严重急性呼吸综合征冠状病毒2致病机制研究进展

从2019年12月开始,在我国湖北武汉出现新型冠状病毒肺炎(corona virus disease 2019,COVID-19)[1],疫情迅速传播,在全国及境外多个国家蔓延,形式十分严峻。随着该病毒基因组序列公布,被确认为一种新型冠状病毒。为此,世界卫生组织(WHO)将该病毒暂时命名为“2019新型冠状病毒(2019 novelcorona viurs,2019-nCoV)”,后被国际病毒分类学委员会(ICTV)命名为严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)。现已明确其具有强烈的人传人能力,主要传播方式包括飞沫传播和接触传播,COVID-19临床症状有发热、咳嗽、肌痛、呼吸困难等,严重时出现呼吸衰竭甚至死亡[2]。目前,对于SARS-CoV-2如何进入人类世界、入侵宿主、发病机制及介导组织器官损害等尚不清楚,现就其研究进展作一综述。     

SARS:来自病毒成分的结构正开始被揭示出来

严重急性呼吸综合征 (SARS)是冠状病毒家族所致疾病之一。冠状病毒具有复杂的遗传组织 ,因此人们对它的复制周期知之甚少。冠状病毒家族有大量的复制基因 ,它们可以加工为大量用于形成复制 /转录复合体的成分。这种复合体包括未知功能的非结构蛋白 (nsp)。已经测定了其中一种nsp9蛋白的结构 ,并揭示出该蛋白结合在单链RNA(ssRNA)上。nsp9是一种二聚体 ,每个单体具有 1个 β螺旋和 7个 β 链的筒状结构。它的序列没有已知的同源结构 ,但其 β 筒状结构与寡糖 /寡核苷酸结合 (OB)折叠的 5 链 β 筒状结构相似 ,主要存在于核酸结合蛋白中…     

新型冠状病毒基因组学研究进展

目的对新型冠状病毒(SARS-CoV-2)的基因组研究进展进行综述,以期为疫情防控相关研究提供参考。方法结合国内外最新研究报道,从SARS-CoV-2基因组结构和进化机制等方面,对SARS-CoV-2的研究进展进行归纳与整理。结果与结论基于基因组序列的遗传进化分析,病毒基因组现阶段没有发生显著的变异和重组,但在人际传播和感染过程中病毒可能发生一定的适应性进化,这对检测和药物研发可能存在影响。未来需要对覆盖全球的患者病毒分离株和野外动物携带病毒株进行基于全基因组测序和进化分析,监控病毒变异和解析适应性进化机制,这有助于疫情防控。     

SARS：来自病毒成分的结构正开始被揭示出

严重急性呼吸综合征(SARS)是冠状病毒家族所致疾病之一。冠状病毒具有复杂的遗传组织，因此人们对它的复制周期知之甚少。冠状病毒家族有大量的复制基因，它们可以加工为大量用于形成复制/转录复合体的成分。这种复合体包括未知功能的非结构蛋白(nsp)。已经测定了其中一种nsp9蛋白的结构，并揭示出该蛋白结合在单链RNA(ssRNA)上。     

SARS-CoV-2刺突蛋白抑制剂活性筛选方法研究进展

严重急性呼吸综合征冠状病毒2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)引起的新型冠状病毒感染(corona virus disease 2019, COVID-19)对全球公共卫生和经济造成了前所未有的影响。SARSCoV-2通过其表面的刺突蛋白与宿主细胞膜上的血管紧张素转换酶2相结合是入侵宿主细胞的关键步骤,以刺突蛋白为靶标的小分子药物成为抗SARS-CoV-2研究的热点。活性筛选是小分子药物研发的关键步骤。鉴于此,本文综述了SARS-CoV-2刺突蛋白小分子抑制剂的活性筛选方法,以期为靶向刺突蛋白的抗病毒药物研发提供参考。     

