流感病毒RNA聚合酶PA亚基:潜在抗流感药物靶点

流感是世界范围内的严重传染性疾病,目前抗流感药物面临的主要问题是病毒耐药性和对高致病性流感病毒的效价低。流感病毒RNA聚合酶是病毒在宿主细胞内完成复制和转录过程的关键性酶,其中PA亚基通过内切酶活性为流感病毒的转录过程提供引物,成为潜在抗流感药物靶点。该文对PA亚基的结构、功能及内切酶抑制剂类抗流感药物研究进展进行概述,为PA亚基的深入研究及针对此靶点的抗流感药物发现提供信息指导。     

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。     

新型Cap依赖性内切酶抑制剂玛巴洛沙韦治疗流感的临床研究进展

玛巴洛沙韦是一种具有全新作用机制的抗流感病毒新药,作为Cap依赖性内切酶抑制剂,通过抑制流感病毒RNA聚合酶PA亚基的内切酶活性,特异性阻断流感病毒的增殖过程,用于治疗12岁及以上、流感症状不超过48 h的急性无并发症流感患者。玛巴洛沙韦相比于神经氨酸酶抑制剂具有服药次数少、抗病毒疗效快、不良反应少等优点,且可以快速缓解甲型流感成年患者的呼吸困难。     

以流感病毒RNA聚合酶为靶点的抗病毒药物筛选和药效学评价方法的建立

流感病毒RNA聚合酶对流感病毒基因组的复制和表达至关重要。编码聚合酶各亚基的基因序列高度保守的特点使其成为极具发展潜力的抗流感药物靶标。本研究通过构建流感病毒RNA聚合酶活性依赖的荧光素酶报告系统,在细胞水平上建立了以流感病毒RNA聚合酶为靶点的抗流感药物筛选模型。特异性评价和统计学分析表明,该筛选方法灵敏可靠、重复性好,可以用于针对流感病毒RNA聚合酶的抗流感药物筛选。     

抗流行性感冒病毒药物研究进展

流行性感冒(流感)是由流感病毒引起的传染性呼吸道疾病.虽然接种疫苗是减轻流感流行的有效手段,但面对新的大流行病毒的传播和复杂住院流感患者,抗流感病毒药物的应用必不可少.目前,正处于非临床和临床研究阶段的抗流感病毒药物主要包括血凝素抑制剂、M2离子通道蛋白抑制剂、RNA依赖性RNA聚合酶(RdRp)抑制剂和神经氨酸酶抑制...     

靶向流感病毒RNA依赖的RNA聚合酶的小分子抑制剂研究进展

流感病毒严重威胁人类的生命健康。由于流感病毒固有的高变异性,目前上市的抗流感病毒药物已出现临床耐药突变株。因此,亟需开发具有新靶标、新机制的抗流感药物。RNA依赖的RNA聚合酶直接负责病毒RNA的转录和复制,在病毒的生命周期中发挥关键作用,是抗流感药物的重要靶标。本文精选近十年典型研究实例,从药物化学角度总结了靶向流感病毒RNA依赖的RNA聚合酶抑制剂的研究进展,以期为研发抗流感病毒药物提供参考。     

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。     

抗流感病毒药物的研究进展

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，抗流感病毒药物研究显得更加重要。目前，离子通道阻断剂和神经氨酸酶抑制剂正式应用于临床，但有耐药性和部分不良反应；流感病毒吸附抑制剂、细胞一病毒膜融合抑制剂和反义寡核苷酸正处于实验室研究阶段，在体内外实验中有良好的抗病毒活性；RNA干扰在抗流感病毒方面具有诸多优势，已有实验证实小干扰RNA具有抑制流感病毒作用，可能成为新一代抗流感病毒药物。     

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。     

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。     

PA subunit of RNA polymerase as a promising target for anti-influenza virus agents

RNA polymerase of influenza virus is a specific enzyme necessary for the viral replication. A siRNA against the RNA polymerase and the RNA polymerase inhibitor L-742,001 reduced accumulation of viral RNAs in the infected cells. L-742,001 strongly inhibited virus re-growth after removal of the agent from the culture, whereas the neuraminidase inhibitor zanamivir did not. L-742,001-resistant mutants showed a Thr-20 to Ala substitution in the PA subunit of RNA polymerase. The drug-resistant virus showed a slight reduction in the susceptibility to L-742,001 in both the plaque assay (threefold reduction) and enzyme assay (two- to three-fold reduction). The resistance levels were lower than those of zanamivir-resistant mutants in the plaque assay. Against zanamivir-resistant mutants, L-742,001 retained the same antiviral activity as against the wild-type strain. These results indicate that L-742,001 is most likely to act at the PA subunit, and possesses a unique profile. It is suggested that PA subunit of RNA polymerase is a promising target for anti-influenza virus agents.     

Approaches for discovery of small-molecular antivirals targeting to influenza A virus PB2 subunit

Influenza is an acute respiratory infectious disease caused by influenza virus, leading to huge morbidity and mortality in humans worldwide. Despite the availability of antivirals in the clinic, the emergence of resistant strains calls for antivirals with novel mechanisms of action. The PB2 subunit of the influenza A virus polymerase is a promising target because of its vital role in the ‘cap-snatching’ mechanism. In this review, we summarize the technologies and medicinal chemistry strategies for hit identification, hit-to-lead and lead-to-candidate optimization, and current challenges in PB2 inhibitor development, as well as offering insights for the fight against drug resistance.     

