tetano
Editor, Senior Moderator
Cell Death Dis
. 2022 May 25;13(5):498.
doi: 10.1038/s41419-022-04961-z.
Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants
Daniela Iaconis[SUP] #[/SUP][SUP] 1 [/SUP], Licia Bordi[SUP] #[/SUP][SUP] 2 [/SUP], Giulia Matusali[SUP] #[/SUP][SUP] 2 [/SUP], Carmine Talarico[SUP] 1 [/SUP], Candida Manelfi[SUP] 3 [/SUP], Maria Candida Cesta[SUP] 4 [/SUP], Mara Zippoli[SUP] 1 [/SUP], Francesca Caccuri[SUP] 5 [/SUP], Antonella Bugatti[SUP] 5 [/SUP], Alberto Zani[SUP] 5 [/SUP], Federica Filippini[SUP] 5 [/SUP], Laura Scorzolini[SUP] 2 [/SUP], Marco Gobbi[SUP] 6 [/SUP], Marten Beeg[SUP] 6 [/SUP], Arianna Piotti[SUP] 6 [/SUP], Monica Montopoli[SUP] 7 [/SUP], Veronica Cocetta[SUP] 7 [/SUP], Silvia Bressan[SUP] 7 [/SUP], Enrico M Bucci[SUP] 8 [/SUP], Arnaldo Caruso[SUP] 5 [/SUP], Emanuele Nicastri[SUP] 2 [/SUP], Marcello Allegretti[SUP] 3 [/SUP], Andrea R Beccari[SUP] 1 [/SUP]
Affiliations
Abstract
The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to obtain quick answers to medical emergencies. Following a virtual screening campaign on the most relevant viral proteins, we identified the drug raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a new potential agent to treat mild-to-moderate COVID-19 patients. In this paper we report a comprehensive pharmacological characterization of raloxifene in relevant in vitro models of COVID-19, specifically in Vero E6 and Calu-3 cell lines infected with SARS-CoV-2. A large panel of the most common SARS-CoV-2 variants isolated in Europe, United Kingdom, Brazil, South Africa and India was tested to demonstrate the drug's ability in contrasting the viral cytopathic effect (CPE). Literature data support a beneficial effect by raloxifene against the viral infection due to its ability to interact with viral proteins and activate protective estrogen receptor-mediated mechanisms in the host cells. Mechanistic studies here reported confirm the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies, and show that the drug treatment does not directly affect Spike/ACE2 interaction or viral internalization in infected cell lines. Interestingly, raloxifene can counteract Spike-mediated ADAM17 activation in human pulmonary cells, thus providing new insights on its mechanism of action. A clinical study in mild to moderate COVID-19 patients (NCT05172050) has been recently completed. Our contribution to evaluate raloxifene results on SARS-CoV-2 variants, and the interpretation of the mechanisms of action will be key elements to better understand the trial results, and to design new clinical studies aiming to evaluate the potential development of raloxifene in this indication.
. 2022 May 25;13(5):498.
doi: 10.1038/s41419-022-04961-z.
Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants
Daniela Iaconis[SUP] #[/SUP][SUP] 1 [/SUP], Licia Bordi[SUP] #[/SUP][SUP] 2 [/SUP], Giulia Matusali[SUP] #[/SUP][SUP] 2 [/SUP], Carmine Talarico[SUP] 1 [/SUP], Candida Manelfi[SUP] 3 [/SUP], Maria Candida Cesta[SUP] 4 [/SUP], Mara Zippoli[SUP] 1 [/SUP], Francesca Caccuri[SUP] 5 [/SUP], Antonella Bugatti[SUP] 5 [/SUP], Alberto Zani[SUP] 5 [/SUP], Federica Filippini[SUP] 5 [/SUP], Laura Scorzolini[SUP] 2 [/SUP], Marco Gobbi[SUP] 6 [/SUP], Marten Beeg[SUP] 6 [/SUP], Arianna Piotti[SUP] 6 [/SUP], Monica Montopoli[SUP] 7 [/SUP], Veronica Cocetta[SUP] 7 [/SUP], Silvia Bressan[SUP] 7 [/SUP], Enrico M Bucci[SUP] 8 [/SUP], Arnaldo Caruso[SUP] 5 [/SUP], Emanuele Nicastri[SUP] 2 [/SUP], Marcello Allegretti[SUP] 3 [/SUP], Andrea R Beccari[SUP] 1 [/SUP]
Affiliations
- PMID: 35614039
- DOI: 10.1038/s41419-022-04961-z
Abstract
The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to obtain quick answers to medical emergencies. Following a virtual screening campaign on the most relevant viral proteins, we identified the drug raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a new potential agent to treat mild-to-moderate COVID-19 patients. In this paper we report a comprehensive pharmacological characterization of raloxifene in relevant in vitro models of COVID-19, specifically in Vero E6 and Calu-3 cell lines infected with SARS-CoV-2. A large panel of the most common SARS-CoV-2 variants isolated in Europe, United Kingdom, Brazil, South Africa and India was tested to demonstrate the drug's ability in contrasting the viral cytopathic effect (CPE). Literature data support a beneficial effect by raloxifene against the viral infection due to its ability to interact with viral proteins and activate protective estrogen receptor-mediated mechanisms in the host cells. Mechanistic studies here reported confirm the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies, and show that the drug treatment does not directly affect Spike/ACE2 interaction or viral internalization in infected cell lines. Interestingly, raloxifene can counteract Spike-mediated ADAM17 activation in human pulmonary cells, thus providing new insights on its mechanism of action. A clinical study in mild to moderate COVID-19 patients (NCT05172050) has been recently completed. Our contribution to evaluate raloxifene results on SARS-CoV-2 variants, and the interpretation of the mechanisms of action will be key elements to better understand the trial results, and to design new clinical studies aiming to evaluate the potential development of raloxifene in this indication.