登录
 机构网站
  1. 首页
  2. 情报产品
  3. 快讯详情

《Cell，3月30日，OP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation》

  • 来源专题：COVID-19科研动态监测
  • 编译者： zhangmin
  • 发布时间：2021-04-02

  • TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation.
    Jessica Sook Yuin Ho ∗
    Bobo Wing-Yee Mok ∗
    Laura Campisi
    Christopher Benner
    Juergen A. Richt
    Ivan Marazzi 31
    Show all authors
    Show footnotes
    Published:March 30, 2021DOI:https://doi.org/10.1016/j.cell.2021.03.051

    Summary
    The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe COVID-19 in humans.

  • 原文来源：https://www.cell.com/cell/fulltext/S0092-8674(21)00382-2#%20
125浏览量
原文链接
相关报告

  • 《Cell，3月30日，Antibody evasion by the P.1 strain of SARS-CoV-2》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2021-04-02
    • Antibody evasion by the P.1 strain of SARS-CoV-2 Wanwisa Dejnirattisai # Daming Zhou # Piyada Supasa # Jingshan Ren David I. Stuart Gavin R. Screaton Show all authors Show footnotes Open AccessPublished:March 30, 2021DOI:https://doi.org/10.1016/j.cell.2021.03.055 Summary Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations: P.1 from Brazil, B.1.351 from South Africa and B.1.1.7 from the UK (12, 10 and 9 changes in the spike respectively). All have mutations in the ACE2 binding site with P.1 and B.1.351 having a virtually identical triplet: E484K, K417N/T and N501Y, which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine induced antibody responses than B.1.351 suggesting that changes outside the RBD impact neutralisation. Monoclonal antibody 222 neutralises all three variants despite interacting with two of the ACE2 binding site mutations, we explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.
    123浏览量
    原文链接

  • 《Cell，3月16日，BET Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV-2 Infection》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2021-03-23
    • BET Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV-2 Infection Richard J. Mills Sean J. Humphrey Patrick RJ. Fortuna Tobias Bald David E. James James E. Hudson Show all authors Published:March 16, 2021DOI:https://doi.org/10.1016/j.cell.2021.03.026 Summary Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory ‘cytokine-storm’, a cocktail of interferon gamma, interleukin 1β and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids and hearts of SARS-CoV-2 infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCO and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the FDA breakthrough designated drug apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.
    117浏览量
    原文链接