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。     

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。     

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。     

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。     

流感病毒神经氨酸酶抑制剂的研究进展

流行性感冒是一种由流感病毒引起的高致病率和高致死率的传播性疾病,神经氨酸酶在流感病毒的子病毒的释放和传播过程中起着不可或缺的重要作用,加上其相对保守的分子结构,使其成为一个理想的抗流感病毒的药物靶点。随着研究的深入,发现了神经氨酸酶的新活性位点和新结构类型的抑制剂,本文简要综述近几年来神经氨酸酶抑制剂的发展状况。     

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。     

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。     

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。     

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。     

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。     

抗流感病毒药物研究进展

介绍近年来临床主要应用的2类抗流感病毒药物:M2离子通道蛋白抑制剂和神经氨酸酶抑制剂的作用机制、临床应用特点及不良反应,并简要介绍了其他一些在我国常用的抗流感病毒药物.     

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。     

神经氨酸酶抑制剂的新用途及新结构

神经氨酸酶抑制剂不仅在多方面优于金刚烷胺类的防治A，B型流感的新型药，而且具有许多其他方面的作用。现介绍神经氨酸酶抑制剂在防治禽流感、防治并发细菌感染、抑制血凝素、抑制血凝素一神经氨酸酶、抑制部分细胞程序死亡等方面的新用途，并对神经氨酸酶抑制剂的新化合物进行了简述。     

Lack of pharmacokinetic interaction between the oral anti-influenza neuraminidase inhibitor prodrug oseltamivir and antacids

AIMS: Oseltamivir is an oral ester prodrug of its active metabolite Ro 64-0802, a potent and selective neuraminidase inhibitor of the influenza virus. The object of this study was to evaluate whether the oral absorption of oseltamivir was reduced in the presence of two main classes of antacid, Maalox(R) suspension (containing magnesium hydroxide and aluminium hydroxide) and Titralac(R) tablets (containing calcium carbonate). METHODS: Twelve healthy volunteers completed a randomized, single dose, three-period crossover study. Each volunteer received in a fasted state, 150 mg oseltamivir alone (Treatment A), 150 mg oseltamivir with a 20 ml Maalox suspension (Treatment B), and 150 mg oseltamivir with four Titralac tablets (Treatment C), with 7-10 days washout in between treatments. Plasma and urine concentrations of oseltamivir and Ro 64-0802 were measured using a validated h.p.l.c./MS/MS assay. Pharmacokinetic parameters were calculated for oseltamivir and Ro 64-0802. Since antacids are locally acting drugs and generally not expected to be absorbed substantially into the systemic system, no plasma or urine concentrations of antacids were measured. RESULTS: Bioequivalence was achieved for the primary pharmacokinetic parameters Cmax and AUC(0, infinity ) of Ro 64-0802 following administration of oseltamivir with either Maalox suspension or Titralac(R) tablets vs administration of oseltamivir alone. The bioavailability (90% confidence intervals) of Ro 64-0802 following administration of oseltamivir together with Maalox suspension vs administration of oseltamivir alone, was 90% (83.6, 96.9%) for C(max) and 94.1% (91.4, 96.9%) for AUC(0, infinity); similarly, for Titralac tablets, the equivalent values were 95.1% (88.3, 102%) for C(max) and 94.7% (91.9, 97.5%) for AUC(0, infinity). CONCLUSIONS: The coadministration of either Maalox suspension or Titralac tablets with oseltamivir has no effect on the pharmacokinetics of either oseltamivir or Ro 64-0802, and conversely, there is no evidence that coadministration with oseltamivir has an effect on the safety and tolerability of either Maalox suspension or Titralac tablets. There was no pharmacokinetic interaction between oseltamivir with either antacid, demonstrating that the oral absorption of oseltamivir was not impaired in the presence of antacids containing magnesium, aluminium or calcium.     

Investigational hemagglutinin-targeted influenza virus inhibitors

Introduction: Seasonal influenza and pandemic outbreaks typically result in high mortality and morbidity associated with severe economic burdens. Vaccines and anti-influenza drugs have made great contributions to control the infection. However, antigenic drifts and shifts allow influenza viruses to easily escape immune neutralization and antiviral drug activity. Hemagglutinin (HA)is an important envelope protein for the entry of influenza viruses into host cells, thus, HA-targeted agents may be potential anti-influenza drugs.

Areas covered: In this review, we describe arbidol, a unique licensed drug targeting HA; discuss and summarize HA-targeted anti-influenza agents been tested before or being tested currently in clinical trials, including monoclonal antibodies, small molecule inhibitors, proteins and peptides. Other small molecule inhibitors are also briefly introduced.

Expert opinion: Exploring new clinical applications for existing drugs can provide additional anti-influenza candidates with promising safety and bioavailability, and largely shortened time and costs. To enhance therapeutic efficacy and avoid drug-resistance, combination therapy involving in HA-targeted anti-influenza agent is reasonable and attractive. For drug discovery, it is helpful to keep an eye on the development of methodology in organic synthesis and probe into the co-crystal structure of HA in complex with small molecule.     

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.     

Recent advances in sialidase inhibitors

Viruses and bacteria cause diseases of vast economic importance. Sialidase inhibitors offer an opportunity to prevent or ameliorate these diseases. They have been investigated ostensibly as antiviral agents particularly against influenza viruses. The patent literature covering sialidase inhibitor compounds, their design and synthesis is reviewed from 1995 to mid-1998 with reference to the primary scientific literature. Patents are discussed by company or institution. The importance of different compound types is indicated.