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

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

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.