scholarly journals Stapled Peptides Based on Human Angiotensin-Converting Enzyme 2 (ACE2) Potently Inhibit SARS-CoV-2 Infection In Vitro

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Francesca Curreli ◽  
Sofia M. B. Victor ◽  
Shahad Ahmed ◽  
Aleksandra Drelich ◽  
Xiaohe Tong ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Angiotensin Converting Enzyme ◽  
Human Plasma ◽  
Human Lung ◽  
Host Cells ◽  
Converting Enzyme ◽  
Stapled Peptides ◽  
Angiotensin Converting Enzyme 2 ◽  
Stapled Peptide ◽  
Potent Antiviral Activity

ABSTRACT SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as the primary receptor to enter host cells and initiate the infection. The critical binding region of ACE2 is an ∼30-amino-acid (aa)-long helix. Here, we report the design of four stapled peptides based on the ACE2 helix, which is expected to bind to SARS-CoV-2 and prevent the binding of the virus to the ACE2 receptor and disrupt the infection. All stapled peptides showed high helical contents (50 to 94% helicity). In contrast, the linear control peptide NYBSP-C showed no helicity (19%). We have evaluated the peptides in a pseudovirus-based single-cycle assay in HT1080/ACE2 cells and human lung cell line A549/ACE2, overexpressing ACE2. Three of the four stapled peptides showed potent antiviral activity in HT1080/ACE2 (50% inhibitory concentration [IC50]: 1.9 to 4.1 μM) and A549/ACE2 (IC50: 2.2 to 2.8 μM) cells. The linear peptide NYBSP-C and the double-stapled peptide StRIP16, used as controls, showed no antiviral activity. Most significantly, none of the stapled peptides show any cytotoxicity at the highest dose tested. We also evaluated the antiviral activity of the peptides by infecting Vero E6 cells with the replication-competent authentic SARS-CoV-2 (US_WA-1/2020). NYBSP-1 was the most efficient, preventing the complete formation of cytopathic effects (CPEs) at an IC100 of 17.2 μM. NYBSP-2 and NYBSP-4 also prevented the formation of the virus-induced CPE with an IC100 of about 33 μM. We determined the proteolytic stability of one of the most active stapled peptides, NYBSP-4, in human plasma, which showed a half-life (T1/2) of >289 min. IMPORTANCE SARS-CoV-2 is a novel virus with many unknowns. No vaccine or specific therapy is available yet to prevent and treat this deadly virus. Therefore, there is an urgent need to develop novel therapeutics. Structural studies revealed critical interactions between the binding site helix of the ACE2 receptor and SARS-CoV-2 receptor-binding domain (RBD). Therefore, targeting the entry pathway of SARS-CoV-2 is ideal for both prevention and treatment as it blocks the first step of the viral life cycle. We report the design of four double-stapled peptides, three of which showed potent antiviral activity in HT1080/ACE2 cells and human lung carcinoma cells, A549/ACE2. Most significantly, the active stapled peptides with antiviral activity against SARS-CoV-2 showed high α-helicity (60 to 94%). The most active stapled peptide, NYBSP-4, showed substantial resistance to degradation by proteolytic enzymes in human plasma. The lead stapled peptides are expected to pave the way for further optimization of a clinical candidate.

scholarly journals Stapled peptides based on Human Angiotensin-Converting Enzyme 2 (ACE2) potently inhibit SARS-CoV-2 infection in vitro

2020 ◽  
Author(s):  
Francesca Curreli ◽  
Sofia M B Victor ◽  
Shahad Ahmed ◽  
Aleksandra Drelich ◽  
Xiaohe Tong ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Converting Enzyme ◽  
Stapled Peptides ◽  
Angiotensin Converting Enzyme 2 ◽  
Stapled Peptide ◽  
Human Lung Cells ◽  
Critical Binding

AbstractSARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as the primary receptor to enter host cells and initiate the infection. The critical binding region of ACE2 is a ∼30 aa long helix. Here we report the design of four stapled peptides based on the ACE2 helix, which is expected to bind to SARS-CoV-2 and prevent the binding of the virus to the ACE2 receptor and disrupt the infection. All stapled peptides showed high helical contents (50-94% helicity). On the contrary, the linear control peptide NYBSP-C showed no helicity (19%). We have evaluated the peptides in a pseudovirus based single-cycle assay in HT1080/ACE2 and human lung cells A549/ACE2, overexpressing ACE2. Three of the four stapled peptides showed potent antiviral activity in HT1080/ACE2 (IC50: 1.9 – 4.1 µM) and A549/ACE2 cells (IC50: 2.2 – 2.8 µM). The linear peptides NYBSP-C and the double-stapled peptide StRIP16, used as controls, showed no antiviral activity. Most significantly, none of the stapled peptides show any cytotoxicity at the highest dose tested. We also evaluated the antiviral activity of the peptides by infecting Vero E6 cells with the replication-competent authentic SARS-CoV-2 (US_WA-1/2020). NYBSP-1 was the most efficient preventing the complete formation of cytopathic effects (CPEs) at an IC100 17.2 µM. NYBSP-2 and NYBSP-4 also prevented the formation of the virus-induced CPE with an IC100 of about 33 µM. We determined the proteolytic stability of one of the most active stapled peptides, NYBSP-4, in human plasma, which showed a half-life (T1/2) of >289 min.

scholarly journals ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19

2020 ◽  
Vol 222 (4) ◽  
pp. 556-563 ◽  
Author(s):  
Bruna G G Pinto ◽  
Antonio E R Oliveira ◽  
Youvika Singh ◽  
Leandro Jimenez ◽  
Andre N A Gonçalves ◽  
...  
Keyword(s):  
Systems Biology ◽  
Angiotensin Converting Enzyme ◽  
Obstructive Lung Disease ◽  
Human Lung ◽  
Chronic Obstructive Lung Disease ◽  
Host Cells ◽  
Chronic Obstructive ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Network Analyses

Abstract Patients who died from COVID-19 often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. Although angiotensin-converting enzyme 2 (ACE2) is crucial for SARS-CoV-2 to bind and enter host cells, no study has systematically assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples from patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. Our systems biology approach offers a possible explanation for increased COVID-19 severity in patients with certain comorbidities.

Angiotensin Converting Enzyme 2 (ACE2) Expression in the Visual System

2021 ◽  
Author(s):  
James M. Hill ◽  
Christian Clement ◽  
L. Arceneaux ◽  
Walter Lukiw
Keyword(s):  
Signal Processing ◽  
Angiotensin Converting Enzyme ◽  
Occipital Lobe ◽  
Cell Types ◽  
Receptor Expression ◽  
Host Cells ◽  
Visual Signal ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The Brain

Abstract Background: Multiple lines of evidence currently indicate that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)gains entry into human host cells via a high-affinity interaction with the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor. Research has further shown the widespread expression of the ACE2 receptor on the surface of many different immune, non-immune and neural host cell types, and that SARS-CoV-2 has there markable capability to attack many different types of human-host cells simultaneously. One principal neuroanatomical region for highACE2 expression patterns occurs in the brainstem, an area of the brain containing regulatory centers for respiration, and this may in part explain the predisposition of many COVID-19 patients to respiratory distress. Early studies also indicated extensive ACE2 expression in the whole eye and the brain’s visual circuitry. In this study we analyzed ACE2 receptor expression at the mRNA and protein level in multiple cell types involved in human vision, including cell types of the external eye and several deep brain regions known to be involved in the processing of visual signals.Methods: ACE2 mRNA and protein analysis; multiple eye and brain cells and tissues; gamma32P-adenosine tri-phosphate ([γ-32P]dATP) radiolabeled probes; Northern analysis; ELISA.Results: The four main findings were: (i)that many different optical and neural cell types of the human visual system provide receptors essential for SARS-CoV-2 invasion; (ii)the remarkable ubiquity of ACE2 presence in cells of the eye and anatomical regions of the brain involved in visual signal processing; (iii)that ACE2 receptor expression in different ocular cell types and visual processing centers of the brain provide multiple compartments for SARS-CoV-2 infiltration; and (iv)a gradient of increasing ACE2 expression from the anterior surface of the eye to the visual signal processing areas of the occipital lobe and the primary visual neocortex.Conclusion: A gradient of ACE2 expression from the eye surface to the occipital lobe provide the SARS-CoV-2 virus a novel pathway from the outer eye into deeper anatomical regions of the brain involved in vision. These findings may explain, in part, the many recently reported neuro-ophthalmic manifestations of SARS-CoV-2infection in COVID-19 affected patients.

scholarly journals Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

2021 ◽  
Vol 2 (1) ◽  
pp. 16-27
Author(s):  
Zahra Sharifinia ◽  
◽  
Samira Asadi ◽  
Mahyar Irani ◽  
Abdollah Allahverdi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Spike Protein ◽  
Potential Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

