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: 10632154
• 负责人: JOHN S. LAZO
• 金额: $ 0.65万
• 依托单位: KEVIRX INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10632154
• 关键词: 2019-nCoV; ACE2; Acute; Acute Lung Injury; Acute 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; 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; Pulmonary Inflammation; 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; 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.

严重急性呼吸综合征冠状病毒(SARS-CoV-2)是目前新冠肺炎的罪魁祸首 大流行。像其他冠状病毒一样，SARS-CoV-2感染人的呼吸道并通过其S(Spike)蛋白进入细胞， 它与人血管紧张素转换酶2(ACE2)结合，并由宿主丝氨酸蛋白酶启动 TMPRSS2.ACE2和TMPRSS2在肺微血管上皮细胞和 内皮细胞。新冠肺炎患者的一部分出现急性呼吸窘迫综合征和 随后，感染性休克和多器官衰竭；大约一半会死亡。晚期临床恶化 新冠肺炎的发生被认为是由于SPEKE蛋白与肺微血管内皮细胞结合所致 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。目前还没有FDA批准的药物/疗法来治疗肺损伤和 与新冠肺炎相关的不良反应。KeViRx正在提议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PTP4A3磷酸酶抑制剂， 良好的体内药代动力学特性和类药物特性。此外，小鼠耐受多个 KVX-053对人卵巢上皮细胞或成纤维细胞无细胞毒性 浓度高达25微米。令人惊讶的是，我们发现KVX-053显著增强了肺组织 细菌脂多糖和血管损伤前后的微血管屏障功能 内皮生长因子。已知PTP4A3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的释放。此第一阶段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性反应中的前哨作用 COVID-19的回应。该项目的目标是重新调整KVX-053的用途，使其用于患有新冠肺炎和 应对未来涉及急性肺损伤的大流行。此第一阶段SBIR应用程序有三个概念验证 具体任务。特殊任务1将确定一种新的、有效的、变构的、小分子PTP4A3的能力 阻断剂KVX-053阻断SARS-CoV-2 Spike 1蛋白介导的肺内皮细胞屏障功能丧失 和细胞因子的体外释放。具体任务2将确定KVX-053阻断SARS-CoV-2尖峰的能力 1体外蛋白介导的肺泡上皮屏障功能及细胞因子释放。特定任务3 将确定KVX-053对SARS-CoV-2 Spike 1引起的小鼠急性肺损伤的抑制能力 蛋白。

项目成果

An acute respiratory distress syndrome drug development collaboration stimulated by the Virginia Drug Discovery Consortium.

• DOI: 10.1016/j.slasd.2023.02.001
• 发表时间: 2023-09
• 期刊: SLAS DISCOVERY
• 影响因子: 3.1
• 作者: Lazo, John S.;Colunga-Biancatelli, Ruben M. L.;Solopov, Pavel. A.;Catravas, John D.
• 通讯作者: Catravas, John D.