HTS Core

总结 SARS-CoV-2成为全球大流行，全球死亡人数超过4，800，000， 暴露了控制、治疗和预防病毒感染所需的抗病毒治疗的缺乏， 大流行的可能性。尽管成功开发和部署了多种高效疫苗， 疫苗的犹豫和逃逸突变体的不断出现破坏了疾病控制， 迫切需要小分子药物来补充疫苗。在该提议中，高吞吐量 基于靶点和基于细胞的筛选方法正在被追求以提供一种全面的药物 发现计划来识别直接作用的抗病毒药物。抗病毒药物和流行病中心 准备（CAMPP）高通量筛选（HTS）核心（核心A）将协调和执行 筛选Scripps Calibr的> 800，000个小分子探针文库，其中包括重点抗病毒 收集，适当的全功能片段文库，获得DNA编码的文库和化学多样性， 小分子文库。这将导致识别经验证的筛选命中并执行命中跟踪- 与药物化学核心协调开展研究。CAMPP成功的关键是HTS 核心通过管理小分子探针库，筛选数据， 化合物后续和药物化学支持。HTS Core在以下方面拥有丰富的经验： 这些功能，管理超过352内部和外部屏幕在其存在的九年。其中包括一个全面的 建立化合物管理团队，科学家完成初始测定优化（或从 具有抗病毒专业知识的合作者），开发使用荧光的小型化（384孔和1536孔）测定， 除了数据分析、存储和传播之外， 团队成员HTS Core还具有完全启用的BSL 3工作流程，可用于评估和表征抗病毒药物 在高通量活病毒测定中对SARS-CoV-2的活性。总的来说，拟议的CAMPP包括 一个科学家的集体团队，真正无与伦比的非营利性药物发现与工业级的整合， 与世界领先的结构生物学家、病毒学家和化学家合作开发高通量筛选设施 并应用创新的检测方法，概括了病毒发病机制的未充分研究的方面， 开发新的抗病毒治疗方法。

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.