Covid-19: Fast-tracking treatment by exploiting the steroid hormone receptor/TMPRSS2 axis

Covid-19：利用类固醇激素受体/TMPRSS2 轴进行快速治疗

• 批准号: 10341159
• 负责人: Kerry L Burnstein
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341159
• 关键词: 2019-nCoV; ACE2; Acute; Acute Respiratory Distress Syndrome; Address; Adrenal Cortex Hormones; Affect; Agonist; Androgen Antagonists; Androgen Receptor; Antiandrogen Therapy; Binding; COVID-19; COVID-19 mortality; COVID-19 patient; COVID-19 treatment; Cell Line; Cell surface; Clinical Trials; Collaborations; Colorado; Communities; Consensus Sequence; DNA; Data; Diabetes Mellitus; Disease; Drug usage; Elderly; Enrollment; Epithelial; Epithelial Cells; Etiology; FDA approved; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Health; Health Personnel; Heart Diseases; Hormonal; Human; Hydrocortisone; Hypertension; Individual; Interdisciplinary Study; Interleukin-6; Ligands; Link; Luciferases; Lung; Lung Adenocarcinoma; Malignant neoplasm of prostate; Measures; Modeling; Nuclear Receptors; Outcome; Patients; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Prostate Cancer therapy; Proteins; Proteolysis; Publishing; Receptor Inhibition; Regulation; Reporter; Reproducibility; Research; Resistance; Response Elements; SARS-CoV-2 entry inhibitor; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Serine Protease; Smoking; Stanolone; System; TMPRSS2 gene; Testing; Therapeutic; Universities; Veterans; Viral; Virus; Woman; World Health Organization; advanced prostate cancer; airway epithelium; antagonist; biosafety level 3 facility; castration resistant prostate cancer; chronic inflammatory disease; comorbidity; cytokine; demographics; drug repurposing; glucocorticoid receptor alpha; high risk; human model; loved ones; mRNA Expression; male; malignant breast neoplasm; men; post SARS-CoV-2 infection; protein expression; receptor upregulation; response; severe COVID-19; steroid hormone receptor; therapeutic evaluation; transcriptome; viral entry inhibitor

COVID-19 poses a tremendous health threat, particularly to individuals overrepresented in the US Veteran community. COVID-19 mortality is greater in men than in women; while this disparity is at least partially due to factors such as higher rates of smoking, a hormonal link is likely and can be rapidly tested therapeutically by repurposing existing drugs. The viral etiologic agent of COVID-19, SARS-CoV-2 (CoV-2), attaches to human airway epithelium via the viral spike (S) protein, which binds to angiotensin-converting enzyme 2 (ACE2) on the host cell surface. Viral entry requires S protein cleavage by the serine protease TMPRSS2, which is a known transcriptional target of the androgen receptor (AR). Lung epithelial cells (a target of CoV-2 infection) express transcriptionally active AR. We hypothesize that AR up-regulates TMPRSS2 in lung epithelial cells and thereby promotes viral entry and infectivity. We propose that FDA-approved AR antagonists will decrease CoV-2 entry and spread and can be rapidly repurposed for COVID-19. IL-6 is the major cytokine released in moderate and severe COVID-19 cases and both published and our preliminary data show that IL-6 enhances AR transcriptional activity. We will therefore also examine the contribution of interleukin 6 (IL-6) to AR regulation of TMPRRS2. To facilitate these studies in a robust manner, we propose to isolate the SARS-CoV-2 entry mechanism through the use of luciferase-expressing pseudovirions that harbor the SARS-CoV-2 S protein. Such a reporter system has high reproducibility, versatility and dynamic range, allowing for the rapid, accurate and specific assessment of a large range of viral entry regulators into primary human lung epithelial cells and lung adenocarcinoma cell lines under BSL2+ conditions. We will test whether AR inhibition reduces TMPRSS2 and the requisite S protein processing thereby decreasing CoV-2 entry into host lung epithelial cells. Subsequently, we will confirm results on a subset of promising compounds using live SARS-Cov-2 in an approved BSL3 facility. Safe and effective AR antagonists are FDA approved for prostate cancer and this study will provide rationale to repurpose these drugs for use in clinical trials for COVID-19. The glucocorticoid receptor (GR) shares a common DNA response element consensus sequence with AR. Furthermore, GR upregulation of TMPRSS2 has been shown in advanced prostate cancer. Therefore, in parallel, we will examine whether TMPRSS2 is regulated by glucocorticoids (cortisol) and blocked by a GR antagonist in models of human lung epithelia. Patients taking corticosteroids (including the elderly and individuals with diabetes, hypertension and chronic inflammatory disease) are at the highest risk of death from COVID-19. The World Health Organization has provided interim guidance to avoid glucocorticoids in COVID- 19 patients with severe acute respiratory distress syndrome. Therefore, understanding GR regulation of TMPRSS2 is also essential to repurposing the TMPRSS2-inhibitory FDA-approved agents for COVID-19. Our aims are to: (1) Evaluate steroid hormone receptor (AR and GR) regulation of TMPRSS2 in human primary airway and lung epithelial cells and lung adenocarcinoma cell line models and (2) Examine the capacity of FDA-approved AR and GR antagonists to block CoV-2 entry and infectivity in human primary airway and lung epithelial cells. US Veterans represent several demographics acutely afflicted by COVID-19. Older US Veterans are particularly vulnerable because of higher comorbidities including smoking, diabetes, heart disease and hypertension. Burden on the Veteran community is also proportionally higher given the propensity for poor outcome in men as compared to women following COVID-19 infection. Since the anti-androgen therapies to be tested are FDA approved for prostate cancer treatment and have also been used safely in women with breast cancer, our study has potential for immediate impact to all veterans.

