FUNCTION AND MECHANISM OF ANGIOTENSIN-CONVERTING ENZYME-2 RECEPTOR TO TRANSPORT SARS-COV-2 INTO THE HOST CELLS―A REVIEW

Novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly spread across the world. SARS-CoV-2 is viewed as a continuous global health threat resulting in an alarming number of fatalities worldwide. Angiotensin-converting enzyme-2 (ACE2) has been recognized as one of the vital receptors for the SARS-CoV-2, leading to viral entry into the host cells. It also helps many other receptors, which initiate the entry of SARS-CoV-2 in the host body. A variety of proteins and enzymes are involved in triggering the transport mechanism. The route of viral infection depends on the distribution and expression of receptors, as the virus reaches the cell by binding to cell receptors to complete intracellular replication, virus release, and cause cytotoxicity. In addition to alveolar lung tissues, ACE2 also plays a pivotal role in other organs. Due to the abundant presence in lung cells, SARS-CoV-2 mostly affects the lungs and causes their destruction. The spike protein utilizes the digestion of ACE2, which strongly contributes to the pathogenesis of severe lung failure. Different experiments show that ACE2 not only helps the virus to migrate in the host cell but also allow us to fight against this pandemic disease. This review article summarizes the current progress that highlights the critical biological functionalities and mechanisms of ACE2 as the novel receptor to transport SARS-CoV-2 into host cells matrix.

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ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

Human Genomics ◽

10.1186/s40246-021-00304-9 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Sally Badawi ◽

Bassam R. Ali

Keyword(s):

Cell Surface ◽

Angiotensin Converting Enzyme ◽

The Novel ◽

Converting Enzyme ◽

Post Translational Modifications ◽

Angiotensin Converting Enzyme 2 ◽

Viral Attachment ◽

Novel Coronavirus ◽

Effective Medication ◽

Potential Use

AbstractWith the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.

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ACE-2-derived Biomimetic Peptides for the Inhibition of Spike Protein of SARS-CoV-2

10.26434/chemrxiv.12335933.v1 ◽

2020 ◽

Author(s):

Saroj Kumar Panda ◽

Parth Sarthi Sen Gupta ◽

Satyaranjan Biswal ◽

Abhik Kumar Ray ◽

Malay Kumar Rana

Keyword(s):

Principal Component ◽

Host Cells ◽

Spike Protein ◽

Peptide Inhibitor ◽

The Novel ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Inhibition Assay ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus

<p>SARS-CoV-2, a novel coronavirus causing overwhelming death and infection worldwide, has emerged as a pandemic. Compared to its predecessor SARS-CoV, SARS-CoV-2 is more infective for being highly contagious and exhibiting tighter binding with host angiotensin-converting enzyme 2 (hACE-2). The entry of the virus into host cells is mediated by the interaction of its spike protein with hACE-2. Thus, a peptide that has a resemblance to hACE-2 but can overpower the spike protein-hACE-2 interaction will be a potential therapeutic to contain this virus. The non-interacting residues in the receptor-binding domain of hACE-2 have been mutated to generate a library of 136 new peptides. Out of this library, docking and virtual screening discover seven peptides that can exert a stronger interaction with the spike protein than hACE-2. A peptide derived from simultaneous mutation of all the non-interacting residues of hACE-2 yields two-fold stronger interaction than hACE-2 and thus turns out here to be the best peptide-inhibitor of the novel coronavirus. The binding of the spike protein and the best peptide-inhibitor with hACE-2 is explored further by molecular dynamics, free energy, and principal component analysis to demonstrate its efficacy. Further, the inhibition assay study with the best peptide inhibitor is in progress. </p>

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

Molecules ◽

10.3390/molecules25173980 ◽

2020 ◽

Vol 25 (17) ◽

pp. 3980 ◽

Cited By ~ 4

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.

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Impact of Thiol-Disulfide Balance on the Binding of Covid-19 Spike Protein with Angiotensin Converting Enzyme 2 Receptor

10.1101/2020.05.07.083147 ◽

2020 ◽

Cited By ~ 4

Author(s):

Sanchita Hati ◽

Sudeep Bhattacharyya

Keyword(s):

