病毒感染,由于抗病毒谱广,耐受性良好,出现耐药性的可能性低于M2抑制剂,是流感治疗领域取得的主要进步。     

流感病毒神经氨酸酶抑制剂的设计策略及研究进展

流感对人类的健康构成很大威胁,尤其在流感暴发期,能够造成大量人员死亡。神经氨酸酶（NA）为流感病毒表面蛋白,在病毒的生命过程中起着重要作用,是抗流感药物设计的重要靶点。自从1983年NA结构被解析出来后,基于结构的药物设计以及计算化学的运用极大地促进了NA抑制剂（NAI）的发展,到目前为止,已有两种抗流感药物上市——扎那米韦和奥司他韦。本文将以这两种药物的开发为例,简要介绍NAI的设计策略及最近几年的研究进展。     

抗流感病毒药物神经氨酸酶抑制剂的研究进展

由于高致病性禽流感H5N1病毒在亚洲的爆发和H1N1病毒的全球性传播,设计与开发新型抗流感药物尤为迫切。目前,神经氨酸酶(唾液酸苷酶)抑制剂类的抗流感药物的研发是整个研究领域的热点。该文回顾了此类上市药物(Relenza和Tamiflu)的发展历程,综述近几年来具有神经氨酸酶抑制活性的化合物和它们的构效关系。对今后新型抑制剂的设计方向提出了建议。     

流感病毒神经氨酸酶抑制剂构效关系研究

神经氨酸酶在流感病毒的感染和传播过程中起着重要作用。针对酶活性位点进行基于结构的合理药物设计，开发各类流感病毒神经氨酸酶抑制剂，业已成为药物研究的热点之一。根据化学结构的不同，综述各类神经氨酸酶抑制剂的作用机制及构效关系。     

靶向于流感病毒神经氨酸酶新位点的抑制剂研究进展

流感是由流感病毒引起的一种严重影响人类生命健康的传染性疾病。神经氨酸酶是流感病毒表面的一种重要糖蛋白,在病毒的复制周期中起着关键作用,是抗流感病毒合理药物设计的理想靶点。自2006年以来,结构生物学研究发现了神经氨酸酶新的配体结合位点,为新型神经氨酸酶抑制剂的设计提供了依据。本文综述了靶向于神经氨酸酶新结合位点的抑制剂的研究。     

抗流感病毒药物神经氨酸酶抑制剂奥司他韦研究进展

高致病性禽流感H5N1病毒在亚州的爆发和2009新型H1N1病毒的全球性传播,提示设计与研发新型的抗流感药物尤为迫切。神经氨酸酶在病毒复制和传播中发挥重要作用,且活性中心高度保守,其抑制剂成为抗流感药物研发的热点。该文回顾了临床广泛使用的奥司他韦（osehamivir）药动学、药效学及耐药性方面的研究进展,为此药今后的临床应用提出建议。     

新型抗流感病毒神经氨酸酶抑制剂帕拉米韦研究进展

神经氨酸酶(NA)抑制剂是近年来开发的一类抗流感病毒药物,具有对各亚型流感病毒广谱的有效性、低耐药性、良好的患者耐受性等优点,成为当前抗击人感染高致病性禽流感和新型甲型H1N1流感病毒最主要的一类药物。帕拉米韦作为一种新型NA抑制剂,可以抑制多种甲、乙型流感病毒的NA活性,已进入临床研究阶段,但存在口服生物利用度不高的问题。此文介绍了帕拉米韦的研发历程、理化性质、NA抑制作用及其药动学、药效学及临床实验等研究状况。     

神经氨酸酶抑制剂对流感的临床疗效回顾

目的：病毒神经氨酸酶抑制剂是继金刚烷胺和流感疫苗后的一类全新作用机制的流感防治药物，本介绍其进展和临床对抗流感的效果。方法：采用国内外献综述方法。结果和结论：神经氨酸酶抑制剂能选择性地抑制病毒表面神经氨酸酶的活性，阻止子代病毒颗粒在宿主细胞的复制和释放，有效地预防感冒和缓解症状，在感冒初期应用，可明显缩短疾病的持续时间。     

Synthesis of influenza neuraminidase inhibitors

Influenza neuraminidase inhibitors provide a means to combat flu, a potentially very serious disease. For the first time, there is a way to treat influenza by blocking the influenza enzyme neuraminidase to stop or slow the progression of infection. The diverse structures and synthesis of several influenza neuraminidase inhibitors are discussed. Contributions from chemical process development groups are highlighted for those compounds that have reached the market, such as zanamivir and oseltamivir phosphate.     