COVID-19构成了巨大的健康威胁，特别是对美国过分代表的个人 资深社区。男性比女性的死亡率更高。虽然这种差异至少是 部分由于吸烟率较高的因素，可能是荷尔蒙连接的，并且可以迅速测试 通过重新利用现有药物进行治疗。 COVID-19，SARS-COV-2（COV-2）， 通过病毒尖峰（S）蛋白附着在人类气道上皮上，该蛋白与血管紧张素转换结合 宿主细胞表面上的酶2（ACE2）。病毒输入需要丝氨酸蛋白酶的蛋白质切割 TMPRSS2，这是雄激素受体（AR）的已知转录靶标。肺上皮细胞（靶标 COV-2感染）表达转录活性AR。我们假设AR上调TMPRSS2 肺上皮细胞，从而促进病毒的进入和感染力。我们建议FDA批准 AR拮抗剂将减少COV-2进入和扩散，并可以快速重新利用Covid-19。 IL-6 是在中度和重度Covid-19病例中释放的主要细胞因子，并且均出版，我们的 初步数据表明IL-6增强了AR转录活性。因此，我们还将检查 白介素6（IL-6）对TMPRRS2的AR调节的贡献。为了促进这些研究以强大的方式 我们建议通过使用表达荧光素酶来隔离SARS-COV-2进入机制 具有SARS-COV-2 S蛋白的伪动物。这样的记者系统具有很高的可重复性， 多功能性和动态范围，可以对大量病毒进行快速，准确和具体的评估 在BSL2+下，将调节剂进入原代人肺上皮细胞和肺腺癌细胞系 状况。我们将测试AR抑制是否会减少TMPRSS2和必要的S蛋白处理 从而减少COV-2进入宿主肺上皮细胞。随后，我们将在 使用实时SARS-COV-2在批准的BSL3设施中使用Live SARS-COV-2的有希望化合物的子集。安全有效的AR 拮抗剂已获得FDA批准用于前列腺癌，这项研究将提供重新利用这些的理由 用于Covid-19的临床试验中的药物。 糖皮质激素受体（GR）共享一个常见的DNA响应元件共识序列 ar。此外，在晚期前列腺癌中已经显示了TMPRSS2的GR上调。因此，在 并行，我们将检查TMPRSS2是否受糖皮质激素（皮质醇）调节并被GR阻塞 人肺上皮菌模型的拮抗剂。服用皮质类固醇的患者（包括老年人和 患有糖尿病，高血压和慢性炎症性疾病的个体）是死亡的最高风险 新冠肺炎。世界卫生组织已提供了临时指导，以避免在Covid- 19例严重急性呼吸窘迫综合征。因此，了解对 TMPRSS2对于重新利用TMPRSS2抑制性FDA批准的代理对于COVID-19也是必不可少的。我们的 目的是：（1）评估人类原发性TMPRSS2的类固醇激素受体（AR和GR）调节 气道和肺上皮细胞以及肺腺癌细胞系模型，（2）检查能力 FDA批准的AR和GR拮抗剂可阻止人类主要气道和肺中的COV-2进入和感染力 上皮细胞。 美国退伍军人代表了几个受人口统计学的人口，急性折磨了Covid-19。美国退伍军人是 特别容易受到较高的合并症，包括吸烟，糖尿病，心脏病和 高血压。考虑到贫困的倾向 与19岁感染后的女性相比，男性的结果与男性相比。由于抗雄激素疗法为 经过测试的FDA已批准用于前列腺癌治疗，并且还安全地用于乳房的女性 癌症，我们的研究有可能立即对所有退伍军人产生影响。