Pharmacological Significance of Hesperidin and Hesperetin, Two Citrus Flavonoids, as Promising Antiviral Compounds for Prophylaxis Against and Combating COVID-19

Agrawal, Pawan K.; Agrawal, Chandan; Blunden, Gerald

doi:10.1177/1934578x211042540

Cited by 33 publications

(28 citation statements)

References 203 publications

(195 reference statements)

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“…Wherein lies its anti-inflammatory properties [ 46 ]. It modulates inflammatory markers such as (Interleukin) IL-6, IL-1β, and TNF-α, in addition to pro-inflammatory cytokines such as IFN-γ and IL-2, in various vital organs in animal models [ 47 ]. Moreover, by downregulating the abnormal levels of Angiotensin 2 in hypertensive rodents, hesperidin has been shown to attenuate inflammation.…”

Section: Resultsmentioning

confidence: 99%

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

Kumar

Paul

Yadav

et al. 2022

Computers in Biology and Medicine

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The advent and persistence of the Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-CoV-2)-induced Coronavirus Disease (COVID-19) pandemic since December 2019 has created the largest public health emergency in over a century. Despite the administration of multiple vaccines across the globe, there continues to be a lack of approved efficacious non-prophylactic interventions for the disease. Flavonoids are a class of phytochemicals with historically established antiviral, anti-inflammatory and antioxidative properties that are effective against cancers, type 2 diabetes mellitus, and even other human coronaviruses. To identify the most promising bioactive flavonoids against the SARS-CoV-2, this article screened a virtual library of 46 bioactive flavonoids against three promising targets in the SARS-CoV-2 life cycle: human TMPRSS2 protein, 3CLpro, and PLpro. By examining the effects of glycosylation and other structural-activity relationships, the presence of sugar moiety in flavonoids significantly reduces its binding energy. It increases the solubility of flavonoids leading to reduced toxicity and higher bioavailability. Through protein-ligand contact profiling, it was concluded that naringin formed more hydrogen bonds with TMPRSS2 and 3CLpro. In contrast, hesperidin formed a more significant number of hydrogen bonds with PLpro. These observations were complimented by the 100 ns molecular dynamics simulation and binding free energy analysis, which showed a considerable stability of docked bioflavonoids in the active site of SARS-CoV-2 target proteins. Finally, the binding affinity and stability of the selected docked complexes were compared with the reference ligands (camostat for TMPRSS2, GC376 for 3CLpro, and GRL0617 for PLpro) that strongly inhibit their respective SARS-COV-2 targets. Overall analysis revealed that the selected flavonoids could be potential therapeutic agents against SARS-CoV-2. Naringin showed better affinity and stability for TMPRSS2 and 3CLpro, whereas hesperidin showed a better binding relationship and stability for PLpro.

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Section: Resultsmentioning

confidence: 99%

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

Kumar

Paul

Yadav

et al. 2022

Computers in Biology and Medicine

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show abstract

“…Notably, the broad-spectrum antiviral activity of hesperidin has previously been reported against a range of viruses such as poliovirus, parainfluenza virus, herpes simplex virus, vesicular stomatitis virus, vaccinia virus, rotavirus, human immunodeficiency virus, canine distemper virus, hepatitis B virus, and sindbis virus [ 56 , 58 – 63 ]. Recently, it has been shown that hesperidin actively inhibits SARS-CoV-2 replication in the cell culture model [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease

