抗流感药奥司他韦

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，奥司他韦(oseltamivir)作为一种最新研制的神经氨酸酶抑制剂，具有对A、B型流感病毒均有效、不易耐药和患者耐受性好等优点，为流感的防治提供了一个新的有效选择。     

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。     

抗流感病毒药物的研究进展

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，常规疫苗目前尚不能有效预防流感暴发与流行，因此抗流感病毒药物研究在流感治疗中具有重要意义。已应用和正在研究的抗流感病毒药物有金刚烷胺类药物、流感病毒神经氨酸苷酶抑制剂、流感病毒受体阻断剂和抗流感病毒反义寡核苷酸等。金刚烷胺和金刚乙胺是常用临床治疗药物，但对Ｂ型流感无效，易产生耐药性并具有神经毒性；流感病毒神经氨酸苷酶抑制剂研究已     

神经氨酸酶抑制剂在对抗流感病毒中的作用

流感是流感病毒引起的急性呼吸道传染病，由于抗原变异频繁，疫苗的预防效果不理想，所以抗流感病毒药物的研究显得更加重要。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均有效，不易耐药和患者耐受性好等优点，为流感的防治提供了一个新的有效选择。     

抗流感小分子药物研究进展

流感病毒种类多、变异快,是对人类健康威胁最大的呼吸道病毒。季节性流感每年均会造成地区性疫情,大流行流感每隔几年导致全球性的流感大暴发,高致病性禽流感病情凶险,死亡率高。而流感病毒极高的基因重配效率严重影响了流感疫苗的效果。因此,抗流感药物成为流感疫情防控的核心手段。随着金刚烷胺、金刚乙胺的长期使用和作为动物饲料添加剂,季节性流感和新发流感病毒对其几乎全部耐药,而随着奥司他韦的广泛使用,流感病毒对神经氨酸酶抑制剂耐药也存在潜在的趋势,加快推进新型抗流感药物研发迫在眉睫。本文从流感病毒感染复制周期入手,对近年来抗流感药物新靶点、新药物实体进行综述,并重点阐述处于临床研究阶段的抗流感新药品种。     

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。     

新型流感病毒聚合酶抑制剂——ZSP1273

流感是一种由流感病毒引起的急性呼吸道传染病。抗病毒药物可以缩短病程和减少严重并发症的发生。ZSP1273是一种甲型流感病毒RNA依赖RNA聚合酶（RdRp）聚合酶碱性亚基2(PB2)抑制剂类小分子抗流感病毒药物。Ⅲ期临床试验结果表明,ZSP1273较安慰剂可显著缩短流感症状缓解时间和发热缓解时间,较安慰剂或奥司他韦更快、更有效地降低甲型流感病毒载量,显著缩短病毒转阴时间,并且表现出良好的安全性和耐受性。本文就ZSP1273的基本信息、作用机制、药动学、临床前研究及临床研究等进行概述。     

新型抗甲型流感药物——Pimodivir

Pimodivir是Vertex Pharmaceuticals公司正在开发中的一种口服抗甲型流感药物,是一种非核苷类甲型流感病毒RNA依赖的RNA聚合酶(RdRp) PB2亚基抑制剂。临床前试验研究证实,Pimodivir可以有效抑制对金刚烷胺和神经氨酸酶抑制剂耐药的各类甲型流感病毒,并且与神经氨酸酶抑制剂类药物奥司他韦有协同作用。Ⅰ期临床试验结果证实在健康志愿者中,Pimodivir 600 mg每日2次的剂量没有安全性问题,并且Pimodivir和奥司他韦联合用药未出现与临床相关的药物-药物相互作用。Ⅱ期临床实验结果显示Pimodivir不仅可以降低患者的病毒载量,而且耐受性良好。本文就Pimodivir的基本信息、作用机制、药效学、药代动力学和临床研究等作一概述。     

黄酮类化合物的神经氨酸酶抑制活性及构效关系研究进展

神经氨酸酶(neuraminidase,NA)为A型和B型流感病毒表面的一种糖蛋白,是抗流感病毒药物的靶点之一。近年来,国内外研究者发现一些黄酮类化合物具有很好的NA抑制活性,其结构骨架不同于已上市NA抑制剂奥司他韦和扎那米韦,有望解决流感病毒耐药性和当前药物NA亚型依赖性等问题。有些黄酮类化合物与奥司他韦联用能显著增强后者对不同亚型NA的抑制活性,因此该类药物的研发上市将为临床治疗方案提供新的选择。现综述不同结构类型黄酮类化合物的NA抑制活性及构效关系研究进展,为新型黄酮类NA抑制剂先导化合物的发现和结构改造提供参考。     

FDA禁止抗病毒药用于禽类

2006年3月20日，FDA发布了一个新规章，禁止金刚烷类（金刚烷胺、金刚乙胺）和神经氨酸酶抑制剂类（奥司他韦和扎那米韦）抗流感病毒药品用于禽类。FDA采取此项措施是为了确保人类使用这些药品防治流感的有效性。     

Recent advances in the discovery and development of anti-influenza drugs

Breakthrough advances in the chemotherapy of influenza have been achieved in recent years and the approval of zanamivir (Relenza^TM, Biotech Holdings) by the United States FDA in July 1999 for the treatment of type A and type B influenza marked the first new influenza treatments since the approval of rimantadine in 1993. This was followed by the approval of oseltamivir (Tamiflu^TM, Gilead Sciences) for the treatment of both type A and type B influenza in October 1999 and, subsequently, for the prevention of influenza A and B infection in adults and adolescents over the age of 13 years. Both zanamivir and oseltamivir are inhibitors of influenza neuraminidase, one of two surface glycoproteins of influenza virus and they represent a new class of anti-influenza agent. The successful launch of zanamivir and oseltamivir has prompted continued effort to discover and develop neuraminidase inhibitors with improved properties. Indeed, most of the anti-influenza drug discovery activity in recent years has been centred on neuraminidase inhibition, although efforts on improved preparation and formulation of the anti-influenza vaccine continues. This is evidenced by 22 patent applications filed between January 1998 and October 2001 concerning the chemotherapy of influenza all dealt with neuraminidase inhibition. This article will give a critical review of the recent advances in this area.     

