Inflammation is the body’s defense mechanism to fight pathogens. However, when generalized and excessive, it can aggravate the pathology and even lead to death. One of the ways this overresponse occurs is called a cytokine storm, an inflammatory process produced by these proteins, cytokines, which send a signal that triggers the immune system. “This answer is often the cause of death in those affected by SARS-CoV-2 rather than the virus itself,” says Óscar Fernández-Capetillo, head of the genomic instability group at the National Cancer Research Center (CNIO). He is one of the authors of the article published today in Scientific reports, which lays out a hierarchical list of compounds that could potentially help reduce mortality in the most severe COVID patients, based on their power to stop this chemical storm. Their use could also be extended to other pathologies in which this inflammatory phenomenon also occurs.
Although respiratory failure associated with acute respiratory distress syndrome (ARDS) is the leading cause of death from COVID-19, accumulating evidence shows that lethality in a subgroup of severe patients occurs due to the late onset of inflammatory disease. cytokine stormpaper notes.
In order to find ‘antidotes’, the researchers used the nascent scientific studies that emerged from April 2020 that identified changes in gene expression in lung cells from deceased SARS-CoV-2 patients. following a cytokine storm. These data were then used to probe the Connectivity Map database, developed by the Broad Institute, part of MIT and Harvard University, which contains gene expression changes induced by approximately 5,000 compounds, including all drugs approved for clinical use.
Cancer treatments as possible antidotes to SARS-CoV-2
The goal was to identify potential “antidotes”, compounds that induce changes in gene expression opposite to those seen in patients with COVID-19.
The study predicted that glucocorticoids such as dexamethasone should be effective in combating mortality in patients with COVID-19, which was heartening because, in fact, these drugs, along with others, are already being used in hospitals to combat death from COVID-19. “
Óscar Fernández-Capetillo, Head of the Genomic Instability Group, National Cancer Research Center (CNIO)
To their surprise, the researchers identified – then validated in vitro– that MEK protein inhibitors, commonly used in cancer treatments, had a strong anti-inflammatory effect. “I think this anti-inflammatory property of MEK inhibitors is quite unknown, and more needs to be known as it augments our arsenal of anti-inflammatory compounds that could help mitigate cytokine storms that can occur in multiple settings, such than after transplants, chemotherapy and other infectious diseases, including COVID-19,” explains the biochemist.
The researchers emphasize that, in any case, any anti-inflammatory therapy – including glucocorticoids – should be limited to the late and severe phases of COVID-19, since the use of anti-inflammatory therapies in the early stages of the disease would limit the effectiveness of the immune system in its fight against infection.
Another important aspect is that all the analyzes conducted in the study converged to indicate that female hormones could help fight the cytokine storm, which could explain why men tend to contract more severe forms of COVID. “Furthermore, this would be consistent with the fact that the difference in mortality by sex is attenuated at older ages, when menopause occurs and estrogen levels decline,” says Fernández-Capetillo.
The book, which offers an overview of known and available drugs with the potential to fight the cytokine storm, was placed in a public repository at the end of 2020, “with the aim of making knowledge accessible to as many people as possible”. , while the document was under review . “Virtually all of the molecules we predicted at the time have been validated in subsequent work by other groups, which is gratifying,” says the researcher.
Finally, in addition to predicting drugs that could combat the cytokine storm, the article also reports on compounds that could potentially worsen this pathology. As you might expect, this list includes drugs that activate the immune system or increase inflammation. But, in addition, it reveals possible interactions with certain oncological treatments or with the insulin signaling pathway.
With the help of the CNIO’s Bioinformatics Unit, the study “was largely the result of the perseverance and work of Laura Sánchez-Burgos, a student who, during the harsh confinement in Madrid, resorted to to computer approximations so that, even if she was at home, she could be useful and investigate relevant issues associated with SARS-CoV-2, ”says Fernández-Capetillo.
In any case, as the authors specify in the text of the article itself, the purpose of this study is not to propose specific clinical indications for one or other of these agents, but simply to to make a contribution, in the context of the current health crisis, by providing ideas on drugs that could help combat mortality in patients with COVID-19, and that other groups could test experimentally in preclinical models of the disease.
Center National de Investigaciones Oncológicas (CNIO)
Sanchez-Burgos, L., et al. (2022) In silico analysis identifies drugs potentially modulating cytokine storm triggered by SARS-CoV-2 infection. Scientific reports. doi.org/10.1038/s41598-022-05597-x.