03004nas a2200661   4500000000100000000000100001008004100002260001200043653001800055653001900073653002000092653001800112653001500130100001600145700001600161700001800177700001300195700002000208700001700228700001800245700001900263700001600282700001700298700001500315700002300330700002200353700001700375700001900392700003100411700001900442700001700461700001600478700001700494700001900511700001800530700001500548700002000563700001600583700001600599700001800615700001700633700002000650700001700670700002000687700002600707700001900733700001900752700002300771700002000794700002500814700002100839245011200860856005500972300001201027490000601039520128301045022001402328       2021                            d  c2021-0810aAssay systems10aDrug screening10aInfluenza virus10aLab-on-a-chip10aSARS-CoV-21 aLonglong Si1 aHaiqing Bai1 aMelissa Rodas1 aWuji Cao1 aCrystal Yuri Oh1 aAmanda Jiang1 aRasmus Moller1 aDaisy Hoagland1 aKohei Oishi1 aShu Horiuchi1 aSkyler Uhl1 aDaniel Blanco-Melo1 aRandy A. Albrecht1 aWen-Chun Liu1 aTristan Jordan1 aBenjamin E. Nilsson-Payant1 aIlona Golynker1 aJustin Frere1 aJames Logue1 aRobert Haupt1 aMarisa McGrath1 aStuart Weston1 aTian Zhang1 aRoberto Plebani1 aMercy Soong1 aAtiq Nurani1 aSeong Min Kim1 aDanni Y. Zhu1 aKambez H. Benam1 aGirija Goyal1 aSarah E. Gilpin1 aRachelle Prantil-Baun1 aSteven P. Gygi1 aRani K. Powers1 aKenneth E. Carlson1 aMatthew Frieman1 aBenjamin R. tenOever1 aDonald E. Ingber00aA human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics  uhttps://www.nature.com/articles/s41551-021-00718-9  a815-8290 v53 aThe rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential.  a2157-846X