Hesperetin

With the growing global threat of the 2019 Novel Coronavirus (COVID-19), it's important to maintain an effective arsenal of antiviral protection to mitigate transmission. The naturally citrus fruit derived anti-coronaviral compound hesperetin is an ideal candidate to add to this arsenal. A bioflavonoid derived from oranges, hesperetin has demonstrated potential for preventing coronaviral infections, inhibiting the ability of the viral particles to self-assemble. This delays viral spread, giving the immune system more time to fight off potential infection before it occurs.

Hesperetin is able to inhibit SARS-coronavirus replication via dose dependent inhibition of 3C-like protease, an enzyme required to cleave viral peptides into the active proteins required to form new viruses (1). Coronaviruses, like all viruses, are made up of many specifically arranged proteins. When they are replicating, via the hijacking of microscopic human cell machinery (ribosomes), the viruses generate multiple proteins as one long peptide strand, connected together. Much like an Airfix model, these proteins must be cut apart ('popped out') before they are able to be properly assembled into an active viral particle. As such, inhibition of the viral protease by hesperetin reduces the rate at which new viruses form, allowing more time for the cell to destroy the large strand of inactive peptide before the viral proteins can be formed from it. The IC50 (concentration at which 50% of protease enzymes are inhibited at any one time) of hesperetin for the protease is 8.3μM, very promising for a natural compound (2).

Hesperetin can also be obtained in a potentially longer acting form, as the glycoside hesperidin. Depicted right, hesperidin has a rutinoside sugar moiety attached, which is first cleaved by the body before forming the active hesperetin. This also potentially protects the active hesperetin from metabolism for longer. One paper indicates that intake of 444mg of hesperidin (from 1L of orange juice), following conversion to hesperetin in the body, results in a peak plasma concentration of 1.28μM hesperetin (3). This indicates that only a few grams of hesperidin could potentially raise plasma concentrations of hesperetin sufficiently to elicit the anti-coronaviral effect expected at the IC50 of 8.3μM mentioned prior. A paper by researchers from Stanford and Hong Kong universities even suggested that hesperetin would be a viable compound to be used in drug development for preventing spread of COVID-19 (4).

Please note that despite the promising science behind hesperetin and hesperidin, they are not a clinically trialed substitute for medical interventions and should only be used prophylactically in the absence of human trials.

1 - De Clercq, E. (2006). Potential antivirals and antiviral strategies against SARS coronavirus infections. Expert review of anti-infective therapy, 4(2), 291-302.

2 - Lin, C. W., Tsai, F. J., Tsai, C. H., Lai, C. C., Wan, L., Ho, T. Y., & Chao, P. D. L. (2005). Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral research, 68(1), 36-42.

3 - Manach, C. 1., Morand, C., Gil-Izquierdo, A., Bouteloup-Demange, C., & Remesy, C. (2003). Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice. European journal of clinical nutrition, 57(2), 235-242.

4 - Chen, H., & Du, Q. (2020). Potential Natural Compounds for Preventing 2019-nCoV Infection.

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Hesperetin

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Hesperidin (hesperetin glycoside)