Discovery of Chemical Probes and Therapeutic Leads, Phase 2

化学探针和治疗先导化合物的发现，第二阶段

• 批准号: 10853967
• 负责人: JOSEPH M FOX
• 金额: $ 94.43万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10853967
• 关键词: Adverse effects; Amino Acid Sequence; Animals; Award; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Biological Markers; Biology; Biosensor; COVID-19; Cell Adhesion; Cell surface; Cells; Cellular biology; Centers of Research Excellence; Chemicals; Clinical; Clinical Trials; Collaborations; Collection; Complex; Core Facility; Data; Development; Diagnostic; Disease; Disintegrins; Drug Screening; Enzymes; Ephrin-B1; Family; Fluorescence Resonance Energy Transfer; Functional disorder; Future; Generations; Goals; Grant; Health; Human; In Vitro; Infection; Inflammatory; International; Knowledge; Lead; Libraries; Mass Spectrum Analysis; Mediating; Metalloproteases; Methods; Molecular; Molecular Conformation; Mus; Natural Products; Pathology; Pathway interactions; Pediatric Hospitals; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Physiological; Property; Recombinants; Research; Research Personnel; Role; Safety; Sampling; Signal Transduction; Site; Solid Neoplasm; Source; Structural Biologist; Structure; Structure-Activity Relationship; Testing; Therapeutic; Virus; X-Ray Crystallography; clinical application; experience; feasibility testing; high throughput screening; human disease; in vitro Assay; in vitro activity; in vivo; inhibitor; novel; novel therapeutics; potential biomarker; prognostic; programs; protein aminoacid sequence; rational design; skills; small molecule; small molecule inhibitor; therapeutic target; tool

PROJECT SUMMARY The goal of the parental COBRE award, entitled Discovery of Chemical Probes and Therapeutic Leads, is to develop chemical approaches for probing biology, to discover and apply new chemical biological tools for the study of disease-associated biological pathways, and to understand the interactions between small molecules and their biological targets using computational approaches. In this supplement award application, we propose to develop probes and inhibitors and use these new tools to study the fundamental biochemical properties of ADAM9, a cell-surface metalloproteinase that is a biomarker and a potential therapeutic target for multiple human diseases. Aim 1 of this application (led by Dr. Wei) will be focused on developing sensitive and selective fluorescent peptide substrates for ADAM9, which are currently unavailable. These peptide substrates are necessary for high-throughput screens to identify ADAM9 inhibitors, and for generating biosensors to detect endogenous ADAM9 activity in animal and clinical samples as a biomarker. Aim 2 (led by Dr. Schmitz) will investigate the molecular basis of ADAM9-inhibitor interactions by using an ADAM9 inhibitor that we recently identified. This information is crucial for guiding future identification and optimization of ADAM9 inhibitors. In Aim 3 (led by Dr. Langhans), we will test the feasibility of identifying new ADAM9 inhibitors by conducting a medium-throughput screen with a library containing thousands of compounds. Hits identified in this screen will serve as leads for further optimization to develop potent and selective ADAM9 inhibitors for research and clinical purposes. The proposed study will leverage the unique and complementary skill set of each co-project leader: Dr. Wei is an experienced researcher specializing in metalloproteinase biochemistry and cell biology, Dr. Schmitz is a structural biologist focusing on protease structure-function relationship, and Dr. Langhans, the acting director of the High-Throughput Screen Core Facility at Nemours Children’s Hospital, will contribute her expertise in drug screen. The collaboration will be highly synergistic, as extensive interactions among the three research groups are anticipated for each aim. At the completion of this project, we expect to submit a multi-PI R01 application using the data generated from this study to continue and deepen our collaboration. In conclusion, the proposed collaborative research will have a long-term and transformative impact on understanding the pathology of the related diseases and developing new drugs to treat these diseases.

