β-Cyclodextrins as affordable antivirals to treat coronavirus infection

Dalia Raich-Regue, Raquel Tenorio, Isabel Fernandez de Castro, Ferran Tarres-Freixas, Martin Sachse, Daniel Perez-Zsolt, Jordana Munoz-Basagoiti, Sara Y. Fernandez-Sanchez, Marcal Gallemi, Paula Ortega-Gonzalez, Alberto Fernandez-Oliva, Jose A. Gabaldon, Estrella Nunez-Delicado, Josefina Casas, Nuria Roca, Guillermo Cantero, Monica Perez, Carla Usai, Cristina Lorca-Oro, Julia-Vergara AlertJoaquim Segales, Jorge Carrillo, Julia Blanco, Bonaventura Clotet Sala, Jose P. Ceron-Carrasco, Nuria Izquierdo-Useros, Cristina Risco

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3 Cites (Scopus)

Resum

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.

Idioma originalAnglès
Número d’article114997
Nombre de pàgines18
RevistaBiomedicine and Pharmacotherapy
Volum164
Data online anticipadade juny 2023
DOIs
Estat de la publicacióPublicada - d’ag. 2023
Publicat externament

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