新型冠状病毒小分子药物的临床效果及其合成方法概述

冠状病毒是一类广泛存在且对人及家畜具有严重危害的病原体,具有较高的传播性及致死率。2019年末爆发的新型冠状病毒（SARS-CoV-2）所引发的全球疫情持续至今,累计感染人数已经超过三亿,并造成了五百多万的死亡病例。随着病毒不断变异,造成疫苗的防护效率不断下降,时刻威胁着人们的健康安全,因此针对新型冠状病毒的小分子药物的开发就显得尤为必要。本文针对一些重要的新型冠状病毒的小分子药物进行概述,介绍了它们的作用靶点、合成情况、治疗效果以及所处的开发阶段,以期为抗新冠病毒药物的研发和临床研究提供一些参考。     

新型冠状病毒肺炎临床诊治及质谱组学研究进展

新型冠状病毒肺炎(COVID-19)是由严重急性呼吸系统综合征冠状病毒2型(SARS-CoV-2)引发的一种呼吸系统传染性疾病,自2019年末爆发以来,在全球范围内迅速蔓延。该传染性疾病是本世纪以来全球遭遇的感染范围最广、防控难度最大的重大突发公共卫生事件,其对人类健康和社会经济发展造成严重影响。全球多个实验室针对SARS-CoV-2开发了一系列检测方法,包括分子生物学方法和血清学检测方法等。近年来,高分辨质谱分析技术的飞速发展,其驱动的多组学方法策略已经被广泛应用于各类传染性疾病的精准诊断、病原序列测定以及药物靶点发掘等研究。基于此,本文对新冠肺炎的发病机理、诊断方法、预防手段和治疗策略进行简要归纳总结,重点聚焦于基于质谱的组学技术在新型冠状病毒肺炎诊疗过程中的应用实践研究,包括分子诊断、病源机理解析和药物开发等,以期为COVID-19的诊疗和防控提供新的思路和方法借鉴。     

抗病毒涂层

随着COVID-19在全世界范围内的大规模传播,对世界人民的身体健康造成了严重的损害,人们认识到病毒除了可以通过各种飞沫传播外,还会因人体接触到受污染的表面而传播。然而,作为常用的表面抗病毒手段,消毒剂存在不能持续灭活病毒的缺点,这不利于抑制各种传染性病毒的传播。因此,全球迫切需要保护日常物体表面免受病毒的污染,以消除各种呼吸道病毒(如新型冠状病毒SARS-CoV-2)的传播。从这个角度出发,设计开发出有效的抗病毒涂层是十分重要的。本文从不同类型的抗病毒涂层出发,针对新型冠状病毒,探讨了纳米材料抗病毒涂层和聚合物抗病毒涂层的工作机制、性能评价方法、加工技术、实际应用和研究进展,还提出了一些策略以设计出更有效的抗病毒涂层。尽管其中一些抗病毒涂层还在实验阶段,但其在抗病毒方面已表现出巨大的潜力。     

分离技术在新型冠状病毒研究和防疫检测中的应用

新型冠状病毒肺炎(COVID-19)疫情的爆发给世界公共卫生安全带来前所未有的挑战。随着新型冠状病毒(SARS-CoV-2)相关研究的不断深入,众多分析检测技术相继被应用,推动了病毒检测、疫苗和创新疗法的研发,从而使疫情早日得到控制。分离技术作为生命科学、医学、药学领域的关键技术,操作简单,分离效率高,选择性强,在新型冠状病毒的分离、检测、诊疗及防疫中起到不可替代的作用。该文以SARS-CoV-2或COVID-19为关键词在ISI Web of Science中进行主题检索,归纳了2020年度新型冠状病毒相关的研究论文,简要介绍主要的研究方向,并对国际顶级学术期刊Nature, Science, Cell的论文发表情况进行了统计。通过检索影响因子较高的期刊,综述了新型冠状病毒研究中主要应用的分离技术,并从亲和色谱和尺寸排阻色谱、液相色谱、磁珠分离、离心、微纳分离以及电泳6个方面进行说明。综述统计了亲和色谱和尺寸排阻色谱纯化的病毒相关蛋白,并介绍了其在新型冠状病毒传播、感染机制以及药物筛选中的应用;介绍了液相色谱对病毒候选药物评估以及复杂基质中单一成分的鉴定;介绍了磁珠分离在细胞分离、核酸提取和免疫学检测中的应用;介绍了离心对病毒颗粒、细胞以及血清的分离;介绍了微纳分离结合其他技术以实现病毒蛋白的高灵敏检测;简要介绍了电泳在聚合酶链式反应(PCR)产物分析中的应用。该文综述了2020年度新型冠状病毒研究和防疫检测中分离技术的应用情况,分析了分离技术在新型冠状病毒检测中发挥的作用,旨在为从事分离研究的科研工作者提供一些参考。     

