Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Yale School of Medicine, New Haven, CT 06510, USA.
Cell Stem Cell. 2020 Dec 3;27(6):876-889.e12. doi: 10.1016/j.stem.2020.11.009. Epub 2020 Nov 17.
SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and that genetic variants that increase androgen levels are associated with higher disease severity. These findings offer insights on the mechanism of disproportionate disease susceptibility in men and identify antiandrogenic drugs as candidate therapeutics for COVID-19.
SARS-CoV-2 感染导致了全球健康危机，然而我们对该疾病的理解和潜在的治疗选择仍然有限。该感染通过病毒与细胞膜上的血管紧张素转化酶 2（ACE2）结合发生。在这里，我们建立了一种筛选策略，以鉴定降低人胚胎干细胞（hESC）衍生的心肌细胞和肺类器官中 ACE2 水平的药物。命中化合物的靶向分析显示雄激素信号是 ACE2 水平的关键调节剂。用抗雄激素药物治疗可降低 ACE2 的表达，并可保护 hESC 衍生的肺类器官免受 SARS-CoV-2 感染。最后，COVID-19 患者的临床数据表明，与雄激素升高相关的前列腺疾病是重要的危险因素，并且增加雄激素水平的遗传变异与更高的疾病严重程度相关。这些发现为男性疾病易感性不成比例的机制提供了见解，并确定了抗雄激素药物作为 COVID-19 的候选治疗药物。
