TY - JOUR
T1 - β-Cyclodextrins as affordable antivirals to treat coronavirus infection
AU - Raich-Regue, Dalia
AU - Tenorio, Raquel
AU - de Castro, Isabel Fernandez
AU - Tarres-Freixas, Ferran
AU - Sachse, Martin
AU - Perez-Zsolt, Daniel
AU - Munoz-Basagoiti, Jordana
AU - Fernandez-Sanchez, Sara Y.
AU - Gallemi, Marcal
AU - Ortega-Gonzalez, Paula
AU - Fernandez-Oliva, Alberto
AU - Gabaldon, Jose A.
AU - Nunez-Delicado, Estrella
AU - Casas, Josefina
AU - Roca, Nuria
AU - Cantero, Guillermo
AU - Perez, Monica
AU - Usai, Carla
AU - Lorca-Oro, Cristina
AU - Alert, Julia-Vergara
AU - Segales, Joaquim
AU - Carrillo, Jorge
AU - Blanco, Julia
AU - Sala, Bonaventura Clotet
AU - Ceron-Carrasco, Jose P.
AU - Izquierdo-Useros, Nuria
AU - Risco, Cristina
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/8
Y1 - 2023/8
N2 - 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.
AB - 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.
KW - Antiviral
KW - COVID-19
KW - Coronavirus
KW - Cyclodextrin
KW - Drug repurposing
KW - SARS-CoV-2
KW - β-cyclodextrin
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:001024824400001&DestLinkType=FullRecord&DestApp=WOS
UR - http://www.scopus.com/inward/record.url?scp=85161350853&partnerID=8YFLogxK
U2 - 10.1016/j.biopha.2023.114997
DO - 10.1016/j.biopha.2023.114997
M3 - Article
SN - 0753-3322
VL - 164
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
M1 - 114997
ER -