基于靶标结构及作用机制的抗艾滋病药物研究进展

人体免疫缺陷病毒(Human immunodeficiency virus,HIV)是一种主要以CD4~+T淋巴细胞和巨噬细胞等免疫细胞为靶点的感染性逆转录病毒,HIV感染的最终阶段为出现获得性免疫缺陷综合征(Acquired immunodeficiency syndrome,AIDS).HIV迄今为止已经夺去近3300万人生命,是全球最大的公共卫生挑战之一.自从抗逆转录病毒治疗(Antiretrovial therapy,ART)出现以后,抗逆转录药物的联合使用使艾滋病从致死性疾病变成慢性可控性疾病.为了开发新的抗艾滋病药物,基于病毒复制周期中的不同靶标将近年发展的抗艾滋病药物进行分类简述,重点关注于药物的作用机制研究、临床应用现状及未来发展方向.     

新型冠状病毒(SARS-CoV-2)快速诊断技术的研究现状

新型冠状病毒(SARS-CoV-2)及相关新型冠状病毒肺炎(COVID-19)的爆发引起人们对全球健康问题的极大关注,也给全球经济造成了巨大损失。由于SARS-CoV-2具有较长潜伏期及无症状感染者的出现使疫情形势更加严峻,因而对可疑病例进行早期诊断和及时管控是控制病毒传播的重要措施。开发简单、快速、灵敏、准确的SARS-CoV-2诊断技术是疫情防控的关键。本文对SARS-CoV-2的结构进行了简单介绍,对目前常用的SARS-CoV-2诊断技术的研究现状进行了详细介绍,并对有望应用于即时医疗的检测技术进行了概述,对未来的发展趋势进行了展望,以期为研究人员开发高度准确、廉价、便携的SARSCoV-2诊断技术提供研究思路,为COVID-19及其他新兴传染病的紧急防御和快速部署提供参考。     

基于比色荧光纳米球的新冠病毒N蛋白侧向层析检测北大核心CSCD

新型冠状病毒传播速率快,且能导致严重呼吸综合征,危及生命安全。及时检测该病毒尤为重要。目前的检测手段各有优势,但仍需进一步提高。本文制备了一种比色荧光纳米球用于新冠病毒核衣壳蛋白(N protein)的侧向层析检测。该纳米球内有多个量子点可用于荧光定量检测,外有多个金纳米粒子用于比色定性检测。荧光检测限可达2.1 nmol/L。该方法重现性和特异性好,具有较强抗干扰能力。本研究为新冠病毒的快速检测提供了一种新方法。     

糖基化在新型冠状病毒侵染中的机制及药物研发中的应用

冠状病毒(Coronavirus, CoV)是一类具有包膜的正股单链RNA病毒,可感染人类和多种动物。2019年末,一种新的β-冠状病毒SARS-CoV-2(Severe acute respiratory syndrome-coronavirus-2)开始在人际间传播,该病毒引发的疾病“COVID-19”(Coronavirus disease 2019)对全球公共卫生构成严重威胁。糖基化是一种存在于蛋白质上的翻译后修饰,可影响蛋白质的折叠、稳定性及和受体之间的结合等,研究表明SARS-CoV-2包膜中的病毒嗜性决定因子-刺突蛋白(Spike,S)及宿主细胞上的主要受体血管紧张素转化酶2(Angiotensin-converting enzyme 2, ACE2)均为高度糖基化蛋白。为探明糖基化修饰在SARS-CoV-2病毒侵染及与宿主免疫应答中的作用,本文综述了该病毒的侵染机制,体外重组病毒S蛋白和宿主受体ACE2的糖基化类型及糖基化对病毒与宿主相互作用的影响,并提出基于糖基化的COVID-19诊断和药物研发新策略。     

