Identification of SARS-CoV-2 Inhibitors using Lung and Colonic Organoids

Han, Yuling; Duan, Xiaohua; Yang, Liuliu; Nilsson-Payant, Benjamin E.; Wang, Pengfei; Duan, Fuyu; Tang, Xuming; Yaron, Tomer M.; Zhang, Tuo; Uhl, Skyler; Bram, Yaron; Richardson, Chanel; Zhu, Jiajun; Zhao, Zeping; Redmond, David; Houghton, Sean; Nguyen, Duc-Huy T.; Xu, Dong; Wang, Xing; Jessurun, Jose; Borczuk, Alain; Huang, Yaoxing; Johnson, Jared L.; Liu, Yuru; Xiang, Jenny; Wang, Hui; Cantley, Lewis C.; tenOever, Benjamin R.; Ho, David D.; Pan, Fong Cheng; Evans, Todd; Chen, Huanhuan Joyce; Schwartz, Robert E.; Chen, Shuibing

There is an urgent need to create novel models using human disease-relevant cells to study SARS-CoV-2 biology and to facilitate drug screening. As SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs, particularly alveolar type II-like cells, are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines upon SARS-CoV-2 infection, similar to what is seen in COVID-19 patients. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes(1). We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high throughput screen of FDA-approved drugs and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid (MPA), and quinacrine dihydrochloride (QNHC). Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.