COVID-19: Nafamostat and Pegasys (IFNα) can effectively suppress infection

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Countries with greater resources are opening up for a more normal life. But COVID-19 and the SARS-CoV-2 virus are still a significant threat in large parts of the world.

The lack of medicines that are effective, easy to distribute and easy to obtain are a significant part of the problem. However, recent research on a new drug combination is showing promising results.

The combined use of nafamostat and Pegasys (IFNα) meets all availability and efficacy requirements.

“This combination effectively suppresses the infection,” says Professor Denis Kainov at the Norwegian University of Science and Technology’s (NTNU) Department of Clinical and Molecular Medicine (IKOM). The experiments were performed in cell cultures and hamsters. This does not necessarily mean that the combination works in humans, but it is a good sign.

Nafamostat is already in use as a monotherapy against COVID-19 and is undergoing extensive testing in Japan, among other places.

Pegasys (IFNα) is currently used mainly to treat hepatitis C. Combining the two appears to have a positive effect.

“Both drugs attack a factor in our cells called TMPRSS2, which plays a critical role in viral replication,” says Magnar Bjørås, a professor in the Department of Clinical and Molecular Medicine.

Only low doses of the combination medicine are needed, as well.

“The low doses of the drugs in combination may have several clinical advantages. including fewer adverse events and improved outcomes for patients,” says Aleksandr Ianevski, a doctoral research fellow affiliated with the Department of Clinical and Molecular Medicine.

In other words, the combination medicine can both save lives and make life easier for patients. Nafamostat is relatively inexpensive.

The downside of Pegasys (IFNα) is its higher cost.

Officially, 4.55 million people have died from COVID-19 worldwide. But unreported numbers are most likely very large in parts of the world where the cause of death is not always accurately recorded.


The afamostat mesylate is an existing Japanese drug used for acute pancreatitis and disseminated intravascular coagulation (DIC), effectively inhibits MERS-CoV S protein-mediated membrane fusion by targeting TMPRSS2 priming activity. 

Nafamostat, a structural analogue of camostat, is a repurposed drug which was originally approved as a short-acting anticoagulant and is also used for the treatment of pancreatitis [14]. It is currently in clinical trials for treatment of COVID-19 (NCT04623021, NCT04473053, NCT04390594, and NCT04483960).

IFNαs and its pegylated forms are also repurposed drugs which have been shown to be effective for COVID-19 patients [15,16]. Because previous studies have demonstrated the high therapeutic potential of both nafamostat and IFNα as separate antiviral treatments, we hypothesized that IFNα–nafamostat combinational therapy may represent an even more practical therapeutic option against SARS-CoV-2 infection.


Discussion

Our findings clearly indicate that nafamostat mesylate, the most effective TMPRSS2 inhibitor so far reported, potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and viral infection in vitro in a cell-type-dependent manner. Furthermore, EC50 values for Calu-3 cells with the pretreatment were around 10 nM, similar to our previous findings with MERS-CoV infection [8]. This extremely high sensitivity to nafamostat mesylate may be because the TMPRSS2-dependent entry pathway predominates in lung epithelium-derived Calu-3 cells [8,14,18].

Camostat mesylate-mediated inhibition of TMPRSS2 significantly reduced SARS-CoV-2 infection of primary human airway epithelial cells [14], suggesting that the TMPRSS2-dependent entry pathway is likely dominant in lung epithelial cells. This idea is also supported by the single-cell RNA-seq data analysis demonstrating high expression of TMPRSS2 in alveolar type 1 and 2 cells [5,6].

Given that blood concentrations of nafamostat mesylate were maintained at 30–240 nM when it was administered intravenously through continuous infusion according to the standard protocol for DIC patients [19], nafamostat mesylate could be used to treat COVID-19. In contrast, significantly higher doses of nafamostat mesylate are required to block SARS-CoV-2 infection of monkey kidney VeroE6/TMPRSS2 cells as reported previously [20], which is probably due to the significant contribution of the TMPRSS2-independent, cathepsin-dependent endosome pathway [17].

Since a pharmacokinetics study using rats revealed the maximum concentration of intact nafamostat mesylate in the lung after infusion to be about 60-fold higher in comparison with the maximum blood concentration [21], such an accumulation may partially suppress SARS-CoV-2 infection of VeroE6/TMPRSS2-like cells, in which the endosome entry pathway predominates [17]. Therefore, identification and characterization of cells that play a key role in virus spread and disease development are required.

Hoffmann et al. have recently reported that nafamostat mesylate blocks activation of SARS-CoV-2 [22]. However here we clearly demonstrated that nafamostat mesylate blocked the membrane fusion step of the virus entry and its activity to block SARS-CoV-2 infection was cell type dependent. These findings are crucial for developing therapeutic strategies. It has been reported recently that abnormal coagulation with elevated concentrations of D-dimer, characteristic of DIC with enhanced fibrinolysis, may influence the prognosis of COVID-19 [23,24].

Furthermore, in a murine asthma model, nafamostat mesylate attenuates respiratory inflammation by blocking activation of NF-κB, a critical transcription factor for inflammatory cytokine production [25]. Therefore, nafamostat mesylate is expected to have multiple therapeutic effects. Since nafamostat mesylate has been prescribed in Japan for many years and adequate clinical data regarding safety have accumulated, we suggest that it should be evaluated in COVID-19 patients by itself or in combination with other antiviral drugs that target separate processes needed for virus production.

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354595/


More information: Aleksandr Ianevski et al, Nafamostat–Interferon-α Combination Suppresses SARS-CoV-2 Infection In Vitro and In Vivo by Cooperatively Targeting Host TMPRSS2, Viruses (2021). DOI: 10.3390/v13091768

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