Raïch-Regué, DaliaTenorio, RaquelFernández de Castro, IsabelTarrés-Freixas, FerranSachse, MartinPerez-Zsolt, DanielMuñoz-Basagoiti, JordanaFernández-Sánchez, Sara YGallemí, MarçalOrtega-González, PaulaFernández-Oliva, AlbertoGabaldón, José ANuñez-Delicado, EstrellaCasas, JosefinaRoca, NúriaCantero, GuillermoPérez, MónicaUsai, CarlaLorca-Oró, CristinaAlert, Júlia-VergaraSegalés, JoaquimCarrillo, JorgeBlanco, JuliàClotet Sala, BonaventuraCerón-Carrasco, José PIzquierdo-Useros, NuriaRisco, Cristina2023-12-152023-12-152023-08Biomed Pharmacother. 2023 Aug:164:114997.http://hdl.handle.net/20.500.12105/16824The SARS-CoV-2 pandemic made evident that there are only a few drugs against coronavirus. Here we aimed to identify a cost-effective antiviral with broad spectrum activity and high safety profile. Starting from a list of 116 drug candidates, we used molecular modelling tools to rank the 44 most promising inhibitors. Next, we tested their efficacy as antivirals against α and β coronaviruses, such as the HCoV-229E and SARS-CoV-2 variants. Four drugs, OSW-1, U18666A, hydroxypropyl-β-cyclodextrin (HβCD) and phytol, showed in vitro antiviral activity against HCoV-229E and SARS-CoV-2. The mechanism of action of these compounds was studied by transmission electron microscopy and by fusion assays measuring SARS-CoV-2 pseudoviral entry into target cells. Entry was inhibited by HβCD and U18666A, yet only HβCD inhibited SARS-CoV-2 replication in the pulmonary Calu-3 cells. Compared to the other cyclodextrins, β-cyclodextrins were the most potent inhibitors, which interfered with viral fusion via cholesterol depletion. β-cyclodextrins also prevented infection in a human nasal epithelium model ex vivo and had a prophylactic effect in the nasal epithelium of hamsters in vivo. All accumulated data point to β-cyclodextrins as promising broad-spectrum antivirals against different SARS-CoV-2 variants and distant alphacoronaviruses. Given the wide use of β-cyclodextrins for drug encapsulation and their high safety profile in humans, our results support their clinical testing as prophylactic antivirals.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/AntiviralCOVID-19CoronavirusCyclodextrinDrug repurposingSARS-CoV-2β-cyclodextrinCOVID-19beta-CyclodextrinsDermatologic AgentsHumansSARS-CoV-2Antiviral AgentsAttribution-NonCommercial-NoDerivatives 4.0 Internacional3731127916411499710.1016/j.biopha.2023.1149971950-6007Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapieopen access