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Celastrol exhibits potential anti-SARS-CoV-2 activity

 


On March 11, 2020, the World Health Organization (WHO) announced that Coronavirus Disease 2019 (COVID-19) will be a pandemic. The disease is highly infectious and is caused by a new positive chain β-coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Globally, the virus has had devastating effects on public health and the economy. Scientists believe that only the discovery of effective vaccines and potential drugs can contain an ongoing pandemic.

Although vaccination programs have been launched in many countries, more vaccination strategies are needed due to the high demand and certain restrictions on mass production of vaccines.

Many more new vaccines are in clinical trials, but vaccine development is complex. Some detailed evaluation is required at each stage of vaccine production before it can be approved by regulators such as the US Food and Drug Administration (FDA). These assessments focus on many factors, including side effects, efficacy levels, dosing procedures, storage requirements, the appearance of SARS-CoV-2 mutants, and induction of long-term immunological memory. The above complexity increases the need for drug diversion to deal with the reuse of existing drugs with well-established side effects.This is an investment strategy that can reduce SARS-CoV-2 Viral load It is effectively used to treat COVID-19.

While studying the immunopathology of COVID-19, researchers discovered that it causes associated non-hemostatic inflammation. Cytokine storm.. Cytokine storms occur via several mediators, such as interleukin-6 (IL-6). Interleukin-6 is also considered a biomarker of disease severity. For drug discovery, computational biology and bioinformatics are the two most powerful tools for diverting approved drugs or drugs in clinical trials. In the current scenario, some of the strategies adopted to discover drugs for COVID-19 disease are:

  • Identification of a host or virus target, such as a receptor binding domain (RBD) present in the spike Glycoprotein Angiotensin converting enzyme II (ACE2) promotes the interaction between the virus and the host cell.
  • Identification of proteins or enzymes from viral biosynthesis mechanisms. For example, main protease (Mpro) or RNA-dependent RNA polymerase (RdRp).
  • Reversal of host gene expression associated with SARS-CoV-2 infection.

New research published in bioRxiv* Preprint servers focus on in silico predictions for reusing existing drug compounds. It may have the ability to reverse SARS-CoV-2 gene expression induced in host cells. These agents target proteins or enzymes essential to the SARS-CoV-2 life cycle or inhibit the expression of interleukin 6 (IL-6), which functions as both pro-inflammatory cytokines and anti-inflammatory myokines. There is likely to be. Thereby, these drugs can be used as potential drugs for the treatment of COVID-19 disease.

In this study, researchers identified 39 reusable drug candidates that are promising effective treatments for COVID-19. These drug compounds may be able to restore the genetic characteristics of SARS-CoV-2 infected cells and have a high affinity for viral targets (proteins or enzymes). Celastrol has been found to be one of the most suitable agents capable of suppressing the release of virion particles and the secretion of IL-6 by SARS-CoV-2 infected cells. Currently, both computational and studies demonstrate the findings of previous studies that claimed the efficacy of Celastrol as a potent drug in the treatment of COVID-19.

Docking analysis of molecular interactions between viral targets and drugs that can reverse the SARS-CoV-2 gene signature.  (A) Typical structures of SARS-CoV-2 molecular targets (Mpro, RBD, and RdRp). Atoms are represented by lines, secondary structures are represented as cartoons, spirals are highlighted in magenta, and sheets are highlighted in yellow. The colored line circles (red-Mpro; RDB1-blue; RBD2-orange; RdRp-green) indicate the binding sites used for docking associated with known inhibition of key regions from each viral target19. , 24–27.  (B) Box plots show some structural conformations of 39 drugs and each viral site (Mpro = 83;

Docking analysis of molecular interactions between viral targets and drugs that can reverse the SARS-CoV-2 gene signature. (A) Typical structures of SARS-CoV-2 molecular targets (Mpro, RBD, and RdRp). Atoms are represented by lines, secondary structures are represented as cartoons, spirals are highlighted in magenta, and sheets are highlighted in yellow. The colored line circles (red-Mpro; RDB1-blue; RBD2-orange; RdRp-green) indicate the binding sites used for docking associated with known inhibition of key regions from each viral target19. , 24–27. (B) Box plots show the affinity obtained from several structural conformations of 39 drugs and docking analysis between each viral site (Mpro = 83; RDB1 = 10; RBD2 = 10; and RdRp = 10 structures). It shows the sex binding energy (kcal.mol-1). .. Reverser drugs were classified based on descending Q-scores, which showed the potential to reverse the genetic characteristics of SARS-CoV-2 infection. The dotted line is the affinity defined for each virus target (Mpro = -7.3; RDB1 = -6.2; RBD2 = -6.7; and RdRp = -7.2 kcal.mol-1), taking into account all the drugs investigated. It shows the median value of sex binding energy.

