A PTP4A3 inhibitor for SARS-CoV-2-mediated acute lung injury

严重急性呼吸系统综合征冠状病毒（SARS-CoV-2）是导致当前COVID-19的罪魁祸首。 流行病与其他冠状病毒一样，SAR-CoV-2感染人类气道并通过其S（刺突）蛋白进入细胞， 其与人血管紧张素转化酶2（ACE 2）结合并由宿主丝氨酸蛋白酶引发 TMPRSS 2. ACE 2和TMPRSS 2均在肺微血管上皮细胞上观察到， 内皮细胞一部分COVID-19患者会出现急性呼吸窘迫综合征（ARDS）， 随后是败血性休克和多器官衰竭;大约一半会死亡。后期临床恶化 COVID-19的发病被认为是由刺突蛋白结合到肺微血管内皮引起的， 上皮，导致呼吸道受损并最终导致全身炎症反应，或 细胞因子风暴目前没有FDA批准的治疗肺损伤的药物/治疗剂， 与COVID-19相关的ARDS。KeViRx正在开发一种全新的治疗策略， 预防或减轻最初的肺损伤并阻止致命的细胞因子风暴。 我们的先导化合物KVX-053是一种可逆的、选择性的、变构的PTP 4A 3磷酸酶抑制剂， 优异的体内药代动力学性质和药物样性质。此外，小鼠耐受多种 在培养物中，KVX-053对人卵巢上皮细胞或成纤维细胞没有细胞毒性， 浓度高达25 µM。令人惊讶的是，我们发现KVX-053显著增强了肺内 细菌脂多糖致血管损伤前后微血管屏障功能的变化 内皮生长因子已知PTP 4A 3磷酸酶在SARS-CoV后12小时在肺细胞中被诱导 感染和控制细胞因子释放。第一阶段SBIR应用的总体假设是， PTP 4A磷酸酶家族在ARDS的急性肺损伤和全身炎症反应中起着重要的前哨作用。 该项目的目标是将KVX-053重新用于COVID-19患者， 未来的流行病包括急性肺损伤。此阶段I SBIR应用程序具有三个概念验证 具体任务。具体任务1将确定一种新的、有效的、变构的小分子PTP 4A 3 抑制剂KVX-053阻断SARS-CoV-2 Spike 1蛋白介导的肺内皮屏障功能丧失 和体外细胞因子释放。具体任务2将确定KVX-053阻断SARS-CoV-2 Spike的能力 1蛋白介导的肺泡上皮屏障功能和细胞因子释放的体外研究。具体任务3 将确定KVX-053抑制由SARS-CoV-2 Spike 1引起的小鼠急性肺损伤的能力 蛋白

The Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) is responsible for the current COVID-19 pandemic. SAR-CoV-2, like other coronaviruses, infects human airways and enters cells via its S (Spike) protein, which binds to the human angiotensin-converting enzyme 2 (ACE2) and is primed by the host serine protease TMPRSS2. Both ACE2 and TMPRSS2 have been observed on pulmonary microvascular epithelium and endothelium. A subset of COVID-19 patients develop acute respiratory distress syndrome (ARDS) and subsequently septic shock and multi-organ failure; about half will die. The clinical worsening in the later phases of COVID-19 are thought to result from Spike protein binding to the pulmonary microvascular endothelium and epithelium, which leads to a damaged respiratory tract and ultimately a systemic inflammatory response or cytokine storm. There are currently no FDA-approved drugs/therapeutics that treat the pulmonary damage and ARDS associated with COVID-19. KeViRx is proposing to develop an entirely new therapeutic strategy that prevents or mitigates the initial pulmonary damage and halts the lethal cytokine storm. Our lead compound, KVX-053, is a reversible, selective, allosteric inhibitor of PTP4A3 phosphatase with excellent in vivo pharmacokinetic properties and drug-like properties. Moreover, mice tolerated multiple exposures to KVX-053 In culture KVX-053 was not cytotoxic to human ovarian epithelial cells or fibroblasts at concentrations up to 25 µM. Surprisingly, we found that KVX-053 markedly enhanced the pulmonary microvascular barrier function before and after injury caused by bacterial lipopolysaccharide and vascular endothelial growth factor. PTP4A3 phosphatase is known to be induced in lung cells 12 h after SARS-CoV infection and to control cytokine release. The overall hypothesis of this Phase I SBIR application is that the PTP4A phosphatase family has a sentinel role in the acute lung injury of ARDS and the systemic inflammatory response in COVID-19.The goal of the project is to repurpose KVX-053 for use in individuals with COVID-19 and for future pandemics involving acute lung injury. This Phase I SBIR application has three proof-of-concept Specific Tasks. Specific Task 1 will determine the ability of a novel, potent, allosteric, small molecule PTP4A3 inhibitor, KVX-053, to block SARS-CoV-2 Spike 1 protein-mediated loss of pulmonary endothelial barrier function and cytokine release in vitro. Specific Task 2 will determine the ability of KVX-053 to block SARS-CoV-2 Spike 1 protein-mediated pulmonary alveolar epithelial barrier function and cytokine release in vitro. Specific Task 3 will determine the ability of KVX-053 to inhibit acute lung injruy in mice caused by the SARS-CoV-2 Spike 1 protein.