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β-Cyclodextrins as affordable antivirals to treat coronavirus infection Raïch-Regué, Dalia Tenorio, Raquel Fernández de Castro, Isabel Tarrés Freixas, Ferran Sachse, Martin Perez-Zsol, Daniel Muñoz Basagoiti, Jordana Fernández-Sánchez, Sara Y. Gallemí, Marçal Ortega-González, Paula Fernández-Oliva, Alberto Gabaldón, José A. Nuñez-Delicado, Estrella Casas, Josefina Roca, Núria Cantero, Guillermo Pérez, Mónica Usai, Carla Lorca-Oró, Cristina Serra Gironella, Joan Segalés, Joaquim Carrillo, Jorge Blanco, Julià Clotet Sala, Bonaventura Cerón-Carrasco, José P. Izquierdo-Useros, Nuria Risco, Cristina Producció Animal Sanitat Animal The 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. 2023-06-08 info:eu-repo/semantics/article Raïch‐Regué, Dàlia, Raquel Tenorio, Castro Isabel Fernández De, Ferran Tarrés-Freixas, Martin Sachse, Daniel Perez-Zsolt, Jordana Muñoz-Basagoiti, et al. 2023. “β-Cyclodextrins as Affordable Antivirals to Treat Coronavirus Infection.” Biomedicine & Pharmacotherapy 164 (August): 114997. doi:10.1016/j.biopha.2023.114997. 0753-3322 http://hdl.handle.net/20.500.12327/2381 https://doi.org/10.1016/j.biopha.2023.114997 eng Biomedicine and Pharmacotherapy MICIU/Programa Estatal de I+D+I orientada a los retos de la sociedad/RTI2018-094445-B-I00/ES/BUSQUEDA DE NUEVOS ANTIVIRALES DE AMPLIO ESPECTRO: TRANSPORTE DE LIPIDOS Y PROTEINAS MITOCONDRIALES COMO DIANAS/ MICINN/Programa Estatal de I+D+I orientada a los retos de la sociedad/PID2020-117145RB-I00/ES/NUEVAS TERAPIAS ANTIVIRALES E INMUNOMODULADORAS FRENTE AL SARS-COV-2/ EU/HE/101046118/EC/RBD Dimer recombinant protein vaccine against SARSCoV2/RBDCOV FEDER/ / /EU/ / http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 International Elsevier