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.

摘要 READDI AViDD中心（READDI-AC）将创建新的广谱直接作用抗病毒（DAA）药物 治疗当前和新出现的流行病威胁的候选人。Discovery Core B将作为发现 用于识别新的抑制性化学物质（hits）的引擎，验证化学上易处理的分子 靶点，并将支持药理学工具（化学探针）和线索的优化， MedChem Core D.我们将与项目2-5和酶学核心C一起， 为项目团队和工业合作伙伴提供化合物，以补充现有资产。 这项提案带来了一个世界领先的团队，所有附属于，或合作者，结构基因组学 财团（SGC）。SGC是一个开放的科学伙伴关系，支持药理学鉴定， 是一个新的药物靶点，是一个世界领先的生成，表征和分配高质量的 化学探针-最具影响力的靶标验证工具之一，也是药物治疗的重要早期里程碑 的发现SGC使用蛋白质家族（又名靶类）方法来提高开发效率， 化学探针通过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一起准备应对READDI-AC产品组合 的目标，其中跨越三个主要家族的病毒酶：RNA聚合酶，RNA解旋酶， 半胱氨酸和丝氨酸蛋白酶。 Discovery Core B旨在通过产生高水平的 高质量的化学探针，将加速创新的直接作用的抗病毒药物的开发。 目标1.产品组合创建：发现核心B将与酶学核心C、MedChem 核心D和项目2-5，以选择跨四个病毒家族的易于处理的DAA靶位点组合， 三个主要的酶靶蛋白家族，这样每年有八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 在>10种测定形式中的一种或多种中使用纯化的重组酶进行命中发现的HTS。点击率将是 通过强大的工作流程进行验证，以产生数据包（Hit CV），供进一步优化考虑。 目标3. H2P（Hit-to-Probe）Discovery Core B将通过快速执行支持MedChem Core D 分析和X射线晶体学，以支持在本发明中制备和/或设计的化合物的结构引导SAR。 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份高质量的Hit CV，供Adman Core A考虑 作为点击探测/线索优化的起点，并支持项目的点击探测活动。所有 将向科学界公开提供化学探针，用作药理学工具。