Friday Hope: Quercetin: From Possible Therapeutic Considerations in 2020 to Proven Therapeutic Implications in 2024

Quercetin has demonstrated its worth as a major preventative/prophylactic polyphenol in the prevention and treatment of pathologies of SARS-CoV-2 and its Spike Protein.

When the SARS-CoV-2 Pandemic first began, there was much discussion as to what natural therapeutics (i.e., ready to use) may be employed in fighting the disease. Quercetin (Que) came to mind as it had shown promise in treating Coronaviruses. Interestingly, it also was shown to bind to the Spike Protein! 

First the historical findings regarding Que and Coronaviruses (including the original SARS). 

Que has been investigated for its possible antiviral effect on several members of the Coronaviridae family. To the best of our knowledge, one of the first reports exploring the antiviral effect of Que on coronaviruses appeared in 1990 suggesting that it reduced infectivity of human and bovine coronaviruses, OC43 and NCDCV, respectively, by 50% at a concentration of 60 µg/mL.56 On a different Coronaviridae of veterinarian interest, PEDV, quercetin 7-O-rhamnoside inhibited PEDV replication in Vero cells with an IC50 of 0.014 µg/mL and a 50% cytotoxicity concentration (CC50) of 100 µg/mL.113 Luteolin and Que showed the capacity to block the entry of SARS-CoV into host cells.114 Luteolin inhibited, in a dose-dependent manner, SARS-CoV infection of Vero E6 cells with a half-effective concentration (EC50) value of 10.6 µM (CC50 = 155 µM), while Que antagonized HIV-luc/SARS pseudo-type virus entry with an EC50 of 83.4 µM.114 Thus, Que offers great promise as a potential drug in the clinical treatment of SARS. 

And the findings on Que’s ability to strongly bind Spike Protein. 

In silico modeling of the interaction between the SARS-CoV-2 Viral Spike Protein and ACE2 protein identified Que, from a database of known drugs, metabolites, and natural products, as one of the top 5 most potent compounds for binding to the interface site and potentially disrupting the initiating infection process.134 In support of this hypothesis, Que was active against infection in a model of virus cell entry and also inhibited the 3C-like protease of SARS-CoV in vitro. 

The anti-inflammatory and thrombin-inhibitory actions of Que were also noted early on. 

In any case, based on the strong inflammatory cascade and the blood-clotting phenomena triggered during SARS‐CoV‐2 infection, the multifaceted aspect of Que, which has been well described as exerting both anti-inflammatory (Que dose‐dependently decreases the messenger RNA and protein levels of intercellular adhesion molecule-1, IL‐6, IL‐8, and monocyte chemoattractant protein-1) and thrombin‐inhibitory actions,143-145 should be taken into consideration. 

A quote from researchers in Montreal best sums up the early attitudes towards Que. 

According to researchers at the Montreal Clinical Research Institute “A cell has a lock, and the virus has a key [to enter and infect the cell];” Chrétien said, “But quercetin puts glue in the lock.”157 Therefore, we anticipate that Que could be a therapeutic tool to be assayed against COVID-19, either alone or in combination with other nutritional substances, antivirals, or other drugs. 

Quercetin: Antiviral Significance and Possible COVID-19 Integrative Considerations 
https://journals.sagepub.com/doi/full/10.1177/1934578X20976293 

For those who may not know, what is Quercetin? 

Quercetin belongs to a group of plant pigments called flavonoids that give many fruits, flowers, and vegetables their colors. 

Flavonoids, such as quercetin, are antioxidants. They scavenge particles in the body known as free radicals which damage cell membranes, tamper with DNA, and even cause cell death. Antioxidants can neutralize free radicals. They may reduce or even help prevent some of the damage free radicals cause. In test tubes, quercetin has strong antioxidant properties. But researchers are not sure whether taking quercetin (and many other antioxidants) has the same effects inside the body. 

Fruits and vegetables are the primary dietary sources of quercetin, particularly citrus fruits, apples, onions, parsley, sage, tea, and red wine. Olive oil, grapes, dark cherries, and dark berries such as blueberries, blackberries, and bilberries are also high in quercetin and other flavonoids. 

Quercetin 
https://www.mountsinai.org/health-library/supplement/quercetin 

What we discussed earlier was information being disseminated almost half a decade ago. Let’s move forward to the present. A major review was published in May of this year, which confirms much of what was hypothesized. I highly recommend reading the entire review. If you do not currently supplement Quercetin, you may wish to speak with your Primary Care Provider about its use. Its benefits, beyond SARS-CoV-2 and the Spike Protein, are profound. 

