Hesperidin Demonstrates Potential As A Plant Based Phenolic Antiviral Agent Against SARS-CoV-2 Main Protease

Resear\"\"chers from Department of Phytochemistry and Plant Systematics, Pharmaceutical Division, National Research Centre, Cairo, Egypt have in a new study found that the phenolic phytochemical Hesperidin demonstrates potential as an antiviral agent against the SARS-CoV-2 main protease and also mediates antiviral zinc oxide nanoparticles.

The research involved the silico comparison study of ten phenolic antiviral agents against SARS-CoV-2, as well as isolation of the most active metabolite from natural sources. Zinc oxide nanoparticles (ZnO NPs) were also then prepared using these metabolite as a reducing agent. All tested compounds showed predicted anti-SARS-CoV-2 activity.

However Hesperidin showed the highest docking score, leading the study team to isolate it from the orange peels and to confirm its structure by conventional spectroscopic analysis.  Interestingly synthesis of hesperidin zinc oxide nanoparticles was characterized by UV, IR, XRD and TEM.

 Also in vitro antiviral activity of hesperidin and ZnO NPs was evaluated against hepatitis A virus as an example of RNA viruses. H

The study team however found that although ZnO NPs and hesperidin showed antiviral activity against HAV, ZnO NPs showed a higher activity than hesperidin.

The study findings found that hesperidin and its mediated ZnO nanoparticles are willing antiviral agents against the SARS-CoV-2 coronavirus.

The study findings were published in the peer reviewed journal: Colloids and Surfaces B: Biointerfaces. https://www.sciencedirect.com/science/article/pii/S0927776521001685

The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus has the medical fraternity and the pharmaceutical industry frantically searching for effective antivirals. Although SARS-CoV-2 vaccine development moves forward at an unparalleled speed, advances in new therapeutics to treat COVID-19 are unsuccessful, and only a handful of repurposed therapeutics have been approved to treat the disease.

Although most of the mild to moderate SARS-CoV-2 infections are easily recovered, with severe COVID-19, the associated risks of hospitalization and mortality are high.

To date, SARS-CoV-2 is responsible for 174.5 million infections and over 3.76 million deaths the world over. Yet, curative solutions for COVID-19 disease are unavailable.

In order to address this issue, the Egyptian and Saudi Arabian study team led by Professor Dr Mohamed El Raey of the National Research Centre, Dokki, Cairo, Egypt, looked at phytopharmaceuticals and nutraceuticals as potential antivirals against SARS-CoV-2.

The study team studied several phytopharmaceutical phenolic compounds from commonly used medicinal plants and foods (nutraceuticals) in silico to explore the antiviral activity against SARS-CoV-2 main protease (Mpro).

Next the team experimentally tested the highest docking score compound with its mediated ZnO nanoparticles against the Hepatitis A virus (HAV), an RNA virus similar to SARS−COV-2.

The findings showed that all the tested compounds exhibited the predicted anti-SARS-CoV-2 activity.

The study team tabulated the binding mode, type of interaction, and binding energy of phenolic compounds under study.

The team also isolated an active metabolite ie Hesperidin from natural sources (such as orange peels) and used it as a reducing agent to prepare zinc oxide nanoparticles (ZnO NPs) in a green synthesis process.

Utilizing spectroscopic analysis, the study team confirmed the structure of hesperidin and characterized the hesperidin zinc oxide nanoparticles.

With hepatitis A virus (HAV) as an example of RNA viruses, they evaluated the in vitro antiviral activity of hesperidin and ZnO NPs. While both showed antiviral activity against HAV, they observed higher activity in ZnO NPs.

In the last few years, the discovery of antiviral medicines extracted from natural sources, either directly or indirectly, has increased significantly. The study team screened natural compound libraries by computational screening methods as molecular dockingThis method saves considerable time and money in the drug development process.

The team then selected the ten nutraceuticals phenolic compounds according to their availability and spreading as pharmaceutical dosage forms derived from natural edible food sources.

These nutraceuticals in this study were diosmin, rutin, naringenin, quercetin 3-O-glucuronide, myricetin 3-O-xylosyl-(1→2)-rhamnoside, myricetin, epigallocatechin-3-O-gallate, corilagin, and lyoniresinol.

Zinc (Zn) is an essential element in our body and physiology, with antiviral properties. Zn-containing compounds are recently reported to display anti-SARS-CoV-2 activity. Because ZnO NPs are more easily absorbed by the body than zinc, ZnO NPs were used in this study.

The phytochemical Hesperidin from citrus peels has been reported in previous studies to have antiviral activity.

Based on in silico screening, the study team predicted hesperidin to target the interaction site between SARS-CoV-2 Spike and ACE2 receptors – thus blocking the entry of the virus into the human lung cells. Therefore, hesperidin could be a promising prophylactic drug against COVID-19, the researchers noted.

This research elucidated the binding mode of the phenolic compounds to the crystal structure of COVID-19 main protease 6lu7 using molecular docking.

Interpreting the inhibition mechanism of the main protease COVID-19, the docking study also confirmed that hesperidin forms electrostatic interactions and pi-stacking interaction.

The study team discussed the binding and the inhibition activity of the phenolic compounds in the published preprint. The team reported that hesperidin showed the highest docking score.

The important highlights of this study were:

  • In silicodocking comparison study of antiviral nutraceutical phenolics against SARS-CoV-2 main protease.
  • Isolation and identification of hesperidin from orange peels.
  • Green synthesis of ZnO NPs using hesperidin.
  • Evaluation of hesperidin and ZnO NPs against hepatitis A virus.

The process of rediscovering and repurposing existing compounds from natural sources and evaluating these compounds against the SARS-CoV-2 could be an effective strategy to accelerate the drug discovery process.

The study team presented hesperidin and its mediated ZnO nanoparticles as possible antiviral agents. Thus, further experimental investigation of these compounds against SARS-CoV-2 as a potential treatment is recommended.

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