COVID-19 Diets: Study Shows That Diets Rich in Citrus Fruits Containing Hesperidin Might Be A Healthy Option For Dealing With SARS-CoV-2

COVID-19 Diets: Interestingly among the many approaches to COVID-19 prevention, the possible role of diet has so far been somewhat marginal. Nutrition is very rich in substances with a potential beneficial effect on health and some of these could have an antiviral action or in any case be important in modulating the immune system and in defending cells from the oxidative stress associated with infection.

Now Italian researchers from the University of Verona Medical School and the Scientific Committee of Fondazione Allineare Sanità e Salute have conducted a study drawing attention to the components of Citrus fruits and especially of the orange (Citrus sinensis), well known for its vitamin content, but less for the function of its flavonoids especially Hesperidin and its efficacy https://www.preprints.org/manuscript/202006.0321/v1
 
In another published study in Scinece Direct journal: Medical Hypotheses, the flavonoid Hesperidin was proposed a possible prophylaxis for COVID-19 infections. https://www.sciencedirect.com/science/article/pii/S030698772031358X
 
Hesperidin has recently attracted the attention of researchers, because it binds to the key proteins of the SARS-CoV-2 virus. Several computational methods, independently applied by different researchers, showed that hesperidin has a low binding energy both with the coronavirus "spike" protein, and with the main protease that transforms the early proteins of the virus (pp1a and ppa1b) into the complex responsible for viral replication. The affinity of hesperidin for these proteins is comparable if not superior to that of common chemical antivirals. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3599426 and   https://www.mdpi.com/2227-9717/8/5/549 and https://chemrxiv.org/articles/Evaluation_of_Flavonoids_as_2019-nCoV_Cell_Entry_Inhibitor_Through_Molecular_Docking_and_Pharmacological_Analysis/12071508/1
 
The preventive efficacy of vitamin C, at dosage attainable by diet, against viral infections is controversial, but recent reviews suggest that this substance may be useful in case of increased stress on the immune system.
 
The discovery that hesperidin has a chemicalphysical structure suitable for binding to key proteins in the functioning of the SARS-CoV-2 virus has recently aroused scientific interest. At least six searches yielded concordant results. direct.com/science/article/pii/S2211383520302999">https://www.sciencedirect.com/science/article/pii/S2211383520302999 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062204/ and https://www.preprints.org/manuscript/202003.0333/v1 and https://www.preprints.org/manuscript/202003.0214/v1 and
https://pubmed.ncbi.nlm.nih.gov/32362245/ and
https://pubmed.ncbi.nlm.nih.gov/32362245/
 
The researchers started from the detailed knowledge of the virus protein structure to try to verify which molecules, natural or artificial, are capable of binding with a low binding energy (the lower the energy required, the stronger and more specific the binding is). This technique is called "in silico", as it is performed through the computer (with reference to the silicon of the chips). The in silico study is currently applied to simulate drug behaviour and accelerate the detection rate, screening many drugs and reducing the need for expensive laboratory work and limiting efficacy clinical trials to the best candidates.
 
In one past research, the scientists tested SARS-CoV-2 proteins, whose chemical-physical structure is known, with 1066 natural substances with potential antiviral effect, plus 78 antiviral drugs already known in the literature. Of all, hesperidin was the most suitable to bind to the "spike". By superimposing the ACE2 - RBD complex on the hesperidin - RBD complex, a clear overlap of hesperidin with the ACE2 interface is observed, which suggests that hesperidin may disrupt the interaction of ACE2 with RBD. A second theoretical site of low energy binding of hesperidin with SARS-CoV-2 is the main protease that allows the processing of the first proteins transferred from the viral genome - pp1a and pp1ab - into functional proteins in the host cell This enzyme is called “3Clpro” or “Mpro" by the various authors and is the target of many chemical antiviral drugs. This specific binding has also been confirmed by other authors: in a screening of 1500 potential molecules capable of binding to 3CLpro, hesperidin is the second most efficient for binding to chain A with a free energy of -10.1 Kcal mol-1 [24]. Lopinavir (-8.0) and Ritonavir (-7.9) are given as reference drugs, and they show less binding capacity. The binding to chain B occurs with -8.3 Kcal mol-1, while Lopinavir (-6.8) and Ritonavir (- 6.9) have lower binding capacity. https://www.sciencedirect.com/science/article/pii/S2211383520302999
 
