Nicholson Martin W, Huang Ching-Ying, Wang Jyun-Yuan, Ting Chien-Yu, Cheng Yu-Che, Chan Darien Z H, Lee Yi-Chan, Hsu Ching-Chuan, Hsu Yu-Hung, Chang Cindy M C, Hsieh Marvin L, Cheng Yuan-Yuan, Lin Yi-Ling, Chen Chien-Hsiun, Wu Ying-Ta, Hacker Timothy A, Wu Joseph C, Kamp Timothy J, Hsieh Patrick C H
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
Pharmaceuticals (Basel). 2022 Jun 20;15(6):765. doi: 10.3390/ph15060765.
Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.
自2019年12月以来，由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的2019冠状病毒病（COVID-19），截至2022年3月已感染约4.35亿人，并导致约600万人死亡。为抗击COVID-19，人们多次尝试重新利用美国食品药品监督管理局（FDA）批准的药物或复兴旧药。然而，目前许多治疗方案已知会引起药物不良反应。我们采用了一个基于人群的药物筛选平台，使用13种人类白细胞抗原（HLA）纯合的人类诱导多能干细胞（iPSC）系，来评估一线抗COVID-19药物的心脏毒性和神经毒性。我们还感染了iPSC衍生的细胞，以了解心肌细胞和神经元的病毒感染情况。我们发现，iPSC衍生的心肌细胞表达血管紧张素转换酶2（ACE2）受体，这与较高的SARS-CoV-2病毒感染率相关（r = 0.86）。然而，我们未能在神经元中检测到与低感染率相关的ACE2表达。然后，我们评估了抗COVID-19药物的毒性，确定了两种具有心脏毒性的化合物（瑞德西韦和阿比多尔）和四种具有神经毒性的化合物（阿比多尔、瑞德西韦、羟氯喹和氯喹）。这些数据表明，该平台可快速、简便地用于加深我们对细胞特异性感染的理解，并确定潜在治疗方案的药物毒性，帮助临床医生更好地决定治疗方案。
