First-in-class small molecules that enhance lung barrier function during acute respiratory distress syndrome (ARDS) as potential therapeutics for COVID-19

一流的小分子，可增强急性呼吸窘迫综合征 (ARDS) 期间的肺屏障功能，作为 COVID-19 的潜在疗法

• 批准号: 10254996
• 负责人: Frederick M Ausubel
• 金额: $ 25万
• 依托单位: ARTUS THERAPEUTICS INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254996
• 关键词: Acids; Address; Adherens Junction; Adult Respiratory Distress Syndrome; Alveolar; Anti-Inflammatory Agents; Aryl Hydrocarbon Receptor; Attenuated; Bifidobacterium; Biological Assay; Blood Vessels; Blood capillaries; Bone Marrow; COVID-19; COVID-19 patient; COVID-19 therapeutics; COVID-19 treatment; Cell Culture Techniques; Cells; Chemicals; Data; Development; Dose; Drug Kinetics; Dyes; Endothelial Cells; Endothelium; Enzymes; Epithelial; Epithelial Cells; Evans blue stain; Exhibits; Extravasation; Goals; Government; Histamine; Human; Immune; Infection; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Interleukin-6; Intestinal permeability; Lead; Liquid substance; Lung; Mediating; Modeling; Molecular Weight; Mus; Nuclear; Oral; Oral Administration; Patients; Permeability; Persons; Phase; Process; Proteins; Publishing; Pulmonary Inflammation; Rodent; SARS-CoV-2 infection; Serum Proteins; Small Business Innovation Research Grant; Sodium Dextran Sulfate; Stomach; Structure of parenchyma of lung; Symptoms; TNF gene; Testing; Therapeutic; Tight Junctions; Tissues; Toxic effect; Trinitrobenzenesulfonic Acid; Ulcerative Colitis; Up-Regulation; Vascular Endothelial Growth Factors; Vascular Endothelium; Virus Diseases; Work; alveolar epithelium; analog; base; cadherin 5; cytokine; dietary; gastrointestinal epithelium; gut bacteria; interstitial; intestinal epithelium; lead optimization; macrophage; monolayer; mouse model; novel therapeutics; pharmacokinetics and pharmacodynamics; potency testing; small molecule; transcription factor

First-in-class small molecules that enhance lung barrier function during acute respiratory distress syndrome (ARDS) as potential therapeutics for COVID-19 PA-20-260, R43 Phase I SBIR PI: Frederick M. Ausubel Project Summary Infection by SARS-CoV-2 can lead to highly lethal acute respiratory distress syndrome (ARDS). In ARDS, inflammatory-mediated processes cause a breakdown of tight and adherens junctions in the alveolar capillary endothelium as well as tight junctions in the alveolar epithelium. This allows fluid, serum proteins, and immune cells to leak out of alveolar capillaries into lung interstitial tissues and then through the alveolar epithelium into the alveolar airway. There are no therapeutics approved for ARDS that directly target tight and adherens junctions, even though accumulating evidence suggests that therapeutics that shore up these junctions could be highly efficacious for ARDS patients. To address this unmet need, Artus Therapeutics is developing novel therapeutics that directly enhance both epithelial and endothelial barrier function in the lungs. Artus’s lead compound, ARTX-2, is a low molecular weight orally available molecule inspired by the natural gut metabolite Urolithin A. Oral administration of ARTX-2 decreases vascular leakage into lung tissue in mice treated with LPS to induce pulmonary inflammation. ARTX-2 also induces the upregulation of the endothelial junction protein VE- cadherin in mouse lungs. In endothelial cell cultures, ARTX-2 upregulates VE-cadherin and blocks LPS-elicited permeability. With respect to epithelial barrier function, ARTX-2 up-regulates several tight junction proteins and decreases permeability of intestinal epithelial cells. Oral administration of ARTX-2 dramatically mitigates symptoms in mouse models of ulcerative colitis by restoring gut epithelial barrier function. Further, ARTX-2 blocks LPS-elicited inflammatory cytokines including IL-6 and TNF-a in both LPS-treated mice and in LPS- treated bone marrow derived macrophages. From these data, it appears that ARTX-2 may be efficacious in the treatment of COVID-19 patients because it may enhance both lung endothelial and lung epithelial barrier function and decrease the levels of inflammatory cytokines without being immunosuppressive. In addition to the lead compound ARTX-2, 44 ARTX-2 analogs have been synthesized for lead optimization studies. Two specific aims test the hypotheses that ARTX-2 will decrease permeability in lung epithelium as well as in vascular endothelium, will be efficacious in murine LPS-elicited and viral infection-elicited ARDS models, and that particular ARTX-2 analogs will be more potent than ARTX-2. In Aim 1, we propose to test the potency of 44 ARTX-2 analogs in comparison to ARTX-2 in upregulating the expression of tight junction proteins and VE-cadherin in lung epithelial and lung endothelial cell cultures. The 5 most potent analogs will be prioritized for further study in Aim 2. In Aim 2, we will test the 5 prioritized analogs from Aim 1 to determine if any are more potent than ARTX-2 in LPS- elicited and viral infection-elicited mouse ARDS models. Successful completion of the proposed studies will result in the identification of 2-3 new chemical entities (NCEs) that are highly efficacious in mouse models of ARDS that can be advanced to additional efficacy, toxicity, and PK/PD studies in a Phase II project. The goal of the Phase II project will be to identify potent NCEs that can be moved to IND-enabling studies. Artus Therapeutics PA-20-260 / PI: Frederick M. Ausubel Project Summary - Page 1 of 1