新型冠状病毒肺炎临床治疗药物最新研究进展

新型冠状病毒肺炎(coronavirus disease 2019,COVID-19)正在世界范围内流行。作为冠状病毒,新型冠状病毒(SARS-Co V-2)和严重急性呼吸综合征冠状病毒(SARS-Co V)都通过人血管紧张素转化酶2(ACE2)受体侵入宿主细胞。面对疫情异常严峻的现状,目前尚缺乏疫苗和尚无特异性针对该病毒的抗病毒药物,临床上仍以支持治疗和对症治疗为主。本文简单介绍了新型冠状病毒和ACE2的关系及作用机制,总结了潜在抗新型冠状病毒治疗药物的最新临床疗效,及其相关药物可能的作用机制,以便充分了解COVID-19的发展过程和药物研究方向,为后续探讨COVID-19药物治疗和疫苗研发提供思路。     

我国新型冠状病毒疫苗研发进展及思考

新型冠状病毒(SARS-CoV-2)是继SARS冠状病毒(SARS-CoV)和中东呼吸综合征冠状病毒(MERS-CoV)之后又一严重危害人类的病毒。SARS-CoV-2引起的疾病被世界卫生组织命名为COVID-19,具有较高的传染性和病死率。为控制疫情蔓延,我国正应急开展多种技术路线的COVID-19疫苗研发,包括灭活疫苗、重组蛋白疫苗、病毒载体疫苗和核酸疫苗(DNA和mRNA)等,在加快疫苗研发进程的同时把握应急研发进度和科学性之间的平衡,并行解决相关科学问题,在满足安全性的前提下保证疫苗的有效性和质量可控。目前我国研发的腺病毒载体疫苗已率先进入Ⅰ期临床试验,多家企业进入注册检验和滚动提交审评资料阶段。本文对COVID-19疫苗研究进展进行综述,并提出现阶段对此种新疫苗研发的考虑。     

严重急性呼吸综合征冠状病毒2疫情期间儿童肾脏病房感染防控思维导图

严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染的疫情已经持续了近2个月,现处于疫情胶着的状态。因儿童SARSCoV-2感染症状不典型,慢性肾脏疾病(CKD)患儿是高危感染人群,儿童肾脏专科病房的管理在复工、返校压力下,面临疫情防控的新挑战,国家临床研究中心肾脏病房、重庆市医学会儿科专委会肾脏学组,为进一步做好肾脏专科病房的疫情防控工作,结合目前疫情和相关防控建议,推荐SARS-CoV-2疫情期间儿童肾脏病房感染防控思维导图,以供儿童肾脏专科病房参考。     

新型冠状病毒的起源追溯与探讨

本文以2019年末在武汉发生的新型冠状病毒疫情为背景,探讨了冠状病毒家族与严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)的来源,阐述了病毒与具有免疫系统的长期宿主的共存机制,在免疫压力下长驻病毒群的演化机制,跨物种演化与病毒家族的形成,常驻病毒群和外源病毒群与疾病的关系和致病机制;指出了SARS-CoV-2当属人类冠状病毒的突变株而非源于蝙蝠经多重变异的冠状病毒。因不同的病毒来源对人类有着不同的感染机制、流行规律、致病机制、以及随之相应的临床转归与防治措施。明确SARS-CoV-2的来源对病毒性疫情防治有重大指导意义。     

口服新型冠状病毒肺炎治疗新药——Paxlovid

Paxlovid(奈玛特韦片/利托那韦片组合包装)是辉瑞公司研发的口服新型冠状病毒肺炎(新冠肺炎)治疗新药,核心组分奈玛特韦(Nirmatrelvir,研发代号:PF-07321332)是专门用于对抗严重急性呼吸综合征冠状病毒2(SARS-CoV-2)3CL蛋白酶抑制剂.美国Ⅲ期临床研究表明,Paxlovid能将新冠肺...     

Bioactive natural compounds against human coronaviruses: a review and perspective

Coronaviruses (CoVs), a family of enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, unusually large RNA genome, and unique replication capability. CoVs are known to cause various potentially lethal human respiratory infectious diseases, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the very recent coronavirus disease 2019 (COVID-19) outbreak. Unfortunately, neither drug nor vaccine has yet been approved to date to prevent and treat these diseases caused by CoVs. Therefore, effective prevention and treatment medications against human coronavirus are in urgent need. In the past decades, many natural compounds have been reported to possess multiple biological activities, including antiviral properties. In this article, we provided a comprehensive review on the natural compounds that interfere with the life cycles of SARS and MERS, and discussed their potential use for the treatment of COVID-19.     

