Polyphenols vs. Coronaviruses: How Far Has Research Moved Forward?

Abstract

The epidemic, caused by SARS-CoV-2 at the beginning of 2020, led us to a serious change in our lifestyle that for about three months has confined us to our homes, far from our laboratory routine. In this period, the belief that the work of a researcher should never stop has been the driving force in writing the present paper. It aims at reviewing the recent scientific knowledge about in vitro experimental data that focused on the antiviral role of phenols and polyphenols against different species of coronaviruses (CoVs), pointing up the viral targets potentially involved. In the current literature scenario, the papain-like and the 3-chymotrypsin-like proteases seem to be the most deeply investigated and a number of isolated natural (poly)phenols has been screened for their efficacy.

Keywords: 3-chymotrypsin-like protease; antiviral activity; coronavirus; herbal extracts; papain-like protease; polyphenols.

Figure 1

Number of documents per year dealing with the word “coronavirus.” In the red box documents by subject area published in 2020 (source Scopus Database, accessed on 1 July 2020).

Figure 2

Taxonomy of coronaviruses (CoVs) affecting humans.

Figure 3

CoVs’ structural proteins.

Figure 4

Viral replication scheme.

Figure 5

Phenols and polyphenols, which are shown to exert antiviral activity, originate from shikimate and acetate pathways. Most of them are the result of an intertwining of the two pathways. The shikimate pathway begins through the condensation of phosphoenolpiruvic acid (PEP) and erythrose-4-phosphate (E4P) by 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase to produce 3-deoxy-D-arabino-heptulosonic 7-phosphate acid, which is promptly converted by the 3-dehydroquinate synthase in 3-dehydroquinic acid. This latter undergoes dehydration by the 3-dehydroquinate dehydratase to provide 3-dehydroshikimic acid, which is converted in shikimic acid through the action of shikimate dehydrogenase (SDH). Many intermediates of the shikimate pathway can be branch points leading to different C₆C₀, C₆C₁, C₆C₂ and C₆C₃ aromatic compounds, which can further act as precursors of more complex metabolites. This is the case of gallic acid, from which condensed and hydrolysable tannins are formed. The conversion of shikimic acid in chorismic acid by another PEP moiety condensation favored aromatic amino acids biosynthesis. Indeed, chorismic acid is converted by chorismite mutase via a pericyclic Claisen rearrangement, in prephenic acid, whose conversion to L-phenylalanine and L-tyrosine may occur via two alternative pathways. L-tryptophan is biosynthetized when chorismic acid is converted to anthranilic acid by anthranilate synthase. The nonoxidative deamination of L-phenylalanine by phenylalanine ammonia-lyase (PAL) forms trans-cinnamic acid, which is the parental compound for the biosynthesis of phenylpropanoids (e.g., hydroxycinnamic acids, lignans and coumarins), aromatic polyketide (e.g., diarylheptanoids, flavonoids, stilbenes, flavolignans and isoflavonoids) and terpenoid quinones. The acetate pathway could form fatty acids by fatty acid synthase (FAS) catalysis or polyketide systems by different polyketide synthases. Poly-β-keto chain is highly reactive and could undergo intramolecular aldol or Claisen reactions supplying. Phloroglucinol derives from a polyketomethylene chain formed by three malonyl-CoA units, whereas anthraquinones are from a 16-carbon poly-β-keto chain.

Figure 6

Chemical structures and related plant sources of some promising natural compounds with PLpro inhibiting activity.

Figure 7

Chemical structures and related sources of some promising natural compounds against 3CLpro.

Figure 8

Chemical structures of polyphenols active on CoV nonstructural proteins involved in replication. In the blue box compounds able to inhibit nsp 14 (N7-MTase) are reported. In the three flavonols the chemical feature likely responsible for the activity (ring B) is highlighted. In the red box compounds acting vs. nsp 13 are reported. They share with myricetin the same mode of action, which is different from quercetin (see text for details).

Figure 9

A summarizing picture of the different compounds able to interfere with the viral infection, acting vs. four main targets, highlighted in different colors.