Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS‐CoV‐2 infection in vitro

Schloer, Sebastian; Brunotte, Linda; Mecate-Zambrano, Angeles; Zheng, Shuyu; Tang, Jing; Ludwig, Stephan; Rescher, Ursula

doi:10.1111/bph.15418

Cited by 78 publications

(83 citation statements)

References 65 publications

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“…Next, we determined the number of infectious virus particles in Calu-3 cells that weretreated with a combination of both drugs. On the basis of our recent publications [27] on the antiviral potential of fluoxetine alone or in combination with remdesivir, we now Next, we determined the number of infectious virus particles in Calu-3 cells that weretreated with a combination of both drugs. On the basis of our recent publications [27] on the antiviral potential of fluoxetine alone or in combination with remdesivir, we now analyzed the antiviral effects of a combined fluoxetine/GS-441524 treatment (Figure 3A,B).…”

Section: Resultsmentioning

confidence: 99%

Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro

et al. 2021

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The ongoing SARS-CoV-2 pandemic requires efficient and safe antiviral treatment strategies. Drug repurposing represents a fast and low-cost approach to the development of new medical treatment options. The direct antiviral agent remdesivir has been reported to exert antiviral activity against SARS-CoV-2. Whereas remdesivir only has a very short half-life time and a bioactivation, which relies on pro-drug activating enzymes, its plasma metabolite GS-441524 can be activated through various kinases including the adenosine kinase (ADK) that is moderately expressed in all tissues. The pharmacokinetics of GS-441524 argue for a suitable antiviral drug that can be given to patients with COVID-19. Here, we analyzed the antiviral property of a combined treatment with the remdesivir metabolite GS-441524 and the antidepressant fluoxetine in a polarized Calu-3 cell culture model against SARS-CoV-2. The combined treatment with GS-441524 and fluoxetine were well-tolerated and displayed synergistic antiviral effects against three circulating SARS-CoV-2 variants in vitro in the commonly used reference models for drug interaction. Thus, combinatory treatment with the virus-targeting GS-441524 and the host-directed drug fluoxetine might offer a suitable therapeutic treatment option for SARS-CoV-2 infections.

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Section: Resultsmentioning

confidence: 99%

Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro

et al. 2021

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“…The COVID-19 pandemic and its mental effect (depression) bring us both concerns and opportunities. The combinatory treatment with antidepressants and COVID-19 medications could help to reduce the severity of COVID-19 [ 58 , 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Distinctive Supramolecular Features of β-Cyclodextrin Inclusion Complexes with Antidepressants Protriptyline and Maprotiline: A Comprehensive Structural Investigation

Aree

2021

Pharmaceuticals

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Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the β-CD–TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the β-CD–TCA stability spectrum based on binding constants (Kas) in solution, β-CD–protriptyline (PRT) 1—most stable and β-CD–maprotiline (MPL) 2—least stable. X-ray crystallography unveiled that in the β-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C–H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH2–CH2- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round β-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔEstbs), although the complex stability orders based on Kas and ΔEstbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the β-CD cavity, suggesting the potential application of CDs for efficient drug delivery.

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“…In addition, several repurposed drugs have been introduced which are able to prevent viral entry via different mechanisms. These repurposed drugs, including fluoxetine and itraconazole, which can dysregulate the endosomal cholesterol release and increase endolysosomal cholesterol storage have been suggested as synergistic combinatory therapeutic agents alongside with conventional antiviral therapies (Creeden et al, 2021;Dechaumes et al, 2021;Schloer et al, 2021). According to these promising results, using repurposed therapeutic agents as adjuvant therapy alongside with the two-step strategy seems to be very helpful with comprehensive blockade of viral entry.…”

Section: Discussion and Future Directionmentioning

confidence: 99%

“…Fluoxetine is a functional inhibitor of sphingomyelinase (FIASMA) which accumulates cholesterol in endolysosomes and causes a secondary reduction in the cholesterol content of other cell membranes which reduces the amount of cholesterol available for the virus to produce its envelope. This might also impact TMPRSS2 activity and/or virus-membrane fusion capacity, which might either reduce SARS-CoV-2 entry and/or shift the entry route in favor of an endosomal uptake (Schloer et al, 2021). In another study, Creeden et al (2021) provided evidences that fluoxetine can inhibit IL-6 and NF-κB signaling, and therefore disrupt the production of pro-inflammatory cytokines like IL6 and IL6ST and mitigate the progression of cytokine storm.…”

Section: Supporting Evidences For Strategy Cell Entry Mechanism Of Sars-cov-2mentioning

confidence: 99%

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

Nazerian

Vakili

Ebrahimi

et al. 2021

Front. Cell Dev. Biol.

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Currently, the COVID-19 pandemic is an international challenge, largely due to lack of effective therapies. Pharmacotherapy has not yet been able to find a definitive treatment for COVID-19. Since SARS-CoV-2 affects several organs, treatment strategies that target the virus in a wider range are expected to be ultimately more successful. To this end, a two-step treatment strategy has been presented. In the first phase of the disease, when the patient is newly infected with the virus and the cytokine storm has not yet been developed, a chimeric peptide is used to inhibit virus entry into the host cell cytosol (by inhibiting endosomal pH acidification) and viral replication. After the virus entry and decrease of angiotensin converting enzyme 2 (ACE2) level, some people are unable to properly compensate for the ACE2 pathway and progress toward the cytokine storm. In the beginning of the cytokine storm, sACE2 protein is very effective in regulating the immune system toward the anti-inflammatory pathway, including M2 macrophages. Hence, the genes of 8P9R chimeric peptide and sACE2 would be inserted in an episomal vector with a separate promoter for each gene: the chimeric peptide gene promoter is a CMV promoter, while the sACE2 gene promoter is a NF-κB-sensitive promoter. The NF-κB-sensitive promoter induces the expression of sACE2 gene soon after elevation of NF-κB which is the main transcription factor of inflammatory genes. Thus, as the expression of inflammatory cytokines increases, the expression of sACE2 increases simultaneously. In this condition, sACE2 can prevent the cytokine storm by inhibiting the pro-inflammatory pathways. To deliver the designed vector to the target cells, mesenchymal stem cell-derived (MSC-derived) exosome-liposome hybrids are used. Herein, the strategy can be considered as a personalized clinical therapy for COVID-19, that can prevent morbidity and mortality in the future.

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Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS‐CoV‐2 infection in vitro

Cited by 78 publications

References 65 publications

Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro

Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro

Distinctive Supramolecular Features of β-Cyclodextrin Inclusion Complexes with Antidepressants Protriptyline and Maprotiline: A Comprehensive Structural Investigation

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

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