BREAKING! COVID-19 Drugs: Study Shows That N-Acetylcysteine or NAC Is An Effective Antiviral And Immunomodulatory Drug Against All SARS-CoV-2 Variants!
: A new study by Italian researchers have found that NAC or N-Acetylcysteine is not only an effective antiviral agent against all of the SARS-CoV-2 variants but also has immunomodulatory properties that can help prevent disease severity.
Thailand Medical News had as early as April 2020 written about the benefits of taking NAC or N-Acetylcysteine supplements to help prevent COVID-19 disease severity.
At present, as a result of the rapid evolution and increased mutation rate of the SARS-CoV-2 virus, the emergence of so many SARS-CoV-2 variants and sub-lineages has led to the situation that we are no longer facing surges lead by one or two SARS-CoV-2 variants as in the past but rather we are facing a continuous onslaught of a wide cluster of variants and sub-lineages that are constantly being displaced by newer variants and sub-lineages with better viral fitness.
Many of these new variants are not only more immune evasive and are rendering all known monoclonal therapeutics as infective, but they are also evading protection provided by the current vaccines and most of the approved US FDA antivirals are in reality not the least effective against them.
As most of these new variants and sub-lineages are now resistant to vaccines and drugs targeting viral elements the study team hypothesized that targeting host dependency factors such as cell proteins required for viral replication would help avoid resistance.
However, whether different SARS-CoV-2 variants induce conserved cell responses and exploit the same core host factors is still unclear.
The study team compared three variants of concern and observed that the host transcriptional response was conserved, differing only in kinetics and magnitude.
By utilizing CRISPR screening, the study team identified the host genes required for infection by each variant: most of the identified genes were shared by multiple variants, both in lung and colon cells.
The study team validated their hits with small molecules and repurposed FDA-approved drugs. All drugs were highly effective against all tested variants, including delta and omicron, new variants that emerged during the study.
Mechanistically, the study team identified ROS production as a pivotal step in early virus propagation.
Interestingly, antioxidant drugs, such as N-acetyl cysteine (NAC), were effective against all variants both in human lung cells, and in a humanized mouse model.
The study findings strongly support the immediate use of available antioxidant drugs, such as NAC, as a general and effective anti-COVID-19 approach.
The study findings were published on a preprint server but is currently being peer reviewed.
According to the study team, as obligate intracellular parasites, viruses tightly rely on their host cells: they have evolved to exploit cells for their own purposes by hijacking cellular pathways and to evade the innate immune response by modulating host factors and signaling pathways.
The SARS-CoV-2 virus which is an RNA virus, was found to RNA viruses rely more heavily on the host cell.
At present most therapeutic interventions against COVID-19 however are solely targeted against viral proteins, promoting the emergence of variants escaping vaccine-induced immunity or resistance to antiviral drugs.
The key objective of this COVID-19 Drugs
study was understanding whether targeting host proteins might be an effective and safe strategy against COVID-19, as host genes are not under selective pressure.
The study team started by exploring whether different SARS-CoV-2 variants elicit similar cellular responses upon infection.
The three major SARS-CoV-2 variants of concern that the study team used in their study exhibited varying replication patterns in human lung cells, with the original wildtype Wuhan variant producing fewer transcripts and higher titers of infective viral progenies when compared to D614G and Alpha.
The study team ascribed this diverse behavior to the reported mutations in the Spike protein, which would result in modulated virus-receptor binding affinity and consequent viral entry.
Both D614G and Alpha variants harbor mutations and deletions in the open-reading frame 8 (ORF8), which inhibits the cell interferon-mediated immune response, possibly explaining the enhanced RNA transcription of these two variants.
Interestingly however, analyses of the host transcriptome revealed a qualitatively highly similar transcriptional response among the 3 variants, with differences in just kinetics and magnitude, overall indicating that different variants induce similar cellular responses upon infection.
The study team then applied a genome-wide CRISPR knockout approach to gather deep insights into the host genes exploited by different variants, asking whether some genes are specifically required for the infection of one or more variants.
