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Discovery of SARS-CoV-2 antivirals using a replicon assay

Discovery of SARS-CoV-2 antivirals using a replicon assay
使用复制子测定发现 SARS-CoV-2 抗病毒药物
批准号:
10522048
负责人:
Stefan G Sarafianos
金额:
$65.76万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-08-01 至 2027-07-31

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中文摘要
翻译
项目摘要 严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)可导致人类严重疾病(COVID-19)。 19)对全球公共卫生构成重大威胁。自2019年12月首次报告以来,COVID-19已 成为一种继续蔓延的大流行病,截至2015年,确诊病例超过2.46亿例,死亡人数超过500万人。 11/02/2021.除了人类的悲剧之外,由大流行病引发的全球经济崩溃的规模 经济是巨大的。虽然现在已经有疫苗,但它们的效力似乎随着疾病的发展而降低。 传播病毒株Remdesivir是唯一被批准的靶向SARS-CoV-2的抗病毒药物,但它对 COVID-19死亡率。因此,识别和开发额外的抗病毒药物以对抗病毒感染至关重要。 以下强有力的初步数据使SARS-CoV-2的靶向成为可能: SARS-CoV-2复制子系统的集合,能够实现尖端、快速和经济的高通量 筛选2)稳定表达SARS-CoV-2复制子的细胞系的制备。3)的初步筛选 化学文库导致发现了一种新的SARS-CoV-2抗病毒药物,这种药物已经得到了改进, 通过药物化学的努力进行一轮优化。4)单基因组或 亚基因组(+)或(-)SARS-CoV-2 RNA和同时存在的病毒和/或宿主蛋白。 5)尖端的快速高通量感染性病毒BSL 3检测,可实现动力学、机制、药物 抗性研究。6)10种SARS冠状病毒非结构蛋白的克隆、表达和纯化 (nsps)。7)生物化学和生物物理分析,以测量几种SARS-CoV的酶活性, SARS-CoV-2 nsp蛋白并测量化合物与nsp的结合。 我们假设我们最近开发的复制子系统可以用于发现抗SARS病毒的药物, CoV-2命中,在命中到铅优化后可以成为COVID-19候选药物。为了解决这个 根据这一假设,我们提出以下具体目标: 1.利用SARS-CoV-2复制子质粒系统和SARS-CoV-2复制子表达细胞系筛选 化学库中的抗病毒药物。 2.优先抑制剂的抑制和耐药性研究。 3.命中-领先优化 这些研究将导致具有强大效力和药代动力学特征的抗病毒药物,为 开发SARS-CoV-2抗病毒药物和联合治疗。
英文摘要
PROJECT SUMMARY Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) cause severe diseases in humans (COVID- 19) that presents a major threat for global public health. Since it was first reported in 12/2019, COVID-19 has become a pandemic that continues to spread, with >246 million confirmed cases and >5 million deaths as of 11/02/2021. In addition to the human tragedy, the magnitude of the pandemic-driven implosion of global economies is enormous. Although vaccines are now available, their efficacy appears to be reduced with spreading viral strains. Remdesivir is the only approved antiviral targeting SARS-CoV-2, but it has little effect on COVID-19 mortality. Therefore, it is critical to identify and develop additional antivirals to combat viral infection. The following strong preliminary data enable targeting of SARS-CoV-2: 1) Construction of an extensive collection of SARS-CoV-2 replicon systems that enable cutting-edge, rapid, and economical high-throughput screening. 2) Preparation of cell lines that stably express SARS-CoV-2 replicon. 3) Preliminary screening of chemical libraries led to the discovery of a novel SARS-CoV-2 antiviral, which has already been improved with one round of optimization through medicinal chemistry efforts. 4) Multiplex visualization of single-genomic or subgenomic (+) or (-) SARS-CoV-2 RNA and simultaneously viral and/or host proteins in individual infected cells. 5) Cutting-edge rapid high-throughput infectious virus BSL3 assays that enable kinetic, mechanistic, drug resistance studies. 6) In-house cloning expression and purification of 10 SARS-CoV-2 non-structural proteins (nsps). 7) Biochemical and biophysical assays to measure the enzymatic activities of several SARS-CoV and SARS-CoV-2 nsp proteins and to measure compound binding to nsps. We hypothesize that our recently developed replicon systems can be used for the discovery of anti-SARS- CoV-2 hits, which upon hit-to-lead optimization can become COVID-19 drug candidates. To address this hypothesis, we propose the following specific aims: 1. Use of SARS-CoV-2 replicon plasmid systems and SARS-CoV-2 replicon-expressing cell lines to screen chemical libraries for antiviral hits. 2. Inhibition and resistance studies with prioritized inhibitors. 3. Hit-to-lead optimization These studies will lead to antivirals with strong potency and pharmacokinetic profiles, setting the stage for development of SARS-CoV-2 antivirals and combination therapies.
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Behavior of HIV in Viral Environments (B-HIVE)
  • 批准号:
    10650864
  • 项目类别:
  • 资助金额:
    $675.93万
  • 财政年份:
    2022
  • 负责人:
    Stefan G Sarafianos
  • 依托单位:
Discovery of SARS-CoV-2 antivirals using a replicon assay
  • 批准号:
    10673119
  • 项目类别:
  • 资助金额:
    $64.35万
  • 财政年份:
    2022
  • 负责人:
    Stefan G Sarafianos
  • 依托单位:
Dynamics of HIV Core Interactions
  • 批准号:
    10650881
  • 项目类别:
  • 资助金额:
    $117.14万
  • 财政年份:
    2022
  • 负责人:
    Stefan G Sarafianos
  • 依托单位:
Behavior of HIV in Viral Environments (B-HIVE)
  • 批准号:
    10508443
  • 项目类别:
  • 资助金额:
    $628.9万
  • 财政年份:
    2022
  • 负责人:
    Stefan G Sarafianos
  • 依托单位:
海外基金