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Review
. 2021 Jun 18;22(12):6551.
doi: 10.3390/ijms22126551.

Estrogen Receptor Modulators in Viral Infections Such as SARS-CoV-2: Therapeutic Consequences

Nikita Abramenko  1   2 , Fréderic Vellieux  1 , Petra Tesařová  3 , Zdeněk Kejík  1   2 , Robert Kaplánek  1   2 , Lukáš Lacina  1   4   5 , Barbora Dvořánková  1   4 , Daniel Rösel  6 , Jan Brábek  6 , Adam Tesař  7 , Milan Jakubek  1   2 , Karel Smetana Jr  1   4
Affiliations
Review

Estrogen Receptor Modulators in Viral Infections Such as SARS-CoV-2: Therapeutic Consequences

Nikita Abramenko et al. Int J Mol Sci. .

Abstract

COVID-19 is a pandemic respiratory disease caused by the SARS-CoV-2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient's death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient's organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal.

Keywords: COVID-19; IL-6; SARS−CoV−2; cytokine storm; estrogen; estrogen receptor; viral replication.

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Conflict of interest statement

K.S.J., M.J., D.R. and J.B. cooperates with Oxygen Biotech LLC 108 W 13th St. Wilmington DE 19801. This company had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript or in the decision to publish the results. Other authors, i.e., N.A., F.V., P.T., Z.K., R.K., L.L., A.T. and B.D. declare no conflicts of interest.

Figures

Figure 1
Figure 1
Number of SARS−CoV−2 infections in the Czech Republic until mid-February 2021 according to the data published by the Ministry of Health of the Czech Republic.
Figure 2
Figure 2
Number of deaths in the Czech Republic until mid–February 2021 according to the data published by the Ministry of Health of the Czech Republic.
Figure 3
Figure 3
Effect of hormonal therapy of female breast cancer patients with tamoxifene on the sensi-tivity to SARS−CoV−2 infection. Females treated by this drug were not as sensitive to infection as non-treated patients. The effect of therapy was higher in postmenopausal women without the production of estrogens.
Figure 4
Figure 4
The best docking pose of estrone (above) and bazedoxifene (below) to the SARS−CoV−2 main protease structure (Mpro) (A,C) and papain-like protease (PLpro) trimer (B,B1,D,D1). Pymol representation of the SARS−CoV−2 main protease (PDB id 6y7b) shown as a green ribbon with the secondary structure elements indicated. In blue sticks: the best docking pose for estrone (A) or bazedoxifene (C). The best docking poses of the estrone (B,B1) and bazedoxifene (D,D1) molecule in PLpro trimer (PDB id 6w9c) are localized in the vicinity of the zinc ion present at the central interface of the trimer.
Figure 5
Figure 5
The best docking pose of estrogens (A) and other examples of ERM, such as bazedoxifene, genistein and raloxifene (B) to the SARS−CoV−2 main protease structure (Mpro) with characterization of the interaction including hydrogen bonds.
Figure 6
Figure 6
The best docking pose of oestrogens (A) and other examples of ERM such as bazedoxifene, genistin and raloxifene (B) to the SARS−CoV−2 papain-like protease structure (PLpro) (trimer form) with characterization of the interaction including hydrogen bonds.
Figure 7
Figure 7
Schematic presentation of the proposed receptor-dependent and independent effect of ERMs on the SARS−CoV−2 infection.
See this image and copyright information in PMC

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