scholarly journals Can SARS-CoV-2 Virus Use Multiple Receptors to Enter Host Cells?

2021 ◽  
Vol 22 (3) ◽  
pp. 992
Author(s):  
Laura Kate Gadanec ◽  
Kristen Renee McSweeney ◽  
Tawar Qaradakhi ◽  
Benazir Ali ◽  
Anthony Zulli ◽  
...  
Keyword(s):  
Host Cells ◽  
Viral Immunity ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Viral Susceptibility ◽  
Neuropilin 1 ◽  
Multiple Receptors ◽  
Systemic Spread ◽  
Spread Of Infection

The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.

scholarly journals Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-Cov-2 Infection In Vitro

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 437
Author(s):  
Dean Gilham ◽  
Audrey L. Smith ◽  
Li Fu ◽  
Dalia Y. Moore ◽  
Abenaya Muralidharan ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Host Cells ◽  
Protein Inhibitor ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Surface Receptors ◽  
Bet Inhibitor ◽  
Epigenetic Machinery ◽  
Unexplored Area

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

scholarly journals Current Potential Therapeutic Approaches against SARS-CoV-2: A Review

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1620
Author(s):  
Dharmendra Kumar Yadav ◽  
Desh Deepak Singh ◽  
Ihn Han ◽  
Yogesh Kumar ◽  
Eun-Ha Choi
Keyword(s):  
Wide Spectrum ◽  
Host Cells ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Therapeutic Approaches ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Nucleotide Analogue ◽  
Infection Treatment ◽  
Current Potential

The ongoing SARS-CoV-2 pandemic is a serious threat to public health worldwide and, to date, no effective treatment is available. Thus, we herein review the pharmaceutical approaches to SARS-CoV-2 infection treatment. Numerous candidate medicines that can prevent SARS-CoV-2 infection and replication have been proposed. These medicines include inhibitors of serine protease TMPRSS2 and angiotensin converting enzyme 2 (ACE2). The S protein of SARS-CoV-2 binds to the receptor in host cells. ACE2 inhibitors block TMPRSS2 and S protein priming, thus preventing SARS-CoV-2 entry to host cells. Moreover, antiviral medicines (including the nucleotide analogue remdesivir, the HIV protease inhibitors lopinavir and ritonavir, and wide-spectrum antiviral antibiotics arbidol and favipiravir) have been shown to reduce the dissemination of SARS-CoV-2 as well as morbidity and mortality associated with COVID-19.

Metainflammation in COVID-19

2022 ◽  
Vol 22 ◽  
Author(s):  
Mojtaba Bakhtiari ◽  
Kamyar Asadipooya
Keyword(s):  
Cell Membrane ◽  
Viral Entry ◽  
Virus Entry ◽  
Host Cells ◽  
Elderly Men ◽  
Virus Binding ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Binding Capability

Abstract: A new coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2], has been on the rise. This virus is fatal for broad groups of populations, including elderly, men, and patients with comorbidities among which obesity is a possible risk factor. The pathophysiologic connections between obesity/metainflammation and COVID-19 may be directly related to increasing soluble ACE2 (angiotensin-converting enzyme 2] levels which potentiates the viral entrance into the host cells, or indirectly related to dysregulation of immune system, microvascular injury and hypercoagulability. The SARS-CoV-2 S-glycoprotein interacts mainly with ACE2 or possibly DDP4 receptors to enter into the host cells. The host proteases, especially TMPRSS2 (transmembrane protease serine 2], support the fusion process and virus entry. While membranous ACE2 is considered a port of entry to the cell for SARS-CoV-2, it seems that soluble ACE2 retains its virus binding capability and enhances its entry into the cells. Interestingly, ACE2 on cell membrane may have protective roles by diminishing cytokine storm-related injuries to the organs. Applying medications that can reduce soluble ACE2 levels, antagonizing TMPRSS2 or blocking DDP4 can improve the outcomes of COVID-19. Metformin and statins through immunomodulatory activities, Orlistat by reducing viral replication, and thiazolidinediones by upregulating ACE2 expression have potential beneficial effects against COVID-19. However, the combination of dipeptidyl peptidase-4 (DDP4] inhibitors and spironolactone/eplerenone seems to be more effective by reducing soluble ACE2 level, antagonizing TMPRSS2, maintaining ACE2 on cell membrane and reducing risk of viral entry into the cells.