The broad-spectrum antiviral recommendations for drug discovery against COVID-19

Abstract

Despite to outbreaks of highly pathogenic beta and alpha coronaviruses including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and human coronavirus, the newly emerged 2019 coronavirus (COVID-19) is considered as a lethal zoonotic virus due to its deadly respiratory syndrome and high mortality rate among the human. Globally, more than 3,517,345 cases have been confirmed with 243,401 deaths due to Acute Respiratory Distress Syndrome (ARDS) caused by COVID-19. The antiviral drug discovery activity is required to control the persistence of COVID-19 circulation and the potential of the future emergence of coronavirus. However, the present review aims to highlight the important antiviral approaches, including interferons, ribavirin, mycophenolic acids, ritonavir, lopinavir, inhibitors, and monoclonal antibodies (mAbs) to provoke the nonstructural proteins and deactivate the structural and essential host elements of the virus to control and treat the infection of COVID-19 by inhibiting the viral entry, viral RNA replication and suppressing the viral protein expression. Moreover, the present review investigates the epidemiology, diagnosis, structure, and replication of COVID-19 for better understanding. It is recommended that these proteases, inhibitors, and antibodies could be a good therapeutic option in drug discovery to control the newly emerged coronavirus.

• Highlights

• COVID-19 has more than 79.5% identical sequence to SARS-CoV and a 96% identical sequence of the whole genome of bat coronaviruses.

• Acute respiratory distress syndrome (ARDS), renal failure, and septic shock are the possible clinical symptoms associated with COVID-19.

• Different antivirals, including interferons, ribavirin, lopinavir, and monoclonal antibodies (mAbs) could be the potent therapeutic agents against COVID-19.

• The initial clinical trials on hydroquinone in combination with azithromycin showed an admirable result in the reduction of COVID-19.

• The overexpression of inflammation response, cytokine dysregulation, and induction of apoptosis could be an well-organized factors to reduce the pathogenicity of COVID-19.

     

Lithium as a candidate treatment for COVID-19: Promises and pitfalls

The pandemic of respiratory illness caused by a novel coronavirus (SARS-nCoV-2) is a global health crisis. Despite numerous preliminary results, there is as yet no treatment of proven efficacy for this condition. In this context, the pharmacological properties of lithium, better known as a treatment for mood disorders, merit closer examination. Lithium has shown in vitro efficacy at inhibiting the replication of coronaviruses responsible for gastrointestinal and respiratory diseases in animals. It has immunomodulatory properties that may be of additional benefit in moderating the host inflammatory response to the novel coronavirus (SARS-CoV-2). Furthermore, there is evidence that lithium may exert a protective action against upper respiratory infections and influenza-like illnesses in patients taking it for other indications. These promising reports must be balanced against the narrow therapeutic index and high risk of toxicity associated with lithium therapy, its documented interactions with several commonly used drugs, and the absence of evidence of its efficacy against coronaviruses responsible for human disease. Nevertheless, naturalistic studies of the risk of COVID-19 in patients already receiving lithium could provide indirect evidence of its efficacy, and understanding the putative antiviral and immune-regulatory mechanisms of lithium in models of SARS-CoV-2 infection may provide leads for the development of safer and more effective treatments with a specific action against COVID-19.     

Remdesivir: Review of Pharmacology,Pre-clinical Data,and Emerging Clinical Experience for COVID-19

The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an urgent need for effective antivirals. Remdesivir (formerly GS-5734) is a nucleoside analogue pro-drug currently being evaluated in COVID-19 clinical trials. Its unique structural features allow high concentrations of the active triphosphate metabolite to be delivered intracellularly and it evades proofreading to successfully inhibit viral RNA synthesis. In pre-clinical models, remdesivir has demonstrated potent antiviral activity against diverse human and zoonotic β-coronaviruses, including SARS-CoV-2. In this article, we critically review available data on remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics, and in vitro activity against coronaviruses as well as clinical experience and current progress in COVID-19 clinical trials.     

A highly potent and stable pan-coronavirus fusion inhibitor as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases

The development of broad-spectrum antivirals against human coronaviruses (HCoVs) is critical to combat the current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, as well as future outbreaks of emerging CoVs. We have previously identified a polyethylene glycol-conjugated (PEGylated) lipopeptide, EK1C4, with potent pan-CoV fusion inhibitory activity. However, PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo. Therefore, we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment (HR2-CF) of HCoV-OC43. Among these lipopeptides, EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike (S) mutants, as well as other HCoVs and some bat SARS-related coronaviruses (SARSr-CoVs) tested. The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes, better metabolic stability in mouse serum, higher thermostability than the PEGylated lipopeptide EK1C4, suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.     

