Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions

Abstract

In the pursuit of suitable and effective solutions to SARS-CoV-2 infection, we investigated the efficacy of several phenolic compounds in controlling key cellular mechanisms involved in its infectivity. The way the SARS-CoV-2 virus infects the cell is a complex process and comprises four main stages: attachment to the cognate receptor, cellular entry, replication and cellular egress. Since, this is a multi-part process, it creates many opportunities to develop effective interventions. Targeting binding of the virus to the host receptor in order to prevent its entry has been of particular interest. Here, we provide experimental evidence that, among 56 tested polyphenols, including plant extracts, brazilin, theaflavin-3,3’-digallate, and curcumin displayed the highest binding with the receptor-binding domain of spike protein, inhibiting viral attachment to the human angiotensin-converting enzyme 2 receptor, and thus cellular entry of pseudo-typed SARS-CoV-2 virions. Both, theaflavin-3,3’-digallate at 25 μg/ml and curcumin above 10 μg/ml concentration, showed binding with the angiotensin-converting enzyme 2 receptor reducing at the same time its activity in both cell-free and cell-based assays. Our study also demonstrates that brazilin and theaflavin-3,3’-digallate, and to a still greater extent, curcumin, decrease the activity of transmembrane serine protease 2 both in cell-free and cell-based assays. Similar pattern was observed with cathepsin L, although only theaflavin-3,3’-digallate showed a modest diminution of cathepsin L expression at protein level. Finally, each of these three compounds moderately increased endosomal/lysosomal pH. In conclusion, this study demonstrates pleiotropic anti-SARS-CoV-2 efficacy of specific polyphenols and their prospects for further scientific and clinical investigations.

Polyphenols: From Theory to Practice

“…If in vitro assays may lead to improper understanding of mechanism of action of polyphenols, in some cases, because the poor bioavailability of these natural products, also they could propose unplausible biological effects. It is the current state of the research on antiviral activity of polyphenols [83], with particular regard on the activity against SARS-CoV-2. To date, more than 110 papers have been published in only 2 years to describe the potential of polyphenols as agents against the new SARS-CoV-2 in vitro and a similar number of computational studies were performed; again, resveratrol, curcumin, EGCG and quercetin emerged as promising molecules.…”

Inhibition of the SARS-CoV-2 3CLpro main protease by plant polyphenols

“…However, the vast majority of studies that have investigated the interactions of polyphenols with SARS-CoV-2 proteins have only applied in-silico methods. Nevertheless, selected polyphenols have been shown to interact with different SARS-CoV-2 proteins in-vitro , including the receptor binding domain of the Spike glycoprotein ( Goc et al, 2021 ), and the 3CL pro which are among the most studied SARS-CoV-2 drug targets.…”

Molecular Mechanisms of Possible Action of Phenolic Compounds in COVID-19 Protection and Prevention

“…None of these three molecules affected the expression of hACE2 in human alveolar epithelial A549 cells. Inhibition of host proteases, TMPRSS2 and cathepsin L, was also observed, which is essential for cleavage of S protein and subsequent viral fusion to host cell membrane [96].…”