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Source: COVID-19 Drugs  Nov 02, 2020  3 years, 5 months, 2 weeks, 1 day, 10 hours, 57 minutes ago

COVID-19 Drugs: 5-Amino Levulinic Acid And Ethacridine Identified As Potential SARS-CoV-2 Inhibitors In Two Separate Studies

COVID-19 Drugs: 5-Amino Levulinic Acid And Ethacridine Identified As Potential SARS-CoV-2 Inhibitors In Two Separate Studies
Source: COVID-19 Drugs  Nov 02, 2020  3 years, 5 months, 2 weeks, 1 day, 10 hours, 57 minutes ago
COVID-19 Drugs: With the current COVID-19 pandemic fast escalating and no effective drugs to date, researchers around the world are desperately trying to find suitable drug candidates to further explore their efficacy against the SARS-CoV-2 coronavirus. In two separate studies, two possible drug candidates that demonstrated to inhibit the SARS-CoV-2 virus were identified, one being 5-Amino Levulinic Acid and the other Ethacridine.


 
In the first study, Japanese researchers from Nagasaki University tested 5-amino levulinic acid in vitro in human-derived cells and found it prevents SARS-CoV-2 infection. Because it is safe and ubiquitous in plants and animals, it could be a potential therapeutic against SARS-CoV-2.
 
The study findings were published on a preprint server and have yet to be peer reviewed. https://www.biorxiv.org/content/10.1101/2020.10.28.355305v1
 
5-amino levulinic acid (5-ALA) is a natural amino acid,  found in plants, animals, bacteria, and fungi,  and it forms protoporphyrin IX (PPIX) when eight molecules come together. PPIX can generate heme when combined with a ferrous ion. 5-ALA has been used in various therapies, such as metabolic improvement, because of its ability to improve aerobic energy metabolism and cancer diagnosis and therapy using a photosensitive feature of PPIX.
Recent studies suggest 5-ALA also has antiviral properties against human pathogens like dengue virus, Zika virus, and SARS-CoV-2.
 
In order to test the potency of 5-ALA compounds against SARS-CoV-2, the study team isolated the virus from a nasal swab of a patient in Japan and propagated it in VeroE6 cells. They quantified the infection using an immunofluorescence assay they developed using an antibody for the SARS-CoV-2 N protein.
 
The team found that when VeroE6 cells were treated with 5-ALA for 72 hours before infection, it prevented SARS-CoV-2 infection. However, a shorter pretreatment time of 48 hours did not prevent the infection. The authors found that PPIX gradually accumulated inside the cells. This could be why there is a time-dependent effect on virus inhibition.
 
Interestingly adding sodium ferrous citrate (SFC) along with 5-ALA also helped prevent infection, but only with 72 hours of pretreatment. This is likely because SFC supplies iron for generating heme, along with 5-ALA.
 
The study team next tested the antiviral effect of 5-ALA in Caco-2 cells derived from the human colon, which can metabolize 5-ALA.
 
The researchers found that both 72 and 48-hour pretreatment, with and without SFC was effective in preventing treatment. This indicates 5-ALA has antiviral effects in humans.
 
The study team found that the IC50, which is the amount of a drug needed to inhibit a biological process by 50%, for inhibiting SARS-CoV-2 infection in VeroE6 cells using 5-ALA was 570 mm without SFC and 695 mm with SFC.
 
Significantly, the antiviral effect was much more powerful in human cells, with the IC50 being 39 mm and 63 mm with and without SFC, respectively. The authors also tested if the compound was toxic, and they found 5-ALA was not toxic to cells up to a concentration of 2000 mm.
 
The study team suggests a G-quadruplex (G4) structure could be a potential target of the antivirals, and compounds binding to it could inhibit SARS-CoV-2 infection. G4 is a tetrahelical structure formed by guanine-rich regions of DNA or RNA. It is also found in coronaviruses and can affect virus replication. https: