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：
10449301
负责人：
Houjian Cai
金额：
$ 18.88万
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/10449301
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 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 Persons Pharmaceutical Preparations 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 Symptoms TMPRSS2 gene Therapeutic Time Tissues Toxic effect Transgenic Mice Viral Viral Fusion Proteins Virus Virus Diseases abiraterone airway epithelium androgen biosynthesis dosage enzalutamide in vivo influenza infection inhibitor male mortality mouse model pharmacologic 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感染了超过5100万，负责超过127万人死亡全球。迫切需要采取干预措施来解决预防和治疗。感染SARS-COV- 2需要宿主丝氨酸蛋白酶TMPRSS2激活病毒峰值蛋白以与宿主相互作用 ACE2受体并进入宿主细胞。 TMPRSS2水平受雄激素受体显着调节前列腺癌细胞中的信号传导，但在呼吸性上皮细胞中未知。许多抑制剂已经开发用于靶向AR信号。这些抑制剂的毒性，有效剂量和副作用已经有据可查的。我们假设通过阻止AR信号来降低TMPRSS2水平会阻止激活 SARS-COV-2的尖峰蛋白在呼吸性上皮细胞中，从而防止其进入宿主细胞呼吸系统。我们的初步数据表明遗传和药理抑制AR信号传导抑制TMPRSS2水平，AR信号抑制剂显着抑制了假型病毒感染前列腺癌细胞。在此提案中，我们将检查AR信号抑制剂是否会抑制TMPRSS2 呼吸性上皮细胞的水平导致抑制TMPRSS2催化的SARS-COV-2催化蛋白水解体外尖峰蛋白，随后降低其感染效率。接下来，我们将调查是否针对 TMPRSS2水平将通过体内呼吸道抑制SARS-COV-2感染。特别是，我们会检查缺乏TMPRSS2或雄激素产生的小鼠的SARS-COV-2感染效率。我们将调查AR信号抑制剂是否会在体内降低TMPRSS2水平，并减轻SARS-COV-2感染呼吸系统。该建议的目的是将TMPRSS2作为目标检查并确定有效的药物从当前已知的AR信号抑制剂中抑制SARS-COV-2感染。尽管SARS-COV-2疫苗是在开发中，这项研究可能是有效的，将提供抑制治疗方法宿主中的SARS-COV-2感染，从而降低了COVID-19症状的严重程度，并最终阻止 Covid-19的死亡。