HTS Core

摘要 SARS-CoV-2疫情在全球范围内造成480万人死亡， 暴露了控制、治疗和预防猪流感病毒感染所需的抗病毒疗法的缺乏 大流行的可能性。尽管成功开发和部署了多种高效疫苗， 疫苗的犹豫不决和逃逸突变的持续出现破坏了疾病控制，并使 迫切需要小分子药物来补充疫苗。在此方案中，高吞吐量 正在寻求基于靶点和基于细胞的筛选方法，以提供一种全面的药物 发现计划，以识别直接作用的抗病毒药物。抗病毒药物和流行病研究中心 准备(CAMPP)高通量筛选(HTS)核心(核心A)将协调和执行 Scripps Calibr&gt；80万个集中抗病毒小分子探针库的筛选 收藏，适当的全功能片段文库，对DNA编码文库的访问和化学多样性， 小分子图书馆。这将导致确认有效的筛选命中并执行命中跟踪- 与药物化学核心协作的UP研究。CAMPP成功的关键是HTS Core通过管理小分子探针库、筛查数据 复合随访和药物化学支持。HTS Core在以下方面拥有丰富的经验 这些功能，在其存在的九年中管理352个内部和外部屏幕。这包括一个完整的 建立化合物管理团队，科学家完成初步的分析优化(或从 具有抗病毒专业知识的合作者)，开发使用荧光的微型(384孔和1536孔)分析， 发光或高含量成像读数，以及数据分析、存储和传播 团队成员。HTS Core也有一个完全启用的BSL3工作流来评估和表征抗病毒药物 高通量活病毒检测中的抗SARS-CoV-2活性。综上所述，拟议的CAMPP包括 一个真正在非营利性药物发现方面无与伦比的科学家集体团队，与工业级的 高通量筛选设备，由世界领先的结构生物学家、病毒学家和化学家共同开发 并应用创新的分析方法，概括了病毒发病机制未被研究的方面，以识别和 开发新的治疗抗病毒方法。

SUMMARY The emergence of SARS-CoV-2 into a worldwide pandemic has accounted for > 4,800,000 deaths worldwide, has exposed the dearth of antiviral therapeutics needed to control, treat and prevent infections from viruses of pandemic potential. Despite the successful development and deployment of multiple vaccines with high efficacy, vaccine hesitancy and continued emergence of escape mutants have undermined disease control and placed an urgent need for small-molecule medicines to supplement vaccines. Within this proposal, high throughput target-based and cell-based screening approaches are being pursued to provide a comprehensive drug discovery program to identify direct-acting antivirals. The Center for Antiviral Medicines and Pandemic Preparedness (CAMPP) High-throughput Screening (HTS) Core (Core A) will coordinate and execute the screening of Scripps Calibr’s >800,000 small molecule probe libraries which includes focused antiviral collections, propriety fully functional fragment libraries, access to DNA-encoded libraries and chemically diverse, small-molecule libraries. This will lead to the identification of validated screening hits and execution of hit follow- up studies in coordination with the Medicinal Chemistry Core. Essential to the success of CAMPP is the HTS core’s ability to support internal and external screening by managing small molecule probe libraries, screen data, compound follow-up and medicinal chemistry support. The HTS Core has extensive experience with each of those functions, managing > 352 internal and external screens in its nine years of existence. This includes a fully established compound management team, scientists to complete initial assay optimization (or transfer from a collaborator with antiviral expertise), developing miniaturized (384- and 1536-well) assays using fluorescent, luminescence or high-content imaging readouts in addition to data analysis, storage and dissemination among team members. The HTS Core also has a fully enabled BSL3 workflow to evaluate and characterize antiviral activity against SARS-CoV-2 in high-throughput live virus assays. Together, the proposed CAMPP is comprised of a collective team of scientists truly unmatched in non-profit drug discovery integrated with an industry-grade high-throughput screening facility with world-leading structural biologists, virologists and chemists to develop and apply innovative assays that recapitulate understudied aspects of the viral pathogenesis to identify and development new therapeutic antiviral approaches.