02889nas a2200673   4500000000100000008004100001260004400042653002200086653001600108100001100124700001000135700001100145700001200156700000900168700001100177700001200188700001200200700001000212700001200222700001200234700001100246700001600257700000900273700001100282700001000293700001200303700001100315700001200326700000900338700000900347700001000356700001000366700000900376700001100385700001200396700001100408700001500419700001100434700000900445700001000454700001300464700001000477700001000487700001100497700001000508700001200518700001200530700001000542700001100552700001000563700001000573700001000583700001400593700001100607245006800618856006900686520143500755022002502190       2021                            d  bSpringer Science and Business Media LLC10aMultidisciplinary10aClofazimine1 aYuan S1 aYin X1 aMeng X1 aChan JF1 aYe Z1 aRiva L1 aPache L1 aChan CC1 aLai P1 aChan CC1 aPoon VK1 aLee AC1 aMatsunaga N1 aPu Y1 aYuen C1 aCao J1 aLiang R1 aTang K1 aSheng L1 aDu Y1 aXu W1 aLau C1 aSit K1 aAu W1 aWang R1 aZhang Y1 aTang Y1 aClausen TM1 aPihl J1 aOh J1 aSze K1 aZhang AJ1 aChu H1 aKok K1 aWang D1 aCai X1 aEsko JD1 aHung IF1 aLi RA1 aChen H1 aSun H1 aJin D1 aSun R1 aChanda SK1 aYuen K00aClofazimine broadly inhibits coronaviruses including SARS-CoV-2  uhttps://www.nature.com/articles/s41586-021-03431-4_reference.pdf3 aCOVID-19 pandemic is the third zoonotic coronavirus (CoV) outbreak of the century after severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) since 20122. Treatment options for CoVs are largely lacking. Here we show that clofazimine, an anti-leprosy drug with a favourable safety profile3, possesses pan-coronaviral inhibitory activity, and can antagonize SARS-CoV-2 and MERS-CoV replication in multiple in vitro systems. The FDA-approved molecule was found to inhibit viral spike-mediated cell fusion and viral helicase activity. In a hamster model of SARS-CoV-2 pathogenesis, prophylactic or therapeutic administration of clofazimine significantly reduced viral load in the lung and faecal viral shedding, and also mitigated inflammation associated with viral infection. Combinatorial application of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted upper respiratory tract viral shedding. Since clofazimine is orally bioavailable and has a comparatively low manufacturing cost, it is an attractive clinical candidate for outpatient treatment and remdesivir-based combinatorial therapy for hospitalized COVID-19 patients, particularly in developing countries. Taken together, our data provide evidence that clofazimine may have a role in the control of the current pandemic SARS-CoV-2, and, possibly most importantly, emerging CoVs of the future.  a0028-0836, 1476-4687