Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread all over the world, creating a devastating socio-economic impact. Even though protective vaccines are starting to be administered, an effective antiviral agent for the prevention and treatment of COVID-19 is not available yet. Moreover, since new and deadly CoVs can emerge at any time with the potential of becoming pandemics, the development of therapeutic agents against potentially deadly CoVs is a research area of much current interest. In the search for anti-coronaviral drugs, researchers soon turned their heads towards glycosylated flavonoids. Glycosyl flavonoids, widespread in the plant kingdom, have received a lot of attention due to their widely recognized antioxidant, anti-inflammatory, neuroprotective, anticarcinogenic, antidiabetic, antimicrobial, and antiviral properties together with their capacity to modulate key cellular functions. The wide range of biological activities displayed by glycosyl flavonoids, along with their low toxicity, make them ideal candidates for drug development. In this review, we examine and discuss the up-to-date developments on glycosyl flavonoids as evidence-based natural sources of antivirals against coronaviruses and their potential role in the management of COVID-19.

A multi-targeted approach to identify potential flavonoids against three targets in the SARS-CoV-2 life cycle

“…Therefore, we propose that glycosylation plays an important inhibitory role in the binding mechanism of flavonoids against these targets ( Table S1 ). Such flavonoids could mechanistically block attachment and disrupt the entry of virions into host cells while interfering with various stages of viral replication, translation, and polyprotein processing in order to prevent the release of the viruses [ 43 ].…”

“…Glycosylated flavonoids consist of a base flavan structure and sub-class specific –R groups in addition to a sugar moiety such as arabinose, rhamnose, rutinose, galactose, or glucose; which impacts their respective biological activities [ 43 ]. Moreover, flavonoids without sugar moieties are seen to be largely insoluble in water.…”

“…Thus clinical applications of such compounds have always been in doubt due to their inherent tendency to form polymers. However, glycosylation of flavonoids leads to higher bioavailability and reduces the potential for toxicity due to their newfound solubility provided by the sugar moieties [ 43 ]. The sugar moiety block and thereby protects the phenolic group from oxidative degradation.…”

“…For decades, flavonoids were lauded for their antioxidant and anti-inflammatory properties, and glycosylation complements this effect. For example, hesperidin, one of the molecules of interest in this study, has demonstrated high antioxidant activity through radical scavenging and an ability to reduce tissue damage via antioxidant cellular defenses using the ERK/Nrf2 signaling pathway [ 43 , 45 ]. The same glycosylated flavonoid downregulates inducible Nitric oxide synthase (iNOS) and Cyclooxygenase-2 (COX-2).…”

The Role of Micronutrients to Support Immunity for COVID-19 Prevention

“…A recent study demonstrated that flavonoids are able to inhibit both coronavirus protease enzymes 3C-like-protease (3CLpro) and papain-like cysteine protease (PLpro) which play an essential role in viral replication in host membranes (Russo et al 2020). On the other hand, studies have observed that flavonoids contribute to the reduction of ROS accumulation decelerates the coronavirusactivated apoptotic signalling (Diniz et al 2020;Godinho et al 2021). In silico molecular docking studies have been performed to evaluate and validate the inhibitory effect of flavonoids based on the hydrogen-bonding distance between selected amino acid residues of the catalytic site from 3CLpro and PLpro SARS-CoV-2 proteases and flavonoids (Leal et al 2021).…”