Development and Effects of Influenza Antiviral Drugs

Influenza virus is a highly contagious zoonotic respiratory disease that causes seasonal outbreaks each year and unpredictable pandemics occasionally with high morbidity and mortality rates, posing a great threat to public health worldwide. Besides the limited effect of vaccines, the problem is exacerbated by the lack of drugs with strong antiviral activity against all flu strains. Currently, there are two classes of antiviral drugs available that are chemosynthetic and approved against influenza A virus for prophylactic and therapeutic treatment, but the appearance of drug-resistant virus strains is a serious issue that strikes at the core of influenza control. There is therefore an urgent need to develop new antiviral drugs. Many reports have shown that the development of novel bioactive plant extracts and microbial extracts has significant advantages in influenza treatment. This paper comprehensively reviews the development and effects of chemosynthetic drugs, plant extracts, and microbial extracts with influenza antiviral activity, hoping to provide some references for novel antiviral drug design and promising alternative candidates for further anti-influenza drug development.     

Bioassay-Guided Fractionation of Siparuna glycycarpa n-Butanol Extract with Inhibitory Activity against Influenza A(H1N1)pdm09 Virus by Centrifugal Partition Chromatography (CPC)

Siparuna glycycarpa occurs in the Amazon region, and some species of this genus are used in Brazilian folk medicine. A recent study showed the inhibitory effect of this species against influenza A(H1N1)pdm09 virus, and in order to acquire active fractions, a polar solvent system n-butanol-methanol-water (9:1:10, v/v) was selected and used for bioassay-guided fractionation of n-butanol extract by centrifugal partition chromatography (CPC). The upper phase was used as stationary phase and the lower phase as mobile (descending mode). Among the collected fractions, the ones coded SGA, SGC, SGD, and SGO showed the highest antiviral inhibition levels (above 74%) at 100 µg·mL⁻¹ after 24 h of infection. The bioactive fractions chemical profiles were investigated by LC-HRMS/MS data in positive and negative ionization modes exploring the Global Natural Products Social Molecular Networking (GNPS) platform to build a molecular network. Benzylisoquinoline alkaloids were annotated in the fractions coded SGA, SGC, and SGD collected during elution step. Aporphine alkaloids, O-glycosylated flavonoids, and dihydrochalcones in SGO were acquired with the change of mobile phase from lower aqueous to upper organic. Benzylisoquinolinic and aporphine alkaloids as well as glycosylated flavonoids were annotated in the most bioactive fractions suggesting this group of compounds as responsible for antiviral activity.     

氧化石墨烯修饰腐蚀型长周期光纤光栅的禽流感病毒免疫传感器

提出了一种使用基于氧化石墨烯修饰包层腐蚀型长周期光纤光栅应用于检测禽流感病毒的免疫传感器.氧化石墨烯通过氢键结合在包层腐蚀型长周期光纤光栅表面上,并通过共价键将禽流感病毒单克隆抗体与氧化石墨烯表面的羧基相结合.利用氧化石墨烯上吸附的禽流感病毒单克隆抗体与禽流感病毒抗原的特异性结合引起的长周期光纤光栅谐振波长变化进行检测.结果表明,该氧化石墨烯修饰包层腐蚀型长周期光纤光栅免疫传感器对禽流感病毒的检测极限为40 ng/mL,传感器的解离常数为~1.6×10^-7 mol/L,检测范围为40 ng/mL^200μg/mL.通过对禽流感病毒空白尿囊液、禽流感病毒尿囊液和新城疫病毒尿囊液进行检测,表明免疫传感器具有良好的特异性和临床性.该免疫传感器具有应用于禽流感病毒的快速和早期诊断的可能.     

喷射式流动注射电化学发光免疫检测禽流感H9亚型

利用磁分离和生物素亲和素技术,形成亲和素化磁微球-生物素化抗体-抗原-钌标抗体的免疫夹心复合物,初步建立了体外免疫诊断试剂的制备方法,并利用喷射式流动注射电化学发光体系对制备出的禽流感病毒H9免疫复合物进行检测。实验选择最适的包被抗体,检测抗体和封闭剂,优化Ru标抗体的最佳稀释度。在生物素化的兔抗H9多抗作为亲和素化的磁微球的结合抗体,鼠抗H9单抗作为Ru(bpy)32+标记抗体,2%BSA作为封闭剂,1:50倍稀释的Ru-鼠抗H9单抗条件下,非特异性吸附最低。测定不同浓度的H9抗原,发现抗原浓度在3.125～100μg/mL范围内与电化学发光强度呈较好的线性关系。实验还测定了不同亚型的禽流感病毒、不同来源的毒株和鸡的棉拭子样品。     

