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

用于治疗 SARS-CoV-2 介导的急性肺损伤的 PTP4A3 抑制剂

• 批准号: 10330408
• 负责人: JOHN S. LAZO
• 金额: $ 25.22万
• 依托单位: KEVIRX INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330408
• 关键词: 2019-nCoV; ACE2; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Binding; Binding Proteins; Blood Vessels; COVID-19; COVID-19 pandemic; COVID-19 patient; Cells; Clinical; Coronavirus; Coronavirus spike protein; Development; Drug Kinetics; Electrical Resistance; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Exhibits; Exposure to; FDA approved; Family; Fibroblasts; Functional disorder; Funding; Future; Goals; Human; In Vitro; Individual; Infection; Inflammation; Inflammatory; Influenza; Injury; Kinetics; Lead; Link; Lipopolysaccharides; Lung; Lung Inflammation; Measures; Mediating; Multiple Organ Failure; Mus; Outcome; Ovarian; PTP4A2 gene; Pathologic; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphoric Monoester Hydrolases; Population; Pre-Clinical Model; Prevention; Property; Proteins; Recombinants; Respiratory System; Role; SARS coronavirus; SARS-CoV-2 inhibitor; SARS-CoV-2 spike protein; Sentinel; Septic Shock; Serine Protease; Small Business Innovation Research Grant; Specificity; TMPRSS2 gene; Testing; Therapeutic; Time; Vascular Endothelial Growth Factors; Viral; Virus; alveolar epithelium; analog; clinical development; cytokine; cytokine release syndrome; in vivo; inhibitor/antagonist; innovation; lung injury; macrophage; monocyte; monolayer; mouse model; neutrophil; novel; novel therapeutic intervention; pandemic disease; preclinical development; prevent; real time monitoring; small molecule; systemic inflammatory response

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.

严重急性呼吸系统综合症冠状病毒 (SARS-CoV-2) 是造成当前 COVID-19 的罪魁祸首 大流行。 SAR-CoV-2 与其他冠状病毒一样，感染人类呼吸道并通过其 S（刺突）蛋白进入细胞， 与人血管紧张素转换酶 2 (ACE2) 结合并由宿主丝氨酸蛋白酶引发 TMPRSS2。 ACE2 和 TMPRSS2 均在肺微血管上皮细胞中观察到 内皮细胞。一部分 COVID-19 患者出现急性呼吸窘迫综合征 (ARDS)，并且 随后出现感染性休克和多器官衰竭；大约一半会死。后期临床恶化 COVID-19 的发生被认为是由 Spike 蛋白与肺微血管内皮结合引起的 上皮细胞，导致呼吸道受损，最终导致全身炎症反应或 细胞因子风暴。目前尚无 FDA 批准的药物/疗法可以治疗肺部损伤和 与 COVID-19 相关的 ARDS。 KeViRx 提议开发一种全新的治疗策略 预防或减轻最初的肺部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、选择性、PTP4A3 磷酸酶变构抑制剂，具有 优异的体内药代动力学特性和类药特性。此外，小鼠耐受多种 暴露于 KVX-053 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 显着增强了肺功能 细菌脂多糖损伤前后微血管屏障功能及血管 内皮生长因子。已知 SARS-CoV 感染后 12 小时，肺细胞中会诱导 PTP4A3 磷酸酶 感染并控制细胞因子的释放。第一阶段 SBIR 应用的总体假设是 PTP4A磷酸酶家族在ARDS急性肺损伤和全身炎症中具有前哨作用 COVID-19 的响应。该项目的目标是重新调整 KVX-053 的用途，用于患有 COVID-19 的个人和 以应对未来涉及急性肺损伤的大流行。该第一阶段 SBIR 应用程序具有三个概念验证 具体任务。具体任务 1 将确定新型、有效、变构小分子 PTP4A3 的能力 抑制剂 KVX-053，可阻断 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 蛋白质介导的肺泡上皮屏障功能和体外细胞因子释放。具体任务3 将确定 KVX-053 抑制 SARS-CoV-2 Spike 1 引起的小鼠急性肺损伤的能力 蛋白质。