一流的小分子，可增强急性呼吸窘迫期间综合征肺屏障功能 (ARDS) 作为 COVID-19 的潜在疗法 PA-20-260，R43 I 期 SBIR PI：弗雷德里克·M·奥苏贝尔 项目概要 SARS-CoV-2 感染可导致高度致命的急性呼吸窘迫综合征 (ARDS)。 炎症介导的过程导致肺泡毛细血管中紧密连接和粘附连接的破坏 内皮以及肺泡上皮中的紧密连接允许液体、血清蛋白和免疫。 细胞从肺泡毛细血管渗漏到肺间质组织中，然后通过肺泡上皮进入 目前还没有批准用于直接针对紧密和粘连的 ARDS 的治疗方法。 尽管越来越多的证据表明支撑这些连接的疗法可能是 为了满足这一未满足的需求，Artus Therapeutics 正在开发新型药物。 Artus 的领先疗法可直接增强肺部上皮和内皮屏障功能。 化合物 ARTX-2 是一种低分子量口服分子，灵感来自天然肠道代谢物 尿石素 A. 口服 ARTX-2 可减少 LPS 治疗小鼠的血管渗漏至肺组织 ARTX-2 还可诱导内皮连接蛋白 VE- 上调。 在内皮细胞培养物中，ARTX-2 上调 VE-钙粘蛋白并阻断 LPS 诱导的钙粘蛋白。 就上皮屏障功能而言，ARTX-2 上调多种紧密连接蛋白和 降低肠上皮细胞的通透性，口服 ARTX-2 可以显着缓解。 ARTX-2 通过恢复肠道上皮屏障功能来改善溃疡性结肠炎小鼠模型的症状。 在 LPS 处理的小鼠和 LPS- 小鼠中阻断 LPS 引发的炎症细胞因子，包括 IL-6 和 TNF-a 从这些数据来看，ARTX-2 可能对骨髓来源的巨噬细胞有效。 治疗 COVID-19 患者，因为它可以增强肺内皮和肺上皮屏障功能 并降低炎症细胞因子的水平，而不具有免疫抑制作用。 化合物 ARTX-2，已合成 44 个 ARTX-2 类似物，用于先导化合物优化研究的两个具体目标。 检验 ARTX-2 会降低肺上皮和血管内皮的通透性的假设， 将在小鼠 LPS 引发和病毒感染引发的 ARDS 模型中有效，并且特定的 ARTX-2 类似物将比 ARTX-2 更有效 在目标 1 中，我们建议测试 44 个 ARTX-2 类似物的效力。 与ARTX-2上调肺上皮紧密连接蛋白和VE-钙粘蛋白表达的比较 和肺内皮细胞培养物将优先在目标 2 中进行进一步研究。 2，我们将测试目标 1 中的 5 个优先类似物，以确定是否有任何比 LPS 中的 ARTX-2 更有效- 诱发和病毒感染诱发的小鼠ARDS模型将成功完成拟议的研究。 鉴定 2-3 个新化学实体 (NCE)，这些化学实体在 ARDS 小鼠模型中非常有效 可以在 II 期项目中推进额外的功效、毒性和 PK/PD 研究。 第二阶段项目将确定可以转移到 IND 支持研究的有效 NCE。 Artus Therapeutics PA-20-260 / PI：Frederick M. Ausubel 项目摘要 - 第 1 页，共 1 页