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

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>

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

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>

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

Molecules ◽  
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.

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 Plasma from recovered COVID19 subjects inhibits spike protein binding to ACE2 in a microsphere-based inhibition assay

2020 ◽  
Author(s):  
Edward P. Gniffke ◽  
Whitney E. Harrington ◽  
Nicholas Dambrauskas ◽  
Yonghou Jiang ◽  
Olesya Trakhimets ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Antibody Response ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Inhibition Assay ◽  
Serological Tests ◽  
Angiotensin Converting Enzyme 2 ◽  
A Cell ◽  
Inhibitory Antibodies

AbstractHigh throughput serological tests that can establish the presence and functional activity of anti-SARS-COV2 antibodies are urgently needed. Here we present microsphere-based Flow Cytometry assays that quantify both anti-spike IgGs in plasma, and the ability of plasma to inhibit the binding of spike protein to angiotensin converting enzyme 2 (ACE2). First, we detected anti-spike-trimer IgGs in 22/24 and anti-spike-receptor-binding-domain (RBD) IgGs in 21/24 COVID+ subjects at a median of 36 (range 14-73) days following documented SARS-CoV-2 RNA (+) secretions. Next, we find that plasma from all 22/24 subjects with anti-trimer IgGs inhibited ACE2-trimer binding to a greater degree than controls, and that the degree of inhibition correlated with anti-trimer IgG levels. Depletion of trimer-reactive Igs from plasma reduced ACE2-trimer inhibitory capacity to a greater degree than depletion of RBD-reactive Igs, suggesting that inhibitory antibodies act by binding both within and outside of the RBD. Amongst the 24 subjects, presence of fever was associated with higher levels of anti-trimer IgG and inhibition of binding to human ACE2. This inhibition assay may be broadly useful to quantify the functional antibody response of recovered COVID19 patients or vaccine recipients in a cell-free assay system.

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

2020 ◽  
Vol 8 (Spl-1-SARS-CoV-2) ◽  
pp. S190-S201
Author(s):  
Muhammad Bilal ◽  
◽  
Muhammad Iqbal Sarfaraz ◽  
Muhammad Iqbal Husnain ◽  
Nimra Sardar ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Viral Entry ◽  
Host Cells ◽  
Lung Cells ◽  
The Novel ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Lung Failure ◽  
Novel Coronavirus ◽  
Severe Lung

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.

scholarly journals The Role of Renin: Angiotensin: Aldosterone System in the Pathogenesis and Pathophysiology of COVID-19

2021 ◽  
Author(s):  
Ozlem G. Sahin
Keyword(s):  
Spike Protein ◽  
The Novel ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Binding Assays ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin ◽  
Protein Receptor ◽  
Novel Coronavirus

The novel coronavirus also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whose origin is still having uncertainties related to the existence of an intermediate host, has created the currently ongoing pandemic of coronavirus disease 2019. (COVID-19) The binding assays of SARS-CoV-2 spike protein receptor binding domain disclosed enhanced affinity with human angiotensin II-converting enzyme receptor (hACE2) comparing to the bat ACE2 receptors. ACE2, is an essential component of the regulatory mechanism of the renin-angiotensin-aldosterone system, (RAAS) and this pathway is considered to interact with the pathophysiology of COVID-19. In this chapter, we will discuss the key role of RAAS in the pathogenesis of SARS-CoV-2.

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

Coronaviruses ◽  
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.

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

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.

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.

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