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Blocking TMPRSS2 expression for prevention of SARS-CoV-2 infection

阻断 TMPRSS2 表达以预防 SARS-CoV-2 感染

基本信息

批准号：
10303752
负责人：
Houjian Cai
金额：
$ 22.65万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-12 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303752
关键词：
2019-nCoV ACE2 Address Androgen Receptor Androgen Response Element Androgen Suppression Androgens Bicalutamide Binding Biological Markers COVID-19 mortality COVID-19 patient COVID-19 severity COVID-19 treatment COVID-19 vaccine Castration Cell membrane Cells Cessation of life Cleaved cell Data Development Disease Down-Regulation Epithelial Cells Flutamide Genetic Genetic Transcription Goals Human Metapneumovirus In Vitro Infection Influenza Intervention K-18 conjugate Ketoconazole Kidney Luciferases Lung Mediating Membrane Mesylates Mus N-myristoyltransferase Nilutamide Ovary Pancreas Peptide Hydrolases Pharmaceutical Preparations Pharmacology Prevention Process Production Promoter Regions Prostate Prostate Cancer therapy Proteins Proteolysis Receptor Signaling Reporter Genes Respiratory System Route SARS coronavirus SARS-CoV-2 entry inhibitor SARS-CoV-2 infection SARS-CoV-2 inhibitor SARS-CoV-2 spike protein Serine Protease Site Structure of respiratory epithelium Symptoms TMPRSS2 gene Therapeutic Time Tissues Toxic effect Transgenic Mice Viral Viral Fusion Proteins Virus Virus Diseases abiraterone androgen biosynthesis dosage in vivo influenza infection inhibitor/antagonist male mortality mouse model prevent prostate cancer cell receptor respiratory side effect treatment strategy

项目摘要

Summary/Abstract SARS-CoV-2 has infected over 51 million and is responsible for the death of over 1.27 million people globally. Interventions to address both prevention and treatment are urgently needed. Infection of SARS-CoV- 2 requires the host serine protease TMPRSS2 to activate the virus spike protein for interaction with the host ACE2 receptor and entry into host cells. TMPRSS2 levels are significantly regulated by androgen receptor signaling in prostate cancer cells, but unknown in respiratory epithelial cells. Numerous inhibitors have been developed to target AR signaling. The toxicity, effective dosage, and side effects of these inhibitors have been well-documented. We hypothesize that reducing TMPRSS2 levels by blocking AR signaling will block activation of the spike protein of SARS-CoV-2 in respiratory epithelial cells, thereby preventing its entry into host cells in the respiratory system. Our preliminary data indicate that genetic and pharmacological inhibition of AR signaling suppresses TMPRSS2 levels, and an AR signaling inhibitor significantly inhibits pseudotype virus infection in prostate cancer cells. In this proposal, we will examine whether AR signaling inhibitors will suppress TMPRSS2 levels in respiratory epithelial cells leading to inhibition of TMPRSS2-catalyzed proteolysis of the SARS-CoV-2 spike protein in vitro, subsequently mitigating its infection efficiency. Next, we will investigate if targeting TMPRSS2 levels will inhibit SARS-CoV-2 infection through the respiratory route in vivo. In particular, we will examine the SARS-CoV-2 infection efficiency in mice deficient in TMPRSS2 or androgen production. We will investigate if AR signaling inhibitors will reduce TMPRSS2 levels in vivo, and mitigate SARS-CoV-2 infection in respiratory system. The goal of this proposal is to examine TMPRSS2 as a target and identify an effective drug from currently known AR signaling inhibitors to inhibit SARS-CoV-2 infection. Although SARS-CoV-2 vaccine is under development and might be effective, this study will provide a therapeutic treatment option of suppressing SARS-CoV-2 infection in the host, thus reducing the severity of COVID-19 symptoms and ultimately preventing deaths from COVID-19.

摘要/摘要 SARS-CoV-2已经感染了5100多万人，并造成127万人死亡在全球迫切需要采取干预措施，既解决预防问题，又解决治疗问题。感染SARS冠状病毒 2需要宿主丝氨酸蛋白酶TMPRSS 2来激活病毒刺突蛋白以与宿主相互作用 ACE 2受体和进入宿主细胞。TMPRSS 2水平受雄激素受体显著调节在前列腺癌细胞中的信号传导，但在呼吸道上皮细胞中未知。许多抑制剂已经是针对AR信号的这些抑制剂的毒性、有效剂量和副作用已被研究。记录良好我们假设通过阻断AR信号传导降低TMPRSS 2水平将阻断AR的激活。呼吸道上皮细胞中SARS-CoV-2的刺突蛋白，从而阻止其进入宿主细胞，呼吸系统。我们的初步数据表明，AR信号的遗传和药理学抑制抑制TMPRSS 2水平，AR信号传导抑制剂显著抑制假型病毒感染，前列腺癌细胞在这个提议中，我们将研究AR信号传导抑制剂是否会抑制TMPRSS 2 呼吸道上皮细胞中的水平导致抑制TMPRSS 2催化的SARS-CoV-2蛋白水解刺突蛋白，随后降低其感染效率。下一步，我们将调查是否针对 TMPRSS 2水平将抑制体内通过呼吸途径的SARS-CoV-2感染。特别是要检测SARS-CoV-2在缺乏TMPRSS 2或雄激素产生的小鼠中的感染效率。我们将研究AR信号传导抑制剂是否会降低体内TMPRSS 2水平，并减轻SARS-CoV-2感染，呼吸系统。该提案的目标是将TMPRSS 2作为靶点进行检查，并确定有效的药物从目前已知的AR信号传导抑制剂来抑制SARS-CoV-2感染。虽然SARS-CoV-2疫苗正在开发中，可能是有效的，这项研究将提供一种治疗选择，抑制宿主中的SARS-CoV-2感染，从而降低COVID-19症状的严重程度，并最终预防死于COVID-19