This drug has anti-inflammatory and antiviral properties. Celastrol is a triterpene that is also effective against the inflammatory response induced by HIV-1Tat. Previous studies have shown that Celastrol blocks the production of pro-inflammatory chemokines, such as CXCL1. In addition, by activating the expression of IFN-α and inducing a downstream antiviral reaction, it is possible to suppress the replication of the serotype of dengue virus. In silico prediction has also untrained other drugs that may treat COVID-19 disease, such as CGP-60474, dasatinib, canertinib, and geldanamycin.

Previous and current studies have identified several genes whose expression changes during SARS-CoV-2 infection. The production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, etc.), chemokines (CXCL1 and CCL20), and genes associated with the NF-κB pathway is altered after infection. These changes are directly correlated with the progression and severity of COVID-19. This study further validated the discovery of in-silico in in vitro experiments. Researchers report that Celastrol can reduce the viral load of SARS-CoV-2 infected cell lines.

Detailed chemical interactions between the highest ranked drugs and the site of inhibition of the SARS-CoV-2 molecular target. A 2D targeted drug interaction diagram for the best structural construction of a viral molecular target was determined using Discovery Studio® software (version-2020). Celastrol had the most attractive median ΔGbind of affinity energies for three targets (Mpro, RBD1, and RBD2) and WZ-4-145 (RdRp) for one.  The distance between the B-ring C6 and the sulfur atom of Cys145 residue may be related to the possibility of Michael adduct formation for the highest energy pose in each Mpro structure, 0.43 to 1.33 nm. In the range, the average value was 0.63 nm.  (Black dashed line).

Detailed chemical interactions between the highest ranked drugs and the site of inhibition of the SARS-CoV-2 molecular target. A 2D targeted drug interaction diagram for the best structural construction of a viral molecular target was determined using Discovery Studio® software (version-2020). Celastrol had the most attractive median ΔGbind of affinity energies for three targets (Mpro, RBD1, and RBD2) and WZ-4-145 (RdRp) for one. The distance between the B-ring C6 and the sulfur atom of Cys145 residue may be related to the possibility of Michael adduct formation for the highest energy pose in each Mpro structure, 0.43 to 1.33 nm. In the range, the average value was 0.63 nm. (Black dashed line).

Scientists have shown that SARS-CoV-2 infection induces IL-6 production. Such outbreaks were found in both COVID-19 patients and in vitro SARS-CoV-2 infection models. Scientists report that Celastrol can down-regulate infection-induced IL-6 production, causing a reduction in SARS-CoV-2 loading. Previous studies have also shown that this candidate has many functions. For example, gene expression in PC-3 prostate cancer cells can be down-regulated, RAW264 can suppress LPS-induced IL-6 production, and mRNA can be expressed in influenza A-infected MDCK cells. In addition to these, scientists have developed an model of acute respiratory distress syndrome. They reported that Celastrol can reduce lung damage by producing IL-6 and pro-inflammatory mediators in the lung airways.

Although some studies have pointed out the effectiveness of Celastrol as a treatment, there are some limitations. One of the limitations is low solubility and low bioavailability. Cytotoxicity studies using a mouse model have shown that it is safe even at higher concentrations. However, more research is needed to assess its toxicity to humans. Celastrol is currently undergoing clinical trials for the treatment of various diseases such as neurodegenerative diseases, various types of cancer, and inflammatory conditions (rheumatoid arthritis, psoriasis, Crohn’s disease).

*Important Notices

bioRxiv Publish preliminary scientific reports that should not be considered definitive as they are not peer-reviewed, guide clinical practice / health-related behaviors, and should not be treated as established information.

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