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Review
. 2020 Sep 1:328:109211.
doi: 10.1016/j.cbi.2020.109211. Epub 2020 Jul 28.

Roles of flavonoids against coronavirus infection

Maria Russo  1 , Stefania Moccia  1 , Carmela Spagnuolo  1 , Idolo Tedesco  1 , Gian Luigi Russo  2
Affiliations
Review

Roles of flavonoids against coronavirus infection

Maria Russo et al. Chem Biol Interact. .

Abstract

In terms of public health, the 21st century has been characterized by coronavirus pandemics: in 2002-03 the virus SARS-CoV caused SARS; in 2012 MERS-CoV emerged and in 2019 a new human betacoronavirus strain, called SARS-CoV-2, caused the unprecedented COVID-19 outbreak. During the course of the current epidemic, medical challenges to save lives and scientific research aimed to reveal the genetic evolution and the biochemistry of the vital cycle of the new pathogen could lead to new preventive and therapeutic strategies against SARS-CoV-2. Up to now, there is no cure for COVID-19 and waiting for an efficacious vaccine, the development of "savage" protocols, based on "old" anti-inflammatory and anti-viral drugs represents a valid and alternative therapeutic approach. As an alternative or additional therapeutic/preventive option, different in silico and in vitro studies demonstrated that small natural molecules, belonging to polyphenol family, can interfere with various stages of coronavirus entry and replication cycle. Here, we reviewed the capacity of well-known (e.g. quercetin, baicalin, luteolin, hesperetin, gallocatechin gallate, epigallocatechin gallate) and uncommon (e.g. scutellarein, amentoflavone, papyriflavonol A) flavonoids, secondary metabolites widely present in plant tissues with antioxidant and anti-microbial functions, to inhibit key proteins involved in coronavirus infective cycle, such as PLpro, 3CLpro, NTPase/helicase. Due to their pleiotropic activities and lack of systemic toxicity, flavonoids and their derivative may represent target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections.

Keywords: Coronavirus; Flavonoids; MERS-CoV; SARS-CoV; SARS-CoV-2.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Basic skeleton (C6–C3–C6) of flavonoids and representative examples of compounds able to counteract coronavirus infection.
Fig. 2
Fig. 2
A. Coronaviruses form enveloped and spherical particles of 100–160 nm in diameter. They contain a positive-sense, single-stranded RNA (ssRNA) genome and nucleocapside proteins (N) that bind to RNA genome forming the nucleocapsid. The trimeric Spike glycoprotein (S) localizes on the surface of virus envelope and is essential for virus entry into the host cells. It recognizes the host receptor protein ACE2 on cell membrane after cleavage and activation by two host serine-proteases: TMPRSS2 and FURIN. Membrane or matrix protein (M) and small envelope protein (E) are both essential for the assembly and release of virions. B. SARS-CoV-2 genome, genes and proteins. There are 10 open reading frames (ORFs). The first ORF (67% of the genome) encodes not structural proteins (NSP), while the remaining ORFs give rise to accessory and structural proteins. ORF1a/b translates two polyproteins: pp1a and pp1b for the presence of a frameshift between ORF1a and ORF1b. These polyproteins are processed by a main protease known as 3C-like-protease (3CLpro) and one or two papain–like proteases (PLpro) into 16 NSPs. NSPs produce replicase complex essential for viral replication: NSP12 encodes RNA dependent RNA Polimerase (RdPd) and NSP13 encodes Helicase. ORFs 2–10 encode viral structural proteins: Spike (S), Envelope (E), Membrane (M), Nucleocapsid (N) and other auxiliary proteins. In particular, Spike protein comprises two regions: S1 with the receptor-binding domain (RBD) essential for the recognition of host receptor and S2, essential for membrane fusion and entry. Between S1 and S2 subunits there is the polybasic sequence recognized by host endo-proteases Furin. The activation site of S protein, is recognized by serine protease TMPRSS2 in region S2′ of S2 domain.
Fig. 3
Fig. 3
Graphical representation of computer docking screening indicating the interaction of flavonoids and the binding pocket of SARS-CoV 3CLpro.
Fig. 4
Fig. 4
A. Predicted interaction of kaempferol with the catalytic site of SARS-CoV 3CLpro by hydrogen bond formation. B. Hydrogen bond and hydrophobic interactions between quercetin-3-β-galactoside and the active site of SARS-CoV 3CLpro.
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