Objective: The receptor-binding domain (RBD) of the S1 domain of the SARS-CoV- 2 Spike protein performs a key role in the interaction with Angiotensin-converting enzyme 2 (ACE2), leading to both subsequent S2 domain-mediated membrane fusion and incorporation of viral RNA in host cells. Methods: In this study, we investigated the inhibitor’s targeted compounds through existing human ACE2 drugs to use as a future viral invasion. 54 FDA approved drugs were selected to assess their binding affinity to the ACE2 receptor. The structurebased methods via computational ones have been used for virtual screening of the best drugs from the drug database. Key Findings: The ligands “Cinacalcet” and “Levomefolic acid” highaffinity scores can be a potential drug preventing Spike protein of SARS-CoV-2 and human ACE2 interaction. Levomefolic acid from vitamin B family was proved to be a potential drug as a spike protein inhibitor in previous clinical and computational studies. Besides that, in this study, the capability of Levomefolic acid to avoid ACE2 and Spike protein of SARS-CoV-2 interaction is indicated. Therefore, it is worth to consider this drug for more in vitro investigations as ACE2 and Spike protein inhibition candidate. Conclusion: The two Cinacalcet and Levomefolic acid are the two ligands that have highest energy binding for human ACE2 blocking among 54 FDA approved drugs.

scholarly journals Increasing Host Cellular Receptor—Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection

2020 ◽  
Author(s):  
Pei-Hui Wang ◽  
Yun Cheng
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Emerging Infectious Diseases ◽  
Cell Receptor ◽  
Host Cells ◽  
Cellular Receptor ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Cell Receptor ◽  
Coronavirus Infection ◽  
Entry Receptor

AbstractThe ongoing outbreak of a new coronavirus (2019-nCoV) causes an epidemic of acute respiratory syndrome in humans. 2019-nCoV rapidly spread to national regions and multiple other countries, thus, pose a serious threat to public health. Recent studies show that spike (S) proteins of 2019-nCoV and SARS-CoV may use the same host cell receptor called angiotensin-converting enzyme 2 (ACE2) for entering into host cells. The affinity between ACE2 and 2019-nCoV S is much higher than ACE2 binding to SARS-CoV S protein, explaining that why 2019-nCoV seems to be more readily transmitted from the human to human. Here, we reported that ACE2 can be significantly upregulated after infection of various viruses including SARS-CoV and MERS-CoV. Basing on findings here, we propose that coronavirus infection can positively induce its cellular entry receptor to accelerate their replication and spread, thus drugs targeting ACE2 expression may be prepared for the future emerging infectious diseases caused by this cluster of viruses.

scholarly journals Structural Dissection of Viral Spike-Protein Binding of SARS-CoV-2 and SARS-CoV-1 to the Human Angiotensin-Converting Enzyme 2 (ACE2) as Cellular Receptor

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1038
Author(s):  
Deborah Giordano ◽  
Luigi De Masi ◽  
Maria Antonia Argenio ◽  
Angelo Facchiano
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico Analysis ◽  
Host Cells ◽  
Spike Protein ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The World ◽  
Silico Analysis

An outbreak by a new severe acute respiratory syndrome betacoronavirus (SARS-CoV-2) has spread CoronaVirus Disease 2019 (COVID-19) all over the world. Immediately, following studies have confirmed the human Angiotensin-Converting Enzyme 2 (ACE2) as a cellular receptor of viral Spike-Protein (Sp) that mediates the CoV-2 invasion into the pulmonary host cells. Here, we compared the molecular interactions of the viral Sp from previous SARS-CoV-1 of 2002 and SARS-CoV-2 with the host ACE2 protein by in silico analysis of the available experimental structures of Sp-ACE2 complexes. The K417 amino acid residue, located in the region of Sp Receptor-Binding Domain (RBD) of the new coronavirus SARS-CoV-2, showed to have a key role for the binding to the ACE2 N-terminal region. The R426 residue of SARS-CoV-1 Sp-RBD also plays a key role, although by interacting with the central region of the ACE2 sequence. Therefore, our study evidenced peculiarities in the interactions of the two Sp-ACE2 complexes. Our outcomes were consistent with previously reported mutagenesis studies on SARS-CoV-1 and support the idea that a new and different RBD was acquired by SARS-CoV-2. These results have interesting implications and suggest further investigations.