纳米技术在水中病毒灭活中的应用:对新型冠状病毒SARS-CoV-2传播阻断的启示

新型冠状病毒肺炎(COVID-19)疫情给人类社会发展和生命健康造成了巨大威胁,由于新型冠状病毒(SARS-CoV-2)在水中的稳定性,城市污水成为该病毒最集中的污染源之一,因此如何杀灭主要水媒介中的病毒也成为了科学领域关注的重要问题。新冠病毒在结构上由具有遗传效应的RNA链和蛋白衣壳组成,可受活性氧物种(ROS)攻击解体而被灭活。生化代谢的阻断和结构的破坏也是新冠病毒灭活的有效方法。纳米材料因其表面和界面效应、独特的微观结构及优异的物化性质,在新冠病毒杀灭中有很好的应用前景。本文在探讨新型冠状病毒结构组成以及其在水环境中的存活及传播特征的基础上,全面综述了纳米材料在光催化、非均相催化高级氧化、离子毒性灭活和结构效应等方面于灭活病毒中的应用,深入探究了病毒灭活行为及机理。基于此,结合新冠病毒的结构组成及传播特征,深入探讨了不同纳米技术的新冠病毒灭活中的潜在应用。该综述可为环境纳米技术应用于水中新冠病毒灭活及其在水媒介中的次生传播阻断提供理论依据和实践参考。     

基于分子识别的免疫层析技术用于新冠肺炎感染的快速诊断

目前由新型冠状病毒(SARS-CoV-2)引发的新冠肺炎疫情仍在全球蔓延. 快速筛查并隔离感染者(包括无症状感染者)是遏制疫情传播的重要手段之一. 免疫层析技术是一种相对成熟的快速检测技术, 由于其操作简单、 反应时间短且结果稳定, 在生物标志物检测领域具有广阔的应用前景. 本文总结了目前免疫层析检测技术在新冠肺炎感染筛查领域的研究进展, 涵盖病毒抗体、 蛋白、 核酸等检测靶标, 并对不同检测方法的优势、 局限性进行了简要评述, 最后简单介绍了目前用于新冠肺炎感染筛查的免疫层析试纸的实际应用情况.     

安第斯病毒抑制肽的优化设计

安第斯病毒是汉坦病毒的一种,能引起汉坦病毒肺综合征,严重威胁人类的健康和生命安全,但目前尚缺乏有效的治疗办法,病毒抑制肽具有潜在的应用价值。本文利用多肽分子整体描述符,对一组安第斯病毒抑制肽进行定量构效关系(QSAR)研究,建立模型;并以模型为指导对多肽进行优化设计,以进一步提高其活性。结果表明,基于遗传算法-偏最小二乘算法建立的QSAR模型显示了较好的预测能力(R20.80,Q2ext0.58);依据模型设计出一组具有较高预测活性的多肽,为高活性抗病毒多肽的合成和实验验证打下了基础。     

Insights into the synthesis and mechanism of green synthesized antimicrobial nanoparticles,answer to the multidrug resistance

Emergence of the multidrug resistant human pathogenic strains is posing a serious health challenge. Resistant strains carry mutations which help them to resist conventional drugs. Therefore, it is required to produce more effective agents that are able to degrade the resistant pathogenic bacterial strains. The antimicrobial properties of nanoparticles (NPs) by eco-friendly green synthetic methods have pulled attention everywhere owing to their exceptional properties and small particle size of 100 nm. NPs are considered to belong to a group of antimicrobial agents which have ability to go inside microbial cells and kill them. In this comprehensive review, we are discussing the green synthetic methods used for the synthesis of NPs targeting the microbes. Additionally, several characterization techniques of antimicrobial NPs are also discussed. Subsequently, various methods used for the analysis of antimicrobial activities and their mechanisms are also examined.     

