Core B: Discovery Core

核心B：发现核心

• 批准号: 10513681
• 负责人: Kenneth Hugh Pearce
• 金额: $ 938.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513681
• 关键词: Antiviral Agents; Binding; Binding Sites; Biological Assay; Biology; Biophysics; Bromodomain; Caspase; Chemicals; Communities; Complement; Computing Methodologies; DNA; DNA-Directed RNA Polymerase; Data; Development; Diamond; Drug Targeting; Enzymatic Biochemistry; Enzymes; Family; Generations; Human; Industrialization; Lead; Libraries; Ligands; Light; Methodology; Methyltransferase; Molecular Target; Pharmaceutical Chemistry; Pharmacology; Phase; Probability; Protein Binding Domain; Protein Family; Proteins; RNA Helicase; Recombinant Proteins; Recombinants; Scientist; Serine Protease; Site; Source; Structure; Structure-Activity Relationship; Technology; Tertiary Protein Structure; Trust; Validation; Viral; Viral Physiology; Virus; WD Repeat; Work; X-Ray Crystallography; antiviral drug development; assay development; base; clinical candidate; deep learning; design; drug candidate; drug discovery; experience; innovation; knowledge base; lead optimization; learning strategy; new therapeutic target; novel; open data; pandemic disease; programs; protein expression; screening; structural genomics; tool

ABSTRACT The READDI AViDD Center (READDI-AC) will create new broad spectrum direct acting antiviral (DAA) drug candidates to treat current and emerging pandemic threats. Discovery Core B will serve as the discovery engine for identification of new inhibitory chemical matter (hits), validation of chemically tractable molecular target sites, and will support the optimization of hits to pharmacological tools (chemical probes) and Leads by MedChem Core D. Together and also with Projects 2-5 and Enzymology Core C, we will feed a pipeline of Lead compounds to the Project teams and industrial partners to complement existing assets. This proposal brings a world-leading team, all affiliated with, or collaborators of, the Structural Genomics Consortium (SGC). The SGC is an open science partnership that supports the pharmacological identification of new drug targets and is a world leader in the generation, characterization, and distribution of high-quality chemical probes – one of the most impactful tools for target validation, and an important early milestone in drug discovery. The SGC uses a protein family (aka target class) approach to drive efficiency in development of chemical probes. Through our strong experience with open science and protein family chemical probe development, Discovery Core B together with MedChem Core D are poised to tackle the READDI-AC portfolio of targets, which spans three main families of viral enzymes: RNA polymerases, RNA helicases, and cysteine and serine proteases. Discovery Core B aims to prime the READI-AC and global DAA drug discovery pipeline by generating high- quality chemical probes that will accelerate the development of innovative direct acting anti-viral drugs. Aim 1. Portfolio creation: The Discovery Core B will work closely with the Enzymology Core C, MedChem Core D and Projects 2-5 to select a portfolio of tractable DAA target sites across the four virus families and three main enzyme target protein families, such that eight target sites enter the hit discovery phase each year. Aim 2. Hit discovery and Validation: The Discovery Core B will use both diversity- and knowledge-based HTS for hit discovery using purified recombinant enzyme in one or more of >10 assay formats. Hits will be validated though a robust workflow to yield a data package (Hit CV) for consideration for further optimization. Aim 3. Hit-to-Probe (H2P) activities. Discovery Core B will support MedChem Core D with rapid execution of assays and X-ray crystallography to support structure-guided SAR of compounds made and/or designed in MedChem Core D. We will also evaluate viral-active compounds for selectivity against related human enzymes. Discovery Core B will deliver at least 12 high-quality Hit CVs every year, for consideration by Adman Core A as starting points for Hit-to-Probe/Lead optimization, and support the Hit-to-Probe activities by the Projects. All chemical probes will be made openly available to the scientific community for use as pharmacological tools.

抽象的 READDI AViDD 中心 (READDI-AC) 将开发新的广谱直接作用抗病毒 (DAA) 药物 Discovery Core B 将作为治疗当前和新出现的流行病威胁的候选药物。 用于识别新的抑制性化学物质（命中）的引擎，验证化学上可处理的分子 目标位点，并将支持药理学工具（化学探针）和先导化合物的优化 MedChem Core D. 与项目 2-5 和 Enzymology Core C 一起，我们将提供一系列 为项目团队和工业合作伙伴提供化合物，以补充现有资产。 该提案带来了世界领先的团队，全部隶属于结构基因组学或结构基因组学的合作者 联盟 (SGC) 是一个开放的科学合作伙伴关系，支持药物的药理学鉴定。 新药靶点，在高质量药物的生成、表征和分销方面处于世界领先地位 化学探针——靶标验证最有影响力的工具之一，也是药物领域重要的早期里程碑 SGC 使用蛋白质家族（又称目标类别）方法来提高开发效率。 凭借我们在开放科学和蛋白质家族化学探针方面的丰富经验。 Discovery Core B 与 MedChem Core D 一起准备解决 READDI-AC 产品组合 目标，涵盖病毒酶的三个主要家族：RNA聚合酶、RNA解旋酶和 半胱氨酸和丝氨酸蛋白酶。 Discovery Core B 旨在通过产生高 优质化学探针将加速创新直接作用抗病毒药物的开发。 目标 1. 产品组合创建：Discovery Core B 将与 Enzymology Core C、MedChem 密切合作 核心 D 和项目 2-5 用于在四个病毒家族中选择一系列易于处理的 DAA 靶位点， 三个主要酶靶蛋白家族，每年有 8 个靶位点进入命中发现阶段。 目标 2. 命中发现和验证：发现核心 B 将使用基于多样性和基于知识的技术 使用纯化的重组酶以 >10 种检测形式中的一种或多种进行命中发现的 HTS 将是。 通过强大的工作流程进行验证，生成数据包 (Hit CV)，以供进一步优化考虑。 目标 3. Hit-to-Probe (H2P) 活动将支持 MedChem Core D 的快速执行。 的分析和 X 射线晶体学，以支持结构引导的 SAR 制造和/或设计的化合物 MedChem Core D。我们还将评估病毒活性化合物对相关人类酶的选择性。 Discovery Core B 每年将提供至少 12 份高质量热门简历，供 Adman Core A 考虑 作为 Hit-to-Probe/Lead 优化的起点，并支持所有项目的 Hit-to-Probe 活动。 化学探针将向科学界公开提供，用作药理学工具。