Severe respiratory SARS-CoV2 infection: Does ACE2 receptor matter?

Perrotta, Fabio; Matera, Maria Gabriella; Cazzola, Mario; Bianco, Andrea

doi:10.1016/j.rmed.2020.105996

Cited by 166 publications

(176 citation statements)

References 51 publications

(61 reference statements)

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“… 75 , 76 Many of the HPB suppressors affect ACE2 gene expression in a tissue-specific manner. 77 − 79 To the best of our knowledge, no experimental result has been published about the effect of ACE2-specific drugs on the affinity of ACE2 for S1 of SARS-CoV-2. Some studies reported the effect of binding of some molecules to ACE2 in the closed conformation on the affinity of ACE2 for the SARS spike.…”

Section: Resultsmentioning

confidence: 99%

Studying the Effects of ACE2 Mutations on the Stability, Dynamics, and Dissociation Process of SARS-CoV-2 S1/hACE2 Complexes

Hadi-Alijanvand

Rouhani

2020

J. Proteome Res.

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A highly infectious coronavirus, SARS-CoV-2, has spread in many countries. This virus recognizes its receptor, angiotensin-converting enzyme 2 (ACE2), using the receptor binding domain of its spike protein subunit S1. Many missense mutations are reported in various human populations for the ACE2 gene. In the current study, we predict the affinity of many ACE2 variants for binding to S1 protein using different computational approaches. The dissociation process of S1 from some variants of ACE2 is studied in the current work by molecular dynamics approaches. We study the relation between structural dynamics of ACE2 in closed and open states and its affinity for S1 protein of SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Studying the Effects of ACE2 Mutations on the Stability, Dynamics, and Dissociation Process of SARS-CoV-2 S1/hACE2 Complexes

Hadi-Alijanvand

Rouhani

2020

J. Proteome Res.

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“…Its most recognized activity is inhibition of Na,K-ATPase through blockade of ATP binding sites. Other membrane-positioned enzymes requiring ATP include ACE-2 which has now been shown to be an entry receptor for SARS-CoV-2 (22). The potential role of oleandrin as an active principle ingredient in the botanical drug (PBI-05204) designed to treat malignant disease has been reported (12)(13)(14)19).…”

Section: Discussionmentioning

confidence: 99%

Prophylactic and Therapeutic Inhibition of In Vitro SARS-CoV-2 Replication by Oleandrin

Plante

Fernández

et al. 2020

Preprint

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With continued expansion of the COVID-19 pandemic, antiviral drugs are desperately needed to treat patients at high risk of life-threatening disease and even to limit spread if administered early during infection. Typically, the fastest route to identifying and licensing a safe and effective antiviral drug is to test those already shown safe in early clinical trials for other infections or diseases. Here, we tested in vitro oleandrin, derived from the Nerium oleander plant and shown previously to have inhibitory activity against several viruses. Using Vero cells, we found that prophylactic oleandrin administration at concentrations down to 0.05 μg/ml exhibited potent antiviral activity against SARS-CoV-2, with an 800-fold reduction in virus production, and a 0.1 μg/ml dose resulted in a greater than 3,000-fold reduction in infectious virus production. The EC50 values were 11.98ng/ml when virus output was measured at 24 hours post-infection, and 7.07ng/ml measured at 48 hours post-infection. Therapeutic (post-infection) treatment up to 24 hours after infection of Vero cells also reduced viral titers, with the 0.1 μg/ml dose causing greater than 100-fold reductions as measured at 48 hours, and the 0.05 μg/ml dose resulting in a 78-fold reduction. The potent prophylactic and therapeutic antiviral activities demonstrated here strongly support the further development of oleandrin to reduce the severity of COVID-19 and potentially also to reduce spread by persons diagnosed early after infection.IMPORTANCECOVID-19, a pandemic disease caused by infection with SARS-CoV-2, has swept around the world to cause millions of infections and hundreds-of-thousands of deaths due to the lack of vaccines and effective therapeutics. We tested oleandrin, derived from the Nerium oleander plant and shown previously to reduce the replication of several viruses, against SARS-CoV-2 infection of Vero cells. When administered both before and after virus infection, nanogram doses of oleandrin significantly inhibited replication by up to 3,000-fold, indicating the potential to prevent disease and virus spread in persons recently exposed to SARS-CoV-2, as well as to prevent severe disease in persons at high risk. These results indicate that oleandrin should be tested in animal models and in humans exposed to infection to determine its medical usefulness in controlling the pandemic.

