Drugs-COVID-19: Spanish Researchers Identify 4-Phenylbutiric Acid (4-PBA) As Drug Candidate To Treat Inflammatory Issues In COVID-19
: Spanish researchers from the Department of Cell Biology at the University of Malaga (UMA) and the Andalusian Centre for Nanomedicine and Biotechnology (BIONAND) have identified 4-Phenylbutiric acid or 4-PBA as a possible drug candidate to treat the various inflammatory and immune issues resulting from the SARS-CoV-2 coronavirus infection that causes COVID-19 disease.
The study findings are published in the peer-reviewed journal: Cytokine & Growth Factor Reviews. https://www.sciencedirect.com/science/article/pii/S1359610120301258?via%3Dihub
4-Phenylbutiric acid (4-PBA) has been used since the 80 s to treat urea cycle disorders. It effectively reduces the effects of misfolded and aggregated proteins but more importantly, it reduces the inflammatory response in many conditions related with pulmonary and cardiovascular disease, liver failure, pancreatitis, diabetic encephalopathy, osteoarthritis, osteolysis among others. Also 4-PBA is already an approved drug.
The study team from Spain made progress in finding new rapid implementation therapies to combat the COVID-19 pandemic, identifying a new drug that could prevent or mitigate the consequences derived from SARS-CoV-2 infection.
The study team led by the researchers of the UMA Dr Iván Durán and Dr Fabiana Csukasi will in the next few months continue to study how 4-Phenylbutiric acid (4-PBA) treatment modulates the inflammatory response produced in severe cases of COVID-19.
The research project has been financed by the COVID-19 Fund of the Government of Andalusia, with an initial endowment of EUR 90,000 and the possibility of a three-year renewal.
The unique inflammatory process identified in severe cases of coronavirus causes an uncontrolled and excessive release of certain cytokines ie molecules in charge of organizing the body's defenses which could even trigger vascular hyperpermeability and multi-organ failure.
The study team from UMA proposes finding ways starting from the cells that release these cytokines to control the overall inflammatory condition.
Dr Iván Duránm lead researcher and Professor from the department of cell biology at University of Malaga told Thailand Medical News, “It is known that when cells are stressed by infection, they invoke 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."
The study team say that repurposing the 4-PBA anti-stress drug, approved for clinical use against other diseases and, hence, easy to apply clinically, could modulate such cellular stress, which is also present in pathologies like diabetes, aging or carcinogenesis, which, in turn, are classified as risk factors for COVID-19.
Dr Duran added, "Our preliminary results conducted on animal models have demonstrated that 4-PBA fully curbs mortality caused by respiratory failure derived from cellular stress.”
He also explained that in the initial studies the team conducted, they f
ound that the endoplasmic reticulum resident protein "BiP" (Binding Immunoglobulin Protein) was a stress blood marker ie as indicator of cellular stress situations, and that it could likely to be used to measure such cellular stress in affected patients.
Hence using this biomarker, as Dr Durán points out, BiP levels, apart from determining the efficacy of 4-PBA treatment, could serve as early indicators of COVID-19 risk groups, establishing a correlation between high levels and the inflammatory severity after the viral infection.
Celular stress modulates inflamatory signals related to COVID19. A. Infected patients without previous cellular stress related conditions usually respond to SARS-CoV-2 infections through controled cytokine response as asymptomatic or mild COVID19 disease. B. Patients with previous conditions related to celular stress diseases such as diabetes, cardiovascular or certain pro-inflammatory pathologies predispose to a hiperinflammatory process that leads to cytokine storm and severe COVID19 disease. Credit: University of Malaga
He further added, "There are individuals 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 ie we can detect susceptibility before infection occurs and know how to treat it in due time.”
A huge study team has been assembled to further the research to confirm the effectiveness and security of 4-PBA treatment through in vitro and in vivo studies of cytokine storm and SARS-CoV-2 infection.
This study team besides Dr Csukasi and Dr Durán additional work at the Biomedical Research Institute of Malaga (IBIMA)m involves the collaborative efforts of Dr José María Reguera and Dr Javier Sánchez from the Regional University Hospital of Malaga and Virgen de la Victoria University Hospital.
Dr Deborah Krakow, researcher of the University of California, Los Angeles, as well as the researchers Dr Manuel Mari-Beffa, Dr Gustavo Rico, Dr José Miguel Tejeiro, Dr Rick Visser and Dr David Baglliet from the Bioengineering and Tissue Regeneration Laboratory (LABRET), directed by Professor José Becerra, who are also members of the Cellular Therapy Network, CIBER-BBN and CIBER-NED.
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