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Article ; Online: ACE2, Metformin, and COVID-19.

Malhotra, Atul / Hepokoski, Mark / McCowen, Karen C / Y-J Shyy, John

iScience

2020 Volume 23, Issue 9, Page(s) 101425

Abstract: ... as the binding of SARS-CoV-2 spike protein (S protein) is required for viral entry and development of COVID-19 ... are currently available. Angiotensin converting enzyme 2 (ACE2) is essential to COVID-19 pathogenesis ... ACE2 regulates the protective arm of the renin-angiotensin-aldosterone system (RAAS) that endows ...

Abstract	COVID-19 is becoming a leading cause of mortality throughout the world, and few effective therapies are currently available. Angiotensin converting enzyme 2 (ACE2) is essential to COVID-19 pathogenesis, as the binding of SARS-CoV-2 spike protein (S protein) is required for viral entry and development of COVID-19. ACE2 regulates the protective arm of the renin-angiotensin-aldosterone system (RAAS) that endows anti-hypertensive and anti-inflammatory effects in the cardiovascular and pulmonary systems. Preclinical data suggest ACE2 might be downregulated after SARS-CoV-2 binding, and treatments that increase ACE2 may prevent cardiopulmonary injury. Development, testing, and mass production of novel ACE2 therapies may take years, whereas more effective treatments for COVID-19 are needed urgently. Metformin is a widely available anti-diabetic agent that has an excellent safety profile, and clinical and preclinical data suggest metformin may offer cardiopulmonary protection in COVID-19 via enhanced ACE2 expression.
Keywords	covid19
Language	English
Publishing date	2020-07-31
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2020.101425
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Riding the Wave: Unveiling the Conformational Waves from RBD to ACE2

Maroli, Nikhil

bioRxiv

Abstract: ... in the promiscuity of viral entry as it may allow the receptor to interact with various related and unrelated ligands ... The binding affinity between angiotensin-converting enzyme 2 (ACE2) and the receptor binding domain ... that determines the binding affinity between ACE2 and RBD. These induced structural changes or conformational ...

Abstract	The binding affinity between angiotensin-converting enzyme 2 (ACE2) and the receptor binding domain (RBD) plays a crucial role in the transmission and re-infection of SARS CoV2. Here, microsecond molecular dynamics simulations revealed that point mutations in the RBD domain induced conformational transitions that determines the binding affinity between ACE2 and RBD. These induced structural changes or conformational waves propagate through the RBD domain, leading to changes in the orientation of both ACE2 and the RBD residues at the binding site. The ACE2 receptor shows significant structural heterogeneity, whereas its binding to the RBD domain indicates a much greater degree of structural homogeneity. We found that the receptor is more flexible in its unbound state, and the binding of RBD domains changes it through induced structural transitions. The structural heterogeneity observed in the ACE2 unbound form plays a role in the promiscuity of viral entry as it may allow the receptor to interact with various related and unrelated ligands. Furthermore, rigidity may be important for stabilizing the complex and ensuring the proper orientation of the RBD-binding interface with ACE2. The greater structural homogeneity observed in the ACE2-RBD complex revealed the effectiveness of neutralizing antibodies and vaccines that are primarily directed towards the RBD-binding interface. Binding of the B38 antibody revealed restricted conformational transitions in the RBD and ACE2 receptor due to tight binding of the monoclonal neutralizing antibody.
Keywords	covid19
Language	English
Publishing date	2023-05-12
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.05.12.540230
Database	COVID19

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Article ; Online: Coronaviruses use ACE2 monomers as entry receptors

Eiring, Patrick / Klein, Teresa / Backes, Simone / Streit, Marcel / Doose, Soeren / Beliu, Gerti / Sauer, Markus

bioRxiv

Abstract: ... spike (S) proteins protruding from the viral surface. It has been suggested that trimeric S proteins ... The angiotensin-converting enzyme 2 (ACE2) has been identified as entry receptor on cells enabling ... preferably bind to plasma membrane areas with high concentrations of preferably multimeric ACE2 receptors ...

