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Source: Herbs and Phytochemicals  Nov 28, 2020  2 years ago
Herbs and Phytochemicals: Molecular Docking And In Vitro Studies Show Potential Of Phycobilins Found In Algae As Antivirals For COVID-19
Herbs and Phytochemicals: Molecular Docking And In Vitro Studies Show Potential Of Phycobilins Found In Algae As Antivirals For COVID-19
Source: Herbs and Phytochemicals  Nov 28, 2020  2 years ago
Herbs and Phytochemicals: A new study involving both molecular docking and in vitro research covering a variety of phytochemicals by scientists from Tennessee State University and Meharry Medical College-Nashville has found that phycobilins found In algae can basically function as potential antivirals to inhibit SARS-CoV-2 replication.

Phycobilins are light-capturing pigments or bilins found in cyanobacteria and in the chloroplasts of red algae, glaucophytes and some cryptomonads (But not in green algae and plants). Most of their molecules consist of a chromophore which makes them coloured. They are unique among the photosynthetic pigments in that they are bonded to certain water-soluble proteins, known as phycobiliproteins. Phycobiliproteins then pass the light energy to chlorophylls for photosynthesis.
The phycobilins are especially efficient at absorbing red, orange, yellow, and green light, wavelengths that are not well absorbed by chlorophyll. Organisms growing in shallow waters tend to contain phycobilins that can capture yellow/red light, while those at greater depth often contain more of the phycobilins that can capture green light, which is relatively more abundant there.
There are four types of phycobilins: 1. Phycoerythrobilin, which is red,
2. Phycourobilin, which is orange, 3. Phycoviolobilin (also known as phycobiliviolin) found in phycoerythrocyanin and 4.Phycocyanobilin (also known as phycobiliverdin), which is blue.

