Could drugs derived from microalgae be effective against COVID-19?
Drugs effective against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) normally work by reducing the rate at which the virus replicates or by reducing the damaging inflammation caused by the disease.
To study: Bioprospecting of microalgal metabolites against cytokine storm syndrome during COVID-19. Image Credit: Chokniti Khongchum / Shutterstock.com
Remdesivir, a drug that has shown promising results in treating patients during outbreaks of Middle East Respiratory Syndrome (MERS), 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, thus preventing the production of new viral RNA and viral replication. Hydroxychloroquine was supposed to work on the same principle; however, other evidence has shown worrying side effects.
Acetaminophen and paracetamol both work through the other mechanism. The high fever triggered by SARS-CoV-2 infection is caused by the elevation of pyrogenic cytokines such as interleukins, which signal receptors such as prostaglandin E2 (PCE2). Acetaminophen reduces the production of PGE2, which in turn reduces fever, leading to less death among endothelial cells surrounding the lungs. Other drugs, such as tocilizumab and Anankira, block interleukin receptors in order to achieve the same result.
Researchers at the University of Malaysia Terengganu studied the ability of certain microalgal metabolites to prevent cytokine storm syndrome during coronavirus disease 2019 (COVID-19). To this end, researchers are focusing on molecules that could mimic the effects of these drugs, with the goal of using them alongside existing generic drugs. The cytokine storm normally occurs due to 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 shown its ability to block 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 of viral cells. However, the compromise of ACE-2 can also lead to higher levels of angiotensin II (Ang-II) in the blood, thus resulting in aberrant RAS signaling, amplified cytokines in the bloodstream and, therefore, increased inflammation.
ACE converts Ang-I into the active form, Ang-II. This unique peptide could help reduce inflammation by lowering the level of Ang-II in the blood by blocking ACE. Application of the peptide to cultured cells showed reduced levels of adhesion molecules and a pathway by which oxidative stress could be reduced.
Activated B-cell nuclear factor kappa-light-chain-enhancer (NF-kB) and mitogen-activated protein kinase (MAPK) pathways both play key roles in inflammation. Specifically, the NF-kB pathway stimulates the Janus kinase / signal transducer and activates the transcription pathway (JAK / STAT3), resulting in the transcription of several immunomodulatory and immunostimulatory genes. NF-kB also governs many other inflammatory responses.
Researchers have 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 has revealed that when infection with SARS-CoV-2 leads to the activation of IkB kinase (IKK) via pattern recognition receptors (PRRs), pathogen-associated molecular models (PAMPs) and myeloid differentiation factor 88 (MyD88), IKK then catalyzes the phosphorylation of IkB, releasing NF-kB. This can then activate the target NF-kB genes, activating more pro-inflammatory cytokines and other molecules that lead to extensive inflammation.
The aforementioned peptides and carotenoids, as well as a molecule called violaxanthin, have shown their ability to reduce the translocation of NF-kB p65 / 50 dimers in the nucleus, thereby 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 NF-kB pathways. These eicosanoids are also involved in the cyclooxygenase (COX) and lipooxygenase (LO) pathways. Metabolites of several microalgae have been identified and exhibit the same capacity as Cox-2, including oxylipins, peptides, sterols, carotenoids and lipids.
Only two clinical trials have examined the capacity of metabolites of microalgae in humans. While none of these trials focused on COVID-19, the diseases they examined have known inflammatory pathologies, including activation of many of the aforementioned pathways.
One study focuses on rheumatoid arthritis, with patients receiving a supplement of Schizochytrium sp. which competes with arachidonic acid (AA) for the production of eicosanoids, thereby reducing serum levels of pro-inflammatory products of the AA pathway. The other study provided Chlorella vulgaris tablets to patients with non-alcoholic fatty liver disease, who exhibited potent anti-inflammatory drugs.
The success of these tests suggests that the metabolites of microalgae are safe for humans. Although drugs from metabolites of microalgae are probably far from development, they could be a powerful tool against future pandemics with inflammatory pathologies.
- Wan Afifudeen, CL, Teh, KY & Cha, TS (2021). Bioprospecting of microalgal metabolites against cytokine storm syndrome during COVID-19. Molecular biology reports. doi: 10.1007 / s11033-021-06903-y