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: 10814125
• 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/10814125
• 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; Disparity; Drug usage; Elderly; Enrollment; Epithelial Cells; Epithelium; 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; Prostate Cancer therapy; Proteins; Proteolysis; Publishing; Receptor Inhibition; Receptor Up-Regulation; 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; 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，特别是对美国人口过多的个人 退伍军人社区COVID-19死亡率男性高于女性;而这种差异至少 部分由于吸烟率较高等因素，荷尔蒙的联系很可能，并可以迅速测试 通过改变现有药物的用途进行治疗。COVID-19的病毒病原体SARS-CoV-2（CoV-2）， 通过病毒刺突（S）蛋白附着于人气道上皮，该蛋白结合血管紧张素转化酶 酶2（ACE 2）在宿主细胞表面上。病毒进入需要丝氨酸蛋白酶切割S蛋白 TMPRSS 2是雄激素受体（AR）的已知转录靶标。肺上皮细胞（一种靶细胞） CoV-2感染）表达转录活性AR。我们假设AR上调TMPRSS 2， 肺上皮细胞，从而促进病毒进入和传染性。我们建议FDA批准的 AR拮抗剂将减少CoV-2的进入和传播，并可迅速用于COVID-19。IL-6 是中度和重度COVID-19病例中释放的主要细胞因子， 初步数据显示IL-6增强AR转录活性。因此，我们亦会研究 白细胞介素6（IL-6）对TMPRRS 2的AR调节的贡献。为了以强有力的方式促进这些研究， 我们建议通过使用表达SARS-CoV-2的 携带SARS-CoV-2S蛋白的假病毒体。这样的报告系统具有高再现性， 多功能性和动态范围，允许快速、准确和特异性地评估大范围的病毒 在BSL 2+下进入原代人肺上皮细胞和肺腺癌细胞系的进入调节剂 条件我们将测试AR抑制是否减少TMPRSS 2和必要的S蛋白加工 从而减少CoV-2进入宿主肺上皮细胞。随后，我们将在一个 在批准的BSL 3设施中使用活的SARS-Cov-2的有前途的化合物的子集。安全有效的AR 拮抗剂被FDA批准用于前列腺癌，本研究将提供重新利用这些拮抗剂的基本原理。 用于COVID-19临床试验的药物 糖皮质激素受体（GR）与糖皮质激素受体共享共同的DNA应答元件共有序列。 AR.此外，TMPRSS 2的GR上调已在晚期前列腺癌中显示。因此在 同时，我们将研究TMPRSS 2是否受糖皮质激素（皮质醇）的调节和GR的阻断。 在人肺上皮细胞模型中的拮抗剂。服用皮质类固醇的患者（包括老年人和 患有糖尿病、高血压和慢性炎性疾病的人）死于 2019冠状病毒病。世界卫生组织提供了临时指导，以避免在COVID-19中使用糖皮质激素。 19例严重急性呼吸窘迫综合征患者。因此，了解GR调节 TMPRSS 2对于FDA批准的用于COVID-19的TMPRSS 2抑制剂的再利用也是至关重要的。我们 目的：（1）研究TMPRSS 2对人原发性高血压的类固醇激素受体（AR和GR）的调节作用。 气道和肺上皮细胞以及肺腺癌细胞系模型，以及（2）检查 FDA批准的AR和GR拮抗剂可阻断CoV-2进入人体主要气道和肺中的感染性 上皮细胞 美国退伍军人代表了几个严重受COVID-19影响的人口统计数据。美国退伍军人是 特别脆弱，因为更高的合并症，包括吸烟，糖尿病，心脏病和 高血压鉴于穷人的倾向，退伍军人社区的负担也按比例增加。 COVID-19感染后男性与女性相比的结果。由于抗雄激素治疗是 经FDA批准用于前列腺癌治疗，也可安全用于乳腺癌患者。 癌症，我们的研究有可能对所有退伍军人产生直接影响。