Raloxifene and Bazedoxifene Could Be Promising Candidates for Preventing the COVID-19 Related Cytokine Storm, ARDS and Mortality

Smetana, Karel; Rösel, Daniel; Brábek, Jan

doi:10.21873/invivo.12135

Cited by 38 publications

(32 citation statements)

References 8 publications

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“…Based on the bradykinin hypothesis on the trigger of the cytokine storm in severe Covid-19 [ 12 , 13 , 14 , 15 ], these results suggest that the compound could be used for its treatment. Present results support previous claims suggesting the use of raloxifene based on its capacity to inhibit the IL-6/STAT3 signaling pathway [ 45 ], and also for being a prospective antiviral agent for SARS-Cov2 as inhibitor of the two-pore channel TCP2 [ 48 ]. Very recently a clinical trial in Italy has been approved to test its efficacy in COVID-19 patients with mild symptoms [ 50 ].…”

Section: Discussionsupporting

confidence: 91%

“…The results of this work complement recent comments suggesting the use of raloxifene for the treatment of Covid-19 [ 45 ], based on its capacity to inhibit the IL-6/STAT3 signaling pathway [ 46 , 47 ]. In addition, the presumed antiviral profile of ralixofene against the SARS-Cov2 virus through its capability to block the two-pore channel TCP2 [ 48 ], as found for the ebola virus [ 49 ] has been underlined.…”

Section: Resultssupporting

confidence: 83%

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Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign

Gómez-Gutiérrez

Pérez

2020

IJMS

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Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in illness progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Recently, it was suggested that a dysregulated bradykinin signaling can trigger the cytokine storm observed in patients with severe Covid-19. In the scope of a drug repurposing campaign undertaken to identify bradykinin antagonists, raloxifene was identified as prospective compound in a virtual screening process. The pharmacodynamics profile of raloxifene towards bradykinin receptors is reported in the present work, showing a weak selective partial agonist profile at the B2 receptor. In view of this new profile, its possible use as a therapeutical agent for the treatment of severe Covid-19 is discussed.

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Section: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 83%

Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign

Gómez-Gutiérrez

Pérez

2020

IJMS

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“…This screening confirms previous reports demonstrating anti-SARS-CoV-2 activity of hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, celecoxib, and thioridazine hydrochloride (8)(9)(10)(25)(26)(27), while identifying additional 12 drugs. However, there are seven drugs have been reported when our manuscript was underreview (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). The underlying mechanisms of viral replication inhibition by these drugs are not clear.…”

Section: Discussionmentioning

confidence: 96%

Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2

et al. 2020

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COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.

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“…HHT biology establishes a model by which SERMs lead to endoglin overexpression by endothelial cells. Therefore, these results constitute a rational basis to assess the potential role of SERM receptors in RDEB and also their potential clinical use to combat the exacerbated inflammation caused by the emergent viral infection consequence of the SARS-CoV-2 coronavirus [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Raloxifene and n-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa

Aguado

García

et al. 2020

Cells

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Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the COL7A1 gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins. Raloxifene is a specific estrogen receptor modulator designated as an orphan drug for hereditary hemorrhagic telangiectasia, a rare vascular disease. Raloxifene stimulates endoglin synthesis, which could attenuate fibrosis. By contrast, the antioxidant N-acetylcysteine may have therapeutic value to rectify inflammation, fibrosis and endothelial dysfunction. Thus, we present here a repurposing strategy based on the molecular and functional screening of fibroblasts from RDEB patients with these drugs, leading us to propose the repositioning of these two well-known drugs currently in clinical use, raloxifene and N-acetylcysteine, to counteract fibrosis and inflammation in RDEB. Both compounds modulate the profibrotic events that may ultimately be responsible for the clinical manifestations in RDEB, suggesting that these findings may also be relevant for other diseases in which fibrosis is an important pathophysiological event.

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Raloxifene and Bazedoxifene Could Be Promising Candidates for Preventing the COVID-19 Related Cytokine Storm, ARDS and Mortality

Cited by 38 publications

References 8 publications

Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign

Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign

Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2

Raloxifene and n-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa

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