Kuzikov, M.M.KuzikovCostanzi, E.E.CostanziReinshagen, J.J.ReinshagenEsposito, F.F.EspositoVangeel, L.L.VangeelWolf, M.M.WolfEllinger, B.B.EllingerClaussen, C.C.ClaussenGeisslinger, G.G.GeisslingerCorona, A.A.CoronaIaconis, D.D.IaconisTalarico, C.C.TalaricoManelfi, C.C.ManelfiCannalire, R.R.CannalireRossetti, G.G.RossettiGossen, J.J.GossenAlbani, S.S.AlbaniMusiani, F.F.MusianiHerzog, K.K.HerzogYe, Y.Y.YeGiabbai, B.B.GiabbaiDemitri, N.N.DemitriJochmans, D.D.JochmansJonghe, S.D.S.D.JongheRymenants, J.J.RymenantsSumma, V.V.SummaTramontano, E.E.TramontanoBeccari, A.R.A.R.BeccariLeyssen, P.P.LeyssenStorici, P.P.StoriciNeyts, J.J.NeytsGribbon, P.P.GribbonZaliani, A.A.Zaliani2022-03-062022-03-062021https://publica.fraunhofer.de/handle/publica/26898410.1021/acsptsci.0c00216Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC50 values below 1 mM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.enjournal article