Khan

Rauf

Habib

et al. 2022

BMC Complement Med Ther

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Background Hepatitis C virus infection is the main cause of liver ailments across the globe. Several HCV genotypes have been identified in different parts of the world. Effective drugs for combating HCV infections are available but not affordable, particularly to infected individuals from resource-limited countries. Hence, cost-effective drugs need to be developed against important HCV drug targets. As Citrus fruits naturally contain bioactive compounds with antiviral activities, the current study was designed to identify antiviral inhibitors from Citrus fruit extracts against an important drug target, NS3 protease, of HCV genotype 3a which is found predominantly in South Asian countries. Methods The full-length NS3 protease alone and the NS3 protease domain in fusion with the cognate NS4A cofactor were expressed in Escherichia coli, and purified by chromatographic techniques. Using the purified protein as a drug target, Citrus extracts were evaluated in a FRET assay, and active ingredients, identified using ESI–MS/MS, were docked to observe the interaction with active site residues of NS3. The best interacting compound was further confirmed through the FRET assay as the inhibitor of NS3 protease. Results Fusion of the NS3 protease domain to the NS4A cofactor significantly improved the purification yield, and NS3-NS4A was functionally more active than the full-length NS3 alone. The purified protein (NS3-NS4A) was successfully employed in a validated FRET assay to evaluate 14 Citrus fruit extracts, revealing that the mesocarp extract of Citrus paradisi, and whole fruit extracts of C. sinesis, C. aurantinum, and C. reticulata significantly inhibited the protease activity of HCV NS3 protease (IC50 values of 5.79 ± 1.44 µg/mL, 37.19 ± 5.92 µg/mL, 42.62 ± 6.89 µg/mL, and 57.65 ± 3.81 µg/mL, respectively). Subsequent ESI-MSn analysis identified a flavonoid, hesperidin, abundantly present in all the afore-mentioned Citrus extracts. Importantly, docking studies suggested that hesperidin interacts with active site residues, and acts as a potent inhibitor of NS3 protease, exhibiting an IC50 value of 11.34 ± 3.83 µg/mL. Conclusions A FRET assay was developed using NS3-NS4A protease, which was successfully utilized for the evaluation of Citrus fruit extracts. Hesperidin, a compound present in the Citrus extracts, was identified as the main flavonoid, which can serve as a cost-effective potent inhibitor of NS3 protease, and could be developed as a drug for antiviral therapy against HCV genotype 3a.

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“…In silico studies indicate that hesperidin may bind to multiple components of SARS-CoV-2 (like Mpro, PLpro, Spike protein) and its human receptor ACE2, reviewed by Agrawal et al [97].…”

Section: Hesperidinmentioning

confidence: 99%

“…Abbreviations: ACE- Various in silico studies demonstrated that quercetin, luteolin, myricetin, naringenin, and hesperidin could interfere with various stages enzymes of SARS-CoV-2 (viral papain such as protease (PLpro) [85], and main protease (Mpro; 3 CLpro, also named 3chymotrypsin-like protease) [92,97], NTPase/helicase) [99] of the coronavirus entry and replication cycle [85,92,95,97]. On the other hand, kaempferol [89], luteolin [92], apigenin [97], and catechin-like flavonoids [99] interact and inhibit (in silico) SARS-CoV-2 spike proteins (especially S2) and hACE-2 receptors, and thus can prevent viral entry inside the host cells [89,92,97,99] (Table 1).…”

Section: Catechinmentioning

confidence: 99%

Does Oxidative Stress Management Help Alleviation of COVID-19 Symptoms in Patients Experiencing Diabetes?

et al. 2022

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Severe acute respiratory syndrome (SARS)-CoV-2 virus causes novel coronavirus disease 2019 (COVID-19) with other comorbidities such as diabetes. Diabetes is the most common cause of diabetic nephropathy, which is attributed to hyperglycemia. COVID-19 produces severe complications in people with diabetes mellitus. This article explains how SARS-CoV-2 causes more significant kidney damage in diabetic patients. Importantly, COVID-19 and diabetes share inflammatory pathways of disease progression. SARS-CoV-2 binding with ACE-2 causes depletion of ACE-2 (angiotensin-converting enzyme 2) from blood vessels, and subsequently, angiotensin-II interacts with angiotensin receptor-1 from vascular membranes that produce NADPH (nicotinamide adenine dinucleotide hydrogen phosphate) oxidase, oxidative stress, and constriction of blood vessels. Since diabetes and COVID-19 can create oxidative stress, we hypothesize that COVID-19 with comorbidities such as diabetes can synergistically increase oxidative stress leading to end-stage renal failure and death. Antioxidants may therefore prevent renal damage-induced death by inhibiting oxidative damage and thus can help protect people from COVID-19 related comorbidities. A few clinical trials indicated how effective the antioxidant therapy is against improving COVID-19 symptoms, based on a limited number of patients who experienced COVID-19. In this review, we tried to understand how effective antioxidants (such as vitamin D and flavonoids) can act as food supplements or therapeutics against COVID-19 with diabetes as comorbidity based on recently available clinical, preclinical, or in silico studies.

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Pharmacological Significance of Hesperidin and Hesperetin, Two Citrus Flavonoids, as Promising Antiviral Compounds for Prophylaxis Against and Combating COVID-19

Cited by 33 publications

References 203 publications

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

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

Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease

Does Oxidative Stress Management Help Alleviation of COVID-19 Symptoms in Patients Experiencing Diabetes?

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