Safety of neuraminidase inhibitors for influenza

Neuraminidase inhibitors, oseltamivir and zanamivir, are used for the treatment of, and protection from, influenza. The safety of these compounds has been assessed in systematic reviews. However, the data presented are somewhat limited by the paucity of good quality adverse event data available. The majority of safety outcomes are based on evidence from just one or two randomised controlled trials. The results of the systematic reviews suggest that neuraminidase inhibitors have a reasonable side effect and adverse effect profile if they are to be used to treat or protect patients against a life-threatening disease. However, if these compounds are to be prescribed in situations in which avoidance of inconvenience or minor discomfort is hoped for, then the balance of harms to benefits will be more difficult to judge.     

环己烯类神经氨酸酶抑制剂的定量构效关系研究

研究了37个环己烯类神经氨酸酶抑制剂结构与其抗流感活性的定量构效关系.采用本实验室提出的三维原子场全息作用矢量对环己烯类神经氨酸酶抑制剂进行结构参数化表征,采用逐步回归对变量进行筛选后运用偏最小二乘回归建模.训练集模型的复相关系数(R2)、交互校验复相关系数(Q2cum)和拟合均方根误差(RMSEE)分别为0.862,0.575和0.4864,预测集RMSEP为0.4435,模型具有良好稳定性和预测能力.结果 表明三维原子场全息作用矢量能较好表征该类分子结构信息,值得进一步推广应用.     

Aromatic sialic acid analogues as potential inhibitors of influenza virus neuraminidase.

The influenza virus neuraminidase (NA) is an enzyme essential for viral infection and offers a potential target for antiviral drug development. We aimed our research at the synthesis of non-carbohydrate molecules able to inhibit NA as transition-state analogues. Aromatic sialic acid analogues (compound 5 and compound 10) were synthesised in good yields starting from commercially available benzoic acids using a suitable synthetic strategy.     

流感病毒RNA聚合酶抑制剂的研究进展

流行性感冒是由流感病毒引起的传染性疾病。流感病毒是一种RNA病毒,流感病毒RNA聚合酶是由PB1、PB2和PA 3个亚基构成的复合体,它们通过相互结合发挥功能,在流感病毒的转录复制过程中发挥着必不可少的作用。因此,如果能够抑制RNA聚合酶的PB1、PB2和PA亚基的生物活性,使其在病毒的转录和复制过程中失去活性,就能够达到抑制流感病毒的效果。本文对流感病毒RNA聚合酶抑制剂的研究进行综述,以期为抗流感病毒RNA聚合酶药物的设计提供参考。     

Screening for potential inhibitors of influenza neuraminidase

AIM: Applying the assay method of neuraminidase(NA) activity established for high throughput screening to find novel inhibitors of influenza virus NA. METHODS: Firstly, a virtual screening strategy was applied to our compound database to select drug-like compounds, and then a high throughput screening model of NA inhibitor was applied to test these compounds. RESULTS:     

Detection of influenza virus resistance to neuraminidase inhibitors by an enzyme inhibition assay.

We previously characterized influenza viruses whose selection in the presence of neuraminidase (NA) inhibitors resulted in a substituted residue (position 119,152,274, or 292) in the NA active center. To identify the most favorable conditions for detecting NA inhibitor-resistant viruses we compared the results of four modifications of the NA inhibition assay utilizing a fluorogenic substrate. The IC50 values were highly dependent upon assay conditions, and most mutant enzymes were more sensitive to changes in assay conditions (e.g. addition of PO4(3-), Ca2+, DMSO, or EDTA) than wild-type enzymes or a mutant NA with an Arg292-->Lys substitution. Although the levels of resistance to zanamivir, oseltamivir carboxylate, and BCX-1812 (RWJ-270201) for each mutant varied among assays, mutants with substitutions at framework residues 119 or 274 exhibited sensitivity to at least one inhibitor. Viruses with substitutions at catalytic residues 152 or 292 were resistant to each inhibitor in all assays. Monitoring resistance in a clinical setting will require a panel of resistant viruses to ensure that assay conditions are favorable for detecting variants with substituted residues in the NA active center. Because variants selected in the presence of one NA inhibitor could be variably resistant to other inhibitors, all three inhibitors should be used in drug susceptibility testing.     

Susceptibility of recent Canadian influenza A and B virus isolates to different neuraminidase inhibitors

Forty-two influenza A and 23 influenza B isolates collected from untreated subjects during the 1999-2000 influenza season in Canada were tested for their susceptibility to three neuraminidase inhibitors (zanamivir, oseltamivir carboxylate and RWJ-270201 or BCX-1812) using a chemiluminescent neuraminidase assay. Influenza B isolates were less susceptible than A viruses to all tested drugs. RWJ-270201 was the most potent drug against both influenza A(H3N2) (mean IC(50): 0.60 nM) and B (mean IC(50): 0.87 nM) viruses. Oseltamivir carboxylate was more active than zanamivir for influenza A(H3N2) isolates (mean IC(50): 0.73 vs. 2.09 nM) whereas it was less potent against B viruses (mean IC(50): 11.53 vs. 4.15 nM).