Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19

Deng, Qu; Rasool, Reyaz ur; Russell, Ronnie M.; Natesan, Ramakrishnan; Asangani, Irfan A.

doi:10.1016/j.isci.2021.102254

Cited by 77 publications

(67 citation statements)

References 67 publications

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“…ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung, kidney, testis, and brain [ 20 , 22 , 58 ]. SARS-CoV-2 enters into the cell through binding of the viral S-protein to the ACE2 receptors [ 15 , 17 ]. The ACE2 receptors diminish the unfavorable effects of angiotensin II in several ways [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…SARS-CoV-2 utilizes molecules to enter the cells, such as angiotensin-converting enzyme 2 (ACE2) to attach to the receptor-binding domain (RBD) and type 2 transmembrane serine proteases (TMPRSS2) to cleave the spike (S) protein [ 15 – 17 ]. SARS-CoV-2 S-protein cleavage by TMPRSS2 initiates viral entry and also helps the virus escape the immune system [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Genetic susceptibility of COVID-19: a systematic review of current evidence

et al. 2021

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Introduction While COVID-19 pandemic continues to spread worldwide, researchers have linked patterns of traits to poor disease outcomes. Risk factors for COVID-19 include asthma, elderly age, being pregnant, having any underlying diseases such as cardiovascular disease, diabetes, obesity, and experiencing lifelong systemic racism. Recently, connections to certain genes have also been found, although the susceptibility has not yet been established. We aimed to investigate the available evidence for the genetic susceptibility to COVID-19. Methods This study was a systematic review of current evidence to investigate the genetic susceptibility of COVID-19. By systematic search and utilizing the keywords in the online databases including Scopus, PubMed, Web of Science, and Science Direct, we retrieved all the related papers and reports published in English from December 2019 to September 2020. Results According to the findings, COVID-19 uses the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry. Previous studies have shown that people with ACE2 polymorphism who have type 2 transmembrane serine proteases (TMPRSS2) are at high risk of SARS-CoV-2 infection. Also, two studies have shown that males are more likely to become infected with SARS-CoV-2 than females. Besides, research has also shown that patients possessing HLA-B*15:03 genotype may become immune to the infection. Conclusion Combing through the genome, several genes related to immune system’s response were related to the severity and susceptibility to the COVID-19. In conclusion, a correlation was found between the ACE2 levels and the susceptibility to SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic susceptibility of COVID-19: a systematic review of current evidence

et al. 2021

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“…This can result in their temporarily decreased production in COVID-19 patients. This principle was proposed and tested in animal experiments and in a limited clinical study performed in COVID-19 patients [ 91 , 92 , 93 ].…”

Section: Therapeutic Consequencesmentioning

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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“…Androgen-AR signaling induces ACE2 (Wu et al, 2020), while knockdowns of AR result in downregulation of ACE2 (Samuel et al, 2020). AR agonists also reduce SARS-CoV-2 spike protein-mediated cellular entry (Deng, Rasool, Russell, Natesan, & Asangani, 2021). Additionally, AR is associated with COVID comorbidities (Dolan et al, 2020), and recently implicated in the severity of COVID-19 in women with polycystic ovarian syndrome, a disorder associate with high androgen levels and androgen sensitivity (Gotluru, Roach, Cherry, & Runowicz, 2021).…”

Section: B Top Erc Interactions Link Ace2 To Covid Pathologiesmentioning

confidence: 99%

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

Cheng

Werren

2021

Preprint

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Angiotensin-converting enzyme 2 (ACE2) is the human cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken a different approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that "coevolve" with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact directly with ACE2, while additional predicted novel interactors with ACE2 are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as coagulation factor V and fibrinogen components FGG, FGB, and FGA, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). Additionally, ACE2 has connections to proteins involved in cytokine signaling and immune response (e.g. IFNAR2, XCR1, and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has also elucidated possible functions for previously uncharacterized proteins and possible additional functions for well-characterized ones. Suggested validation approaches for ERC predicted ACE2 interacting proteins are discussed. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.

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Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19

Cited by 77 publications

References 67 publications

Genetic susceptibility of COVID-19: a systematic review of current evidence

Genetic susceptibility of COVID-19: a systematic review of current evidence

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

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

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