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。     

抗生素在流感大流行中的应用

随着禽流感病毒H5N1的不断蔓延,越来越有可能发生人类流感的大流行。如果现在发生流感的大流行,不仅还没有有效的疫苗,而且还可能造成抗病毒药物的缺乏。目前尚没有证据表明抗流感药物神经氨酸酶抑制剂(neuraminidaseinhibitor对)禽流感和流感大流行的病毒有效,给予神经氨酸酶抑制剂后,感染H5N1禽流感病毒的患者的死亡率仍然很高。而且流感病毒的耐药会进一步限制抗病毒药物的疗效。假如继发性细菌感染是流感常见且重要的致命性并发症,那么抗生素在人类流感大流行中将占有重要的一席地位。     

抗流行性感冒病毒药物研究综述

目的介绍抗流行性感冒病毒(包括H5N1病毒)药物的研究进展、临床应用及耐药性。方法采用近期国内外相关文献进行综述。结果疫苗能有效预防流感的发生,抗病毒药物对流感的预防和治疗都有积极的效果,但其耐药性的发展不容忽视。结论开发应用新疫苗及特异性抗流感病毒药物M2蛋白抑制剂和神经氨酸酶抑制剂等仍是防治流感的基本手段。     

抗流感新药帕拉米韦氯化钠注射液获批

4月5日,国家食品药品监督管理总局批准了抗流感新药帕拉米韦氯化钠注射液。帕拉米韦是一种新型的抗流感病毒药物,现有临床试验数据证明其对甲型和乙型流感有效。H7N9属于甲型流感病毒亚型。帕拉米韦氯化钠注射液是我国首个静脉给药的神经氨酸酶抑制剂,对于那些流感重症患者、无法接受吸入或口服神经氨酸酶抑制剂的患者和对其他神经氨酸酶抑制剂疗效不佳或产生耐药的患者提供了新的治疗选择。     

新型抗流感药物有望问世

H5N1流感病毒所致的禽流感在世界范围内引起了大流行,因此大家更加关注这种病毒是否会获得在人类之间传染的能力并引起禽流感大流行。目前用于治疗这种病毒感染引起的人禽流感的药物有两种,即奥司他韦(Tamiflu)和扎那米韦(Relenza),两者都是作用于病毒的神经氨酸酶。抗药性的出现需要研发新的抗流感药物。A型流感病毒的神经氨酸酶可分为遗传上不同的两种类型:一类包括N1神经氨酸酶,另一类包含N2、N9神经氨酸酶。N2、N9神经氨酸酶已经被作为当前药物设计的结构基础。用X射线衍射晶体分析法发现这两类酶结构上是不同的。前者在其活性位点…     

抗流行性感冒病毒药物研究进展

目的：介绍抗流行性感冒病毒（包括H5N1病毒）药物的研究进展、临床应用及耐药性。方法：采用近期国内外相关文献进行综述。结果：疫苗能有效预防流感的发生，抗病毒药物对流感的预防和治疗都有积极的效果，但其耐药性的发展不容忽视。结论：开发应用新疫苗及特异性抗流感病毒药物M2蛋白抑制剂和神经氨酸酶抑制剂等仍是防治流感的基本手段。     

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。     

喜睹治疗呼吸疾病药物的新切入制剂

天降大任,神经氨酸酶抑制剂为对抗病毒而切入新靶位病毒神经氨酸酶抑制剂(Nueraminidase Inhibitor)是继离子通道阻断剂(Ion Chaneel Bloking)金刚烷胺、金刚乙胺和流感疫苗(Influenza Vaccin)后的一类全新作用机制的抗流感药[1]。即往抗流感病毒的重任曾寄希望于前两者,但流感     

甲型H1N1流感治疗新药扎那米韦

世界卫生组织(WHO)专家警示,2009年秋冬季可能出现甲型H1N1流感大规模暴发.葛兰素史克公司研发生产的神经氨酸酶抑制剂--扎那米韦吸入粉雾剂(zanamivir,依乐韦,Relenza)能有效治疗甲型和乙型流感,是WHO和美国疾病控制与预防中心(CDC)指南推荐的抗流感病毒药物,目前分离自临床的甲型H1N1流感病毒尚未见对该药耐药者.其在国内的成功上市,将进一步完善我国应对流感的防控措施.     

