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

在急性呼吸窘迫综合征期间增强肺屏障功能的一流小分子 (ARDS)作为新冠肺炎的潜在疗法 PA-20-260，R43一期丁苯橡胶 少年派：弗雷德里克·M·奥苏贝尔 项目摘要 感染SARS-CoV-2可导致高度致命的急性呼吸窘迫综合征(ARDS)。在ARDS中， 炎症介导的过程导致肺泡毛细血管紧密连接和粘连连接破裂 肺泡上皮内可见内皮细胞和紧密连接。这使得体液、血清蛋白和免疫 细胞从肺泡毛细血管渗出进入肺间质组织，然后通过肺泡上皮进入 肺泡的呼吸道。目前还没有针对ARDS的直接靶向紧密和粘连的治疗方法。 连接，尽管越来越多的证据表明，支持这些连接的疗法可能是 对ARDS患者非常有效。为了解决这一未得到满足的需求，Artus治疗公司正在开发新的 直接增强肺内皮细胞和内皮细胞屏障功能的治疗方法。阿图斯的领先优势 化合物ARTX-2是一种受天然肠道代谢物启发的低分子口服分子 熊果素A口服ARTX-2可减少脂多糖诱导的小鼠肺组织血管渗漏 以引起肺部炎症。ARTX-2还可诱导内皮细胞连接蛋白VE-2表达上调。 小鼠肺中的钙粘附素。在内皮细胞培养中，ARTX-2上调VE-钙粘蛋白并阻断内毒素诱导 渗透性。在上皮屏障功能方面，ARTX-2上调了几个紧密连接蛋白和 降低肠道上皮细胞的通透性。口服ARTX-2可显著缓解 恢复肠上皮屏障功能的溃疡性结肠炎小鼠模型的症状。此外，ARTX-2 阻断内毒素诱导的炎性细胞因子，包括IL-6和TNF-α在内毒素处理的小鼠和在内毒素- 治疗后的骨髓来源的巨噬细胞。从这些数据来看，ARTX-2可能在治疗慢性前列腺癌方面有效。 新冠肺炎可能同时增强肺内皮细胞和肺上皮屏障功能的治疗 降低炎性细胞因子水平，而不具有免疫抑制作用。除了领头羊 化合物ARTX-2，44个ARTX-2类似物已被合成用于先导优化研究。两个具体目标 测试ARTX-2将降低肺上皮和血管内皮细胞通透性的假设， 在小鼠脂多糖诱导和病毒感染诱导的ARDS模型中将是有效的，并且特定的ARTX-2 类似物将比ARTX-2更强大。在目标1中，我们建议测试44个ARTX-2类似物在 ARTX-2与ARTX-2上调肺上皮细胞紧密连接蛋白和VE-钙粘蛋白表达的比较 和肺内皮细胞培养。5个最有效的类比将被优先用于目标2的进一步研究。 2，我们将测试目标1中的5个优先类似物，以确定是否有任何类似物在内毒素中比ARTX-2更有效- 诱导和病毒感染诱导的小鼠ARDS模型。建议的研究将顺利完成。 在鉴定2-3种在ARDS小鼠模型中高效的新化学实体(NCEs)中 这可以推进到第二阶段项目中的额外疗效、毒性和PK/PD研究。的目标是 第二阶段的项目将是确定可以转移到支持IND的研究中的有效的NCE。 Artus Treateutics PA-20-260/PI：Frederick M.Ausubel项目摘要-第1页，共1页