Light-Triggered Nitric Oxide Release by a Photosensitizer to Combat Bacterial Biofilm Infections

Bacterial biofilms are a serious global health concern, often responsible for persistent infections. New strategies to prevent and treat bacterial infections by eradication of the biofilms are urgently needed. A novel ruthenium-based compound is reported in this study that functions as both a boronic acid-decorated photosensitizer (PS) and a light-triggered nitric oxide (NO) releasing agent. The compound can selectively attach to the bacterial membrane and biofilms and it is highly potent at eradicating Pseudomonas aeruginosa biofilms through the simultaneous release of NO and reactive oxygen species (ROS). The compound, which is more effective than clinical antibiotic tobramycin, also has excellent bacterial specificity and shows no significant cytotoxicity to human cells. The results reveal potential applications of this innovative dual-functional photoactivated ruthenium compound to combat bacterial biofilm infections.     

In silico validation of anti-viral drugs obtained from marine sources as a potential target against SARS-CoV-2 Mpro

COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has threatened the whole world affecting almost 243 million people globally. Originating from China, it has now spread worldwide with USA and India being the two most affected countries which emphasizes the immense potential of the coronaviruses to cause severity in the human population. This study validates the efficacy of some marine antiviral agents to target the viral main protease (Mpro) of SARS-CoV-2 by in silico studies. A total of 14 marine-derived antiviral agents were screened from several databases including PubChem and DrugBank and docked against the crystallised 3D structure of SARS-CoV-2 Mpro. MD simulation of the top two ligands was carried out for 100 ns to validate the protein-ligand stability. Later, their physicochemical, pharmacokinetics, and drug-likeness properties were evaluated and toxicity prediction was performed using eMOLTOX webtool. We found that all the 14 compounds are acting as a good target for Mpro. Among them, avarol and AcDa-1 procured the best docking results with the estimated docking score of −8.05 and −7.74 ​kcal/mol respectively. MD simulation revealed good conformational stability. The docked conformation was visualised and subsequent ligand-amino acid interactions were analysed. Avarol revealed good pharmacokinetic properties with oral bioavailability. The overall finding suggested that these marine compounds may have the potential to be used for the treatment of COVID-19 to tackle this pandemic.     

Plants and Natural Products with Activity against Various Types of Coronaviruses: A Review with Focus on SARS-CoV-2

COVID-19 is a pandemic disease caused by the SARS-CoV-2 virus, which is potentially fatal for vulnerable individuals. Disease management represents a challenge for many countries, given the shortage of medicines and hospital resources. The objective of this work was to review the medicinal plants, foods and natural products showing scientific evidence for host protection against various types of coronaviruses, with a focus on SARS-CoV-2. Natural products that mitigate the symptoms caused by various coronaviruses are also presented. Particular attention was placed on natural products that stabilize the Renin–Angiotensin–Aldosterone System (RAAS), which has been associated with the entry of the SARS-CoV-2 into human cells.     

Innate immune sensing of coronavirus and viral evasion strategies

The innate immune system is the first line of the host defense program against pathogens and harmful substances. Antiviral innate immune responses can be triggered by multiple cellular receptors sensing viral components. The activated innate immune system produces interferons (IFNs) and cytokines that perform antiviral functions to eliminate invading viruses. Coronaviruses are single-stranded, positive-sense RNA viruses that have a broad range of animal hosts. Coronaviruses have evolved multiple means to evade host antiviral immune responses. Successful immune evasion by coronaviruses may enable the viruses to adapt to multiple species of host organisms. Coronavirus transmission from zoonotic hosts to humans has caused serious illnesses, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease-2019 (COVID-19), resulting in global health and economic crises. In this review, we summarize the current knowledge of the mechanisms underlying host sensing of and innate immune responses against coronavirus invasion, as well as host immune evasion strategies of coronaviruses.Subject terms: Infection, Pattern recognition receptors, Immune evasion     

Anti-amyloid nanoclusters for the treatment of brain hazards associated with incurable neurodegenerative diseases

Neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) have no cure and pose a serious threat to human health. The accumulated amyloid has been the therapeutic target of various studies for over a decade, but there is a lack of effective treatments due to various limitations, such as the difficulty to cross the blood-brain barrier (BBB) and unfavorable bioaccumulation. To overcome these challenges, ultra-small metal nanoclusters (MNCs) (<2 nm) have emerged as promising new agents. Simple modifications of MNCs efficiently cross the BBB to reach the brain and dissociate amyloid fibrils into less toxic species. In addition, the enzymatic behavior of MNCs facilitates the scavenging of intracellular reactive oxygen species (ROS) and alleviates neuroinflammation. Herein, we summarize the reported anti-amyloid MNCs. Multiple promising functions of MNCs that may alleviate the harms of neurodegenerative diseases are exhibited. The physicochemical properties that influence the inhibition and degradation of common amyloid fibrils, including alpha-synuclein (α-syn) and amyloid beta-peptide (Aβ) are discussed. The prospect of optimizing MNCs to suppress more harm in the brain is presented to facilitate the development of practical therapies for neurodegenerative diseases.     

A novel cartridge for nucleic acid extraction,amplification and detection of infectious disease pathogens with the help of magnetic nanoparticles

Nucleic acid detection (NAD) based on real-time polymerase chain reaction (real-time PCR) is gold standard for infectious disease detection. Magnetic nanoparticles (MNPs) are widely used for nucleic acid extraction (NAE) because of their excellent properties. Microfluidic technology makes automated NAD possible. However, most of the NAD microfluidic chips are too complex to be applied to point-of-care (POC) testing. In this paper, a simple-structure cartridge was developed for POC detection of infectious diseases. This self-contained cartridge can be divided into a magnetic-controlled NAE part, a valve-piston combined fluidic control part and a PCR chip, which is able to extract nucleic acid from up to 500 µL of liquid samples by MNPs and finish the detection process from “sample in” to “answer out” automatically. Performance tests of the cartridges show that it met the demands of automated NAD. Results of on-cartridge detection of hepatitis B virus (HBV) demonstrated that this system has good uniformity and no cross-contamination between different cartridges, and the limit of detection (LOD) of this system for HBV in serum is 50 IU/mL. Multiplex detections of severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2) with a concentration of 500 copies/mL were carried out on the system and 100% positive detection rate was achieved.     

聚离子液体水凝胶用于中性水中Cr(VI)的去除

随着经济的快速发展,水污染已成为全球关注的紧迫问题。其中,Cr（VI）在废水中含量较高且毒性较强,可引起多种严重疾病。而大多数污染地表水和地下水的pH往往是接近中性的。因此,开发具有近中性pH值下有效去除Cr（VI）的吸附剂对生态系统和公众健康至关重要。本文设计并制备了具有不同结构的三氮唑鎓聚离子液体水凝胶,并将其应用于CrO42-的吸附和释放。该水凝胶可在中性条件下实现水中CrO42-的100%去除,最大吸附量高达356 mg/g。等温吸附结果表明,在较低浓度下CrO42-在聚离子液体水凝胶中为单层吸附。此外,可进一步通过离子交换将吸附于水凝胶中的CrO42-释放出来,实现吸附剂的再生。     

One stone two birds: Degradation of persistent organic pollutants to a valuable industrial chemical production of pentafluoropropionyl fluoride from HFPO oligomers catalyzed by cesium fluoride in tetraglyme

Hexafluoropropylene oxide (HFPO) oligomers are toxic, bioaccumulative, and persistent organic pollutants (POPs). Consuming the harmful chemicals to prevent them from releasing to nature is of serious significance as far as both natural environments and human health are concerned. In this study, investigation on degradation of HFPO oligomers to pentafluoropropionyl fluoride (PPF), a valuable industrial chemical, is reported. Different combinations of alkali metal fluoride in either diglyme or tetraglyme under both flask and batch autoclave conditions were examined. Under the optimal reaction conditions, HFPO oligomers (n = 2-10) were completely degraded to PPF in over 90% yield. Reactions on 200 g scale were tested and no deduction of efficiency was observed, which indicates the potential for practical industrial application of this chemistry.