Plasma exchange in the treatment of complex COVID-19-related critical illness: controversies and perspectives

COVID-19 (coronavirus disease 2019), caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), emerged in Wuhan, China, and has spread worldwide, resulting in over 73 million cases and more than 1 600 000 deaths as of December 2020. Although the disease is asymptomatic in most cases, some patients develop life-threatening disease characterised by acute respiratory distress syndrome, sepsis, multisystem organ failure (MSOF), extrapulmonary manifestations, thromboembolic disease and associated cytokine release syndrome. The rationale for applying therapeutic plasma exchange (TPE) early in the course of fulminant COVID-19 is the suppression of thromboinflammation and amelioration of microangiopathy, thus preventing the ensuing MSOF. In the course of complicated critical illness due to COVID-19, immune dysregulation may be as important as viral replication itself. Moreover, the natural course of SARS-CoV-2 infection remains obscure, as re-infections and/or recurrently positive real-time PCR results have been reported. Although concerns still exist regarding its potential immunosuppressive effects and safety, TPE shows promise in the management of life-threatening COVID-19 as documented by various pilot studies, which remain to be confirmed by future randomised controlled trials. However, current data suggest that TPE could be an adjunctive rescue therapy in complex COVID-19 critical illness.     

New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?

Recently, a novel coronavirus (2019-nCoV), officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Despite drastic containment measures, the spread of this virus is ongoing. SARS-CoV-2 is the aetiological agent of coronavirus disease 2019 (COVID-19) characterised by pulmonary infection in humans. The efforts of international health authorities have since focused on rapid diagnosis and isolation of patients as well as the search for therapies able to counter the most severe effects of the disease. In the absence of a known efficient therapy and because of the situation of a public-health emergency, it made sense to investigate the possible effect of chloroquine/hydroxychloroquine against SARS-CoV-2 since this molecule was previously described as a potent inhibitor of most coronaviruses, including SARS-CoV-1. Preliminary trials of chloroquine repurposing in the treatment of COVID-19 in China have been encouraging, leading to several new trials. Here we discuss the possible mechanisms of chloroquine interference with the SARS-CoV-2 replication cycle.     

Coronaviruses and their therapy

Coronaviruses may cause respiratory, enteric and central nervous system diseases in many species, including humans. Until recently, the relatively low burden of disease in humans caused by few of these viruses hampered development of coronavirus specific therapeutics. However, the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) has prompted the discovery of such drugs. Subsequent studies in animal models demonstrated the efficacy of SARS-CoV specific monoclonal antibodies, pegylated-interferon-alpha and siRNAs against SARS-CoV. Furthermore, several antivirals shown to be effective against other viruses were tested in vitro. Because of availability and shown efficacy, the use of interferons may be considered should SARS-CoV or a related coronavirus (re)-emerge. The more recent design of wide-spectrum inhibitors targeting the coronavirus main proteases may lead to the discovery of new antivirals against multiple coronavirus induced diseases.     

Inhibitors of SARS-CoV-2 main protease: Biological efficacy and toxicity aspects

The emergence of the highly contagious respiratory disease, COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a significant global public health concern. To combat this virus, researchers have focused on developing antiviral strategies that target specific viral components, such as the main protease (M^pro), which plays a crucial role in SARS-CoV-2 replication. While many compounds have been identified as potent inhibitors of M^pro, only a few have been translated into clinical use due to the potential risk-benefit trade-offs. Development of systemic inflammatory response and bacterial co-infection in patients belong to severe, frequent complications of COVID-19. In this context, we analysed available data on the anti-inflammatory and antibacterial activities of the SARS-CoV-2 M^pro inhibitors for possible implementation in the treatment of complicated and long COVID-19 cases. Synthetic feasibility and ADME properties were calculated and included for better characterisation of the compounds' predicted toxicity. Analysis of the collected data resulted in several clusters pointing to the most prospective compounds for further study and design. The complete tables with collected data are attached in Supplementary material for use by other researchers.