Computational study of pomegranate peel extract polyphenols as potential inhibitors of SARS-CoV-2 virus internalization

Abstract

The search for effective coronavirus disease (COVID-19) therapy has attracted a great deal of scientific interest due to its unprecedented health care system overload worldwide. We have carried out a study to investigate the in silico effects of the most abundant pomegranate peel extract constituents on the multi-step process of serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) internalization in the host cells. Binding affinities and interactions of ellagic acid, gallic acid, punicalagin and punicalin were studied on four selected protein targets with a significant and confirmed role in the process of the entry of virus into a host cell. The protein targets used in this study were: SARS-CoV-2 spike glycoprotein, angiotensin-converting enzyme 2, furin and transmembrane serine protease 2. The results showed that the constituents of pomegranate peel extracts, namely punicalagin and punicalin had very promising potential for significant interactions with the selected protein targets and were therefore deemed good candidates for further in vitro and in vivo evaluation.

Pomegranate peel extract polyphenols attenuate the SARS-CoV-2 S-glycoprotein binding ability to ACE2 Receptor: In silico and in vitro studies

“…Umifenovir is a well known synthetic broad-spectrum antiviral agent, which mechanism of action is based on prevention of the S-glycoprotein contact with the host cell receptor [29] . Punicalin with the highest binding affinity was the most promising candidate for the inhibition of S-glycoprotein-ACE2 interaction, which is in accordance with the results from recent in silico studies [13] , [30] . This complex of S-glycoprotein and punicalin is also stabilized with interactions of Pro 463 and Glu 516, which are previously marked as key interactions of ashwagandhanolide, a bioactive herbal ligand with the hydrogen bond interactions at the active site of SARS-CoV-2 S-glycoprotein [31] .…”

“…Considering that for certain pomegranate polyphenols, such as punicalin, the ability to inhibit influenza virus through interaction with its surface glycoproteins has already been shown, it was logical to assume that similar mechanism for SARS-CoV-2 inhibition is involved [12] . In our previous computational study, we confirmed that the most abundant polyphenols from pomegranate peel extract (PoPEx) formed stable interactions with S-glycoprotein residues from the predicted active site and therefore proved to be potential candidates to prevent the process of virus internalization into the host cells [13] . Some other studies have shown that certain hydrolysable tannins including punicalagin and punicalin had the potential not only to intervene in SARS-CoV-2 entry process, but also to interfere with the viral replication process inside the host cell [14] , [15] , [16] .…”

Pomegranate Peel Extract as an Inhibitor of SARS-CoV-2 Spike Binding to Human ACE2 Receptor (in vitro): A Promising Source of Novel Antiviral Drugs

“…In the present study, we found that the polyphenols contained in an ethanolic extract derived from pomegranate peels inhibited the interaction between Spike and ACE2, and reduced the activity of the viral 3CL protease in vitro , potentially suggesting the use of the extract as an adjuvant in the treatment against SARS-CoV-2 infections. Data showed that the most effective polyphenols in the extract were PC and EA possibly through a chemical interaction of the hydroxyl and galloyl groups in their molecules with amino acid residues at the active sites of the protein targets of SARS-CoV-2 or human cells, as supported by other studies based on molecular docking analysis (Surucic et al, 2021 ). The inhibitory effect on Spike/ACE2 binding was confirmed by experiments with a pseudotyped lentivirus, whose entry into the human cells was dependent on Spike protein.…”

Antiviral Effects of Pomegranate Peel Extracts on Human Norovirus in Food Models and Simulated Gastrointestinal Fluids

“…Potential inhibitors and immune-boosting functional food ingredients are crucial in preventing pandemic diseases such as Covid-19 [ 23 ]. A recent study showed that polyphenols from PPE inhibit and reduce viral protein activity and can be used to treat SARS-CoV-2 infections [ 24 ]. Since one of the symptoms of Covid-19 infection and HuNoV is diarrhea, using PPE could be a significant preventive treatment.…”