In Vitro Evaluation of the Antiviral Activity of Methylene Blue Alone or in Combination against SARS-CoV-2

Gendrot, Mathieu; Jardot, Priscilla; Delandre, Océane; Andréani, Julien; Duflot, Isabelle; Bideau, Marion Le; Mosnier, Joël; Fonta, Isabelle; Hutter, Sébastien; Scola, Bernard La; Pradines, Bruno

doi:10.3390/jcm10143007

Cited by 7 publications

(10 citation statements)

References 52 publications

(65 reference statements)

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“…found non-photoactivated MeBlu to inhibit SARS-CoV-2 replication in Vero E6 in vitro with an IC 50 of 0.3 ± 0.03 M [37] and then confirmed it later with two clinically isolated SARS-CoV-2 strains (IHUMI-3 and IHUMI-6; IC 50 s of 0.4 and 1.1 M, respectively) [38]. In line with the observations of Cagno and coworkers, this study by Gendrot and coworkers in Vero E6 cells also suggested that MeBlu interacts at both entry and post-entry stages of SARS-CoV-2 infection [38].…”

Section: Discussionmentioning

confidence: 79%

“…Their results also suggested that the antiviral activity of MeBlu might result from multiple mechanisms of action as the extent of genomic RNA degradation was higher in presence of light and after long exposure. Gendrot, Pradines, and coworkers at Institut de Recherche Biomédicale des Armées (Marseille, France) found non-photoactivated MeBlu to inhibit SARS-CoV-2 replication in Vero E6 in vitro with an IC 50 of 0.3 ± 0.03 μM [37] and then confirmed it later with two clinically isolated SARS-CoV-2 strains (IHUMI-3 and IHUMI-6; IC 50 s of 0.4 and 1.1 μM, respectively) [38]. In line with the observations of Cagno and coworkers, this study by Gendrot and coworkers in Vero E6 cells also suggested that MeBlu interacts at both entry and post-entry stages of SARS-CoV-2 infection [38].…”

Section: Discussionmentioning

confidence: 99%

“…Gendrot, Pradines, and coworkers at Institut de Recherche Biomédicale des Armées (Marseille, France) found non-photoactivated MeBlu to inhibit SARS-CoV-2 replication in Vero E6 in vitro with an IC 50 of 0.3 ± 0.03 μM [37] and then confirmed it later with two clinically isolated SARS-CoV-2 strains (IHUMI-3 and IHUMI-6; IC 50 s of 0.4 and 1.1 μM, respectively) [38]. In line with the observations of Cagno and coworkers, this study by Gendrot and coworkers in Vero E6 cells also suggested that MeBlu interacts at both entry and post-entry stages of SARS-CoV-2 infection [38]. MeBlu was also identified in several drug repurposing (repositioning) high throughput screening (HTS) assays looking for anti-SARS-CoV-2 activity, and then confirmed as having low micromolar activity in concentration-response studies.…”

Section: Discussionmentioning

confidence: 99%

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Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19

Chuang

Papp

Kuczmog

et al. 2022

Preprint

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We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and used for other medical applications, as a small-molecule inhibitor of the protein-protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, the first critical step of the attachment and entry of this coronavirus responsible for the COVID-19 pandemic. Here, we show that methylene blue concentration-dependently inhibits this PPI for the spike protein of the original strain as well as for those of variants of concerns such as the D614G mutant and delta (B.1.617.2) with IC50 in the low micromolar range (1-5 μM). Methylene blue also showed promiscuous activity and inhibited several other PPIs of viral proteins (e.g., HCoV-NL63 - ACE2, hepatitis C virus E - CD81) as well as others (e.g., IL-2 - IL-2Rα) with similar potency. This non-specificity notwithstanding, methylene blue inhibited the entry of pseudoviruses bearing the spike protein of SARS-CoV-2 in hACE2-expressing host cells both for the original strain and the delta variant. It also blocked SARS-CoV-2 (B.1.5) virus replication in Vero E6 cells with an IC50 in the low micromolar range (1.7 μM) when assayed using quantitative PCR of the viral RNA. Thus, while it seems to be a promiscuous PPI inhibitor with low micromolar activity and it has a relatively narrow therapeutic index, methylene blue inhibits entry and replication of SARS-CoV-2, including several of its mutant variants, and has potential as a possible inexpensive, broad-spectrum, orally bioactive small-molecule antiviral for the prevention and treatment of COVID-19.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19

