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

基本信息

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
项目类别：
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

项目摘要

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.

严重的急性呼吸综合征冠状病毒（SARS-COV-2）是当前的Covid-19 大流行。 SAR-COV-2与其他冠状病毒一样，感染人类气道，并通过其S（尖峰）蛋白进入细胞，与人血管紧张素转换酶2（ACE2）结合，并由宿主串行蛋白酶启动 TMPRSS2。在肺微血管上皮和内皮。 COVID-19患者的一部分患有急性呼吸窘迫综合征（ARDS）和随后发生败血性休克和多器官故障；大约一半会死。后来的临床担心 COVID-19的COVID被认为是由于峰值蛋白与肺微血管内皮结合而引起的上皮，导致呼吸道受损，最终导致全身性炎症反应或细胞因子风暴。目前尚无FDA批准的药物/治疗剂来治疗肺部损伤和与Covid-19相关的ARDS。 Kevirx提议制定一种全新的治疗策略防止或减轻初始肺部损伤并停止致命的细胞因子风暴。我们的铅化合物KVX-053是PTP4A3磷酸酶的可逆，选择性，变构抑制剂，优秀的体内药代动力学特性和类似药物样性能。此外，老鼠耐受多个在培养KVX-053中对KVX-053的暴露不是对人卵巢上皮细胞或成纤维细胞的细胞毒性浓度高达25 µm。令人惊讶的是，我们发现KVX-053显着增强了肺部由细菌脂多糖和血管引起的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小时在肺细胞中诱导感染并控制细胞因子释放。该阶段I SBIR应用的总体假设是 PTP4A磷酸酶家族在ARDS的急性肺损伤和全身性炎症中具有前哨角色在Covid-19中的回应。该项目的目的是改革KVX-053，用于Covid-19和Covid-19和对于涉及急性肺损伤的未来大流行。此阶段I SBIR应用程序有三个概念证明特定任务。特定任务1将确定新颖，潜在，变构，小分子PTP4A3的能力抑制剂KVX-053，以阻止SARS-COV-2 SPIKE 1蛋白质介导的肺内皮屏障功能损失和细胞因子在体外释放。特定任务2将确定KVX-053阻止SARS-COV-2 SPIKE的能力 1蛋白介导的肺肺泡上皮屏障功能和细胞因子在体外释放。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INDRUY的能力蛋白质。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.