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

摘要/摘要 SARS-CoV-2已感染5100多万人，造成127万多人死亡 全球范围内。迫切需要针对预防和治疗的干预措施。SARS冠状病毒的感染- 2需要宿主丝氨酸蛋白酶TMPRSS2来激活病毒尖峰蛋白与宿主相互作用 ACE2受体和进入宿主细胞。雄激素受体显著调节TMPRSS2水平 在前列腺癌细胞中的信号转导，但在呼吸道上皮细胞中未知。大量的抑制剂已经被 开发的目标是AR信号。这些抑制剂的毒性、有效剂量和副作用已被 有据可查。我们假设，通过阻止AR信号来降低TMPRSS2水平将阻止激活 SARS-CoV-2刺突蛋白在呼吸道上皮细胞中的表达，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信号的遗传和药物抑制 抑制TMPRSS2水平，AR信号抑制剂显著抑制伪型病毒感染 前列腺癌细胞。在这项提案中，我们将研究AR信号抑制剂是否会抑制TMPRSS2 呼吸道上皮细胞中TMPRSS2对SARS-CoV-2蛋白降解的抑制作用 Spike蛋白在体外，随后减轻其感染效率。接下来，我们将调查是否将目标 在体内，TMPRSS2水平将通过呼吸道途径抑制SARS-CoV-2感染。特别是，我们将 检测TMPRSS2或雄激素产生缺陷小鼠的SARS-CoV-2感染效率。我们会 研究AR信号转导抑制剂是否能降低体内TMPRSS2水平，减轻SARS-CoV-2感染 呼吸系统。这项提案的目标是将TMPRSS2作为靶点进行检查，并确定有效的药物 来自目前已知的AR信号抑制剂，以抑制SARS-CoV-2感染。尽管SARS-CoV-2疫苗是 这项研究正在开发中，可能是有效的，将提供一种抑制的治疗选择 在宿主体内感染SARS-CoV-2，从而减轻新冠肺炎症状的严重程度，最终预防 新冠肺炎导致的死亡人数。

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.