03485nas a2200781   4500000000100000000000100001008004100002260001200043653001200055653002100067653001300088653002800101653001000129653001800139653003300157653001100190653001700201653001100218653002400229653000900253653000900262653000900271653001400280653001500294653001800309653004700327653001800374653002600392100001500418700001700433700001600450700003100466700001700497700001400514700001600528700001900544700001400563700001500577700001500592700002200607700001500629700001600644700001800660700001800678700002200696700001200718700001400730700001800744700001800762700001800780700002100798700001300819700001600832700001300848700002100861700002500882700001600907700001900923700001500942700002400957700002300981700001801004245007701022300001201099490000801111520157001119022001402689       2021                            d  c2021-0110aAnimals10aAntiviral Agents10aCOVID-1910aCOVID-19 Drug Treatment10aColon10aDrug Approval10aDrug Evaluation, Preclinical10aFemale10aHeterografts10aHumans10aIn Vitro Techniques10aLung10aMale10aMice10aorganoids10aSARS-CoV-210aUnited States10aUnited States Food and Drug Administration10aViral Tropism10aVirus Internalization1 aYuling Han1 aXiaohua Duan1 aLiuliu Yang1 aBenjamin E. Nilsson-Payant1 aPengfei Wang1 aFuyu Duan1 aXuming Tang1 aTomer M. Yaron1 aTuo Zhang1 aSkyler Uhl1 aYaron Bram1 aChanel Richardson1 aJiajun Zhu1 aZeping Zhao1 aDavid Redmond1 aSean Houghton1 aDuc-Huy T. Nguyen1 aDong Xu1 aXing Wang1 aJose Jessurun1 aAlain Borczuk1 aYaoxing Huang1 aJared L. Johnson1 aYuru Liu1 aJenny Xiang1 aHui Wang1 aLewis C. Cantley1 aBenjamin R. tenOever1 aDavid D. Ho1 aFong Cheng Pan1 aTodd Evans1 aHuanhuan Joyce Chen1 aRobert E. Schwartz1 aShuibing Chen00aIdentification of SARS-CoV-2 inhibitors using lung and colonic organoids  a270-2750 v5893 aThere 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.  a1476-4687