Abstract	The angiotensin-converting enzyme 2 (ACE2) has been identified as entry receptor on cells enabling binding and infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via trimeric spike (S) proteins protruding from the viral surface. It has been suggested that trimeric S proteins preferably bind to plasma membrane areas with high concentrations of preferably multimeric ACE2 receptors to achieve a higher binding and infection efficiency. However, our current knowledge about the influence of ACE2 expression and organization in the plasma membrane on SARS-CoV-2 infection efficiency remains elusive. Here we used direct stochastic optical reconstruction microscopy (dSTORM) in combination with different labeling approaches to visualize the distribution and quantify the expression of ACE2 on different cells. Our results reveal that endogenous ACE2 receptors are present as monomers in the plasma membrane with densities of only 1-2 receptors um-2. In addition, binding of trimeric S proteins does not induce clustering of ACE2 receptors in the plasma membrane. Supported by infection studies using vesicular stomatitis virus (VSV) particles bearing S proteins our data demonstrate that a single S protein interaction per virus particle with a monomeric ACE2 receptor is sufficient for infection which attests SARS-CoV-2 a high infectivity.
Keywords	covid19
Language	English
Publishing date	2023-01-25
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.01.25.525479
Database	COVID19

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Article ; Online: Modulation of SARS-CoV-2 spike binding to ACE2 through conformational selection

Saha, Prithwidip / Fernanadez, Ignacio / Sumbul, Fidan / Valotteau, Claire / Kostrz, Dorota / Meola, Annalisa / Baquero, Eduard / Sharma, Arvind / Portman, James R. / Stransky, Francois / Boudier, Thomas / Guardado Calvo, Pablo / Gosse, Charlie / Strick, Terence / Rey, Felix A. / Rico, Felix

bioRxiv

Abstract: The first step of SARS-CoV-2 infection involves the interaction between the trimeric viral spike ...

Abstract	The first step of SARS-CoV-2 infection involves the interaction between the trimeric viral spike protein () and the host angiotensin-converting enzyme 2 (2). The receptor binding domain () of adopts two conformations: open and closed, respectively, accessible and inaccessible to 2. Therefore, motions are suspected to affect 2 binding; yet a quantitative description of the underlying mechanism has been elusive. Here, using single-molecule approaches, we visualize opening and closing and probe the /2 interaction. Our results show that RBD dynamics affect 2 binding but not unbinding. The resulting modulation is quantitatively predicted by a conformational selection model in which each protomer behaves independently. Our work reveals a general molecular mechanism affecting binding affinity without altering binding strength, helping to understand coronavirus infection and immune evasion.
Keywords	covid19
Language	English
Publishing date	2024-03-18
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.03.15.585207
Database	COVID19

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Article ; Online: The Two Faces of ACE2

Mira Bosso / Thangavel Alphonse Thanaraj / Mohamed Abu-Farha / Muath Alanbaei / Jehad Abubaker / Fahd Al-Mulla

Molecular Therapy: Methods & Clinical Development, Vol 18, Iss , Pp 321-

The Role of ACE2 Receptor and Its Polymorphisms in Hypertension and COVID-19

2020 Volume 327

Abstract: ... susceptibility to viral host cell entry and propagation. On the other hand, several genetic association studies ... the binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor, well-known for its role in counteracting ... ACE. ACE2 is involved in modulating blood pressure and establishing blood pressure homeostasis ...

