Phytoestrogen β-Sitosterol Exhibits Potent In Vitro Antiviral Activity against Influenza A Viruses
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Lines and Viruses
2.2. Phytochemicals
2.3. Cytotoxicity and Antiviral Assay
2.4. Plaque Reduction Assay (PRA)
2.5. Stage(s) of the Antiviral Action
2.6. Data Collection and Heatmap Construction
2.7. In Silico Docking Studies
2.7.1. Protein Preparation
2.7.2. Ligand Preparation
2.7.3. Docking Setup and Validation of Docking Protocol
2.8. Statistical Analysis
3. Results
3.1. Cytotoxicity and Antiviral Potential of the Investigated Compounds
3.2. Viral titer Reduction in a Concentration-Dependent Manner
3.3. β-Sitosterol and β-Sitosterol-O-Glucoside affects IAV at Multiple Stages of the Virus Replication Cycle
3.4. Docking studies
3.4.1. Validation
3.4.2. Docking Studies against Influenza Hemagglutinin H1 Mutant DH1E
3.4.3. Docking Studies against Influenza A/H1N1 Neuraminidase
3.4.4. Docking Studies against Influenza Proton Channel M2
3.4.5. Docking Studies against Hemagglutinin Head Epitope of Influenza A/H1N1 Virus
3.5. Phytoestrogen β-Sitosterol Is Likely to Hinder IAV Replication in an Estrogen-Like Mode
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | CAS No. | Class | Reported Biological Activities | Reference |
---|---|---|---|---|
Silybin | 22888-70-6 | Flavonoids | Anti-inflammatory and antiviral | [27,28] |
7-Hydroxy flavone | 6665-86-7 | Flavonoids | Anti-inflammatory and antiviral | [29,30,31] |
Pinocembrin | 480-39-7 | Flavonoids | Anti-inflammatory, antiallergic, antioxidant, anticarcinogenic, and antiviral | [32,33,34,35] |
Flavanone | 487-26-3 | Flavonoids | Anti-inflammatory | [36] |
Saponin | 8047-15-2 | Triterpene | Antimicrobial, anticancer, antioxidant, antitumor, and antiviral | [37,38,39,40] |
Lupeol | 545-47-1 | Triterpene | Antioxidant and anti-inflammatory, Antiviral (Lupeol synthetic derivatives) | [41,42,43] |
Glucuronic acid | 528-16-5 | Sugar acids | Antioxidant, hepatoprotective, and antiviral | [44,45] |
Galacturonic acid | 9046-38-2 | Sugar acids | Antiviral (As a saponin component) | [45,46,47,48] |
D-sorbitol | 50-70-4 | Sugar alcohol Carbohydrates | Antiviral and laxative. | [49,50] |
β-sitosterol | 83-46-5 | Steroids | Antioxidant, anticarcinogenic, anti-inflammatory, and antiviral | [51,52,53,54] |
β-sitosterol-O-glucoside | 474-58-8 | Steroids | Antidiabetic, anticancer and antiviral | [55,56,57] |
Ouabain | 630-60-4 | Steroid cardiac glycosides | Anticancer and antiviral | [58,59,60,61] |
Digitonin | 11024-24-1 | Steroid saponin glycosides | Lipid solubilizing and antiviral | [62,63,64] |
Arbutin | 497-76-7 | Phenolic glycosides | Antimelanogenesis, antidiuretic, and antiviral | [65,66] |
D- (-) salicin | 138-52-3 | Phenolic glycosides | Antiviral and anti-inflammatory. | [67,68,69] |
Naringin | 10236-47-2 | Flavonoid glycosides | Anti-inflammatory, anticancer, and antiviral | [70,71,72,73] |
Kaempferitrin | 482-38-2 | Flavonoid glycosides | Hypoglycemic, anti-inflammatory, and antiviral | [74,75,76,77] |
Isoquercitrin | 482-35-9 | Flavonoid glycosides | Antioxidant, antipruritic, neuroprotective, antibacterial, hepatoprotective, anti-inflammatory, and antiviral | [78,79,80,81,82] |
Chrysophanic acid | 481-74-3 | Anthraquinones | Antiviral | [83,84] |
Aloe emodin | 481-72-1 | Anthraquinones | Antiviral, anticancer, anti-inflammatory, and antibacterial. | [85,86,87,88,89,90,91] |
O-Coumaric acid | 614-60-8 | Phenols | Antiadipogenesis, antioxidant, and antiviral (as a component of a plant, indirectly) | [92,93,94,95] |
