Hesperidin — a promising adjuvant treatment option against SARS-CoV-2 infection

Hesperidin is a bioflavonoid, a type of plant pigment with antioxidant and anti-inflammatory effects found primarily in citrus fruit (see Figure 1).  Oranges, grapefruit, lemon, and tangerines all contain hesperidin, which is also available in supplement form. Note that hesperidin is present in highest concentration in the peel.

Figure 1.  Citrus fruits

A Traditional Herbal Medicine

Hesperidin is a classical herbal medicine used worldwide for a long time with an excellent safety profile. The safety of hesperidin was confirmed by FASEB (Federation of American Societies of Experimental Biology) upon request of the FDA.

Cellular Entry of Covid-19

Cell entry of Covid-19 depends on two consecutive steps:

1. Binding of the viral spike (S-protein) to host cellular receptors 
2. Followed by priming of S-protein by cell proteases

Recently, researchers showed that COVID-19 uses the ACE-2 receptor for entry and the serine protease TMPRSS2 for priming of S-protein.^[4]

Figure 2.  Hesperidin role in prevention and treatment of COVID 19

Adjuvant treatment option against Covid-19

Host antiviral responses against COVID-19 infection depend on the activation of both the immune systems and cellular self-defense mechanisms. The occurrence of immune over-response or immune deficiency is responsible for the condition of infected Covid-19 patients becoming critical or severe.^[6]

Hesperidin has several pharmacological activities such as anti-atherogenic, antihyperlipidemic, antidiabetic, venotonic, cardioprotective, anti-inflammatory, and antihypertensive actions.  Available evidence supports the promising use of hesperidin in prevention and treatment of Covid-19.  For example, hesperidin can potentially (See Figure 2):^[1]

• Prevent the Covid-19 infection
• Based on virtual screening, hesperidin may disrupt the interaction of ACE2 with RBD of SARS-CoV-2 thus block its entry into the lung cells.^[5]
• Improve host cellular immunity against infection
• A recent study showed that the interferon-MAPK pathway played an important role in the COVID-19 immune response.^[6]
• Hesperidin by its activation to host immunity may help against COVID-19 viral replication and hence its progression which will improve the patient outcome (Figure 1).
• Hesperidin exhibited anti-viral activity against the influenza virus through a significant reduction of virus replication. 
• Treatment of infected cells with hesperidin enhanced cell-autonomous immunity via activation and upregulation of p38 and JNK expression which is essential for cell defense mechanisms against influenza virus.^[2]
• Control cytokine storm
• The anti-inflammatory activity of hesperidin was mainly attributed to its antioxidant defense mechanism and suppression of pro-inflammatory cytokine production.^[3]
• Prevent disease progression
• Activation of coagulation pathways following the immune response to COVID-19 infection promotes clot formation.
• A prophylactic dose of heparin (with low molecular weight, LMWH) is recommended for protection against venous thromboembolism in COVID-19 hospitalized patients.^[8]
• Co-administration of LMWH and Daflon 500 mg can significantly inhibit clot formation and prevent disease progression.^[9]

References

1. Is hesperidin essential for prophylaxis and treatment of COVID-19 Infection?
2. W. Dong, X. Wei, F. Zhang, J. Hao, F. Huang, C. Zhang, et al.  A dual character of flavonoids in influenza A virus replication and spread through modulating cell-autonomous immunity by MAPK signaling pathways Sci Rep, 4 (2014), p. 7237
3. A.A. Zanwar, S.L. Badole, P.S. Shende, M.V. Hegde, S.L. Bodhankar Chapter 76 – Cardiovascular effects of hesperidin: a flavanone glycoside R.R. Watson, V.R. Preedy, S. Zibadi (Eds.), Polyphenols in Human Health and Disease, Academic Press, San Diego (2014), pp. 989-992
4. L. Bao, W. Deng, B. Huang, H. Gao, J. Liu, L. Ren, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature (2020)
5. C. Wu, Y. Liu, Y. Yang, P. Zhang, W. Zhong, Y. Wang, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods.  Acta Pharm. Sin. B (2020)
6. L. Huang, Y. Shi, B. Gong, L. Jiang, X. Liu, J. Yang, J. Tang, C. You, Q. Jiang, B. Long, T. Zeng, M. Luo, F. Zeng, F. Zeng, S. Wang, X. Yang, Z. Yang, Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19, medRxiv, (2020) 2020.2003.2015.20033472.
7. Regulation of JNK and p38 MAPK in the immune system: Signal integration, propagation and termination
8. R.J. Jose, A. Manuel, COVID-19 cytokine storm: the interplay between inflammation and coagulation, The Lancet Respiratory Medicine, (2020).
9. E.C. Tsimoyiannis, G. Floras, N. Antoniou, N. Papanikolaou, P. Siakas, A. Tassis.  Low-molecular-weight heparins and Daflon for prevention of postoperative thromboembolism.  World J Surg, 20 (1996), pp. 968-971 discussion 972
10. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
11. Argentina’s IVERCAR Ivermectin & Carrageenan Study Shows Positive Results Targeting COVID-19