SARS-CoV-2 Entry inhibitors targeting virus-ACE2 or virus-TMPRSS2 interactions

2021 ◽  
Vol 28 ◽  
Author(s):  
Hao Lin ◽  
Srinivasulu Cherukupalli ◽  
Da Feng ◽  
Shenghua Gao ◽  
Dongwei Kang ◽  
...  
Keyword(s):  
Life Cycle ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Entry Inhibitors ◽  
Concise Report ◽  
Surface Receptor ◽  
Transmembrane Serine Protease

: COVID-19 is an infectious disease caused by SARS-CoV-2. The life cycle of SARS-CoV-2 includes the entry into the target cells, replicase translation, replicating and transcribing genomes, translating structural proteins, assembling and releasing new virions. Entering host cells is a crucial stage in the early life cycle of the virus, and blocking this stage can effectively prevent virus infection. SARS enters the target cells mediated by the interaction between the viral S protein and the target cell surface receptor angiotensin-converting enzyme 2 (ACE2), as well as the cleavage effect of type-II transmembrane serine protease (TMPRSS2) on the S protein. Therefore, the ACE2 receptor and TMPRSS2 are important targets for SARS-CoV-2 entry inhibitors. Herein, we provide a concise report/information on drugs with potential therapeutic value targeting virus-ACE2 or virus-TMPRSS2 interactions, to provide a reference for the design and discovery of potential entry inhibitors against SARS-CoV-2.

D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity

2020 ◽  
Author(s):  
Jie Hu ◽  
Chang-Long He ◽  
Qing-Zhu Gao ◽  
Gui-Ji Zhang ◽  
Xiao-Xia Cao ◽  
...  
Keyword(s):  
Host Cells ◽  
Its Sequence ◽  
Elastase Inhibitor ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Functional Differences ◽  
Common Receptor ◽  
Sequence Variations ◽  
Human Igg1 ◽  
Major Target

AbstractCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein that mediates SARS-CoV-2 entry into host cells is a major target for vaccines and therapeutics. Thus, insights into its sequence variations are key to understanding the infection and antigenicity of SARS-CoV-2. A dominant mutational variant at position 614 of the S protein (aspartate to glycine, D614G mutation) was observed in the SARS-CoV-2 genome sequence obtained from the Nextstrain database. Using a pseudovirus-based assay, we identified that S-D614 and S-G614 protein pseudotyped viruses share a common receptor, human angiotensin-converting enzyme 2 (ACE2), which could be blocked by recombinant ACE2 with the fused Fc region of human IgG1. However, S-D614 and S-G614 protein demonstrated functional differences. First, S-G614 protein could be cleaved by serine protease elastase-2 more efficiently. Second, S-G614 pseudovirus infected 293T-ACE2 cells significantly more efficiently than did the S-D614 pseudovirus, especially in the presence of elastase-2. Third, an elastase inhibitor approved for clinical use blocked elastase-enhanced S-G614 pseudovirus infection. Moreover, 93% (65/70) convalescent sera from patients with COVID-19 could neutralize both S-D614 and S-G614 pseudoviruses with comparable efficiencies, but about 7% (5/70) convalescent sera showed reduced neutralizing activity against the S-G614 pseudovirus. These findings have important implications for SARS-CoV-2 transmission and immune interventions.

scholarly journals Bromodomain and extraterminal protein inhibitor, apabetalone (RVX-208), reduces ACE2 expression and attenuates SARS-CoV-2 infection in vitro

2021 ◽  
Author(s):  
Dean Gilham ◽  
Audrey L Smith ◽  
Li Fu ◽  
Dalia Y Moore ◽  
Abenaya Muralidharan ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Host Cells ◽  
Protein Inhibitor ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Surface Receptors ◽  
Bet Inhibitor ◽  
Epigenetic Machinery ◽  
Unexplored Area

AbstractEffective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.Graphical Abstract

scholarly journals The potential role of Bromhexine in the management of COVID-19: Decipher and a real game-changer

2021 ◽  
Vol 5 (01) ◽  
pp. 1-4
Author(s):  
Hayder M. Al-Kuraishy ◽  
Marwa S. Al-Niemi ◽  
Nawar R. Hussain ◽  
Ali I. Al-Gareeb ◽  
Claire Lugnier
Keyword(s):  
Potential Role ◽  
Host Cells ◽  
Bronchial Epithelial ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease ◽  
Game Changer

Primary infection of SARS-CoV-2 (novel coronavirus or 2019-nCoV), which leads to Covid-19, targets specific cells, such as nasal, bronchial epithelial and pneumocytes, through the viral structural spike (S) protein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor. Also, type 2 transmembrane serine protease (TMPRSS2) present in the host cell promotes viral uptake by cleaving ACE2 and triggering the SARS-CoV-2 S protein, which facilitates SARS-CoV-2 entry into host cells. One of the TMPRSS2 inhibitors with a greater distribution capacity into the lung tissue is bromhexine hydrochloride which attenuates the entry and proliferation of SARS-CoV-2. Bromhexine is an effective drug in the management and treatment of Covid-19 pneumonia via targeting ACE2/ TMPRSS2 pathway. However, prospective and controlled clinical trials are recommended to confirm this observation.