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。     

Oseltamivir for influenza

Oseltamivir (pronounced os-el-ta-mi-veer; Tamiflu--Roche), an oral anti-influenza drug that inhibits influenza virus neuraminidase, is now available in the UK. It has recently been licensed throughout the EU for use, when influenza is circulating in the community, in the treatment of patients with early influenza-like symptoms, and for prophylaxis in people who have had close contact with someone with influenza. Oseltamivir is the second neuraminidase inhibitor to be licensed in the UK, the other being zanamivir (Relenza--GlaxoSmithKline), which is taken by inhalation and licensed only for treatment. Previously, we concluded that there was insufficient evidence that treatment with zanamivir prevented serious complications in people most at risk from influenza to recommend its use. Here we review the efficacy and safety of oseltamivir and discuss its role in the management of influenza.     

Peramivir: an intravenous neuraminidase inhibitor

Introduction: Peramivir (BCX-1812, RWJ-270201) is a highly selective inhibitor of influenza A and B neuraminidase that has recently been approved in the USA by the FDA to treat acute, uncomplicated influenza in adults.

Areas covered: This review examines the discovery and development of peramavir as well as its role in the treatment of influenza. Peramivir is currently the only FDA-approved anti-influenza agent that can be given as an intravenous injection, granting it a unique role in therapy with the potential to improve adherence and outcomes in patients who are unable to tolerate oral agents. In vitro, animal, human and safety data are presented as well as information regarding special populations, resistance and drug approval.

Expert opinion: Clinical trial data support the use of peramivir to relieve influenza symptoms in acute, uncomplicated influenza, with improvements over placebo similar to those of other approved anti-influenza treatments. The ability to give a one-time injectable dose offers improved adherence over currently available oral regimens. While not approved for hospitalized patients, available data suggest that multiple dose peramivir may also have a role in treatment of severally ill, hospitalized patients. Supportive data for the use of peramivir in special patient populations such as pediatrics and those especially at-risk to develop severe influenza symptoms are promising; however, they require further study.     

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.     

抗流感病毒药物研究进展

流感病毒是人类健康的一大威胁。应对流感病毒的主要方式是疫苗和药物治疗。对可能大规模爆发的流感疫情来讲, 药物治疗是最好的控制流感病毒传播的手段。目前, 抗流感病毒药物包括已在俄罗斯上市的盐酸阿比朵尔和美国FDA批准的4个抗流感病毒药物, 后者根据作用机制的不同分为M2离子通道蛋白抑制剂和神经氨酸酶 (NA) 抑制剂。其中, NA抑制剂根据结构又可分为唾液酸类似物、苯甲酸衍生物、环己烯衍生物、环戊烷衍生物、吡咯烷衍生物及天然提取物6大类。本文简要介绍了上述各类已上市和临床在研药物的最新研究进展。     

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.     

The medicinal potential of influenza virus surface proteins: hemagglutinin and neuraminidase

Nowadays, influenza virus is still a big threat to human. Hemagglutinin (HA) and neuraminidase (NA) are the two viral surface proteins, which play important roles in the life cycle of influenza virus. Current influenza vaccines and anti-influenza drugs work mainly by interfering with the functions of the two proteins. In this review, we will display some recent studies about the two proteins. As to HA, this review covers a lot including its fusion function, receptor specificity, antigenic shift hypothesis, novel antibodies and various inhibitors in order to deeply discuss this protein. As to NA, this review mainly focuses on studies about the newly identified 150-cavity of group-1 NAs and shows some untypical NA inhibitors aiming to provide a broader range of lead compounds for anti-influenza drug design.     

Recent advances in pharmacophore modeling and its application to anti-influenza drug discovery

Introduction: The emergence of the highly pathogenic avian influenza (HPAI) H5N1 virus and the recent global circulation of H1N1 swine-origin influenza virus in 2009 have highlighted the need for new anti-influenza therapies. This has been made all the more important with the emergence of antiviral-resistant strains. Recent progress in achieving three-dimensional (3D) crystal structures of influenza viral proteins and efficient tools available for pharmacophore-based virtual screening are aiding us in the discovery and design of new antiviral compounds.

Areas covered: This review discusses pharmacophore modeling as a potential cost-effective and time-saving technology for new drug discovery as an alternative to high-throughput screening. Based on this technical platform, the authors discuss current progress and future prospects for developing novel influenza antivirals against pre-existing or emerging novel targets.

Expert opinion: Although it might be at an infant stage of development, the availability of the 3D crystal structures of influenza viral proteins is expected to accelerate the application of structure-based drug design (SBDD) and pharmacophore modeling. Furthermore, the neuraminidase inhibitor, one of the most successful examples of a SBDD, still receives great attention because of its superb antiviral activities and the resistance of influenza strains to oseltamivir. However, despite much success, pharmacophore-based virtual screening exhibits limited predictive power in hit identification. Further improvements in pharmacophore detection algorithms, proper combinations of in silico methods as well as judicious choosing of compounds are expected to improve the hit rate. With the help of these technologies, the discovery of anti-influenza agents will be accelerated.