Quercetin is a natural flavonoid widely represented in the plant kingdom. Cumulative evidence has demonstrated that quercetin and its derivatives have various pharmacological properties including anti-cancer, anti-hypertension, anti-hyperlipidemia, anti-hyperglycemia, anti-microbial, antiviral, neuroprotective, and cardio-protective effects, because it is a potential treatment for severe inflammation and acute respiratory distress syndrome. Furthermore, it is the main life-threatening condition in patients with COVID-19. This article provides a comprehensive review of the primary literature on the predictable effectiveness of quercetin and its derivatives docked to multi-target of SARS-CoV-2 and host cells via in silico and some of validation through in vitro, in vivo, and clinically to fight SARS-CoV-2 infections, contribute to the reduction of inflammation, which suggests the preventive and therapeutic latency of quercetin and its derived-products against COVID-19 pandemic, multisystem inflammatory syndromes (MIS), and long-COVID. 

There are two highlights I would like to focus on. The first is the evidence that Quercetin does, indeed, bind Spike Protein preventing its ability to enter cells. It also interferes with other replicative proteins of the virus. 

Another in vitro study also validated the ligands-protein interactions of SARS-CoV-2 by using fluorescence quenching methods and showed that the IC50 of quercetin on RdRp, Mpro and S-protein about 82 nM, 62 nM and 52 nM, respectively, as well as catechin had similar anti-COVID-19 potential. Its inhibiting efficacy on RdRp, Mpro and S-protein with 71 nM, 93 nM and 65 nM of IC50, respectively [120]. The nsp15 is uridylate specific endoribonuclease of SARS-CoV-2 that cleaved the viral own negative-sense RNA to evade the innate immune response [121]. In vitro results showed epigallocatechin gallate (EGCG) and baicalin inhibits nsp15 with 1.67 μM and 3.56 μM of IC50, respectively [122]. Further, another in vitro study tested the anti-COVID-19 effects of different combinations that mixed quercetin with different natural compounds to indicate the combination by resveratrol, broccoli extract, curcumin, quercetin, naringenin, baicalin, theaflavin, vitamin C, and N-acetylcysteine had the highest anti-SARS-CoV-2 potential. In vitro treatments with this combination (10 μg/mL) inhibited 90 % S-protein binding to ACE2, and 53 % RdRp activity to inhibit SARS-CoV-2 infection and replication. 

The second highlight I would like to make is the evidence that Quercetin contributes to a very significant positive outcome for those with Acute COVID. 

Based on the ClinicalTrials. gov website (https://clinicaltrials.gov/), in 15 clinical trial enrollments, quercetin supplementation was used as a COVID-19 treatment. We also found other reports of six studies in PubMed (https://pubmed.ncbi.nlm.nih.gov/). In all clinical trials, quercetin was used as a supplement combined with standard care (SC) for symptomatic and antiviral treatment of COVID-19 patients (Table 3, Table 4). Outpatients with mild SARS-CoV-2 infections were treated with quercetin for two weeks (600 and 400 mg/daily of quercetin in the first and second weeks, respectively) in combination with SC, which significantly shortened the period of viral clearance, alleviated symptom occurrence, and attenuated the levels of lactate dehydrogenase (LDH) and ferritin in serum [128]. In the early stages of COVID-19, quercetin supplementation resulted in marked improvements in the ratio of hospitalized patients, decreased the oxygen needs of patients, and shortened the days of hospitalization [129]. Patients with severe SARS-CoV-2 infection were treated with 1000 mg/day of quercetin in combination with clinical antiviral drugs (such as remdesivir and favipiravir), which significantly decreased the levels of q-C-reactive protein (q-CRP), LDH, and alkaline phosphatase (ALP) in the serum and reduced the period of hospitalization. 

Therapeutic implications of quercetin and its derived-products in COVID-19 protection and prophylactic 
https://www.cell.com/heliyon/fulltext/S2405-8440(24)06111-5 

I will continue to study Quercetin, as well as other therapeutics. I agree with the authors of this paper that Quercetin should be therapeutic against Post-COVID, Long COVID and MIS-C. 

The heat has broken, and it is a splendid summer day with a light breeze and temps in the upper 70s. Vermont Summer Heaven! Thank you, as always, for your support, dialog and readership. Please have a blessed and joy filled weekend.