Promising Antiviral Activities of Natural Flavonoids against SARS-CoV-2 Targets: Systematic Review

Abstract

The ongoing COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a globally leading public health concern over the past two years. Despite the development and administration of multiple vaccines, the mutation of newer strains and challenges to universal immunity has shifted the focus to the lack of efficacious drugs for therapeutic intervention for the disease. As with SARS-CoV, MERS-CoV, and other non-respiratory viruses, flavonoids present themselves as a promising therapeutic intervention given their success in silico, in vitro, in vivo, and more recently, in clinical studies. This review focuses on data from in vitro studies analyzing the effects of flavonoids on various key SARS-CoV-2 targets and presents an analysis of the structure-activity relationships for the same. From 27 primary papers, over 69 flavonoids were investigated for their activities against various SARS-CoV-2 targets, ranging from the promising 3C-like protease (3CLpro) to the less explored nucleocapsid (N) protein; the most promising were quercetin and myricetin derivatives, baicalein, baicalin, EGCG, and tannic acid. We further review promising in silico studies featuring activities of flavonoids against SARS-CoV-2 and list ongoing clinical studies involving the therapeutic potential of flavonoid-rich extracts in combination with synthetic drugs or other polyphenols and suggest prospects for the future of flavonoids against SARS-CoV-2.

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

“…Our previous work supports the position that, overall, the presence of multiple hydroxyl groups on the B-ring of flavonoids reflects positively on the binding affinities of respective flavonoids to the viral targets [ 28 ]. Hesperidin and naringin are promising compounds against all the targets examined in this study, but especially against the human TMPRSS2 protein as per the structure-function tests.…”

“…Phytochemicals are hailed for their effectiveness in combatting major public health concerns, including cancer and diabetes. Within the last two decades, coronaviruses such as those causing SARS and MERS [ 1 , [26] , [27] , [28] ].…”

“…Interestingly, Cheng et al report that both these flavanones possess the ability to downregulate the protein expression of hACE2 and hTMPRSS2 in normal (Beas 2B cell) and malignant lung (H460) cells post-transcriptionally through their interaction with heat-shock proteins (HSP70/90). Clinical trials such as NCT04452799 were launched to investigate the flavonoid's role in prophylactic and treatment mechanisms against the disease; this, along with other trials such as those reviewed by Kaul et al [ 28 ] represent what clinicians must closely follow to discover possible therapeutics for the increasing number of patients.…”

The Mechanism of a Retro-Diels–Alder Fragmentation of Luteolin: Theoretical Studies Supported by Electrospray Ionization Tandem Mass Spectrometry Results

“…Apart from being the most common yellow natural colorants, flavonoids exhibit a wide range of biological activities [ 3 , 4 , 5 , 6 ]. As such bioactive compounds, these systems are of great interest in nutrition and pharmacology, mostly due to their outstanding anti-inflammatory, antioxidant, antibacterial, antifungal, and antitumor properties [ 2 , 7 , 8 , 9 , 10 ]. Among numerous flavonoids, luteolin is a substance found in many vegetables, e.g., celery, broccoli, green pepper, sweet bell peppers, carrots, onion leaves, parsley, and thyme [ 11 ].…”

Treating Cancers Using Nature’s Medicine: Significance and Challenges

“…The marine environment, microbes (bacteria and fungi), slime molds, lichens, and unexpected sources of medicinal remedy, such as the saliva of the Gila monster (the compound found in the saliva, which turned out to be the basis for exenatide, a synthetic anti-diabetic drug), have yielded remarkable therapeutic agents for the treatment of numerous diseases [ 26 ]. Analgesics (painkillers), anti-biotics/anti-microbials, anti-malarials, drugs to treat metabolic and cardiovascular diseases as well as diseases of the nervous and digestive systems, and potential drugs to treat COVID-19, are just few examples of the many therapeutic benefits that humanity has received from from nature [ 27 , 28 , 29 , 30 , 31 ].…”