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.

scholarly journals Identification of a Putative Coreceptor on Vero Cells That Participates in Dengue 4 Virus Infection

2001 ◽  
Vol 75 (17) ◽  
pp. 7818-7827 ◽  
Author(s):  
José de Jesús Martı́nez-Barragán ◽  
Rosa M. del Angel
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Vero Cells ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
Virus Binding ◽  
Dengue Virus Infection ◽  
Surface Receptor ◽  
A Cell

ABSTRACT Dengue virus infects target cells by attaching to a cell surface receptor through the envelope (E) glycoprotein, located on the surface of the viral membrane. On Vero and BHK cells, heparan sulfate (HS) moieties of proteoglycans are the receptors for dengue virus; however, additional proteins have also been described as putative dengue virus receptors on C6/36, HL60, and BM cells. HS can also act as a receptor for other types of viruses or as an attachment molecule for viruses that require additional host cell molecules to allow viral penetration. In this study we searched for molecules other than HS that could participate in dengue virus infection of Vero cells. Labeled dengue 4 virus bound with high affinity to two molecules of 74 and 44 kDa. Binding of dengue virus to the 74-kDa molecule was susceptible to protease and sodium periodate treatment and resistant to heparinase treatments. Lectins such as concanavalin A and wheat germ agglutinin prevented dengue virus binding to both the 74- and the 44-kDa protein in overlay assays, while phytohemagglutinin P did not affect binding, suggesting that carbohydrate residues (α-mannose orN-acetylglucosamine) are important in virus binding to host cells. Protease susceptibility, biotin labeling, and immunofluorescence with a polyclonal antibody raised against the 74-kDa protein consistently identified the protein on the surfaces of Vero cells. Moreover, the antibody against the 74-kDa protein was able to inhibit dengue virus infection. These data suggest that HS might serve as a primary receptor, probably concentrating virus particles on the surfaces of Vero cells, and then other molecules, such as the 74-kDa protein, might participate as coreceptors in viral penetration. The 74-kDa protein possibly constitutes part of a putative receptor complex for dengue virus infection of Vero cells.

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 SARS-CoV-2 Cellular Entry Is Independent of the ACE2 Cytoplasmic Domain Signaling

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1814
Author(s):  
Thankamani Karthika ◽  
Jeswin Joseph ◽  
V. R. Akshay Das ◽  
Niranjana Nair ◽  
Packirisamy Charulekha ◽  
...  
Keyword(s):  
Cytoplasmic Domain ◽  
Confocal Imaging ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Soluble Form ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Endosomal Acidification ◽  
Internalization Process ◽  
Surface Receptor

Recently emerged severe acute respiratory syndrome coronavirus (SARS-CoV)-1 and -2 initiate virus infection by binding of their spike glycoprotein with the cell-surface receptor angiotensin-converting enzyme 2 (ACE2) and enter into the host cells mainly via the clathrin-mediated endocytosis pathway. However, the internalization process post attachment with the receptor is not clear for both SARS-CoV-1 and -2. Understanding the cellular factor/s or pathways used by these CoVs for internalization might provide insights into viral pathogenesis, transmission, and development of novel therapeutics. Here, we demonstrated that the cytoplasmic tail of ACE2 is not essential for the entry of SARS-CoV-1 and -2 by using bioinformatics, mutational, confocal imaging, and pseudotyped SARS-CoVs infection studies. ACE2 cytoplasmic domain (cytACE2) contains a conserved internalization motif and eight putative phosphorylation sites. Complete cytoplasmic domain deleted ACE2 (∆cytACE2) was properly synthesized and presented on the surface of HEK293T and BHK21 cells like wtACE2. The SARS-CoVs S1 or RBD of spike protein binds and colocalizes with the receptors followed by internalization into the host cells. Moreover, pseudotyped SARS-CoVs entered into wtACE2- and ∆cytACE2-transfected cells but not into dipeptidyl peptidase 4 (DPP4)-expressing cells. Their entry was significantly inhibited by treatment with dynasore, a dynamin inhibitor, and NH4Cl, an endosomal acidification inhibitor. Furthermore, SARS-CoV antibodies and the soluble form of ACE2-treated pseudotyped SARS-CoVs were unable to enter the wtACE2 and ∆cytACE2-expressing cells. Altogether, our data show that ACE2 cytoplasmic domain signaling is not essential for the entry of SARS-CoV-1 and -2 and that SARS-CoVs entry might be mediated via known/unknown host factor/s.

scholarly journals Bovine Colostrum Derived Antibodies Against SARS-CoV-2 Show Great Potential to Serve as a Prophylactic Agent

2021 ◽  
Author(s):  
Kadri Kangro ◽  
Mihhail Kurashin ◽  
Kiira Gildemann ◽  
Eve Sankovski ◽  
Eva Zusinaite ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Human Subjects ◽  
Cell Surface Receptor ◽  
In Vitro Assays ◽  
Additional Measure ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Prophylactic Agent ◽  
Surface Receptor

