Pain reliever shows anti-viral activity against flu — ScienceDaily – Mar 2013 – Source: American Society for Microbiology
This was a total surprise to me and, considering the specter of a new coronavirus spreading across the globe, I thought this information could be very useful.
New influenza vaccines must be developed annually, because the surface proteins they target mutate rapidly. The researchers found a much more stable, reliable target for anti-influenza activity.
The so-called ribonucleoprotein complexes are necessary for replication, and the researchers realized they could target the nucleoprotein, preventing assembly of the complexes. Because of its vital function, the nucleoprotein is highly conserved, making it a good potential target for antiviral drugs.
Naproxen protected Madin-Darby canine kidney (MDCK) cells against viral challenges with the H1N1 and H3N2 viral strains and was much more effective than other cyclooxygenase inhibitors in decreasing viral titers of MDCK cells
The nucleoprotein’s three dimensional structure, solved in 2006, provided the basis for searching for new drugs that could interfere with its action.
The researchers did a virtual screening within the Sigma-Aldrich online catalog of biochemicals. That screening identified Naproxen, better known as the over-the-counter pain reliever Aleve, and as expected, it bound to the nucleoprotein, and impeded RNA binding.
In further testing, it reduced the viral load in cells infected with H1N1 and H3N2 influenza A virus, and in mice it demonstrated a therapeutic index against influenza A that was superior to that of any other anti-inflammatory drug.
- blocks the RNA binding groove of the nucleoprotein,
- preventing formation of the ribonucleoprotein complex,
- thus taking the vital nucleoproteins out of circulation
As an already approved drug, naproxen could become a treatment against influenza relatively quickly, the researchers write. Its status as a non-steroidal anti-inflammatory drug (NSAID), which inhibits the COX-2 pathway, as well as an antiviral would boost its efficacy.
Below is the study referenced for the article above:
We report here that monomeric nucleoprotein can be inhibited by a small molecule binding in its RNA binding groove, resulting in a novel antiviral against influenza A virus.
In a mouse model of intranasal infection, naproxen treatment decreased the viral titers in mice lungs.
Naproxen binds to the targeted site in the RNA groove of NP.
In this work, we aimed at inhibiting the binding of the nucleoprotein to RNA for interference with NP function. To achieve this goal, part of the RNA binding groove was blocked by naproxen, a compound identified by virtual screening which binds within the RNA binding groove of the nucleoprotein.
Direct evidence for naproxen binding to the nucleoprotein was given by the specific signal of the naproxen-NP complex using NP attached to the surface. SPR also showed that naproxen binding to NP was competitive with RNA and disrupted the RNA-NP complex.
Antiviral and anti-inflammatory effects of naproxen in IAV-infected cells.
Cyclooxygenase type 2 (COX-2) is a component of the arachidonic acid cascade thought to be involved in inflammatory and immune responses; naproxen is a COX-2 inhibitor used to treat these symptoms in humans.
Influenza A viruses induce high levels of proinflammatory cytokines in macrophages and alveolar epithelial cells, and COX-2 plays a regulatory role in induction of H5N1-mediated proinflammatory responses in vitro.
Such cytokine deregulation was proposed to be a major contributor to the pathogenesis of H5N1 disease in humans.
the naproxen antiviral effect was significantly more potent than those of nimesulide and the other COX-2 selective inhibitors tested.
our results are potentially very significant on the basis of the following considerations.
- Naproxen constitutes a lead compound to be improved by drug design; its main binding site is known and was shown by the use of site-directed mutants. Docking experiments identified residues involved in additional binding modes of naproxen.
- Naproxen is equally effective against the viral variants H1N1 and H3N2.
- Importantly, we demonstrated that blockade of the RNA binding groove of NP in its monomeric form results in antiviral effects, presumably through sequestration of active NP monomers.
In conclusion, in the era of dual pharmacology, where the efficacy of a drug is improved by reaching more than one target while being nontoxic, naproxen has the advantage of inhibiting both COX-2 and the nucleoprotein of influenza A virus.
Naproxen is more potent than COX-2 inhibitors such as nemesulide against influenza A virus challenge.
Importantly, naproxen is a safe, potential pharmaceutical readily available for cases of resistance to antiviral and if an IAV infection pandemic emerges.
After reading this, I searched the NIH National Library of Medicine for further research and found surprisingly few studies pursuing this promising lead. However, I found a few more studies that back up these findings from 2015, 2018, and the most recent from 2019.
Naproxen is a non-steroidal anti-inflammatory drug that has previously been shown to exert antiviral activity against influenza A virus by inhibiting nucleoprotein (NP) binding to RNA. Here, we show that naproxen is a potential broad, multi-mechanistic anti-influenza virus therapeutic, as it inhibits influenza B virus replication both in vivo and in vitro.
This study reveals a crucial mechanism of broad-spectrum anti-influenza virus activity of naproxen, suggesting that the existing drug naproxen may be used as an anti-influenza drug.
The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects.
Here we designed and synthesized two new series of naproxen analogues called derivatives 2, 3, and 4 targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2
We recently identified naproxen as a drug competing with RNA binding to NP with antiinflammatory and antiviral effects against influenza A virus.
Here, we designed novel derivatives of naproxen by fragment extension for improved binding to NP.
Naproxen C0 is a potential antiviral candidate blocking influenza nucleoprotein function.