Drugs effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) normally work by either reducing the rate at which the virus multiplies or by reducing the harmful inflammation that causes the disease.
Study: Bioprospecting of microalgae metabolites against the cytokine storm syndrome during COVID-19. Image Credit: Chokniti Khongchum/Shutterstock.com
Remdesivir, a drug that has shown promising results in treating patients during Middle East Respiratory Syndrome (MERS) outbreaks, was approved for emergency use against SARS-CoV-2 in January 2020. Remdisivir blocks ribonucleic acid (RNA)-dependent RNA polymerase (RdRP) by acting as a chain terminator, preventing the production of new viral RNA and viral replication. Hydroxychloroquine was believed to work on the same principle; however, further evidence showed troubling side effects.
Acetaminophen and acetaminophen both work through the different mechanism. The high fever caused by SARS-CoV-2 infection is caused by the elevation of pyrogenic cytokines such as interleukins, which signal signal receptors such as prostaglandin E2 (PCE2). Acetaminophen reduces the production of PGE2, which in turn reduces the fever, resulting in less death among the endothelial cells that surround the lungs. Other drugs, such as tocilizumab and Anankira, block interleukin receptors in an attempt to achieve the same result.
Researchers from University Malaysia Terengganu have investigated the ability of some microalgae metabolites to prevent cytokine storm syndrome during the 2019 coronavirus disease (COVID-19). The researchers are focusing on molecules that can mimic the effects of these drugs, with the aim of using them alongside existing generic drugs. Cytokine storm normally arises as a result of the most severe inflammatory responses to viral infection and can be caused by the overactivation of many different signaling pathways.
The renin-angiotensin system (RAS) is used to maintain homeostasis of vascular functions in Isochrysis zhanjiangenesis. As part of this system, a new peptide has been shown to block the angiotensin-converting enzyme (ACE).
The receptor binding domain (RBD) on the S1 subunit of the SARS-CoV-2 spike protein binds to the ACE-2 receptor on the host cell to allow entry into the viral cell. However, compromising ACE-2 can also lead to higher levels of angiotensin II (Ang-II) in the blood, resulting in aberrant RAS signaling, enhanced cytokines in the bloodstream and, as a result, increased inflammation.
ACE converts Ang-I to the active form, Ang-II. This unique peptide can help reduce inflammation by lowering levels of Ang-II in the blood by blocking ACE. Application of the peptide to cells in culture showed reduced levels of adhesion molecules and a pathway through which oxidative stress could be reduced.
The nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) and mitogen-activated protein kinase (MAPK) pathways both play key roles in inflammation. More specifically, the NF-kB pathway stimulates the Janus kinase/signal transducer and activates the transcription (JAK/STAT3) pathway, resulting in the transcription of multiple immunomodulatory and immune stimulatory genes. NF-kB also regulates many other inflammatory responses.
The researchers identified several extracts of microalgae that act on the NF-kB pathway by downregulating related cytokines, including carotenoids, whole cell extracts and certain peptides. Previous research found that when SARS-CoV-2 infection leads to the activation of IkB kinase (IKK) via pattern recognition receptors (PRR), pathogen-associated molecular patterns (PAMPs), and myeloid differentiation factor 88 (MyD88), the activated IKK catalyzes then phosphorylation of IkB, releasing NF-kB. This can then activate NF-kB target genes, activating more pro-inflammatory cytokines and other molecules that lead to extensive inflammation.
The above-mentioned peptides and carotenoids, as well as a molecule called violaxanthin, have shown the ability to reduce translocation of NF-kB p65/50 dimers to the nucleus, preventing the next cascade of inflammatory signals.
Cyclooxygenase 2 (Cox-2) is an enzyme known to inhibit products of the arachidonic acid (AA) pathway, which produces eicosanoids that act as regulators of the NF-kB pathways. These eicosanoids are also involved in the cyclooxygenase (COX) and lipooxygenase (LO) pathways. Metabolites of several microalgae exhibiting the same potency as Cox-2 have been identified, including oxylipins, peptides, sterols, carotenoids and lipids.
Only two clinical studies have examined the potential of microalgae metabolites in humans. While none of these studies focused on COVID-19, the diseases they examined have known inflammatory pathologies, including activation of many of the above pathways.
One study focuses on rheumatoid arthritis, in which patients were given a supplement of: Schizochytrium sp. which competes with arachidonic acid (AA) during eicosanoids production, lowering blood serum levels of pro-inflammatory products of the AA pathway. The other study delivered Chlorella vulgaris tablets to patients with non-alcoholic fatty liver disease, who exhibited strong anti-inflammatory products.
The success of these trials suggests that microalgae metabolites are safe for use in humans. Although drugs of microalgae metabolites are probably still a long way from development, they could be a powerful tool against future pandemics with inflammatory pathologies.
- Wan Afifudeen, CL, Teh, KY & Cha, TS (2021). Bioprospecting of microalgae metabolites against the cytokine storm syndrome during COVID-19. Molecular Biology Reports. doi:10.1007/s11033-021-06903-y