Vanillin | 121-33-5 | Phenols | Antiviral, antimicrobial, anti-inflammatory, antiapoptotic, neuroprotective, and antioxidant | [96,97,98,99,100] |
Zanamivir | 139110-80-8 | NAIs | Anti-influenza | [101] |
Compound | Virus | CC50 (mg/mL) | IC50 (mg/mL) | SI |
---|---|---|---|---|
Silybin | H1N1 | 9.48 | N/A | ND |
H5N1 | N/A | ND | ||
7-Hydroxy flavone | H1N1 | 5.83 | 0.360 | 16.194 |
H5N1 | N/A | ND | ||
Naringin | H1N1 | >10 | 0.0206 | >485.43 |
H5N1 | N/A | ND | ||
Pinocembrin | H1N1 | >10 | >10 | >1 |
H5N1 | N/A | ND | ||
Kaempferitrin | H1N1 | >10 | 0.0478 | >209.20 |
H5N1 | N/A | ND | ||
Flavanone | H1N1 | 0.45 | N/A | ND |
H5N1 | N/A | ND | ||
Isoquercitrin | H1N1 | 0.71 | 0.167 | 4.25 |
H5N1 | N/A | ND | ||
Saponin | H1N1 | >10 | 0.326 | >30.674 |
H5N1 | N/A | ND | ||
Lupeol | H1N1 | 0.56 | 0.0936 | 5.98 |
H5N1 | N/A | ND | ||
D-Glucuronic acid | H1N1 | 10.26 | N/A | ND |
H5N1 | N/A | ND | ||
D-Galacturonic acid | H1N1 | 9.61 | N/A | ND |
H5N1 | N/A | ND | ||
β-sitosterol | H1N1 | 9.9 | 0.000975 | 10,154 |
H5N1 | 0.000295 | 33,559 | ||
β-sitosterol-O-glucoside | H1N1 | 1.75 | 0.000719 | 2434 |
H5N1 | 0.000613 | 2855 | ||
Ouabain | H1N1 | 0.176 | N/A | ND |
H5N1 | N/A | ND | ||
Digitonin | H1N1 | 0.442 | 0.0215 | 20.56 |
H5N1 | N/A | ND | ||
Chrysophanic acid | H1N1 | 0.0461 | N/A | ND |
H5N1 | N/A | ND | ||
Aloe emodin | H1N1 | 2.28 | 0.729 | 3.127 |
H5N1 | N/A | ND | ||
Arbutin | H1N1 | >10 | 0.764 | >13.09 |
H5N1 | N/A | ND | ||
O-Coumaric acid | H1N1 | 9.172 | NA | ND |
H5N1 | N/A | ND | ||
Vanillin | H1N1 | 0.242 | N/A | ND |
H5N1 | N/A | ND | ||
D-sorbitol | H1N1 | >10 | 3.11 | >3.215 |
H5N1 | N/A | ND | ||
D-(-) salicin | H1N1 | >10 | N/A | ND |
H5N1 | N/A | ND | ||
Zanamivir | H1N1 | >10 | 0.000792 | >12,626 |
H5N1 | 0.000265 | >37,736 |
Steroid | Concentration (µg/mL) | Stage of Antiviral Action | ||
---|---|---|---|---|
Viral Replication | Viricidal | Viral Adsorption | ||
β-sitosterol | 1 | 31.8% | 84% | 28% |
10 | 41.2% | 98.5% | 37.5% | |
100 | 52.9% | 99% | 52.5% | |
β-sitosterol-O-glucoside | 1 | 28.7% | 83.6% | 35.8% |
10 | 37.7% | 93.3% | 48.3% | |
100 | 52.8% | 97.1% | 56.9% |
Compound | Hemagglutinin | Neuraminidase | M2 | Hemagglutinin Head Epitope |
---|---|---|---|---|
β-sitosterol | −6.40 | −29.40 | −10.97 | −10.90 |
β-sitosterol-O-glucoside | −6.78 | −30.13 | −10.75 | −8.97 |
6′-Sialyl-N-acetyllactosamine | −5.66 | - | - | - |
Zanamivir | - | −19.28 | - | - |
Rimantadine | - | - | −9.968 | - |
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Shokry, S.; Hegazy, A.; Abbas, A.M.; Mostafa, I.; Eissa, I.H.; Metwaly, A.M.; Yahya, G.; El-Shazly, A.M.; Aboshanab, K.M.; Mostafa, A. Phytoestrogen β-Sitosterol Exhibits Potent In Vitro Antiviral Activity against Influenza A Viruses. Vaccines 2023, 11, 228. https://doi.org/10.3390/vaccines11020228
Shokry S, Hegazy A, Abbas AM, Mostafa I, Eissa IH, Metwaly AM, Yahya G, El-Shazly AM, Aboshanab KM, Mostafa A. Phytoestrogen β-Sitosterol Exhibits Potent In Vitro Antiviral Activity against Influenza A Viruses. Vaccines. 2023; 11(2):228. https://doi.org/10.3390/vaccines11020228
Chicago/Turabian StyleShokry, Sara, Akram Hegazy, Ahmad M. Abbas, Islam Mostafa, Ibrahim H. Eissa, Ahmed M. Metwaly, Galal Yahya, Assem M. El-Shazly, Khaled M. Aboshanab, and Ahmed Mostafa. 2023. "Phytoestrogen β-Sitosterol Exhibits Potent In Vitro Antiviral Activity against Influenza A Viruses" Vaccines 11, no. 2: 228. https://doi.org/10.3390/vaccines11020228