Drug shows potential to fight inflammation associated with Covid

Experiments with animals and human cells carried out at the University of São Paulo (USP) suggest that niclosamide, an already widely used vermifuge, would have antiviral action and could inhibit the exacerbated inflammatory response that often leads to death in patients with the severe form of Covid. -19.

Further studies are still needed to find out whether the effects, described in an article in the journal Science Advances, are confirmed in humans. And, according to the authors, for this it will be necessary to develop a new formulation of the drug, since the one currently available in pharmacies — for oral administration — would have no effect on the lungs.

“The commercially available niclosamide-containing tablet is not absorbed in the stomach, so it works for intestinal worms. But it won’t work for Covid-19 if taken orally.

To get around this problem, it will be necessary to develop a new drug formulation that reaches the lungs directly”, explains Dario Zamboni, professor at the Ribeirão Preto School of Medicine (FMRP-USP) and a member of the Inflammatory Disease Research Center (CRID) —a Center for Research, Innovation and Dissemination (Cepid) of Fapesp The investigation was also funded through two other projects (19/11342-6 and 20/04964-8).

According to Zamboni, the anti-inflammatory effects of niclosamide observed in the study are due to the blocking of an immune mechanism known as an inflammasome — a protein complex present inside the defense cells. When this cellular machinery is activated, pro-inflammatory molecules known as cytokines are produced to warn the immune system of the need to send more defense cells to the site of infection.

In a previous work, the FMRP-USP group had shown that, in patients with the severe form of Covid-19, the inflammasome is usually more activated than normal and remains that way even when the virus has already been eliminated from the body, causing the systemic and exaggerated inflammatory response (cytokine storm) harmful to the lung and other organs (read more here).

The researcher points out, however, that niclosamide should not be used as a prophylactic treatment, that is, to supposedly prevent exacerbated inflammation. “A little inflammation is important to fight infections by pathogenic microorganisms. The problem is when the inflammatory response is exaggerated, as in some more severe cases of Covid-19. Therefore, we are not suggesting the prophylactic use of the drug, as it may not contribute and even impair the recovery of patients who do not have severe cases of Covid-19.”

cell cleaning

On the market for many years, niclosamide has been indicated mainly to treat tapeworm infections (the popular tapeworm). Recently, the drug has aroused the interest of researchers for its antiviral effect. In the study published now in Science Advances, the USP group describes that niclosamide promotes a cellular cleaning process known as autophagy. When autophagy is induced, the cell destroys old organelles, recycles cellular components, and deactivates the inflammasome. This process also inhibits the replication of Sars-CoV-2 within the cell.

The research began with the screening of 2,560 compounds, many of them already used in humans, in an attempt to identify a substance capable of modulating the action of the inflammasome. For this, in vitro tests were carried out in which human defense cells were infected with the Legionella bacterium, known to activate this inflammatory protein complex.

After selecting the three most promising drugs, the researchers carried out tests on mice infected with Sars-CoV-2 and on white blood cells present in the blood of patients with Covid-19. In the experiments, they also verified the action of these drugs on macrophages and monocytes, cells that act on the front lines of the immune system and where, in Covid-19, inflammasome activation mainly occurs. Niclosamide showed the best result.

To verify the antiviral action, the researchers carried out experiments with monocytes infected in vitro with Sars-CoV-2.

“The antiviral activity of niclosamide was already known, so the drug is already in phase 1 clinical trials in patients with Covid-19. Our discovery – that the drug induces autophagy and inhibits inflammasome – may provide essential information for understanding of the immunomodulatory effect of this highly promising drug”, he evaluates.

Effect on other diseases

The discovery of a drug capable of inhibiting the inflammasome opens up prospects for new therapies for a number of other inflammatory-based conditions. That’s because, in addition to Covid-19, the inflammasome is also involved in autoimmune, neurodegenerative diseases, flu, some types of cancer and infectious diseases, including zika, chikungunya and Mayaro fever.

“In this way, although the study was carried out for Covid-19, niclosamide would also work, in theory, to inhibit the inflammasome in these other diseases. These results open possibilities for a series of new research”, he says.

The article “Identification of Immunomodulatory Drugs that Inhibit Multiple Inflammasomes and Impair Sars-CoV-2 Infection” can be read here.