4-PBA could prevent cytokine storm in severe COVID-19

Scientists explore whether the anti-stress drug, 4-Phenylbutiric acid (4-PBA), could prevent cytokine storms causing respiratory failure in COVID-19 patients.

coronavirus particles surrounded by red blood cells

Researchers suggest 4-Phenylbutiric acid (4-PBA), a drug which attenuates cellular endoplasmic reticulum stress, could prevent or mitigate the consequences of cytokine storm in severe COVID-19.

In the next year the team, from the Department of Cell Biology of the University of Malaga (UMA) and the Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), both Spain, will study how 4-PBA modulates the inflammatory response produced by severe COVID-19. Their first study has been published in Cytokine and Growth Factors Review.

In severe SARS-CoV-2 infections – SARS-CoV-2 is the virus which causes COVID-19 – inflammation induces the release of an excessive amount of cytokines. This ‘cytokine storm’ can trigger a range of adverse and potentially fatal effects, including vascular hyperpermeability and multi-organ failure, as well as Acute Respiratory Distress Syndrome (ARDS). Therefore, a huge effort has gone into establishing mechanisms to prevent cytokine storms.

At UMA, the researchers propose controlling cytokine storm through the very cells that are infected by SARS-CoV-2. Study co-leader and researcher at the UMA, Iván Durán, explained: “When cells are stressed by infection, they call the cytokines and the more stressed they are, the more persistent they become, provoking this uncontrolled inflammation. Hence, one possible treatment for COVID-19 is to reduce cellular stress.”

He suggests that repurposing 4-PBA, an anti- stress drug, approved for clinical use against other diseases (and therefore easy to apply clinically), could modulate cellular stress. Adding that cellular stress is also present in several pathologies like diabetes, aging or carcinogenesis, which are risk factors for COVID-19.

Identifying risk groups

“Our preliminary results conducted on animal models have demonstrated that 4-PBA fully curbs mortality caused by respiratory failure derived from cellular stress,” said Durán, who further explained that these first studies also identified the protein Binding Immunoglobulin Protein (BiP) – a marker found in the blood – as an indicator of cellular stress, which could be explored and measured in affected patients.

He suggested that BiP levels could be used to both determine the efficacy of 4-PBA treatment and identify COVID-19 risk groups.

“There are people already suffering from diseases that cause cellular stress and when they become infected with coronavirus, they are more likely to fall ill or die. Therefore, if we know that the patient suffers from cellular stress, we can kill two birds with one stone: we can detect susceptibility before infection occurs and know how to treat it in due time,” Durán concluded.