Research Progress of the Antiviral Bioactivities of Natural Flavonoids

Lin Wang · Junke Song · Ailin Liu · Bin Xiao · Sha Li · Zhang Wen · Yang Lu · Guanhua Du

Natural Products and Bioprospecting, 2020, 10, 271–283

doi : 10.1007/s13659-020-00257-x

Abstract

Flavonoids are now considered as an indispensable component in a variety of nutraceutical and pharmaceutical applications. Most recent researches have focused on the health aspects of flavonoids for humans. Especially, different flavonoids have been investigated for their potential antiviral activities, and several natural flavonoids exhibited significant antiviral properties both in vitro and in vivo. This review provides a survey of the literature regarding the evidence for antiviral bioactivities of natural flavonoids, highlights the cellular and molecular mechanisms of natural flavonoids on viruses, and presents the details of most reported flavonoids. Meanwhile, future perspectives on therapeutic applications of flavonoids against viral infections were discussed.

Keywords : Antiviral bioactivities · Natural flavonoids · Cellular and molecular mechanisms · Therapeutic applications

 

1 Introduction

Flavonoids comprise one of the largest groups of secondary metabolites found in biologically active plants, including vegetables, fruits, seeds, nuts, wine, and tea. Flavonoids are low molecular weight compounds with a simple 15 carbon backbone, and there are more than 9000 varieties of flavonoids that have been structurally identified. The natural flavonoids are an important source of medicines [1].

Typically, flavonoids are divided into flavones, flavonols, flavanones, flavanonols, flavanes, flavanols, chalcones, anthocyanidins, aurones, isoflavones, biflavones [2]. The carbon atoms in flavonoid molecules are assembled in two benzene rings, commonly denoted as A and B, which are connected by an oxygen-containing pyrene ring. A common part of the chemical structure of all flavonoids is the carbon skeleton based on the flavan system (C6–C3–C6) (Fig. 1). Aurone is a type of flavonoid with a heterocyclic ring containing a benzofuran element while biflavonoids are dimers of flavonoid moieties linked by a C–C or C–O–C bond. Condensation of A and B ring leads to the formation of chalcone, which undergoes cyclization involving isomerase and forms flavanone, the initial compound for the synthesis of other group flavonoids [3]. Although the various classes of flavonoids possess different structures, all flavonoids appear multi-bioactivities and complex roles in the system of biology.

Most flavonoids, except for the subclass of catechins, are present in plants bound to sugars as β-glycosides. The common sources of natural flavones were the vegetables such as Chamomile tea (Matricaria chamomilla), leaves of parsley (Petroselinum crispum), celery (Apium graveolens) and spinach (Spinacia oleracea), roots of plants, propolis, and honey and so on [4]. Even the flavonoids could obtain from various of food and vegetables, the molecules with different structures are of different bioactivities. Since the first report in 1938, flavonoids were described as a broad spectrum of biological activities such as anti-inflammation, antioxidant, antibacterial, antiviral, anticancer, and neuroprotection [5]. In this review, we made a literature retrieval for the anti-virus activity of flavonoids. The antiviral activity of flavones was studied and reported from the 1990s, when apigenin showed synergistic effects to acyclovir on herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) in cell culture. Recently, flavones are reported the inhibitory activity on viruses, including A/FM1/1/47(H1N1), H3N2, H5N1 (strain A/Thailand/Kan-1/04), HBV, HCV, HIV, dengue virus (DENV-2), Sendai virus, Zika virus, Coxsackie virus (CVB3) and Japanese encephalitis virus (JEV) [6]. Especially, the latest study showed flavones efficiently inhibited SARS-CoV [7]. However, numerous positive findings have been reported on the in vitro efficacy of flavonoids, but less promising results have been obtained for most compounds in in vivo studies due to poor bioavailability of flavonoids. The low solubility of flavonoid aglycones in water, coupled with its short residence time in the intestine as well as its lower absorption, save humans from the acute toxic effects via the consumption of flavonoids, except for a rare occurrence of allergy [8]. Therefore, the efforts in enhancing the bioavailability of flavonoids upon intake by humans are vitally necessary in order to develop these natural compounds into potential antiviral drugs.

Generally speaking, the absorption of the dietary flavonoids liberated from the food will depend on their physicochemical properties such as molecular size, configuration, lipophilicity, solubility, and pKa [9]. In addition, flavonoid protein interactions are involved in flavonoid bioavailability. Depending upon structure, the flavonoid can be absorbed from the small intestine or has to go to the colon, where they are metabolized via microbial catabolism, conjugation in liver and enterocytes. Due to these conjugation reactions, no free flavonoid aglycones can be found in plasma or urine, except for catechins [10]. The sugar moiety of flavonoid glycosides is an important determinant of their bioavailability [11].

2 Overview of the Research on the Antiviral Effects of Flavonoids

Based on the literature published in the international journals, up to May 2020, more than 1000 researches on the anti-virus activities in vivo and in vitro and 100s of natural flavonoids have been tested in different viruses. But, only about decades were focused, such as coumarin, luteolin, and so on (Fig. 2).

Generally, all the bioactivities found in the flavonoids could be summarized to some main aspects. Flavonoids, including genistein, catechins, and so on, have been shown to reduce the infectivity of a variety of viruses affecting humans and animals, including adenovirus, HSV, HIV, porcine reproductive and respiratory syndrome virus, and rotavirus [12]. Current results about the mechanisms of action underlying their antiviral properties suggest a combination of effects on both the virus and the host cell. Flavonoids have been reported to affect virus adsorption, entry, replication, viral protein translation, the formation of certain virus envelope glycoprotein complexes, and virus release [13–16]. They also affect a variety of host cell signaling processes, including induction of gene transcription factors and secretion of cytokines [17, 18]. Although enormous promising results were from in vitro experiments, a few in vivo results can partly confirm their in vivo efficacy. Flavonoids possess antiviral properties against a wide range of viruses under both in vitro and in vivo conditions (Table 1).

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