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

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COVID-19的潜在治疗药物 PA-20 - 260，R43 I期SBIR PI：Frederick M. Ausubel 项目摘要 SARS-CoV-2感染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中紧密连接和粘附连接的破坏 内皮细胞以及肺泡上皮细胞的紧密连接。这使得液体、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，然后通过肺泡上皮细胞进入 肺泡气道目前还没有批准用于直接靶向粘连性呼吸窘迫综合征的治疗药物 尽管越来越多的证据表明，治疗海岸了这些路口可能是 对ARDS患者非常有效。为了解决这一未满足的需求，Artus Therapeutics正在开发新的 直接增强肺中上皮和内皮屏障功能的治疗剂。阿特斯的领先优势 化合物ARTX-2是一种低分子量的口服分子，其灵感来自天然肠道代谢物 尿石素A口服ARTX-2减少LPS处理小鼠肺组织血管渗漏 诱发肺部炎症。ARTX-2还诱导内皮连接蛋白VE-1的上调。 小鼠肺中的钙粘蛋白。在内皮细胞培养中，ARTX-2上调VE-钙粘蛋白并阻断LPS诱导的内皮细胞凋亡。 磁导率关于上皮屏障功能，ARTX-2上调几种紧密连接蛋白， 降低肠上皮细胞的通透性。口服ARTX-2可显著缓解 通过恢复肠上皮屏障功能，治疗溃疡性结肠炎小鼠模型的症状。ARTX-2 阻断LPS诱导的炎症细胞因子，包括LPS处理的小鼠和LPS诱导的小鼠中的IL-6和TNF-α。 处理的骨髓来源的巨噬细胞。从这些数据来看，似乎ARTX-2在治疗糖尿病中可能是有效的。 治疗COVID-19患者，因为它可能增强肺内皮和肺上皮屏障功能 并降低炎性细胞因子的水平而不具有免疫抑制作用。除了铅 在化合物ARTX-2中，已经合成了44种ARTX-2类似物用于先导物优化研究。两个具体目标 检验ARTX-2将降低肺上皮以及血管内皮的渗透性的假设， 将在鼠LPS诱导的和病毒感染诱导的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，我们提出测试44种ARTX-2类似物在小鼠中的效力。 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 和肺内皮细胞培养物。5种最有效的类似物将优先用于目标2中的进一步研究。在aim中 2，我们将测试来自目标1的5种优先类似物，以确定是否有任何类似物在LPS中比ARTX-2更有效。 诱发和病毒感染诱发的小鼠ARDS模型。成功完成拟议的研究将导致 在鉴定2 - 3种在ARDS小鼠模型中高度有效的新化学实体（NCE）中， 可以在II期项目中进行额外的疗效、毒性和PK/PD研究。的目标 第二阶段的项目将是确定可转入IND赋能研究的有效国家竞争性评价。 Artus Therapeutics PA-20 - 260/PI：Frederick M. Ausubel项目摘要-第1页，共1页

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