Abstract	The mechanism for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires the binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor, well-known for its role in counteracting ACE. ACE2 is involved in modulating blood pressure and establishing blood pressure homeostasis. Recently, a critical debatable question has arisen whether using antihypertensive medications will have a favorable impact on people infected with SARS-CoV-2 or a deleterious one, mainly because angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) therapy can modulate the expression of ACE2 protein. The concern is that the use of ACEIs and ARBs will increase the expression of ACE2 and increase patient susceptibility to viral host cell entry and propagation. On the other hand, several genetic association studies have examined the relationship between ACE2 genetic variants and the risk of developing hypertension in different ethnic populations. In this review, we discuss the ongoing arguments in the literature about ACE2’s role in mortality rate among coronavirus disease 2019 (COVID-19) patients comorbid with hypertension and critically evaluate the current debate about the usage or discontinuation of ACEI/ARB antihypertensive drugs. Moreover, we explore the two opposing roles that ACE2 genetic variants might be playing in COVID-19 by reducing ACE2 receptor effectiveness and mitigating SARS-CoV-2 infectivity.
Keywords	ACE2 ; hypertension ; genetic variants ; angiotensin-renin system ; SARS-CoV-2 ; ACEI ; Genetics ; QH426-470 ; Cytology ; QH573-671 ; covid19
Subject code	610
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of ACE2 modifiers by CRISPR screening

Sherman, Emily J / Mirabelli, Carmen / Tang, Vi T / Khan, Taslima G / Kennedy, Andrew A / Graham, Sarah E / Willer, Cristen / Tai, Andrew W / Sexton, Jonathan Z / Wobus, Christiane E / Emmer, Brian T

bioRxiv

Abstract: SARS-CoV-2 infection is initiated by binding of the viral spike protein to its receptor, ACE2 ... on the surface of host cells. ACE2 expression is heterogeneous both in vivo and in immortalized cell lines ... but the molecular pathways that govern ACE2 expression remain unclear. We now report high-throughput CRISPR screens ...

Abstract	SARS-CoV-2 infection is initiated by binding of the viral spike protein to its receptor, ACE2, on the surface of host cells. ACE2 expression is heterogeneous both in vivo and in immortalized cell lines, but the molecular pathways that govern ACE2 expression remain unclear. We now report high-throughput CRISPR screens for functional modifiers of ACE2 surface abundance. We identified 35 genes whose disruption was associated with a change in the surface abundance of ACE2 in HuH7 cells. Enriched among these ACE2 regulators were established transcription factors, epigenetic regulators, and functional networks. We further characterized individual cell lines with disruption of SMAD4, EP300, PIAS1, or BAMBI and found these genes to regulate ACE2 at the mRNA level and to influence cellular susceptibility to SARS-CoV-2 infection. Collectively, our findings clarify the host factors involved in SARS-CoV-2 entry and suggest potential targets for therapeutic development.
Keywords	covid19
Language	English
Publishing date	2021-06-10
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.06.10.447768
Database	COVID19

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Article ; Online: ACE2 contributes to the maintenance of mouse epithelial barrier function.

Yu, Wei / Ou, Xianhong / Liu, Xiaofan / Zhang, Shuaixu / Gao, Xinxin / Cheng, Hongju / Zhu, Baoliang / Yan, Jing

Biochemical and biophysical research communications

2020 Volume 533, Issue 4, Page(s) 1276–1282

Abstract: ... Given that angiotensin I converting enzyme 2 (ACE2) is the viral entry molecule, understanding ACE2 has become a major ... focus of current COVID-19 research. ACE2 is highly expressed in the gut, but its role has not been fully ... understood and thus COVID-19 treatments intending to downregulate ACE2 level may cause untoward side effects ...