项目概要 家长 COBRE 奖的目标名为“化学探针和治疗先导的发现”， 开发用于探测生物学的化学方法，发现并应用新的化学生物学工具 研究与疾病相关的生物途径，并了解小分子之间的相互作用 使用计算方法的分子及其生物靶标。在本次补充奖励申请中， 我们建议开发探针和抑制剂，并使用这些新工具来研究基本的生化 ADAM9 的特性，一种细胞表面金属蛋白酶，是一种生物标志物和潜在的治疗靶点 多种人类疾病。该应用程序的目标 1（由 Wei 博士领导）将侧重于培养敏感和 ADAM9 的选择性荧光肽底物，目前尚无法获得。这些肽底物 对于识别 ADAM9 抑制剂的高通量筛选以及生成生物传感器来识别 ADAM9 抑制剂是必要的 检测动物和临床样本中的内源性 ADAM9 活性作为生物标志物。目标 2（由 Schmitz 博士领导） 将使用我们的 ADAM9 抑制剂研究 ADAM9 抑制剂相互作用的分子基础 最近确定的。这些信息对于指导 ADAM9 的未来识别和优化至关重要 抑制剂。在目标 3（由 Langhans 博士领导）中，我们将测试通过以下方式识别新 ADAM9 抑制剂的可行性： 对包含数千种化合物的库进行中等通量筛选。确定的命中数 该筛选将作为进一步优化的线索，以开发有效的、选择性的 ADAM9 抑制剂 研究和临床目的。拟议的研究将利用独特且互补的技能 各合作项目负责人：魏博士是一位经验丰富的金属蛋白酶生物化学研究员 和细胞生物学，施密茨博士是一位结构生物学家，专注于蛋白酶结构与功能关系，以及 Langhans 博士是内穆尔儿童医院高通量筛选核心设施的代理主任， 将贡献她在药物筛选方面的专业知识。此次合作将具有高度协同性，范围广泛 每个目标都预计三个研究小组之间的互动。该项目完成后， 我们希望使用本研究生成的数据提交多 PI R01 申请，以继续并 加深我们的合作。总之，拟议的合作研究将具有长期和 对了解相关疾病的病理学和开发新药具有变革性影响 治疗这些疾病。

项目成果

Modulation of the NOD-like receptors NOD1 and NOD2: A chemist's perspective.

NOD样受体NOD1和NOD2的调节：化学家的观点。

• DOI: 10.1016/j.bmcl.2019.03.010
• 发表时间: 2019-05-15
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: D'Ambrosio EA;Drake WR;Mashayekh S;Ukaegbu OI;Brown AR;Grimes CL
• 通讯作者: Grimes CL

Controlling the Release of Small, Bioactive Proteins via Dual Mechanisms with Therapeutic Potential.

• DOI: 10.1002/adhm.201700713
• 发表时间: 2017-12
• 期刊: Advanced healthcare materials
• 影响因子: 10
• 作者: Kharkar PM;Scott RA;Olney LP;LeValley PJ;Maverakis E;Kiick KL;Kloxin AM
• 通讯作者: Kloxin AM

Investigating Peptidoglycan Recycling Pathways in Tannerella forsythia with N-Acetylmuramic Acid Bioorthogonal Probes.

• DOI: 10.1021/acsinfecdis.2c00333
• 发表时间: 2022-09-09
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Wodzanowski, Kimberly A.;Hyland, Stephen N.;Chinthamani, Sreedevi;Sandles, Liam-Michael D.;Honma, Kiyonobu;Sharma, Ashu;Grimes, Catherine L.
• 通讯作者: Grimes, Catherine L.

Destructive fibrotic teamwork: how both microenvironment stiffness and profibrotic interleukin 13 impair alveolar macrophage phenotype and function.

破坏性纤维化团队合作：微环境刚度和纤维化白介素如何损害肺泡巨噬细胞表型和功能。

• DOI: 10.1039/d2bm00828a
• 发表时间: 2022-09-27
• 期刊: BIOMATERIALS SCIENCE
• 影响因子: 6.6
• 作者: Bomb, Kartik;Pradhan, Lina;Zhang, Qi;Jarai, Bader M.;Bhattacharjee, Arnab;Burris, David L.;Kloxin, April M.;Fromen, Catherine A.
• 通讯作者: Fromen, Catherine A.

Deaminative Reductive Methylation of Alkylpyridinium Salts.

• DOI: 10.1021/acs.orglett.1c02458
• 发表时间: 2021-09-17
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Bercher OP;Plunkett S;Mortimer TE;Watson MP
• 通讯作者: Watson MP