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“…Several experimental studies reported that, although not directly affecting ACE2 activity, these drugs are able to upregulate its expression (Ishiyama et al, 2004;Ferrario et al, 2005;Gallagher et al, 2008). Increased expression of ACE2 has also been reported to facilitate SARS-CoV infection in several experimental models and postulated to act in the same way for SARS-CoV-2 (Li et al, 2003;Hofmann et al, 2004;Perrotta et al, 2020).…”

Section: The Controversial Role Of Ace2 Expressionmentioning

confidence: 99%

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

Saponaro

Rutigliano

Sestito

et al. 2020

Front. Mol. Biosci.

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Angiotensin-converting enzyme 2 (ACE2) is related to ACE but turned out to counteract several pathophysiological actions of ACE. ACE2 exerts antihypertensive and cardioprotective effects and reduces lung inflammation. ACE2 is subjected to extensive transcriptional and post-transcriptional modulation by epigenetic mechanisms and microRNAs. Also, ACE2 expression is regulated post-translationally by glycosylation, phosphorylation, and shedding from the plasma membrane. ACE2 protein is ubiquitous across mammalian tissues, prominently in the cardiovascular system, kidney, and intestine. ACE2 expression in the respiratory tract is of particular interest, in light of the discovery that ACE2 serves as the initial cellular target of severe acute respiratory syndrome (SARS)-coronaviruses, including the recent SARS-CoV2, responsible of the COronaVIrus Disease 2019 (COVID-19). Since the onset of the COVID-19 pandemic, an intense effort has been made to elucidate the biochemical determinants of SARS-CoV2-ACE2 interaction. It has been determined that SARS-CoV2 engages with ACE2 through its spike (S) protein, which consists of two subunits: S1, that mediates binding to the host receptor; S2, that induces fusion of the viral envelope with the host cell membrane and delivery of the viral genome. Owing to the role of ACE2 in SARS-CoV2 pathogenicity, it has been speculated that medical conditions, i.e., hypertension, and/or drugs, i.e., ACE inhibitors and angiotensin receptor blockers, known to influence ACE2 density could alter the fate of SARS-CoV-2 infection. The debate is still open and will only be solved when results of properly designed experimental and clinical investigations will be made public. An interesting observation is, however that, upon infection, ACE2 activity is reduced either by downregulation or by shedding. These events might precipitate the so-called "cytokine storm" that characterizes the most severe COVID-19 forms. As evidence accumulates, ACE2 appears a druggable target in the attempt to limit virus entry and replication. Strategies aimed at blocking ACE2 with antibodies, small molecules or peptides, or at neutralizing the virus by competitive binding with exogenously administered ACE2, are currently under investigations. In this review, we will present an overview of the state-of-the-art knowledge on ACE2 biochemistry and pathophysiology, outlining open issues in the context of COVID-19 disease and potential experimental and clinical developments.

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Severe respiratory SARS-CoV2 infection: Does ACE2 receptor matter?

Cited by 166 publications

References 51 publications

Studying the Effects of ACE2 Mutations on the Stability, Dynamics, and Dissociation Process of SARS-CoV-2 S1/hACE2 Complexes

Studying the Effects of ACE2 Mutations on the Stability, Dynamics, and Dissociation Process of SARS-CoV-2 S1/hACE2 Complexes

Prophylactic and Therapeutic Inhibition of In Vitro SARS-CoV-2 Replication by Oleandrin

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

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