抗流感病毒药物的研究进展

病毒神经氨酸酶结晶结构的确证为抗流感病毒药的合理设计提供了有力工具，借助于计算机辅助药物设计，合成筛选出一系列高效低毒的神经氨酸酶抑制剂，使抗流感病毒药的研究取得突破进展，除吸入剂扎那米韦和口服剂oseltamivir获得美国食品与药品管理局批准上市外，正在研究和开发中的病毒神经氨酸酶抑制剂类抗流感染病毒药有4类，即唾液酸类似物，环己烯衍生物，苯甲酸衍生物和环戊烷衍生物，其中环戊烷衍生物Peramivir(RWJ-270201) 正进行Ⅲ期临床研究，已获得的临床研究结果显示，peramivir可缩短流感病时间，明显缓解症状，而且可以预防流感的发生。     

Discovery of dihydro-alkyloxy-benzyl-oxopyrimidines as promising anti-influenza virus agents

A series of novel dihydro-alkyloxy-benzyl-oxopyrimidine derivatives were synthesized and evaluated for their activity against influenza virus in Madin-Darby canine kidney cells. Four dihydro-alkyloxy-benzyl-oxopyrimidine derivatives (4a1, 4a2, 4a3, and 4d1) showed potent activity against influenza virus. Among them, compound 4a3 was the most promising lead with broad activity against influenza A (antiviral EC(50) values of 9 and 18 μm for the A/H1N1 and A/H3N2 subtype, respectively) and influenza B viruses (EC(50) : 33 μm). The antiviral mechanism of action of these dihydro-alkyloxy-benzyl-oxopyrimidine derivatives must be quite different from that of the currently approved anti-influenza virus drugs that target the viral M2 or neuraminidase proteins. The dihydro-alkyloxy-benzyl-oxopyrimidine derivatives represent a new avenue for further optimization and development of novel anti-influenza virus agents.     

Computational studies of influenza A virus at three important targets: hemagglutinin, neuraminidase and M2 protein

While the seasonal influenza viruses spreading around the world cause the annual epidemics, the recent outbreaks of influenza A virus subtype H5N1 and pandemic H1N1 have raised a global human health concerns. In this review, the applicability of computational techniques focused on three important targets in the viral life cycle: hemagglutinin, neuraminidase and M2 proton channel are summarized. Protein mechanism of action, substrate binding specificity and drug resistance, ligand-target interactions of substrate/inhibitor binding to these three proteins either wild-type or mutant strains are discussed and compared. Advances on the novel anti-influenza agents designed specifically to combat the avian H5N1 and pandemic H1N1 viruses are introduced. A better understanding of molecular inhibition and source of drug resistance as well as a set of newly designed compounds is greatly useful as a rotational guide for synthetic and medicinal chemists to develop a new generation of anti-influenza drugs.     

基于计算机辅助药物设计的石荠苧抗流感药效物质多靶向作用研究简

目的 探讨石荠苧抗流感药效物质的多靶向作用机制.方法 以石荠苧中化学成分5-羟基-6,7-二甲氧基黄酮及其衍生物（MF1,MF2,MF3）为候选药物,采用计算机辅助药物设计方法研究其与流感血凝素蛋白（HA）、流感神经氨酸酶（NA）、炎症靶点环氧合酶-2（COX-2）和炎症靶点磷酸二酯酶4（PDE4）受体的对接程度.结果 在各候选药物与相关蛋白的对接中,木犀草素与HA活性位点的匹配度最高;鼠李柠檬素与NA和PDE4活性位点的匹配度最高;槲皮素与COX-2活性位点的匹配度最高;其中MF1,MF2,MF3也均表现出不同程度的匹配.结论 石荠苧中化学成分与流感病毒蛋白靶点和炎症相关蛋白靶点具有一定的结合和抑制效应,从而具多靶向抗流感病毒作用.     

Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses

The gene pool of influenza A viruses in aquatic birds provides all of the genetic diversity required for human and lower animals. Host range selection of the receptor binding specificity of the influenza virus hemagglutinin occurs during maintenance of the virus in different host cells that express different receptor sialo-sugar chains. In this paper, functional roles of the hemagglutinin and neuraminidase spikes of influenza viruses are described in the relation to 1) host range of influenza viruses, 2) receptor binding specificity of human and other animal influenza viruses, 3) recognition of sialyl sugar chains by Spanish influenza virus hemagglutinin, 4) highly pathogenic and potentially pandemic H5N1, H9N2, and H7N7 avian influenza viruses and molecular mechanism of host range variation of influenza viruses, 5) role of the neuraminidase spike for the host range of influenza viruses, and 6) Development of anti-influenza drugs.     