Chuang

Papp

Kuczmog

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Their results also suggest that the antiviral activity of MeBlu might result from multiple mechanisms of action, as the extent of genomic RNA degradation was higher in the presence of light and after long exposure. Gendrot, Pradines, and coworkers at the Institut de Recherche Biomédicale des Armées (Marseille, France) found non-photoactivated MeBlu to inhibit SARS-CoV-2 replication in Vero E6 in vitro with an IC 50 of 0.3 ± 0.03 μM [ 37 ] and then confirmed it later with two clinically isolated SARS-CoV-2 strains (IHUMI-3 and IHUMI-6; IC 50 s of 0.4 and 1.1 μM, respectively) [ 38 ]. In line with the observations of Cagno and coworkers, the study by Gendrot and coworkers in Vero E6 cells also suggested that MeBlu interacts at both entry and postentry stages of SARS-CoV-2 infection [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Gendrot, Pradines, and coworkers at the Institut de Recherche Biomédicale des Armées (Marseille, France) found non-photoactivated MeBlu to inhibit SARS-CoV-2 replication in Vero E6 in vitro with an IC 50 of 0.3 ± 0.03 μM [ 37 ] and then confirmed it later with two clinically isolated SARS-CoV-2 strains (IHUMI-3 and IHUMI-6; IC 50 s of 0.4 and 1.1 μM, respectively) [ 38 ]. In line with the observations of Cagno and coworkers, the study by Gendrot and coworkers in Vero E6 cells also suggested that MeBlu interacts at both entry and postentry stages of SARS-CoV-2 infection [ 38 ]. MeBlu was also identified in several drug repurposing (repositioning) high-throughput screening (HTS) assays looking for anti-SARS-CoV-2 activity and then confirmed as having low micromolar activity in concentration–response studies.…”

Section: Discussionmentioning

confidence: 99%

Methylene Blue Is a Nonspecific Protein–Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19

et al. 2022

View full text Add to dashboard Cite

We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and for other medical applications as a small-molecule inhibitor of the protein–protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, the first critical step of the attachment and entry of this coronavirus responsible for the COVID-19 pandemic. Here, we show that methylene blue concentration dependently inhibits this PPI for the spike protein of the original strain as well as for those of variants of concern such as the D614G mutant and delta (B.1.617.2) with IC50 in the low micromolar range (1–5 μM). Methylene blue also showed promiscuous activity and inhibited several other PPIs of viral proteins (e.g., HCoV-NL63–ACE2, hepatitis C virus E–CD81) as well as others (e.g., IL-2–IL-2Rα) with similar potency. This nonspecificity notwithstanding, methylene blue inhibited the entry of pseudoviruses bearing the spike protein of SARS-CoV-2 in hACE2-expressing host cells, both for the original strain and the delta variant. It also blocked SARS-CoV-2 (B.1.5) virus replication in Vero E6 cells with an IC50 in the low micromolar range (1.7 μM) when assayed using quantitative PCR of the viral RNA. Thus, while it seems to be a promiscuous PPI inhibitor with low micromolar activity and has a relatively narrow therapeutic index, methylene blue inhibits entry and replication of SARS-CoV-2, including several of its mutant variants, and has potential as a possible inexpensive, broad-spectrum, orally bioactive small-molecule antiviral for the prevention and treatment of COVID-19.

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Developing Small-Molecule Inhibitors of Protein-Protein Interactions Involved in Viral Entry as Potential Antivirals for COVID-19

Buchwald

2022

Front. Drug. Discov.

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Blocking protein-protein interactions (PPIs) involved in the initiation of the cell attachment and entry of viruses is an important antiviral mechanism of action including for neutralizing antibodies. Doing it with small-molecule inhibitors (SMIs) is challenging, as it is for all other PPIs, and might require the exploration of chemical space beyond that of typical drug-like structures. However, it could lead to new antiviral agents suitable for oral administration and acting on alternative targets, considerations that are essential for the development of widely acceptable and broad-spectrum preventive or curative therapeutics. Fostemsavir, an antiretroviral that acts via blocking of the gp120–CD4 PPI, supports the feasibility of the concept. Here, a brief review of relevant drug design considerations is presented together with a summary of the progress made toward the identification of SMIs targeting the PPI between the SARS-CoV-2 spike protein and ACE2 that initiates the viral attachment and cellular entry of this coronavirus causing the COVID-19 pandemic. SMIs identified in various screening assays that were also confirmed to have antiviral activity in a live virus or pseudovirus assay with an IC50 < 30 µM so far include several organic dyes (methylene blue, Evans blue, Congo red, direct violet 1), verteporfin, DRI-C23041, and cannabigerolic and cannabidiolic acids. While specificity and activity profiles still need improvement, results so far already provide proof-of-principle evidence for the feasibility of SMIs targeting the SARS-CoV-2-S–hACE2 PPI. Methylene blue, which is approved for clinical use, is orally bioactive, and could act by multiple mechanisms of action, might have potential for repurposing for COVID-19 prevention and treatment.

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In Vitro Evaluation of the Antiviral Activity of Methylene Blue Alone or in Combination against SARS-CoV-2

Cited by 7 publications

References 52 publications

Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19

Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19

Methylene Blue Is a Nonspecific Protein–Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19

Developing Small-Molecule Inhibitors of Protein-Protein Interactions Involved in Viral Entry as Potential Antivirals for COVID-19

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