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Identification of SARS-CoV-2 inhibitors using lung and colonic organoids
Open accessAbstract
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 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 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.
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“high-throughput screens of ≥1,000 drugs approved by the FDA run on colonic and lung organoids identified several SARS-CoV-2 entry inhibitors such as imatinib, mycophenolic acid and quinacrine dihydrochloride111.”
From Human disease models in drug development (2023) · cites this paper as [111]
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“amodiaquine (for example, NCT04532931, NCT04502342)51 and imatinib111 (for example, NCT04394416) have entered clinical trials.”
From Human disease models in drug development (2023) · cites this paper as [111]
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Metadata
- Authors
- Han, Y., Duan, X., Yang, L., Nilsson-Payant, B. E., Wang, P., Duan, F., Tang, X., Yaron, T. M., Zhang, T., Uhl, S., Bram, Y., Richardson, C., Zhu, J., Zhao, Z., Redmond, D., Houghton, S., Nguyen, D.-H. T., Xu, D., Wang, X., Jessurun, J., Borczuk, A., Huang, Y., Johnson, J. L., Liu, Y., Xiang, J., Wang, H., Cantley, L. C., tenOever, B. R., Ho, D. D., Pan, F. C., Evans, T., Chen, H. J., Schwartz, R. E., & Chen, S.
- Affiliations
- Weill Cornell Medicine (US)
- Shanghai Jiao Tong University (CN)
- Icahn School of Medicine at Mount Sinai (US)
- Aaron Diamond AIDS Research Center (US)
- University of Chicago (US)
- University of Illinois Chicago (US)
- Corresponding author
- Wang, Hui
- Cantley, Lewis C.
- tenOever, Benjamin R.
- Ho, David D.
- Pan, Fong Cheng
- Evans, Todd
- Chen, Huanhuan Joyce
- Schwartz, Robert E.
- Chen, Shuibing
- ORCID
- 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
- Zhu, Jiajun
- 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
- Venue
- Nature
- Published
- 2020-10-28
- Volume
- 589
- Issue
- 7841
- Pages
- 270-275
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8034380
- OpenAlex
- W3096177766
- Cited by
- 530
- References
- 33
- Citations by year
- 2026: 35 · 2025: 51 · 2024: 67 · 2023: 94 · 2022: 120 · 2021: 155 · 2020: 7
- FWCI
- 12.35
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-05-29)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- American Diabetes Association (7-20-COVID-211)
- Icahn School of Medicine at Mount Sinai
- Nature
- National Institutes of Health
- Defense Advanced Research Projects Agency (W911NF‐16‐C‐0050)
- Weill Cornell Medical College
- Advanced Research Projects Agency
- National Cancer Institute (R00CA226353, R01CA234614)
- National Institute of Allergy and Infectious Diseases (R01AI107301)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124463, R01DK116075, R01DK119667, 1RO3DK117252, R01DK121072, DP3DK111907, R03DK117252)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- SARS-CoV-2, COVID-19 pandemic, lung organoids, colonic organoids, human pluripotent stem cells, alveolar type II cells, enterocytes, ACE2 expression, entry inhibitors, imatinib, mycophenolic acid, high-throughput drug screening, FDA-approved drugs, antiviral activity, chemokine induction, gastrointestinal manifestations of COVID-19
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Animals, Antiviral Agents, Colon, Drug Evaluation, Preclinical, Female, Humans, Lung, Male, Organoids, United States, United States Food and Drug Administration, Drug Approval, Mice, Virus Internalization, Viral Tropism, Heterografts, In Vitro Techniques
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