Beta-Cyclodextrins as affordable antivirals to treat coronavirus infection

Raich-Regue, D.; Tenorio, R.; Fernandez-de-Castro, I.; Perez-Zsolt, D.; Munoz-Basagoiti, J.; Sachse, M.; Fernandez-Sanchez, S.; Gallemi, M.; Ortega-Gonzalez, P.; Fernandez-Oliva, A.; Gabaldon, J.; Nunez-Delicado, E.; Casas, J.; Tarres, F.; Vergara-Alert, J.; Segales, J.; Carrillo, J.; Blanco, J.; Clotet, B.; Ceron-Carrasco, J.; Izquierdo-Useros, N.; Risco, C.

doi:10.1101/2022.11.16.516726

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bioRxiv · 10.1101/2022.11.16.516726

Beta-Cyclodextrins as affordable antivirals to treat coronavirus infection

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Abstract

The SARS-CoV-2 pandemic made evident that we count with few coronavirus-fighting drugs. Here we aimed to identify a cost-effective antiviral with broad spectrum activity and high safety and tolerability profiles. We began elaborating a list of 116 drugs previously used to treat other pathologies or characterized in pre-clinical studies with potential to treat coronavirus infections. We next employed molecular modelling tools to rank the 44 most promising inhibitors and tested their efficacy as antivirals against a panel of and {beta} coronavirus, e.g., the HCoV-229E and SARS-CoV-2 viruses. Four drugs, OSW-1, U18666A, hydroxypropyl-{beta}-cyclodextrin (H{beta}CD) and phytol, showed antiviral activity against both HCoV-229E (in MRC5 cells) and SARS-CoV-2 (in Vero E6 cells). The mechanism of action of these compounds was studied by transmission electron microscopy (TEM) and by testing their capacity to inhibit the entry of SARS-CoV-2 pseudoviruses in ACE2-expressing HEK-293T cells. The entry was inhibited by H{beta}CD and U18666A, yet only H{beta}CD could inhibit SARS-CoV-2 replication in the pulmonary cells Calu-3. With these results and given that cyclodextrins are widely used for drug encapsulation and can be safely administered to humans, we further tested 6 native and modified cyclodextrins, which confirmed {beta}-cyclodextrins as the most potent inhibitors of SARS-CoV-2 replication in Calu-3 cells. All accumulated data points to {beta}-cyclodextrins as promising candidates to be used in the therapeutic treatments for SARS-CoV-2 and possibly other respiratory viruses.

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Raich-Regue, D., Tenorio, R., Fernandez-de-Castro, I., Perez-Zsolt, D., Munoz-Basagoiti, J., Sachse, M., Fernandez-Sanchez, S., Gallemi, M., Ortega-Gonzalez, P., Fernandez-Oliva, A., Gabaldon, J., Nunez-Delicado, E., Casas, J., Tarres, F., Vergara-Alert, J., Segales, J., Carrillo, J., Blanco, J., Clotet, B., Ceron-Carrasco, J., Izquierdo-Useros, N., Risco, C.. 2022-11-16. Beta-Cyclodextrins as affordable antivirals to treat coronavirus infection. https://doi.org/10.1101/2022.11.16.516726

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