Research finds methylene blue is a low-micromolar inhibitor of the the SARS-CoV-2 spike protein and ACE2 interplay

The speedy outbreak of extreme acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2), a novel coronavirus, prompted the continuing coronavirus illness 2019 (COVID-19). Amongst all of the identified coronaviruses, SARS-CoV-2 has affected the healthcare system and economic system essentially the most. Though a number of COVID-19 vaccines have been developed in opposition to the unique SARS-CoV-2 pressure, their effectiveness has been diminished as a result of emergence of latest variants by way of genomic mutations. That is the rationale why new COVID-19 therapeutics are urgently required.

Study: Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19. Image Credit: Kateryna Kon/Shutterstock
Research: Methylene Blue Is a Nonspecific Protein-Protein Interplay Inhibitor with Potential for Repurposing as an Antiviral for COVID-19. Picture Credit score: Kateryna Kon/Shutterstock


Researchers have indicated that orally bioavailable antivirals are required for COVID-19 therapy. Two new medicine, specifically, molnupiravir (inhibition of protease exercise) and nirmatrelvir (suppresses viral replica), have acquired emergency use authorization by america Meals and Drug Administration (FDA). Lately, researchers have used small‐molecule inhibitors (SMIs) of protein‐protein interactions (PPIs) as a substitute goal for the therapy of SARS-CoV-2 an infection.

On this context, doable inhibitors of the PPIs between the CoV spike (S) protein and its cognate cell floor receptors are required. This inhibitor might forestall cell attachment by way of angiotensin-converting enzyme 2 (ACE2) and subsequent viral entry. Researchers said that the identification of SMIs for PPIs is a difficult activity in comparison with the identification of antibodies. Nevertheless, progress has been made, and three SMIs of PPIs, specifically venetoclax, lifitegrast, and fostemsavir, have acquired approval for medical use.

A brand new research

A brand new research printed on the bioRxiv* preprint server has focussed on screening and identification of doable SMIs of this PPI for COVID-19. In a earlier research by the identical authors, methylene blue (MeBlu), a tricyclic small‐molecule dye, was discovered to be efficient for the therapy of acquired methemoglobinemia. They reported that MeBlu can successfully inhibit SARS‐CoV‐2–ACE2 PPI and the entry of SARS‐CoV‐2‐spike‐bearing pseudoviruses into ACE2 expressing cells.

Within the new research, researchers revealed that MeBlu might successfully inhibit SARS-CoV-2 variants, such because the D614G and Delta pressure. Earlier research have revealed that D614G mutation is accountable for enhanced transmissibility by growing the affinity between S and ACE2.

Key findings

The current research indicated the flexibility of MeBlu to suppress the interplay between SARS‐CoV‐2 S protein and hACE2. Importantly, researchers reported that this dye can inhibit the SARS-CoV-2 Delta pressure, which has been categorized as a variant of concern (VOC). This research strengthened the potential of the MeBlu dye compound as an economical therapeutic antiviral therapy for SARS-CoV-2 an infection.

Earlier research revealed that within the presence of sunshine, MeBlu has a broad‐spectrum virucidal exercise that has been used since 1991 to inactivate viruses in blood merchandise earlier than transfusions. A number of research have additionally proven that MeBlu is efficient in opposition to SARS‐CoV‐2 and influenza virus, even at low micromolar concentrations and with out UV‐activation. These research advised a number of mechanisms of motion related to the antiviral exercise of MeBlu that embrace enhanced genomic RNA degradation within the presence of sunshine. The length of sunshine publicity additionally influences the extent of genomic RNA degradation. 

A number of research utilizing Vero E6 cells have proven that MeBlu interacts at each entry and put up‐entry levels of SARS‐CoV‐2 an infection. Scientists have additionally recognized MeBlu in a number of drug repurposing excessive throughput screening (HTS) assays, which have been carried out to establish doable medicine with anti‐SARS‐CoV‐2 exercise.

Importantly, researchers decided the focus of MeBlu to be 5.0 mM for its medical antiviral applicability, which falls below the vary of oral administration. Earlier research have additionally indicated that oral bioavailability and the terminal elimination half‐lifetime of MeBlu additionally fall throughout the ranges for once-daily oral administration.  

Though MeBlu is taken into account to be secure, it may well trigger dose‐dependent toxicity. A person subjected to greater than 500 mg of MeBlu may expertise nausea, vomiting, hemolysis, and different undesired uncomfortable side effects. Moreover, a contradicting impact of MeBlu has been noticed in an individual below serotonin reuptake inhibitors and in people with hereditary glucose‐6‐phosphate dehydrogenase deficiency.

At current, three trials are being carried out in Mexico, Switzerland, and Iran to evaluate the effectiveness of MeBlu for COVID‐19 therapy. Curiously, a preliminary report confirmed that oral administration of MeBlu has considerably diminished hospital keep and decreased mortality of COVID-19 sufferers. Moreover, scientists revealed a big efficacy with no aspect impact in intravenous MeBlu (1 mg/kg) therapy used as rescue remedy for reasonable to extreme hypoxic COVID‐19 sufferers with acute respiratory misery syndrome (ARDS). Curiously, researchers noticed that nebulized MeBlu therapy in sufferers with COVID‐19 infections confirmed outstanding advantages, together with a lower in inflammatory markers and oxygen necessities. 


The authors of this research revealed that MeBlu is a low‐micromolar inhibitor of the PPI that suppresses interplay between the S protein of SARS-CoV-2 and its cognate receptor ACE2. The dye was additionally discovered to be efficient in opposition to the Delta variant and to suppress virus replication in Vero E6 cells. Scientists imagine that MeBlu might be used as a cheap drug for the therapy of SARS-CoV-2 an infection.

*Necessary discover

bioRxiv publishes preliminary scientific studies that aren’t peer-reviewed and, subsequently, shouldn’t be considered conclusive, information medical observe/health-related conduct, or handled as established data.

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