Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants.

Autor: Iaconis D; Dompé farmaceutici S.p.A., Naples, Italy., Bordi L; National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy., Matusali G; National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy., Talarico C; Dompé farmaceutici S.p.A., Naples, Italy., Manelfi C; Dompé farmaceutici S.p.A., L'Aquila, Italy., Cesta MC; Dompé farmaceutici S.p.A., L'Aquila, Italy. candida.cesta@dompe.com., Zippoli M; Dompé farmaceutici S.p.A., Naples, Italy., Caccuri F; Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy., Bugatti A; Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy., Zani A; Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy., Filippini F; Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy., Scorzolini L; National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy., Gobbi M; Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Beeg M; Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Piotti A; Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Montopoli M; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, VIMM Veneto Institute Molecular Medicine, Padua, Italy., Cocetta V; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, VIMM Veneto Institute Molecular Medicine, Padua, Italy., Bressan S; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, VIMM Veneto Institute Molecular Medicine, Padua, Italy., Bucci EM; Sbarro Health Research Organization, Biology Department CFT, Temple University, Philadelphia, PA, USA., Caruso A; Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy., Nicastri E; National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy., Allegretti M; Dompé farmaceutici S.p.A., L'Aquila, Italy., Beccari AR; Dompé farmaceutici S.p.A., Naples, Italy.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 May 25; Vol. 13 (5), pp. 498. Date of Electronic Publication: 2022 May 25.
DOI: 10.1038/s41419-022-04961-z
Abstrakt: 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. The Author(s).)
Databáze: MEDLINE
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