Drugs potentially capable of reducing mortality associated with COVID-19 identified

Inflammation is a defense of the body to fight against pathogens. However, when it occurs in an excessive and generalized way, it can aggravate the pathology and even cause death.

One of the ways this over-response occurs is known as a cytokine storm, an inflammatory process caused by these proteins, cytokines, signaling the immune system to activate.

"This response is what frequently kills those affected by SARS-CoV-2, and not so much the virus itself," explains Óscar Fernández-Capetillo, head of the Genomic Instability Group of the National Cancer Research Center (CNIO).

This hierarchical list of compounds would help reduce mortality in the most seriously ill patients with COVID-19

Fernández-Capetillo is one of the authors of the Article which is published today in Scientific Reports, a hierarchical list of compounds that would help reduce mortality in the most seriously ill patients with COVID-19, based on their power to stop this chemical storm. Its use could also be extended to other pathologies in which this inflammatory phenomenon also occurs.

As the experts clarify, the objective is not to propose specific clinical indications, but to contribute in the context of the current health crisis, providing ideas on drugs that would combat mortality in patients infected with the coronavirus, and that other groups could experimentally verify their efficacy in preclinical models of the disease.

In search of an antidote

Although respiratory failure associated with Acute Respiratory Distress Syndrome (ARDS) is the leading cause of mortality associated with COVID-19, evidence shows that case-fatality in a subgroup of severely ill patients is due to the late onset of an inflammatory cytokine storm, the article notes .

In order to find 'antidotes', the researchers used scientific studies that emerged from April 2020 and that identified changes in gene expression of lung cells in patients with SARS-CoV-2 who died from a thunderstorm. cytokines.

These data were used to interrogate the database Connectivity Mapdeveloped by the Broad Institutefrom MIT and Harvard University, which contains the changes that induce nearly 5,000 compounds in gene expression, including all drugs approved for clinical use.

Oncological treatments against COVID-19

The goal was to identify compounds that induce changes in gene expression opposite to those seen in COVID-19 patients. "The study predicts that glucocorticoids such as dexamethasone should be effective in combating mortality in patients, a comforting fact since these drugs are, among others, those used in hospitals to combat death from COVID-19," Fernandez-Capetillo points out.

To their surprise, the researchers identified—and later validated in vitro— that MEK protein inhibitors, commonly used in cancer treatments, had a strong anti-inflammatory effect.

"I think that this anti-inflammatory property of MEK inhibitors is quite unknown, and it is important to publicize it because it increases our arsenal of compounds that mitigate the cytokine storm", comments the researcher.

MEK protein inhibitors, commonly used in cancer treatments, have a strong anti-inflammatory effect

This hyperreaction of the organism can occur in several contexts, such as after a transplant, chemotherapy, and other infectious diseases, including COVID-19.

Only for the most severe cases

The researchers emphasize that, in any case, any therapy based on anti-inflammatory drugs —including glucocorticoids— should be restricted to the late and severe phases of COVID-19, since the use of anti-inflammatory therapies in early phases of the disease would limit the effectiveness of the immune system in its fight against infection.

The analyzes of the study published in Scientific Reports indicate that female hormones would combat the incidence of the cytokine storm, which would explain why men suffer a greater severity of the pathology. "Also, it would be consistent with the fact that the difference in mortality by sex is mitigated at advanced ages, when menopause already appears and estrogen levels decrease," explains Fernández-Capetillo.

The work, which offers a panoramic view of known and available drugs with the potential to combat the cytokine storm, was put in a public repository at the end of 2020 "with the aim of making knowledge available to as many people as possible" , while reviewing the article.

Female hormones would combat the incidence of the cytokine storm, which would explain why men suffer a greater severity of the pathology

"Practically all the molecules that we predicted at the time have been validated in later work by other groups, which is gratifying," says the researcher.

Finally, and in addition to predicting compounds that could combat the cytokine storm, the work also reports substances that could aggravate it. This list includes drugs that either activate the immune system or potentiate inflammation, and reveals possible interactions with some cancer treatments or with the insulin signaling pathway, which would increase the severity of the cytokine storm in COVID-19 patients. 19.

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