Identification of Estrogen Receptor Modulators as Inhibitors of Flavivirus Infection

Eyre, Nicholas S.; Kirby, Emily N; Anfiteatro, Daniel R.; Bracho, Gustavo; Russo, Alice G.; White, Peter A.; Aloia, Amanda L.; Beard, Michael R.

doi:10.1128/aac.00289-20

Cited by 23 publications

(27 citation statements)

References 51 publications

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“…These mechanisms were also dependent on the interaction of hormones with their receptors. The inhibitory effect of estrogens on replication was documented [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. in a panel of viruses (for particulars see Table 1 ).…”

Section: Effect Of Oestrogen Receptor Modulators (Erms) On Viral Replicationmentioning

confidence: 99%

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

Abramenko

Vellieux

Tesařová

et al. 2021

IJMS

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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.

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Section: Effect Of Oestrogen Receptor Modulators (Erms) On Viral Replicationmentioning

confidence: 99%

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

Abramenko

Vellieux

Tesařová

et al. 2021

IJMS

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“…To briefly mention something relatively new, it is becoming appreciated that infection (bacterial, viral, yeast) may play a role in the development of Alzheimer’s disease, and it has been proposed that TSPO ligands and fucoidan may counteract such infections [ 28 , 29 , 34 , 108 , 109 ]. Very interestingly, also this year, the SERMs raloxifene hydrochloride and quinestrol were among 15 compounds that were found to effectively inhibit Zika virus (ZIKV), Dengue virus (DENV), and West Nile Virus (WNV) (Kunjin strain) infection at low micromolar concentrations with minimal cytotoxicity in Huh-7.5 hepatoma cells and HTR-8 placental trophoblast cells [ 110 ]. Furthermore, these 15 compounds appear to inhibit viral RNA replication in a manner that is independent of their known effects on estrogen receptor signaling (ERα and ERβ) [ 110 ].…”

Section: Brain Diseases Brain Injuries and Underlying Functions mentioning

confidence: 99%

“…Very interestingly, also this year, the SERMs raloxifene hydrochloride and quinestrol were among 15 compounds that were found to effectively inhibit Zika virus (ZIKV), Dengue virus (DENV), and West Nile Virus (WNV) (Kunjin strain) infection at low micromolar concentrations with minimal cytotoxicity in Huh-7.5 hepatoma cells and HTR-8 placental trophoblast cells [ 110 ]. Furthermore, these 15 compounds appear to inhibit viral RNA replication in a manner that is independent of their known effects on estrogen receptor signaling (ERα and ERβ) [ 110 ]. This may indicate that their effects are via one or more SERM associated nongenomic pathways.…”

Section: Brain Diseases Brain Injuries and Underlying Functions mentioning

confidence: 99%

“…Thus, speculating, raloxifene may stop an infection leading to Alzheimer’s disease in an early stage, but cannot overcome a full-blown infection and its aftermath damage. The study of Eyre et al [ 110 ] also suggests that raloxifene does not combat all types of viruses. This may explain why raloxifene effects on development of Alzheimer’s disease may show the large variability that is seen [ 41 , 98 , 101 ].…”

Section: Brain Diseases Brain Injuries and Underlying Functions mentioning

confidence: 99%

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Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

Veenman

2020

IJMS

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Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects—fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson’s disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health—on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer’s disease, raloxifene may not cure diagnosed Alzheimer’s disease. However, the onset of Alzheimer’s disease may be delayed or arrested by raloxifene’s capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer’s disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer’s disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved.

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“…In recent years, the rapid development of high-throughput screening methods has led to the discovery of a plethora of small-molecule compounds that can inhibit arboviral infection and/or replication in vertebrate cells [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ], and a few also proved to be effective in mosquito cells. These anti-arboviral compounds can impede the circulation of arboviruses between arthropods and humans by either rendering arboviruses more vulnerable in humans or directly inhibiting viral infection and replication in mosquitoes.…”

Section: Introductionmentioning

confidence: 99%

Antiviral Compounds for Blocking Arboviral Transmission in Mosquitoes

Dong

Dimopoulos

2021

Viruses

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Mosquito-borne arthropod-borne viruses (arboviruses) such as the dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV) are important human pathogens that are responsible for significant global morbidity and mortality. The recent emergence and re-emergence of mosquito-borne viral diseases (MBVDs) highlight the urgent need for safe and effective vaccines, therapeutics, and vector-control approaches to prevent MBVD outbreaks. In nature, arboviruses circulate between vertebrate hosts and arthropod vectors; therefore, disrupting the virus lifecycle in mosquitoes is a major approach for combating MBVDs. Several strategies were proposed to render mosquitoes that are refractory to arboviral infection, for example, those involving the generation of genetically modified mosquitoes or infection with the symbiotic bacterium Wolbachia. Due to the recent development of high-throughput screening methods, an increasing number of drugs with inhibitory effects on mosquito-borne arboviruses in mammalian cells were identified. These antivirals are useful resources that can impede the circulation of arboviruses between arthropods and humans by either rendering viruses more vulnerable in humans or suppressing viral infection by reducing the expression of host factors in mosquitoes. In this review, we summarize recent advances in small-molecule antiarboviral drugs in mammalian and mosquito cells, and discuss how to use these antivirals to block the transmission of MBVDs.

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Identification of Estrogen Receptor Modulators as Inhibitors of Flavivirus Infection

Cited by 23 publications

References 51 publications

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

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

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

Antiviral Compounds for Blocking Arboviral Transmission in Mosquitoes

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