Current and future antiviral therapy of severe seasonal and avian influenza

The currently circulating H3N2 and H1N1 subtypes of influenza A virus cause a transient, febrile upper respiratory illness in most adults and children ("seasonal influenza"), but infants, the elderly, immunodeficient and chronically ill persons may develop life-threatening primary viral pneumonia or complications such as bacterial pneumonia. By contrast, avian influenza viruses such as the H5N1 virus that recently emerged in Southeast Asia can cause severe disease when transferred from domestic poultry to previously healthy people ("avian influenza"). Most H5N1 patients present with fever, cough and shortness of breath that progress rapidly to adult respiratory distress syndrome. In seasonal influenza, viral replication remains confined to the respiratory tract, but limited studies indicate that H5N1 infections are characterized by systemic viral dissemination, high cytokine levels and multiorgan failure. Gastrointestinal infection and encephalitis also occur. The licensed anti-influenza drugs (the M2 ion channel blockers, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir) are beneficial for uncomplicated seasonal influenza, but appropriate dosing regimens for severe seasonal or H5N1 viral infections have not been defined. Treatment options may be limited by the rapid emergence of drug-resistant viruses. Ribavirin has also been used to a limited extent to treat influenza. This article reviews licensed drugs and treatments under development, including high-dose oseltamivir; parenterally administered neuraminidase inhibitors, peramivir and zanamivir; dimeric forms of zanamivir; the RNA polymerase inhibitor T-705; a ribavirin prodrug, viramidine; polyvalent and monoclonal antibodies; and combination therapies.     

抗流感病毒抗生素研究开发进展

流感是严重危害人类健康的急性病毒性呼吸道传染病，由于流感病毒抗原变异，常规疫苗尚不能有效预防流感的暴发与流行。因此，抗流感病毒药物研究在流感治疗中具有重要意义。本文就近年来国外抗流感病毒药物研究进展，包括微生物来源的新型抗生素司他弗林(stachyflin)和乙酰司他弗林(acetylstachyflin)，FR198248，FR191512，10-norparvulenone的发现，以及经计算机分子模拟设计的氨基酸类NA抑制剂、环戊烷类NA抑制剂RWJ-270201(BCX-1812)等的开发情况进行概述。     

Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes

Since 2003, highly pathogenic A(H5N1) influenza viruses have been the cause of large-scale death in poultry and the subsequent infection and death of over 140 humans. A group of 55 influenza A(H5N1) viruses isolated from various regions of South East Asia between 2004 and 2006 were tested for their susceptibility to the anti-influenza drugs the neuraminidase inhibitors and adamantanes. The majority of strains were found to be fully sensitive to the neuraminidase inhibitors oseltamivir carboxylate, zanamivir and peramivir; however two strains demonstrated increased IC50 values. Sequence analysis of these strains revealed mutations in the normally highly conserved residues 116 and 117 of the N1 neuraminidase. Sequence analysis of the M2 gene showed that all of the A(H5N1) viruses from Vietnam, Malaysia and Cambodia contained mutations (L26I and S31N) associated with resistance to the adamantane drugs (rimantadine and amantadine), while strains from Indonesia were found to be a mix of both adamantane resistant (S31N) and sensitive viruses. None of the A(H5N1) viruses from Myanmar contained mutations known to confer adamantane resistance. These results support the use of neuraminidase inhibitors as the most appropriate class of antiviral drug to prevent or treat human A(H5N1) virus infections.     

Novel druggable hot spots in avian influenza neuraminidase H5N1 revealed by computational solvent mapping of a reduced and representative receptor ensemble

The influenza virus subtype H5N1 has raised concerns of a possible human pandemic threat because of its high virulence and mutation rate. Although several approved anti-influenza drugs effectively target the neuraminidase, some strains have already acquired resistance to the currently available anti-influenza drugs. In this study, we present the synergistic application of extended explicit solvent molecular dynamics (MD) and computational solvent mapping (CS-Map) to identify putative 'hot spots' within flexible binding regions of N1 neuraminidase. Using representative conformations of the N1 binding region extracted from a clustering analysis of four concatenated 40-ns MD simulations, CS-Map was utilized to assess the ability of small, solvent-sized molecules to bind within close proximity to the sialic acid binding region. Mapping analyses of the dominant MD conformations reveal the presence of additional hot spot regions in the 150- and 430-loop regions. Our hot spot analysis provides further support for the feasibility of developing high-affinity inhibitors capable of binding these regions, which appear to be unique to the N1 strain.     

Drug discovery against H1N1 virus (influenza A virus) via computational virtual screening approach

The H1N1 virus is the causative agent of the recent outbreak of Swine flu pandemic. Neuraminidase is an enzyme that cleave glycosidic linkage of neuraminic acid on viral cell surface and is known to occur as antigen determinant to evoke immune response in host cell. It plays an important role in life cycle of influenza virus. Inhibitors of neuraminidase are, therefore, believed to have a potential in development of new drugs against swine flu. Using a recently published model structure of neuraminidase, we have carried out virtual screening of 70 compounds obtained from Ligand databases. The ligands library also included 57 natural plant metabolites from medicinal plants. The virtual screening was performed via PatchDock & GemDock softwares. Two of the plant metabolites, Hesperidin & Narirutin showed significantly higher docking score than the currently marketed anti-influenza drug Oseltamivir (Tamiflu).