Such a kind of approach has been successfully developed to identify the host factors exploited by other viruses and by SARS-CoV-2 itself.
However, the analysis of available data of previous SARS-CoV-2 CRISPR knockout screenings did not allow the study team to draw conclusions about whether different variants exploit different host factors, because different studies used different combinations of variants, cell lines and CRISPR libraries.
As such, the study team performed a genetic screening directly comparing the 3 variants under identical conditions and looked for the host factors that are conservatively exploited by all of them and, vice versa, those that are required by specific variants.
According to the study team, the rationale of their approach is twofold:
- i) if a host factor is shared by all variants, it more likely belongs to a “core” of host factors essential for the viral infection and
- ii) shared host factors are more likely to be required by new variants of SARS-CoV-2 that will emerge in the future and thus might serve as a better and omni-comprehensive therapeutic target.
By utilizing conditions ensuring high coverage and stringency, the study team retrieved 525 genes, the knockout of which allowed cell survival upon infection; 93.3% were shared by at least 2 out of 3 variants.
Very satisfactorily, all candidates selected by the CRISPR knock-out screening were also confirmed by transient silencing of host genes.
Significantly, the study team failed to identify a single candidate acting specifically on only 1 variant.
The study team concluded that the host factors exploited during infection are highly shared among different SARS-CoV-2 variants.
The study team believed that the knowledge acquired in this study will be instrumental to develop host directed therapies to control SARS-CoV-2 infection.
As a result of their reliance on host cell components, these have reduced likelihood to develop resistance.
In order to further assess the soundness of their hits and provide ready-to-trial drugs able to stop viral infection/replication of present and forthcoming variants, the study team screened a set of U.S. FDA-approved drugs against unrelated diseases, and chemical compounds reported to hamper the main common viral host factor candidates (SLC7A11, RIPK4 and MASTL).
These five tested compounds displayed potent antiviral activity not only against the three tested SARS-CoV-2 variants, but also against the Delta variant, which appeared in late 2021 and has been so far the last variants that caused worrisome rates of hospitalization of infected patients of all ages, regardless of their vaccination status, and was associated with high mortality rate.
The successful antiviral activity of the tested compounds further reinforces the strength of the study team’s screening, and points out that the selected hits are crucial host factors for both the early and latest variants.
The mechanism of action of one of the most promising tested compounds, IKE, was investigated to further validate its target, SLC7A11, against SARS-CoV-2.
The central role of SLC7A11 in the maintenance of ROS intracellular homeostasis and its relevance as host factor in different human viral infections have been previously reported.
The compound IKE was proposed to neutralize SLC7A11-mediated cystine uptake and ROS modulation.
Although increased intracellular ROS levels trigger innate immunity-mediated antiviral mechanisms, counterintuitively, viral infections stimulate ROS production and viruses thrive in increased ROS levels.
The study team’s gene expression analysis suggests reduced oxidative phosphorylation within infected cells, possibly as an attempt the cells make to lower ROS and create a hostile environment for viral replication.
The study findings showed that SARS-CoV-2 stimulates ROS production during the early infective stages in human bronchial cells.
Importantly, reduction of ROS levels, by extended IKE administration, glutathione or NAC treatment, impaired SARS-CoV-2 viral cycle.
It was noted that the effect of NAC treatment in COVID-19-affected patients has been investigated in several retrospective studies leading to suggestive, albeit not definitive, results.
The mechanistic explanation was that the antioxidant, anti-inflammatory and anti-thrombotic effects of NAC counteracted viral pneumonia; however, results from ongoing randomized controlled trials are required to draw accurate conclusions.
Importantly, the study findings also show a direct antiviral effect of NAC on lung epithelial cells, in addition to its immunomodulatory effects.
The study team hence strongly encourages and supports NAC, and other antioxidant drugs, use as a safe and accessible anti-SARS-CoV-2 therapy, against current and future variants.
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, keep on logging to Thailand Medical News.
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