Identification of SARS-CoV-2 inhibitors using lung and colonic organoids

Yuling Han, Xiaohua Duan, Liuliu Yang, Benjamin E. Nilsson-Payant, Pengfei Wang, Fuyu Duan, Xuming Tang, Tomer M. Yaron, Tuo Zhang, Skyler Uhl, Yaron Bram, Chanel Richardson, Jiajun Zhu, Zeping Zhao, David Redmond, Sean Houghton, Duc-Huy T. Nguyen, Dong Xu, Xing Wang, Jose Jessurun, Alain Borczuk, Yaoxing Huang, Jared L. Johnson, Yuru Liu, Jenny Xiang, Hui Wang (), Lewis C. Cantley (), Benjamin R. tenOever (), David D. Ho (), Fong Cheng Pan (), Todd Evans (), Huanhuan Joyce Chen (), Robert E. Schwartz () and Shuibing Chen ()
Additional contact information
Yuling Han: Weill Cornell Medicine
Xiaohua Duan: Weill Cornell Medicine
Liuliu Yang: Weill Cornell Medicine
Benjamin E. Nilsson-Payant: Icahn School of Medicine at Mount Sinai
Pengfei Wang: Columbia University Vagelos College of Physicians and Surgeons
Fuyu Duan: University of Chicago
Xuming Tang: Weill Cornell Medicine
Tomer M. Yaron: Weill Cornell Medicine
Tuo Zhang: Weill Cornell Medicine
Skyler Uhl: Icahn School of Medicine at Mount Sinai
Yaron Bram: Weill Cornell Medicine
Chanel Richardson: Weill Cornell Medicine
Jiajun Zhu: Weill Cornell Medicine
Zeping Zhao: Weill Cornell Medicine
David Redmond: Ansary Stem Cell Institute, Weill Cornell Medicine
Sean Houghton: Ansary Stem Cell Institute, Weill Cornell Medicine
Duc-Huy T. Nguyen: Weill Cornell Medicine
Dong Xu: Weill Cornell Medicine
Xing Wang: Weill Cornell Medicine
Jose Jessurun: Weill Cornell Medicine
Alain Borczuk: Weill Cornell Medicine
Yaoxing Huang: Columbia University Vagelos College of Physicians and Surgeons
Jared L. Johnson: Weill Cornell Medicine
Yuru Liu: University of Illinois College of Medicine
Jenny Xiang: Weill Cornell Medicine
Hui Wang: Shanghai Jiao Tong University School of Medicine
Lewis C. Cantley: Weill Cornell Medicine
Benjamin R. tenOever: Icahn School of Medicine at Mount Sinai
David D. Ho: Columbia University Vagelos College of Physicians and Surgeons
Fong Cheng Pan: Weill Cornell Medicine
Todd Evans: Weill Cornell Medicine
Huanhuan Joyce Chen: University of Chicago
Robert E. Schwartz: Weill Cornell Medicine
Shuibing Chen: Weill Cornell Medicine

Nature, 2021, vol. 589, issue 7841, 270-275

Abstract: Abstract There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, 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 following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes1. 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 drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. 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.

Date: 2021
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DOI: 10.1038/s41586-020-2901-9

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