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The phycobilins fluoresce at a particular wavelength, and are, therefore, often used in research as chemical tags, e.g., by binding phycobiliproteins to antibodies in a technique known as immunofluorescence.
Some past studies have shown that phycobilins have antiviral properties against certain viruses including coronaviruses. https://www.mdpi.com/1420-3049/25/18/4049
The world has witnessed three corona virus outbreaks; SARS in 2003, MERS in 2012 and ongoing pandemic COVID-19 caused by the SARS-CoV-2 coronavirus. To prevent outbreaks by novel mutant strains, the world needs broad-spectrum antiviral agents that are effective against wide array of coronaviruses.
In this research, the study team scientifically investigated potent food bioactive broad-spectrum antiviral compounds by targeting Mpro and PLpro proteases of CoVs using in silico and in vitro approaches.
The study results revealed that phycocyanobilin (PCB) showed potential inhibitor activity against both proteases. PCB had best binding affinity to Mpro and PLpro with IC50 values of 71 μm and 62 μm, respectively
Furthermore, in silico studies of Mpro and PLpro enzymes of other human and animal CoVs indicated broad spectrum inhibitor activity of the PCB. Like PCB, other phycobilins such as phycourobilin (PUB), Phycoerythrobilin (PEB) and Phycoviolobilin (PVB) showed similar binding affinity to SARS-CoV-2 Mpro and PLpro
The study findings are published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.11.21.392605v1
To date, seven viruses from the coronavirus family are known to cause infectious human disease, four of them causing seasonal common colds, and three causing potentially lethal respiratory syndromes.
The SARS-CoV-2 has already killed over 1.45 million individuals worldwide within a year, while the number of infections globally has crossed 62.1 million.
The COVID-19 disease has proved difficult to contain because of SARS-CoV-2’s high transmissibility and a lack of drugs, therapeutic agents or vaccines that can effectively fight against it.
Although many old and new drugs are being tried out, there is a severe lack of clinical data on which to base treatment decisions. To make things worse, many drug and therapeutic scams have emerged in America under the Trump administration and also in Europe involving overpriced and toxic drugs with no efficacy to treat COVID-19 such as remdesivir, tocilizumab and antibody drugs  like bamlanivimab and the casirivimab/ imdevimab antibody cocktail .
This study is an example of an approach that focuses on identifying broad-spectrum antivirals that can inhibit not just this virus but a range of others, both coronaviruses and other novel viral pathogens.
Typically broad-spectrum antivirals (BSA) fall into one of two classes: those which inhibit viral entry by engaging viruses before they enter the host cell, and those which prevent viral replication such that the virus within the host cell cannot initiate productive infection.
However it should be noted that in the case of coronaviruses, the spike (S) protein differs significantly between the other human coronaviruses and is therefore not a fit target for the first class of BSA. However, the coronavirus nonstructural proteins (nsps) that are key to viral replication are highly conserved; their structure remaining the same between different viruses of this family. https://pubmed.ncbi.nlm.nih.gov/30849247/
Numerous researchers have reported SARS-CoV-2 nsps that can be targeted by antivirals, including the main protease MPro, the papain-like protease PLPro, RNA dependent RNA polymerase RdRp, and nsps 14-16. Among these, MPro and PLPro cleave viral polyproteins into functional nsps.
The MPro protease acts on 11 or more cleavage sites of replicase 1ab. At the same time, PLPro catalyzes proteolysis of the peptide linkage at the P1 position to produce nsps 1, 2 and 3, all of which are essential for viral replication.
This research focuses on phytochemicals, which are less toxic than synthetic drugs in many cases, and have been reported to have antiviral activity against multiple viruses, including coronaviruses.
By selecting 15 phytochemicals of various chemical classes based on existing knowledge of their antiviral activity, the study team analyzed their binding interactions with the SARS-CoV-2 MPro and PLPro.
These compounds  besides phycobilins included flavonols like quercetin, flavins like riboflavins, isoflavones such as daidzein and genistein, phenolic ketones like gingerol, and phenolic alkaloids such as capsaicin, all of which are well-known plant phytochemicals.
These phytochemical interactions with the viral enzymes were examined by docking studies.
The study findings showed that the phycobilins (PCB) docked with the best score or binding energy for MPro, followed by riboflavin, cyanidin, daidzein and genistein in a close cluster. There were 12 important residues at the active site involved in these interactions with the phytochemicals.
The molecular docking studies for PLPro were carried out in dimer form, when PCB again had the best score and binding energy. This involved 11 key residues in chain A and 13 in chain B of the enzyme.
The effectiveness of these phytochemicals in silico experiments were validated by in vitro studies comparing the potential inhibitors with established inhibitory compounds for each of the enzymes. With the positive control containing the enzyme without the inhibitor, its activity was set at 100%. The six phytochemicals with the best docking score, as mentioned above, were tested against MPro. In the first phase, PCB was found to have the highest inhibitory activity, with half-maximal inhibitory concentration (IC50) less than half that of the second-place quercetin (71 versus 145 μM).
Interestingly, for PLPro, of the four compounds were earlier screened, it was found again that PCB has the most potent inhibitory activity with IC50 of 62 μM. Thus, PCB is shown to have powerful inhibitory activity against both these enzymes.
Significantly, the ability of PCB to inhibit other coronavirus MPro and PLPro enzymes was assessed using the crystal structures of these enzymes in various human and animal coronaviruses. Docking studies were carried out on both dimeric and monomeric forms. PCB was found to have a high docking affinity for MERS MPro and PLPro. However, for the latter, the dimeric form of the enzyme had a higher binding affinity relative to the monomeric enzyme.
Also when only monomers were compared, the highest docking score for PCB was with MERS-CoV, TGEV and SARS-CoV-2, indicating its potential to be a broad-spectrum inhibitor.
It was found that when other phycobilins, such as phycourobilin (PUB), Phycoerythrobilin (PEB) and Phycoviolobilin (PVB), were explored, they all bound strongly to the binding pockets of these enzymes at specific amino acids, with PCB having the highest or almost the highest docking score for both enzymes. It is notable that these compounds also have other powerful therapeutic properties such as scavenging oxidative radicals, inhibiting cancer cell division and platelet aggregation. They can also be used orally in the form of the phycobilin-protein complex, phycobiliprotein. Once ingested, it is digested in the human gut, and free PCB is released there, which may account for the therapeutic properties of this complex.
The study team calls for “in-vivo studies on inhibition of CoVs infectivity using human cells and animal models.”
The study team suggests that more phycobilin lead compounds could be developed by structure-guided development to “rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-associated diseases.”
The study team concluded, “Natural phytochemicals based drugs are gaining importance in the modern world healthcare sector, because of its less toxicity, effective health benefits and its potential use in conjunction  with preexisting therapies. Several literature studies have been reported antiviral properties of phytochemicals against CoVs and other viruses.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190535/
The team continued, “In view of the issues posed above, the identification of natural broad-spectrum antiviral agents against the CoVs is a more reasonable and attractive prospect and could provide an effective first line of defense against future emerging CoVs related diseases. Herein, we report the natural phycobilins as potent natural broad-spectrum inhibitor compounds against 3CLpro and PLpro of SARS-CoV-2 and other CoVs via in silico and in-vitro approaches.”
For more on Herbs and Phytochemicals to treat COVID-19, please keep on logging to Thailand Medical News.

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