Abstract	Background: The whole world was hit hard by the coronavirus disease-19 (COVID-19). Given that angiotensin I converting enzyme 2 (ACE2) is the viral entry molecule, understanding ACE2 has become a major focus of current COVID-19 research. ACE2 is highly expressed in the gut, but its role has not been fully understood and thus COVID-19 treatments intending to downregulate ACE2 level may cause untoward side effects. Gaining insight into the functions of ACE2 in gut homeostasis therefore merits closer examination, and is beneficial to find potential therapeutic alternatives for COVID-19. Methods: We took advantage of Ace2 knockout out mice and isolated intestinal organoids to examine the role of ACE2 in intestinal stemness. Inflammatory bowel disease (IBD) mouse model was established by 4% dextran sodium sulfate. LGR5 and KI67 levels were quantitated to reflect the virtue of intestinal stem cells (ISCs). FITC-dextran 4 (FD-4) assay was used to assess intestinal barrier function. Results: Western blotting identified the expression of ACE2 in colon, which was consistent with the results of immunofluorescence and RT-PCR. Moreover, Ace2 Conclusions: Our data reveal that ACE2 contributes to the proliferation of intestinal stem cells and hence orchestrates the mucosal homeostasis.
MeSH term(s)	Angiotensin-Converting Enzyme 2/deficiency ; Angiotensin-Converting Enzyme 2/metabolism ; Animals ; Calcium/metabolism ; Cell Membrane Permeability ; Epithelium/metabolism ; Inflammatory Bowel Diseases/enzymology ; Inflammatory Bowel Diseases/pathology ; Intestines/pathology ; Mice, Inbred C57BL ; Mice, Knockout ; Organoids/metabolism ; Stem Cells/cytology ; Stem Cells/metabolism
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Calcium (SY7Q814VUP)
Keywords	covid19
Language	English
Publishing date	2020-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2020.10.002
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Article ; Online: Temperature-dependent Spike-ACE2 interaction of Omicron subvariants is associated with viral transmission

Benlarbi, Mehdi / Ding, Shilei / Belanger, Etienne / Tauzin, Alexandra / Poujol, Raphael / Medjahed, Halima / El Ferri, Omar / Bo, Yuxia / Bourassa, Catherine / Hussin, Julie / Fafard, Judith / Pazgier, Marzena / Levade, Ines / Abrams, Cameron / Cote, Marceline / Finzi, Andres

bioRxiv

Abstract: ... plasma-mediated recognition and neutralization, ACE2 binding, their susceptibility to cold inactivation ... Spike processing, as well as the impact of temperature on Spike-ACE2 interaction. We found that compared ... 5) mRNA vaccine and improve ACE2 binding, particularly at low temperatures. Moreover, BA.2.86 had ...

Abstract	The continued evolution of SARS-CoV-2 requires persistent monitoring of its subvariants. Omicron subvariants are responsible for the vast majority of SARS-CoV-2 infections worldwide, with XBB and BA.2.86 sublineages representing more than 90% of circulating strains as of January 2024. In this study, we characterized the functional properties of Spike glycoproteins from BA.2.75, CH.1.1, DV.7.1, BA.4/5, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.1.5, FD.1.1, EG.5.1, HK.3 BA.2.86 and JN.1. We tested their capacity to evade plasma-mediated recognition and neutralization, ACE2 binding, their susceptibility to cold inactivation, Spike processing, as well as the impact of temperature on Spike-ACE2 interaction. We found that compared to the early wild-type (D614G) strain, most Omicron subvariants Spike glycoproteins evolved to escape recognition and neutralization by plasma from individuals who received a fifth dose of bivalent (BA.1 or BA.4/5) mRNA vaccine and improve ACE2 binding, particularly at low temperatures. Moreover, BA.2.86 had the best affinity for ACE2 at all temperatures tested. We found that Omicron subvariants Spike processing is associated with their susceptibility to cold inactivation. Intriguingly, we found that Spike-ACE2 binding at low temperature was significantly associated with growth rates of Omicron subvariants in humans. Overall, we report that Spikes from newly emerged Omicron subvariants are relatively more stable and resistant to plasma-mediated neutralization, present improved affinity for ACE2 which is associated, particularly at low temperatures, with their growth rates.
Keywords	covid19
Language	English
Publishing date	2024-01-23
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.01.20.576353
Database	COVID19

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Article ; Online: Temperature-dependent Spike-ACE2 interaction of Omicron subvariants is associated with viral transmission