In another detailed molecular docking study of the interaction between hesperidin and Mpro was recently published. In a screening of 33 natural and already known antiviral molecules, the authors found that the lower binding energy (indicating maximum affinity) is characteristic of rutin (- 9.55 kcal / mol), followed by ritonavir (-9.52 kcal / mol), emetine (- 9.07 kcal / mol), hesperidin (- 9.02 kcal / mol), and indinavir (8.84 kcal / mol). Hesperidin binds with various amino acids, among which particularly are the hydrogen bonds with THR24, THR25, THR45, HIS4, SER46, CYS145. Further evidence came from the work by Joshi et al], who identified hesperidin among several natural molecules that strongly binds to SARS-CoV-2 main protease and interestingly also to the viral receptor angiotensin-converting enzyme 2 (ACE-2). https://pubmed.ncbi.nlm.nih.gov/32362245/
 
Yet another research published in "preprint" by Indonesian authors has examined a wide range of active ingredients of the plants Curcuma sp., Citrus sp. (orange), Caesalpinia sappan and Alpinia galanga with evidence of molecular docking towards the main protease of the virus, the Spike protein, and the ACE2 receptor. For the three proteins, hesperidin was the most efficient binding molecule, with docking points of -13.51, -9.61 and -9.50 respectively to the SARS-CoV-2 protease, to the glycoprotein-RBD Spike and to the ACE2 receptor. Hesperidin performs a better interaction with the SARS-CoV-2 protease than Lopinavir, a reference drug used today in the clinical trials for Covid-19. These authors have observed that, in addition to hesperidin, other orange flavonoids less represented quantitatively like tangeretin, naringenin and nobiletine also have a low binding energy (comparable to the reference ligands, Lopinavir and Nafamostat) to the three essential proteins, suggesting that these interactions could also contribute to the inhibitory effect against virus infection. https://www.preprints.org/manuscript/202003.0214/v1
 
According to another "molecular docking" research, out of 26 natural phenolic compounds that are candidates for antiviral action, hesperidin was the one with the highest binding capacity to the crystallized form of the main protease of SARS-CoV-2. It interacts with hydrogen bridges with different amino acids. The link is much more effective than that with the reference drug Nelfinavir (with scores of -178.59 and - There is an important precedent when the authors studied natural compounds capable of inhibiting 3CLpro of the SARS virus [29], using cell-based proteolytic cleavage assays. Out of seven phenolic compounds tested, hemodyne and hesperetin inhibited proteolytic activity in a dose-dependent manner, with IC50 of 366 micromol/L and 8.3 micromol/L respectively. This research offers a demonstration that theoretical models are efficient in predicting real biochemical activity and provides a rough indication of the concentration of the substance capable of showing some effect. It is suggestive that this inhibitory effect occurs with concentrations of hesperidin of the same order of magnitude as those achievable in plasma with a large oral supplement of orange juice. https://www.preprints.org/manuscript/202003.0333/v1
 
Since coronavirus main protease structural backbone and active site conformation are conserved despite sequence variations, it is conceivable that the inhibitory effect of hesperidin previously observed in SARS virus can be exploited also in SARS-Cov-2. Other potentially useful effects Citrus fruits and their respective juices, starting from orange juice, could have positive effects in the course of COVID-19 with additional mechanisms, possibly inhibiting its virulence. As mentioned above, this disease can present, in the more advanced stages, phenomena of hyperactivation of inflammatory reactions and coagulation, with a pathology involving the pulmonary vessels, and not only. https://pubmed.ncbi.nlm.nih.gov/32362245/
 
Furthermore, COVID-19 is known to affect elderly people with other chronic cardiovascular, metabolic and respiratory diseases, especially if in a severe form. Consequently, any lifestyle-related intervention, including dietary interventions, that help to maintain the health of the cardiovascular and respiratory systems during the whole life may make the person infected with SARS-CoV-2 less susceptible to its more severe complications.
 
 A randomized, single-blind, placebo-controlled, cross-over study in subjects with increased cardiovascular risk (aged 27 to 56 years) tested the administration of 500 ml of blood orange juice / day (or 500 ml of placebo / day) for periods of 7 days https://pubmed.ncbi.nlm.nih.gov/22492368/
 
Endothelial function, measured as flowmediated dilation, improved greatly and was normalized (5.7% compared to 7.9%; P beneficial effect is due to hesperidin.
 