分子模拟在生物化学中的应用实例

分子模拟是一种描述和模拟分子和分子体系运动状态和性质的方法.随着电子计算机技术的飞速发展,分子模拟进入了一个前所未有的新时代.在此之前,人们只能通过机械模型和纸笔计算进行简单的分子模拟,现在通过利用电子计算机人们可以做更为复杂、更为全面的分子模拟.本文通过两个实例来简单阐述了分子模拟在生物化学中的应用.一则是通过模拟膦酰基氧化腈和丙乙腈的1,3偶极环加成反应过程,用密度泛函理论方法在B3LYP/6-31G(d,p)水平上解释了得到2∶1的加成产物的现象,来解释1,3偶极环加成反应得到2:1加成产物的现象.一则是通过结构生物信息学的方法建立H5N1高致病性禽流感病毒蛋白的三维结构,模拟其与一些药物分子的相互作用,研究H5N1的活性中心.     

AC electrokinetic immobilization of influenza virus

The use of alternating current (AC) electrokinetic forces, like dielectrophoresis and AC electroosmosis, as a simple and fast method to immobilize sub-micrometer objects onto nanoelectrode arrays is presented. Due to its medical relevance, the influenza virus is chosen as a model organism. One of the outstanding features is that the immobilization of viral material to the electrodes can be achieved permanently, allowing subsequent handling independently from the electrical setup. Thus, by using merely electric fields, we demonstrate that the need of prior chemical surface modification could become obsolete. The accumulation of viral material over time is observed by fluorescence microscopy. The influences of side effects like electrothermal fluid flow, causing a fluid motion above the electrodes and causing an intensity gradient within the electrode array, are discussed. Due to the improved resolution by combining fluorescence microscopy with deconvolution, it is shown that the viral material is mainly drawn to the electrode edge and to a lesser extent to the electrode surface. Finally, areas of application for this functionalization technique are presented.     

Thoughts on What Chemists Can Contribute to Fighting SARS-CoV-2 – A Short Note on Hand Sanitizers,Drug Candidates and Outreach

The SARS-CoV-2 outbreak causing the respiratory disease COVID-19 has left many chemists in academia without an obvious option to contribute to fighting the pandemic. Some of our recent experiences indicate that there are ways to overcome this dilemma. A three-pronged approach is proposed.     

Topology-Matching Design of an Influenza-Neutralizing Spiky Nanoparticle-Based Inhibitor with a Dual Mode of Action

In this study, we demonstrate the concept of “topology-matching design” for virus inhibitors. With the current knowledge of influenza A virus (IAV), we designed a nanoparticle-based inhibitor (nano-inhibitor) that has a matched nanotopology to IAV virions and shows heteromultivalent inhibitory effects on hemagglutinin and neuraminidase. The synthesized nano-inhibitor can neutralize the viral particle extracellularly and block its attachment and entry to the host cells. The virus replication was significantly reduced by 6 orders of magnitude in the presence of the reverse designed nano-inhibitors. Even when used 24 hours after the infection, more than 99.999 % inhibition is still achieved, which indicates such a nano-inhibitor might be a potent antiviral for the treatment of influenza infection.     

Topology‐Matching Design of an Influenza‐Neutralizing Spiky Nanoparticle‐Based Inhibitor with a Dual Mode of Action

In this study, we demonstrate the concept of “topology‐matching design” for virus inhibitors. With the current knowledge of influenza A virus (IAV), we designed a nanoparticle‐based inhibitor (nano‐inhibitor) that has a matched nanotopology to IAV virions and shows heteromultivalent inhibitory effects on hemagglutinin and neuraminidase. The synthesized nano‐inhibitor can neutralize the viral particle extracellularly and block its attachment and entry to the host cells. The virus replication was significantly reduced by 6 orders of magnitude in the presence of the reverse designed nano‐inhibitors. Even when used 24 hours after the infection, more than 99.999 % inhibition is still achieved, which indicates such a nano‐inhibitor might be a potent antiviral for the treatment of influenza infection.