Angiotensin Converting Enzyme ◽

Binding Affinity ◽

Disulfide Bonds ◽

Host Cells ◽

Converting Enzyme ◽

Dynamic Simulations ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus ◽

The Impact ◽

Spike Proteins

AbstractThe novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease (COVID-19), which started in 2019. This is a member of Coronaviridae family in the genus Betacoronavirus, which also includes SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). The angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV and SARS-CoV-2 to enter the host cells. In particular, the interaction of viral spike proteins with ACE2 is a critical step in the viral replication cycle. The receptor binding domain of the viral spike proteins and ACE2 have several cysteine residues. In this study, the role of thiol-disulfide balance on the interactions between SARS-CoV/CoV-2 spike proteins and ACE2 was investigated using molecular dynamic simulations. The study revealed that the binding affinity was significantly impaired when all the disulfide bonds of both ACE2 and SARS-CoV/CoV-2 spike proteins were reduced to thiol groups. The impact on the binding affinity was less severe when the disulfide bridges of only one of the binding partners were reduced to thiols. This computational finding provides a molecular basis for the severity of COVID-19 infection due to the oxidative stress.

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Acute Pancreatitis in a Patient With COVID-19 After the Resolution of Respiratory Symptoms

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/23247096211024773 ◽

2021 ◽

Vol 9 ◽

pp. 232470962110247

Author(s):

Hafiz Muhammad Abrar Jeelani ◽

Muhammad Mubbashir Sheikh ◽

Shirly Susan Samuel ◽

Yetunde Bernice Omotosho ◽

Artem Sharko ◽

...

Keyword(s):

Acute Pancreatitis ◽

Angiotensin Converting Enzyme ◽

Respiratory Symptoms ◽

Epigastric Pain ◽

The Novel ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus

The gastrointestinal (GI) involvement, including acute pancreatitis (AP) from the novel coronavirus disease-2019 (COVID-19), is increasingly being reported. Recent evidence suggests that the pathogenesis of COVID-19 is mediated by the angiotensin-converting enzyme 2 (ACE-2) receptors and transmembrane protease serine 2 (TMPRSS2) for “priming,” which is highly expressed in the pancreas. To our knowledge, there is no other reported case of AP associated with COVID-19 after the respiratory symptoms are resolved. In this article, we present a patient with COVID-19, who came with intractable epigastric pain and resolved respiratory symptoms. A diagnosis of AP complicated with COVID-19 was made after laboratory and imaging workup, which was successfully managed conservatively.

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The Impact of Angiotensin-Converting Enzyme 2 (ACE2) Expression on the Incidence and Severity of COVID-19 Infection

Pathogens ◽

10.3390/pathogens10030379 ◽

2021 ◽

Vol 10 (3) ◽

pp. 379

Author(s):

Ahmed O. Kaseb ◽

Yehia I. Mohamed ◽

Alexandre E. Malek ◽

Issam I. Raad ◽

Lina Altameemi ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Preventive Measures ◽

Vulnerable Groups ◽

The Novel ◽

Converting Enzyme ◽

Potential Therapeutic Target ◽

Angiotensin Converting Enzyme 2 ◽

Incidence And Mortality ◽

Novel Coronavirus ◽

The Impact

The novel coronavirus disease 2019 (COVID-19) pandemic has led to an unprecedented threat to the international community and raised major concerns in terms of public health safety. Although our current understanding of the complexity of COVID-19 pathogenesis remains limited, the infection is largely mediated by the interaction of viral spike protein and angiotensin-converting enzyme 2 (ACE2). The functional importance of ACE2 in different demographic and comorbid conditions may explain the significant variation in incidence and mortality of COVID-19 in vulnerable groups, and highlights its candidacy as a potential therapeutic target. We provide evidence supporting the idea that differences in incidence and severity of COVID-19 infection may be related to ACE2. Emerging data based on the prevalence and severity of COVID-19 among those with established high levels of ACE2 expression strongly support our hypothesis. Considering the burden of COVID-19 infection in these vulnerable groups and the impact of the potential therapeutic and preventive measures that would result from adopting ACE2-driven anti-viral strategies, our hypothesis may expedite global efforts to control the current COVID-19 pandemic.