Contemporary medicinal chemistry strategies for the discovery and optimization of influenza inhibitors targeting vRNP constituent proteins

Influenza is an acute respiratory infectious disease caused by the influenza virus, affecting people globally and causing significant social and economic losses. Due to the inevitable limitations of vaccines and approved drugs, there is an urgent need to discover new anti-influenza drugs with different mechanisms. The viral ribonucleoprotein complex (vRNP) plays an essential role in the life cycle of influenza viruses, representing an attractive target for drug design. In recent years, the functional area of constituent proteins in vRNP are widely used as targets for drug discovery, especially the PA endonuclease active site, the RNA-binding site of PB1, the cap-binding site of PB2 and the nuclear export signal of NP protein. Encouragingly, the PA inhibitor baloxavir has been marketed in Japan and the United States, and several drug candidates have also entered clinical trials, such as favipiravir. This article reviews the compositions and functions of the influenza virus vRNP and the research progress on vRNP inhibitors, and discusses the representative drug discovery and optimization strategies pursued.     

New small-molecule drug design strategies for fighting resistant influenza A

Influenza A virus is the major cause of seasonal or pandemic flu worldwide. Two main treatment strategies–vaccination and small molecule anti-influenza drugs are currently available. As an effective vaccine usually takes at least 6 months to develop, anti-influenza small molecule drugs are more effective for the first line of protection against the virus during an epidemic outbreak, especially in the early stage. Two major classes of anti-influenza drugs currently available are admantane-based M2 protein blockers (amantadine and rimantadine) and neuraminidase (NA) inhibitors (oseltamivir, zanamivir, and peramivir). However, the continuous evolvement of influenza A virus and the rapid emergence of resistance to current drugs, particularly to amantadine, rimantadine, and oseltamivir, have raised an urgent need for developing new anti-influenza drugs against resistant forms of influenza A virus. In this review, we first give a brief introduction of the molecular mechanisms behind resistance, and then discuss new strategies in small-molecule drug development to overcome influenza A virus resistance targeting mutant M2 proteins and neuraminidases, and other viral proteins not associated with current drugs.KEY WORDS: Influenza A virus, Drug discovery, Resistance, M2 ion channel, Neuraminidase     

Oseltamivir-resistant influenza A(H1N1) 2009 virus in Greece during the post-pandemic 2010-2011 season

Information on the drug susceptibility of influenza epidemic strains is important for antiviral resistance monitoring. In Greece, the 2009-2010 pandemic waves were very mild and seroprevalence rates remained low after this influenza season, resulting in exclusive detection of the pandemic strain during the 2010-2011 influenza season. In the present study during the post-pandemic 2010-2011 season, 50 consecutive influenza A(H1N1) 2009 virus-positive samples from patients hospitalised in Greek hospitals were analysed for resistance to the neuraminidase inhibitor oseltamivir. All patients were hospitalised with severe influenza complications and had previously received oseltamivir. Influenza A(H1N1) 2009 virus detection and testing for oseltamivir resistance were performed with real-time PCR amplification assays. The H275Y substitution associated with resistance to oseltamivir was identified in two immunocompetent patients who received oseltamivir treatment for 3 days and 5 days, respectively. In both cases, patients were discharged in good condition despite development of resistance to antiviral treatment.     

Recent Patents on development of nucleic acid-based antiviral drugs against seasonal and pandemic influenza virus infections

Influenza viruses are etiological agents of deadly flu that continue to pose global health threats, and have caused global pandemics that killed millions of people worldwide. The global crisis involving the avian H5N1 influenza provides compelling reasons to accelerate fast track development of novel antiviral drugs against the potential pandemic virus. The availability of neuraminidase inhibitors such as oseltamivir (tamiflu) improves our ability to defend against influenza viruses, but the incidences of tamiflu-resistance are rising rapidly. Nucleic acid-based antiviral drugs are promising classes of experimental antiviral drugs that have been shown in pre-clinical studies to be effective against seasonal and avian influenza viruses. The potency and versatility of these drugs make them potential candidates to be used in seasonal and pandemic influenza scenarios. The review will assess the recent patents, research and development of antisense oligonucleotides, small interfering RNA, immunomodulating RNA for the prevention and treatment of influenza infection.     

Avian influenza A (H5N1) infection: targets and strategies for chemotherapeutic intervention

In an avian flu pandemic, which drugs could be used to treat or prevent infection with influenza A (H5N1) virus? Foremost are the viral neuraminidase inhibitors oseltamivir and zanamivir, which have already been used to treat human influenza A (H1N1 and H3N2) and B virus infections. The use of the M2 ion channel blockers amantadine and rimantadine is compounded by the rapid development of drug resistance. Although formally approved for other indications (i.e. treatment of hepatitis C), ribavirin and pegylated interferon might also be useful for controlling avian flu. Combined use of the currently available drugs should be taken into account and attempts should be made to develop new strategies directed at unexplored targets such as the viral proteins hemagglutinin, the viral polymerase (and endonuclease) and the non-structural protein NS1. As has been shown for other viral infections, RNA interference could be a powerful means with which to suppress the replication of avian H5N1.