Study of antiviral nutraceutical phenolics against SARS-CoV-2 main protease

The COVID-19 (coronavirus disease 2019) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 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.

Most of the mild to moderate SARS-CoV-2 infections are easily recovered; however, with severe COVID-19, the associated risks of hospitalization and mortality are high. To date, SARS-CoV-2 is responsible for 137  million infections and over 2.95 million deaths the world over. Yet, curative solutions for COVID-19 disease are unavailable.

To address this issue, a team of researchers led by Professor Mohamed El Raey of the National Research Centre, Dokki, Cairo, Egypt, looked at phytopharmaceuticals and nutraceuticals as potential antivirals against SARS-CoV-2.

In this work, the researchers 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). Then, the researchers 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.

Publishing their recent work in the journal, Colloids and Surfaces B: Biointerfaces, the researchers showed that all the tested compounds exhibited the predicted anti-SARS-CoV-2 activity.

In the research paper, the researchers have tabulated the binding mode, type of interaction, and binding energy of phenolic compounds under study.

They also isolated an active metabolite – 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.

“Natural products are untapped sources for compounds that can be used in the prevention and treatment of different diseases.”

Using spectroscopic analysis, the researchers 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 decade, the discovery of antiviral medicines extracted from natural sources, either directly or indirectly, has increased significantly. The researchers in this study screened natural compound libraries by computational screening methods as molecular docking. This method saves considerable time and money in the drug development process.

The researchers 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.

Also, 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 are used in this study.

Hesperidin from citrus peels has been reported in previous studies to have antiviral activity. Here, based on in silico screening, the researchers 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 study elucidated the binding mode of the phenolic compounds to the crystal structure of Covid-19 main protease 6lu7 using molecular docking. While interpreting the inhibition mechanism of the main protease COVID-19, the docking study confirmed that hesperidin forms electrostatic interactions and pi-stacking interaction. The researchers discussed the binding and the inhibition activity of the phenolic compounds in the paper. They reported that hesperidin showed the highest docking score.

The highlights of this study are: 1) in silico docking comparison study of antiviral nutraceutical phenolics against SARS-CoV-2 main protease, 2)isolation and identification of hesperidin from orange peels, 3) green synthesis of ZnO NPs using hesperidin, and 4) evaluation of hesperidin and ZnO NPs against hepatitis A virus.

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.

In this study, the researchers 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.

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.