scholarly journals Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system

2020 ◽  
Author(s):  
Ludovico Cantuti-Castelvetri ◽  
Ravi Ojha ◽  
Liliana D. Pedro ◽  
Minou Djannatian ◽  
Jonas Franz ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Olfactory Epithelium ◽  
Cell Entry ◽  
Host Cells ◽  
Blocking Antibody ◽  
Angiotensin Converting Enzyme 2 ◽  
Neuropilin 1 ◽  
The Central Nervous System

SUMMARYThe causative agent of the current pandemic and coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. Understanding how SARS-CoV-2 enters and spreads within human organs is crucial for developing strategies to prevent viral dissemination. For many viruses, tissue tropism is determined by the availability of virus receptors on the surface of host cells2. Both SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a host receptor, yet, their tropisms differ3-5. Here, we found that the cellular receptor neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, which was inhibited by a monoclonal blocking antibody against the extracellular b1b2 domain of NRP1. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial cells and in the epithelial cells facing the nasal cavity. Neuropathological analysis of human COVID-19 autopsies revealed SARS-CoV-2 infected NRP1-positive cells in the olfactory epithelium and bulb. In the olfactory bulb infection was detected particularly within NRP1-positive endothelial cells of small capillaries and medium-sized vessels. Studies in mice demonstrated, after intranasal application, NRP1-mediated transport of virus-sized particles into the central nervous system. Thus, NRP1 could explain the enhanced tropism and spreading of SARS-CoV-2.

scholarly journals Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza

2021 ◽  
Vol 8 ◽  
Author(s):  
Yalda Rahbar Saadat ◽  
Seyed Mahdi Hosseiniyan Khatibi ◽  
Sepideh Zununi Vahed ◽  
Mohammadreza Ardalan
Keyword(s):  
Serine Proteases ◽  
Cathepsin L ◽  
Therapeutic Agents ◽  
Therapeutic Strategies ◽  
Host Cells ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Endosomal Pathway ◽  
Targeted Inhibition ◽  
Human Receptor

The ongoing pandemic illustrates limited therapeutic options for controlling SARS-CoV-2 infections, calling a need for additional therapeutic targets. The viral spike S glycoprotein binds to the human receptor angiotensin-converting enzyme 2 (ACE2) and then is activated by the host proteases. Based on the accessibility of the cellular proteases needed for SARS-S activation, SARS-CoV-2 entrance and activation can be mediated by endosomal (such as cathepsin L) and non-endosomal pathways. Evidence indicates that in the non-endosomal pathway, the viral S protein is cleaved by the furin enzyme in infected host cells. To help the virus enter efficiently, the S protein is further activated by the serine protease 2 (TMPRSS2), provided that the S has been cleaved by furin previously. In this review, important roles for host proteases within host cells will be outlined in SARS-CoV-2 infection and antiviral therapeutic strategies will be highlighted. Although there are at least five highly effective vaccines at this time, the appearance of the new viral mutations demands the development of therapeutic agents. Targeted inhibition of host proteases can be used as a therapeutic approach for viral infection.

scholarly journals Peptide Platform as a Powerful Tool in the Fight against COVID-19

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1667
Author(s):  
Michela Murdocca ◽  
Gennaro Citro ◽  
Isabella Romeo ◽  
Antonio Lupia ◽  
Shane Miersch ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Antigenic Site ◽  
Protein Docking ◽  
In Vivo Studies ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Global Pandemic

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic causing over 195 million infections and more than 4 million fatalities as of July 2021.To date, it has been demonstrated that a number of mutations in the spike glycoprotein (S protein) of SARS-CoV-2 variants of concern abrogate or reduce the neutralization potency of several therapeutic antibodies and vaccine-elicited antibodies. Therefore, the development of additional vaccine platforms with improved supply and logistic profile remains a pressing need. In this work, we have validated the applicability of a peptide-based strategy focused on a preventive as well as a therapeutic purpose. On the basis of the involvement of the dipeptidyl peptidase 4 (DPP4), in addition to the angiotensin converting enzyme 2 (ACE2) receptor in the mechanism of virus entry, we analyzed peptides bearing DPP4 sequences by protein–protein docking and assessed their ability to block pseudovirus infection in vitro. In parallel, we have selected and synthetized peptide sequences located within the highly conserved receptor-binding domain (RBD) of the S protein, and we found that RBD-based vaccines could better promote elicitation of high titers of neutralizing antibodies specific against the regions of interest, as confirmed by immunoinformatic methodologies and in vivo studies. These findings unveil a key antigenic site targeted by broadly neutralizing antibodies and pave the way to the design of pan-coronavirus vaccines.

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