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) until now imposes a serious burden to health systems globally. Despite worldwide vaccination, social distancing and wearing masks, the spread of the virus is still ongoing. One of the mechanisms how neutralizing antibodies (NAbs) block virus entry into cells encompasses interaction inhibition between the cell surface receptor angiotensin-converting enzyme 2 (ACE2) and the spike (S) protein of SARS-CoV-2. SARS-CoV-2 specific NAb development can be induced in the blood of cattle. Pregnant cows produce NAbs upon immunization, and antibodies move into the colostrum just before calving. Here we immunized cows with SARS-CoV-2 S1 receptor binding domain (RBD) protein in proper adjuvant solutions, followed by one boost with SARS-CoV-2 trimeric S protein, and purified immunoglobulins from colostrum. We demonstrate that this preparation indeed blocks interaction between the trimeric S protein and ACE2 in different in vitro assays. Moreover, we describe the formulation of purified immunoglobulin preparation into a nasal spray. When administered to human subjects, the formulation persists on the nasal mucosa for at least 4 hours as determined by a clinical study. Therefore, we are presenting a solution that shows great potential to serve as a prophylactic agent against SARS-CoV-2 infection as an additional measure to vaccination and wearing masks. Moreover, our technology allows for a rapid and versatile adaption for preparing prophylactic treatments against other diseases by using the defined characteristics of antibody movement into the colostrum.

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.

scholarly journals “Molecular Masks” for ACE2 to Effectively and Safely Block SARS-CoV-2 Virus Entry

2021 ◽  
Vol 22 (16) ◽  
pp. 8963
Author(s):  
Satya Prakash Shukla ◽  
Kwang Bog Cho ◽  
Vineeta Rustagi ◽  
Xiang Gao ◽  
Xinping Fu ◽  
...  
Keyword(s):  
Virus Entry ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Pressure Regulation ◽  
Converting Enzyme ◽  
Normal Blood Pressure ◽  
Health Crisis ◽  
Angiotensin Converting Enzyme 2 ◽  
Surface Receptor ◽  
Unique Cell

Coronavirus Disease 2019 (COVID-19) remains a global health crisis, despite the development and success of vaccines in certain countries. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, uses its spike protein to bind to the human cell surface receptor angiotensin-converting enzyme 2 (ACE2), which allows the virus to enter the human body. Using our unique cell screening technology, we identified two ACE2-binding peptoid compounds and developed dimeric derivatives (ACE2P1D1 and ACE2P2D1) that effectively blocked spike protein-ACE2 interaction, resulting in the inhibition of SARS-CoV-2 pseudovirus entry into human cells. ACE2P1D1 and ACE2P2D1 also blocked infection by a D614G mutant pseudovirus. More importantly, these compounds do not decrease ACE2 expression nor its enzyme activity (which is important in normal blood pressure regulation), suggesting safe applicability in humans

Interfering with Host Proteases in SARS-CoV-2 Entry as a Promising Therapeutic Strategy

2021 ◽  
Vol 28 ◽  
Author(s):  
Patrick Müller ◽  
Hannah Maus ◽  
Stefan Josef Hammerschmidt ◽  
Philip Knaff ◽  
Volker Mailänder ◽  
...  
Keyword(s):  
Cathepsin L ◽  
Cell Entry ◽  
New Drugs ◽  
Host Cells ◽  
S Protein ◽  
Cell Receptors ◽  
Current State ◽  
Causative Drug ◽  
Transmembrane Serine Protease ◽  
Global Threat

: Due to its fast international spread and substantial mortality, the coronavirus disease COVID-19 evolved to a global threat. Since currently, there is no causative drug against this viral infection available, science is striving for new drugs and approaches to treat the new disease. Studies have shown that the cell entry of coronaviruses into host cells takes place through the binding of the viral spike (S) protein to cell receptors. Priming of the S protein occurs via hydrolysis by different host proteases. The inhibition of these proteases could impair the processing of the S protein, thereby affecting the interaction with the host-cell receptors and preventing virus cell entry. Hence, inhibition of these proteases could be a promising strategy for treatment against SARS-CoV-2. In this review, we discuss the current state of the art of developing inhibitors against the entry proteases furin, the transmembrane serine protease type-II (TMPRSS2), trypsin, and cathepsin L.

scholarly journals DC-SIGN and L-SIGN Are Attachment Factors That Promote Infection of Target Cells by Human Metapneumovirus in the Presence or Absence of Cellular Glycosaminoglycans

2016 ◽  
Vol 90 (17) ◽  
pp. 7848-7863 ◽  
Author(s):  
Leah Gillespie ◽  
Kathleen Gerstenberg ◽  
Fernanda Ana-Sosa-Batiz ◽  
Matthew S. Parsons ◽  
Rubaiyea Farrukee ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cho Cells ◽  
Experimental System ◽  
Human Metapneumovirus ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
Transmembrane Receptors ◽  
Hmpv Infection ◽  
Attachment Factor