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Angiotensin Converting Enzyme-2: A Doorway for SARS-CoV-2

Coronaviruses ◽

10.2174/2666796702666210222110044 ◽

2021 ◽

Vol 02 ◽

Author(s):

Vikas Pandey ◽

Indu Lata Kanwar ◽

Tanweer Haider ◽

Vishal Gour ◽

Monika Vishwakarma ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Human Body ◽

Spike Protein ◽

Specific Method ◽

The Novel ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus

: The novel coronavirus severe acute respiratory syndrome Corona Virus-2 (SARS-CoV-2) has become a pandemic, as declared by WHO in March 2020 producing the deleterious effects to patients worldwide. The angiotensin-converting enzyme-2 (ACE-2) has been recognized as the co-receptor for SARS-CoV-2 infections and may acts as a therapeutic step in blocking the enzyme to reduce SARS-CoV-2 expression and further cellular entry. Presently, the role of ACE-2 in coronavirus disease 2019 (COVID-19) infection has been known and the experts have started working on the enzyme ACE-2 for the management and treatment of this pandemic disease. The binding of spike (S) protein of SARS-CoV-2 to these receptors is the most important step and plays a key role in viral replication, thus this enzyme is becoming the doorway for the entry and spread in the human body causing asymptomatic pneumonia and severe of which is leading to death. As no specific method to prevent and treat this disease is available, the use of ACE-2 as a targeting ligand with COVID-19 virus spike protein could be helpful in the proper management of SARS-CoV-2 pneumonia.

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ACE-2-derived Biomimetic Peptides for the Inhibition of Spike Protein of SARS-CoV-2

10.26434/chemrxiv.12335933 ◽

2020 ◽

Author(s):

Saroj Kumar Panda ◽

Parth Sarthi Sen Gupta ◽

Satyaranjan Biswal ◽

Abhik Kumar Ray ◽

Malay Kumar Rana

Keyword(s):

Principal Component ◽

Host Cells ◽

Spike Protein ◽

Peptide Inhibitor ◽

The Novel ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Inhibition Assay ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus

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Blocking Effect of Demethylzeylasteral on the Interaction between Human ACE2 Protein and SARS-CoV-2 RBD Protein Discovered Using SPR Technology

Molecules ◽

10.3390/molecules26010057 ◽

2020 ◽

Vol 26 (1) ◽

pp. 57

Author(s):

Zhi-Ling Zhu ◽

Xiao-Dan Qiu ◽

Shuo Wu ◽

Yi-Tong Liu ◽

Ting Zhao ◽

...

Keyword(s):

Therapeutic Strategy ◽

Blocking Effect ◽

Spike Protein ◽

Binding Affinities ◽

The Novel ◽

Converting Enzyme ◽

Primary Method ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus ◽

Effective Drugs

The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019, and there is no sign that the epidemic is abating. Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. In this study, surface plasmon resonance (SPR) was used as the primary method to screen a library of 960 compounds. A compound 02B05 (demethylzeylasteral, CAS number: 107316-88-1) that had high affinities for S-RBD and ACE2 was discovered, and binding affinities (KD, μM) of 02B05-ACE2 and 02B05-S-RBD were 1.736 and 1.039 μM, respectively. The results of a competition experiment showed that 02B05 could effectively block the binding of S-RBD to ACE2 protein. Furthermore, pseudovirus infection assay revealed that 02B05 could inhibit entry of SARS-CoV-2 pseudovirus into 293T cells to a certain extent at nontoxic concentration. The compoundobtained in this study serve as references for the design of drugs which have potential in the treatment of COVID-19 and can thus accelerate the process of developing effective drugs to treat SARS-CoV-2 infections.

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Pathological Role of Angiotensin II in Severe COVID-19

TH Open ◽

10.1055/s-0040-1713678 ◽

2020 ◽

Vol 04 (02) ◽

pp. e138-e144 ◽

Cited By ~ 5

Author(s):

Wolfgang Miesbach

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Treatment Options ◽

Renin Angiotensin System ◽

Target Cells ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Novel Coronavirus

AbstractThe activated renin–angiotensin system induces a prothrombotic state resulting from the imbalance between coagulation and fibrinolysis. Angiotensin II is the central effector molecule of the activated renin–angiotensin system and is degraded by the angiotensin-converting enzyme 2 to angiotensin (1–7). The novel coronavirus infection (classified as COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as acute respiratory distress syndrome, sepsis, and death in a proportion of patients, mostly elderly patients with preexisting comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to enter the target cells, resulting in activation of the renin–angiotensin system. After downregulating the angiotensin-converting enzyme 2, the vasoconstrictor angiotensin II is increasingly produced and its counterregulating molecules angiotensin (1–7) reduced. Angiotensin II increases thrombin formation and impairs fibrinolysis. Elevated levels were strongly associated with viral load and lung injury in patients with severe COVID-19. Therefore, the complex clinical picture of patients with severe complications of COVID-19 is triggered by the various effects of highly expressed angiotensin II on vasculopathy, coagulopathy, and inflammation. Future treatment options should focus on blocking the thrombogenic and inflammatory properties of angiotensin II in COVID-19 patients.

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