新型冠状病毒小课堂

AmadorBio has noticed that the situation of coronovirus outbreak is increasingly severe globally when preparing the COVID-19 series. Our experts leverage the medical expertise and have conducted multiple online trainings on COVID-19 general science and the knowledge of drug development in this area. 

海洋之神优惠大厅主站注意到,在准备这一系列COVID-19科普内容的过程中,新型冠状病毒疫情在国际上的形势日渐严峻。海洋之神优惠大厅主站团队利用自身医学方面的专业知识,开展了一系列与新型冠状病毒相关的线上培训和讲座,分享了在该领域的药物开发经验。

AmadorBio is a highly experienced and well-integrated team of clinical pharmacologists, bioanalytical, translational & clinical scientists, clinical trial management experts, biostatisticians, CMC experts, regulatory specialists, quality assurance auditors, and project managers. 

海洋之神优惠大厅主站是一支经验丰富、综合能力卓越的专业团队,拥有临床药理学家、生物分析专家、转化和临床科学家、生物统计学家和资深临床试验管理人员、CMC专家、上市申报专家、QA审计员和项目管理人员。

Our support includes the technical, operational, quality, compliance and regulatory phases of preclinical and clinical drug development programs. Our experts collaborate with >20 leading biopharma companies on projects from lead candidate profiling to CTD.

我们的服务包括药物开发临床前和临床阶段的技术、运营、质量控制、合规和注册。我们的专家与超过20个领先的生物制药公司进行广泛合作,提供从主要候选产品筛选到CTD阶段的一体化的项目服务。

Brief Introduction

文章导引:

Apart from the vaccine that is still in its trial phase and human body’s immunity, antiviral drugs serve as the driving force to fight viruses by targeting key steps in the viral life cycle. This article introduces the structure of the virus, the mechanism for the virus to enter the cell and the possible targets for COVID-19 treatment. We hope all these contents may facilitate you to have an understanding to this virus.

除却还在研发试验阶段的疫苗和依靠人体自身免疫力,抗病毒药物在对抗COVID-19方面依旧是主力军。本文介绍了新型冠状病毒的结构,病毒入侵细胞机制,以及目前新型冠状病毒治疗的可行性靶点。希望我们准备的这些内容,能够为大家了解冠状病毒有所帮助。

01  Introduction 介绍

  • RNA enveloped beta-coronavirus

新型冠状病毒是具有包膜结构的RNA β病毒

  • Angiotensin converting enzyme 2 (ACE2) receptor as a mechanism of cell entry

新型冠状病毒进入细胞的受体是血管紧张素转化酶2 (ACE2)

  • Hemagglutinin-esterase (HE) enhances S protein-mediated cell entry

血凝素酯酶(HE)增强刺突(S)蛋白对病毒进入细胞的介导作用

Sci China Life Sci. 2020 Jan 21. doi: 10.1007/s11427-020-1637-5

Lancet. 2020 Jan 30. pii: S0140-6736(20)30251-8. doi: 10.1016/S0140-6736(20)30251-8

Possible targets for 2019-nCoV treatment

新型冠状病毒治疗的可行性靶点  

(Block virus entry)

(阻断病毒入胞)

  • Use ACE2 for entry and the cellular protease TMPRSS2 for priming
    • ACE2 antagonist (Chloroquine interferes with terminal glycosylation of ACE2*)
    • TMPRSS2 antagonist (Camostat卡莫司它)
  • Prevent HE mediated membrane fusion
    • Arbidol (阿比多尔)

Possible targets for 2019-nCoV treatment

新型冠状病毒治疗的可行性靶点

(Block endocytosis)

(阻断胞吞)

  • Baricitinib 巴瑞替尼
    • One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1)
    • Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles
    • Janus kinase (JAK) inhibitor Baricitinib binds AAK1 and GAK
  • Chloroquine 氯喹
    • Fusion of viral and cellular membranes is pH dependent
    • Chloroquine acts as an Endocytosis Blocking Agent by increasing endosomal pH required for virus/cell fusion

Possible targets for 2019-nCoV treatment

新型冠状病毒治疗的可行性靶点

(Block viral RNA synthesis)

(阻断病毒RNA合成)

Remdesivir (GS-5734, 瑞德西韦)

  • A nucleotide analogue deactivates viral RNA polymerase
  • Potential Indication: Ebola Virus Infection (Phase 2)
  • To be highly effective in the control of 2019-nCoV infection in cellular level
  • February 6, 2020 a clinical trial of Remdesivir began in China (Phase 3)
  • [NCT04252664 and NCT04257656]
  • February 21, 2020 a clinical trial of Remdesivir began in US (Phase 2)
  • [NCT04280705]

Possible targets for 2019-nCoV treatment

新型冠状病毒治疗的可行性靶点

(Protease and neuraminidase inhibitors)

(蛋白酶和神经氨酸酶抑制剂)

  • Protease inhibitor targets key proteins in replicase-transcriptase complex (RTC) for RNA synthesis:蛋白酶抑制剂在RNA合成上靶向复制-转录酶复合体(RTC)的关键蛋白
    • Coronavirus main proteinase (3CLpro)
    • Papain-like protease (PLpro)
    • Non-structural protein12 (nsp12) encodes RNA-dependent RNA polymerase
    • Nsp13 encodes helicase
  • Neuraminidase inhibitors 神经氨酸酶抑制剂
    • Has been widely used for 2019-nCoV or suspected cases in China hospitals
    • No exact evidence to prove that is effective

2019-nCoV Guidelines from NHC

国家卫建委发布新型冠状肺炎诊疗方案

References

参考文献

Xu, Xintian, et al. “Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission.” Science China Life Sciences (2020): 1-4.

Lu, Roujian, et al. “Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.” The Lancet (2020).

Hoffmann, Markus, et al. “The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells.” bioRxiv (2020).

Richardson, Peter, et al. “Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.” The Lancet (2020).

Holshue, Michelle L., et al. “First case of 2019 novel coronavirus in the United States.” New England Journal of Medicine (2020).

Wang, Manli, et al. “Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.” Cell Research (2020): 1-3.

Kilianski, Andy. Coronavirus proteases as therapeutic targets: Development of biosensors to detect inhibition of protease activity and separation of the multiple functions of coronavirus papain-likeproteases. Diss. Loyola University Chicago, 2014.

Li, Guangdi, and Erik De Clercq. “Therapeutic options for the 2019 novel coronavirus (2019-nCoV).” (2020).