ABSTRACTIt is well established that glycosaminoglycans (GAGs) function as attachment factors for human metapneumovirus (HMPV), concentrating virions at the cell surface to promote interaction with other receptors for virus entry and infection. There is increasing evidence to suggest that multiple receptors may exhibit the capacity to promote infectious entry of HMPV into host cells; however, definitive identification of specific transmembrane receptors for HMPV attachment and entry is complicated by the widespread expression of cell surface GAGs. pgsA745 Chinese hamster ovary (CHO) cells are deficient in the expression of cell surface GAGs and resistant to HMPV infection. Here, we demonstrate that the expression of the Ca2+-dependent C-type lectin receptor (CLR) DC-SIGN (CD209L) or L-SIGN (CD209L) rendered pgsA745 cells permissive to HMPV infection. Unlike infection of parental CHO cells, HMPV infection of pgsA745 cells expressing DC-SIGN or L-SIGN was dynamin dependent and inhibited by mannan but not by pretreatment with bacterial heparinase. Parental CHO cells expressing DC-SIGN/L-SIGN also showed enhanced susceptibility to dynamin-dependent HMPV infection, confirming that CLRs can promote HMPV infection in the presence or absence of GAGs. Comparison of pgsA745 cells expressing wild-type and endocytosis-defective mutants of DC-SIGN/L-SIGN indicated that the endocytic function of CLRs was not essential but could contribute to HMPV infection of GAG-deficient cells. Together, these studies confirm a role for CLRs as attachment factors and entry receptors for HMPV infection. Moreover, they define an experimental system that can be exploited to identify transmembrane receptors and entry pathways where permissivity to HMPV infection can be rescued following the expression of a single cell surface receptor.IMPORTANCEOn the surface of CHO cells, glycosaminoglycans (GAGs) function as the major attachment factor for human metapneumoviruses (HMPV), promoting dynamin-independent infection. Consistent with this, GAG-deficient pgaA745 CHO cells are resistant to HMPV. However, expression of DC-SIGN or L-SIGN rendered pgsA745 cells permissive to dynamin-dependent infection by HMPV, although the endocytic function of DC-SIGN/L-SIGN was not essential for, but could contribute to, enhanced infection. These studies provide direct evidence implicating DC-SIGN/L-SIGN as an alternate attachment factor for HMPV attachment, promoting dynamin-dependent infection via other unknown receptors in the absence of GAGs. Moreover, we describe a unique experimental system for the assessment of putative attachment and entry receptors for HMPV.

scholarly journals Identification of the Cellular Receptor of Clostridium spiroforme Toxin

2012 ◽  
Vol 80 (4) ◽  
pp. 1418-1423 ◽  
Author(s):  
Panagiotis Papatheodorou ◽  
Claudia Wilczek ◽  
Thilo Nölke ◽  
Gregor Guttenberg ◽  
Daniel Hornuss ◽  
...  
Keyword(s):  
Host Cell ◽  
Cell Receptor ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
Content Type ◽  
Recombinant Production ◽  
Host Cell Receptor ◽  
Surface Receptor ◽  
Microscopic Studies ◽  
Host Cell Surface

ABSTRACTClostridium spiroformeproduces the binary actin-ADP-ribosylating toxin CST (C. spiroformetoxin), which has been proposed to be responsible for diarrhea, enterocolitis, and eventually death, especially in rabbits. Here we report on the recombinant production of the enzyme component (CSTa) and the binding component (CSTb) ofC. spiroformetoxin inBacillus megaterium. By using the recombinant toxin components, we show that CST enters target cells via the lipolysis-stimulated lipoprotein receptor (LSR), which has been recently identified as the host cell receptor of the binary toxinsClostridium difficiletransferase (CDT) andClostridium perfringensiota toxin. Microscopic studies revealed that CST, but not the relatedClostridium botulinumC2 toxin, colocalized with LSR during toxin uptake and traffic to endosomal compartments. Our findings indicate that CST shares LSR withC. difficileCDT andC. perfringensiota toxin as a host cell surface receptor.

Identifying plant cell-surface receptors: combining ‘classical’ techniques with novel methods

2014 ◽  
Vol 42 (2) ◽  
pp. 395-400 ◽  
Author(s):  
Susanne Uebler ◽  
Thomas Dresselhaus
Keyword(s):  
Cell Surface ◽  
Affinity Purification ◽  
Cell Communication ◽  
Membrane Receptors ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
Surface Receptors ◽  
Success Stories ◽  
Surface Receptor ◽  
Secreted Peptides

Cell–cell communication during development and reproduction in plants depends largely on a few phytohormones and many diverse classes of polymorphic secreted peptides. The peptide ligands are bound at the cell surface of target cells by their membranous interaction partners representing, in most cases, either receptor-like kinases or ion channels. Although knowledge of both the extracellular ligand and its corresponding receptor(s) is necessary to describe the downstream signalling pathway(s), to date only a few ligand–receptor pairs have been identified. Several methods, such as affinity purification and yeast two-hybrid screens, have been used very successfully to elucidate interactions between soluble proteins, but most of these methods cannot be applied to membranous proteins. Experimental obstacles such as low concentration and poor solubility of membrane receptors, as well as instable transient interactions, often hamper the use of these ‘classical’ approaches. However, over the last few years, a lot of progress has been made to overcome these problems by combining classical techniques with new methodologies. In the present article, we review the most promising recent methods in identifying cell-surface receptor interactions, with an emphasis on success stories outside the field of plant research.

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