A dietary medical history study determined the total dietary intake of 10054 Finnish men and women in the previous year. Intakes of flavonoids in food have been estimated and compared with the incidence of diseases considered by different national public health registers. https://pubmed.ncbi.nlm.nih.gov/12198000/
 
Individuals with higher hesperetin intakes had lower incidence of cerebrovascular disease (RR 0.80; CI 0.64-0.99; P = 0.008) and bronchial asthma (RR 0.64; CI 0.46-0.88 ; P = 0.03). In mouse studies, protective effects of hesperetin were observed in lipopolysaccharide-induced neuroinflammation (LPS), neuronal oxidative stress and memory impairment. While treatment with LPS resulted in microglial activation and astrocytosis and increased the expression of inflammatory mediators such as TNF-alpha and IL-1beta, concurrent treatment with hesperetin (50 mg / kg body weight) significantly reduced the expression of inflammatory cytokines and has attenuated the generation of reactive oxygen species induced by LPS. In addition, hesperetin improved synaptic integrity, cognition and memory processes. https://pubmed.ncbi.nlm.nih.gov/30884890/
 
In a recent review, it was noted that the nutraceutical, antioxidant and anti-inflammatory properties of hesperidin could be useful also in the prevention and treatment of many disorders of the central nervous system. https://pubmed.ncbi.nlm.nih.gov/31949974/
 
Gene expression analysis has shown that hesperidin modulates the expression of genes involved in atherogenesis, inflammation, cell adhesion and cytoskeletal organization. https://pubmed.ncbi.nlm.nih.gov/24425450/
 
Physiologically relevant concentrations of flavanone reduce the adhesion of monocytes to endothelial cells stimulated by TNF-alpha, influencing the expression of related genes and so offering a potential explanation of its vasculoprotective effects. A daily dose of 292 mg of hesperidin, corresponding to 500 ml of orange, was sufficient to achieve the described effects.
 
The scientific literature on the healthy properties of fruit and vegetables and especially of Citrus fruits, is vast and beyond the scope of this article, which has focused on the remarkable and surprising interaction between hesperidin and the key proteins of the SARS-CoV-2 virus. (Please refer to original Italian study as there are more than 58 supporting research studies….https://www.preprints.org/manuscript/202006.0321/v1)
 
Since these methods are now the "gold standard" for screening new drugs and their targets, the researchers feel hopeful about the beneficial effects of hesperidin COVID-19 as well, even if there is still no clinical evidence of therapeutic efficacy. The binding of hesperidin to the central part of the spike and to the main protease is much stronger than that of conventional antivirals, and it can be expected that this molecule may soon be tested in randomized trials of patients with COVID-19 or subjects exposed to contagion.
 
The recently accumulated evidence supports the hypothesis that hesperidin supplementation may be useful as complementary treatment during COVID-disease, as recently suggested by others. https://europepmc.org/article/pmc/pmc7274964
 
It remains to be seen whether regular Citrus consumption, or an increase in consumption, may be advisable among the preventive dietary measures for COVID-19. A dose of Citrus fruits or vitamin C based supplements, higher than that of a typical diet of the Italian population, does not seem suitable for long-term prevention. However, in periods of intense stress (that may be considered similar to the exposure to pathogenic microorganisms during the epidemic peak or during  other infectious diseases, possible benefits from therapeutic doses of vitamin C are expected.
 
It was suggested that the prevention of infection requires dietary intakes of vitamin C (i.e. 100-200 mg / day), which provide adequate plasma levels to optimize cell and tissue levels, while the treatment of established infections requires significantly higher doses high (grams) of vitamin to compensate for the increased inflammatory response and metabolic demand. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC39676/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707683/
 
Dr Paolo Bellavite and Dr Alberto Donzelli, both authors of the study told Thailand Medical News, “If one relies on food, these doses may be reached with a temporary large consumption of juices, taking care to crush well also the albedo, which is the part richest in hesperidin. In our opinion, it is certainly suggestive to think that inside a tasty fruit, given to us by Nature for thousands of years, there may be a molecule potentially useful to fight a virus of the 21st century!”
 
For more on COVID-19 Diets and Hesperidin, keep on Logging to Thailand Medical News.

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