Benlarbi, Mehdi / Ding, Shilei / Bélanger, Étienne / Tauzin, Alexandra / Poujol, Raphaël / Medjahed, Halima / El Ferri, Omar / Bo, Yuxia / Bourassa, Catherine / Hussin, Julie / Fafard, Judith / Pazgier, Marzena / Levade, Inès / Abrams, Cameron / Côté, Marceline / Finzi, Andrés

bioRxiv

Abstract	The continued evolution of SARS-CoV-2 requires persistent monitoring of its subvariants. Omicron subvariants are responsible for the vast majority of SARS-CoV-2 infections worldwide, with XBB and BA.2.86 sublineages representing more than 90% of circulating strains as of January 2024. In this study, we characterized the functional properties of Spike glycoproteins from BA.2.75, CH.1.1, DV.7.1, BA.4/5, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.1.5, FD.1.1, EG.5.1, HK.3 BA.2.86 and JN.1. We tested their capacity to evade plasma-mediated recognition and neutralization, ACE2 binding, their susceptibility to cold inactivation, Spike processing, as well as the impact of temperature on Spike-ACE2 interaction. We found that compared to the early wild-type (D614G) strain, most Omicron subvariants Spike glycoproteins evolved to escape recognition and neutralization by plasma from individuals who received a fifth dose of bivalent (BA.1 or BA.4/5) mRNA vaccine and improve ACE2 binding, particularly at low temperatures. Moreover, BA.2.86 had the best affinity for ACE2 at all temperatures tested. We found that Omicron subvariants Spike processing is associated with their susceptibility to cold inactivation. Intriguingly, we found that Spike-ACE2 binding at low temperature was significantly associated with growth rates of Omicron subvariants in humans. Overall, we report that Spikes from newly emerged Omicron subvariants are relatively more stable and resistant to plasma-mediated neutralization, present improved affinity for ACE2 which is associated, particularly at low temperatures, with their growth rates.
Keywords	covid19
Language	English
Publishing date	2024-01-23
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.01.20.576353
Database	COVID19

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Article ; Online: The flexibility of ACE2 in the context of SARS-CoV-2 infection.

Barros, E P / Casalino, L / Gaieb, Z / Dommer, A C / Wang, Y / Fallon, L / Raguette, L / Belfon, K / Simmerling, C / Amaro, R E

bioRxiv : the preprint server for biology

2020

Abstract: ... many questions remain outstanding on the mechanism of SARS-CoV-2 viral association to angiotensin-converting ... indicate some degree of flexibility in the viral extracellular Spike glycoprotein and at the receptor ... enzyme 2 (ACE2), its main host receptor, and entry in the cell. Structural and biophysical studies ...

Abstract	The COVID-19 pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine developments efforts are underway, many questions remain outstanding on the mechanism of SARS-CoV-2 viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and entry in the cell. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular Spike glycoprotein and at the receptor binding domain-receptor interface, suggesting a role in infection. Here, we perform all-atom molecular dynamics simulations of the glycosylated, full-length membrane-bound ACE2 receptor, in both an apo and spike receptor binding domain (RBD) bound state, in order to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix, while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer, and suggests a mechanical contribution of the host receptor towards the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can be exploited for the rational design of effective SARS-CoV-2 therapeutics. Statement of significance: As the host receptor of SARS-CoV-2, ACE2 has been the subject of extensive structural and antibody design efforts in aims to curtail COVID-19 spread. Here, we perform molecular dynamics simulations of the homodimer ACE2 full-length structure to study the dynamics of this protein in the context of the cellular membrane. The simulations evidence exceptional plasticity in the protein structure due to flexible hinge motions in the head-transmembrane domain linker region and helix mobility in the membrane, resulting in a varied ensemble of conformations distinct from the experimental structures. Our findings suggest a dynamical contribution of ACE2 to the spike glycoprotein shedding required for infection, and contribute to the question of stoichiometry of the Spike-ACE2 complex.
Keywords	covid19
Language	English
Publishing date	2020-09-16
Publishing country	United States
Document type	Preprint
ISSN	2692-8205
ISSN (online)	2692-8205
DOI	10.1101/2020.09.16.300459
Database	MEDical Literature Analysis and Retrieval System OnLINE

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