scholarly journals Novel Evidence of Acute Kidney Injury in COVID-19

2020 ◽  
Vol 9 (11) ◽  
pp. 3547
Author(s):  
Ti-I Chueh ◽  
Cai-Mei Zheng ◽  
Yi-Chou Hou ◽  
Kuo-Cheng Lu
Keyword(s):  
Acute Kidney Injury ◽  
Angiotensin Converting Enzyme ◽  
Kidney Injury ◽  
Host Cells ◽  
Current Evidence ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

The coronavirus 2019 (COVID-19) pandemic has caused a huge impact on health and economic issues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes cellular damage by entry mediated by the angiotensin-converting enzyme 2 of the host cells and its conjugation with spike proteins of SARS-CoV-2. Beyond airway infection and acute respiratory distress syndrome, acute kidney injury is common in SARS-CoV-2-associated infection, and acute kidney injury (AKI) is predictive to multiorgan dysfunction in SARS-CoV-2 infection. Beyond the cytokine storm and hemodynamic instability, SARS-CoV-2 might directly induce kidney injury and cause histopathologic characteristics, including acute tubular necrosis, podocytopathy and microangiopathy. The expression of apparatus mediating SARS-CoV-2 entry, including angiotensin-converting enzyme 2, transmembrane protease serine 2 (TMPRSS2) and a disintegrin and metalloprotease 17 (ADAM17), within the renal tubular cells is highly associated with acute kidney injury mediated by SARS-CoV-2. Both entry from the luminal and basolateral sides of the renal tubular cells are the possible routes for COVID-19, and the microthrombi associated with severe sepsis and the dysregulated renin–angiotensin–aldosterone system worsen further renal injury in SARS-CoV-2-associated AKI. In the podocytes of the glomerulus, injured podocyte expressed CD147, which mediated the entry of SARS-CoV-2 and worsen further foot process effacement, which would worsen proteinuria, and the chronic hazard induced by SARS-CoV-2-mediated kidney injury is still unknown. Therefore, the aim of the review is to summarize current evidence on SARS-CoV-2-associated AKI and the possible pathogenesis directly by SARS-CoV-2.

scholarly journals Natural Flavonoids as Potential Angiotensin-Converting Enzyme 2 Inhibitors for Anti-SARS-CoV-2

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3980 ◽  
Author(s):  
Muchtaridi Muchtaridi ◽  
M. Fauzi ◽  
Nur Kusaira Khairul Ikram ◽  
Amirah Mohd Gazzali ◽  
Habibah A. Wahab
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Converting Enzyme ◽  
Mortality And Morbidity ◽  
Angiotensin Converting Enzyme 2 ◽  
Arterial Blood ◽  
Potential Efficacy ◽  
Novel Coronavirus

Over the years, coronaviruses (CoV) have posed a severe public health threat, causing an increase in mortality and morbidity rates throughout the world. The recent outbreak of a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current Coronavirus Disease 2019 (COVID-19) pandemic that affected more than 215 countries with over 23 million cases and 800,000 deaths as of today. The situation is critical, especially with the absence of specific medicines or vaccines; hence, efforts toward the development of anti-COVID-19 medicines are being intensively undertaken. One of the potential therapeutic targets of anti-COVID-19 drugs is the angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as a key functional receptor for CoV associated with COVID-19. ACE2, which is located on the surface of the host cells, binds effectively to the spike protein of CoV, thus enabling the virus to infect the epithelial cells of the host. Previous studies showed that certain flavonoids exhibit angiotensin-converting enzyme inhibition activity, which plays a crucial role in the regulation of arterial blood pressure. Thus, it is being postulated that these flavonoids might also interact with ACE2. This postulation might be of interest because these compounds also show antiviral activity in vitro. This article summarizes the natural flavonoids with potential efficacy against COVID-19 through ACE2 receptor inhibition.

scholarly journals Quantifying renin-angiotensin-system alterations in COVID-19

2021 ◽  
Author(s):  
Fabrizio Pucci ◽  
Filippo Annoni ◽  
Robson Augusto Souza dos Santos ◽  
Fabio Silvio Taccone ◽  
Marianne Rooman
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Entry Point ◽  
Host Cells ◽  
Pivotal Role ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Physiological Processes

Abstract The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, so many studies have been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical and experimental analyzes, which, for example, quantify the levels and activity of RAS components, in order to disentangle the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. Finally, we discussed the effects of some RAS-targeting drugs, and how they could potentially contribute to restore the normal RAS functionality and minimize COVID-19 severity.

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