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)将创造新的广谱直接作用抗病毒(DAA)药物 应对当前和新出现的大流行威胁的候选人。Discovery Core B将作为Discovery 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 目标部位，并将支持优化对药理工具(化学探针)的命中，并通过 MedChem Core D与项目2-5和Enzymology Core C一起，我们将为 向项目团队和工业合作伙伴领导化合物，以补充现有资产。 这项提议带来了一个世界领先的团队，他们都隶属于结构基因组学，或与结构基因组学合作 联盟(SGC)。SGC是一个开放的科学伙伴关系，支持对阿司匹林的药理鉴定 新药靶标，在高质量药物的产生、表征和分销方面处于世界领先地位 化学探针--靶标验证最有效的工具之一，也是药物早期的一个重要里程碑 发现号。SGC使用蛋白质家族(又名目标类)方法来提高开发效率 化学探头。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 开发、Discovery Core B和MedChem Core D准备应对ReADDI-AC产品组合 靶标，它跨越三个主要的病毒酶家族：RNA聚合酶、RNA解旋酶和 半胱氨酸和丝氨酸蛋白酶。 Discovery Core B的目标是通过产生高性能的 高质量的化学探针，将加速创新的直接作用抗病毒药物的开发。 目标1.投资组合的创建：发现核心B将与酶学核心C，MedChem密切合作 核心D和项目2-5，以选择四个病毒家族和 三个主要的酶靶标蛋白家族，每年有八个靶点进入HIT发现阶段。 目标2.HIT发现和验证：Discovery Core B将同时使用基于多样性和基于知识的 HTS使用一种或多种&gt；10检测格式的纯化重组酶发现HIT。点击率将会是 通过强大的工作流程进行验证，以生成供进一步优化考虑的数据包(HIT简历)。 目标3.命中探测(H 2P)活动。Discovery Core B将通过快速执行支持MedChem Core D 的分析和X射线结晶学，以支持结构引导的合成孔径雷达的制造和/或设计 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份高质量的热门简历，供Adman Core A考虑 作为命中探测/领先优化的起点，并支持项目的命中探测活动。全 将向科学界公开提供化学探针，作为药理学工具使用。