scholarly journals Neuropilin-1 Assists SARS-CoV-2 Infection by Stimulating the Separation of Spike Protein Domains S1 and S2

2021 ◽  
Author(s):  
Zhenlu Li ◽  
Matthias Buck
Keyword(s):  
Molecular Dynamics ◽  
High Probability ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Virus Infectivity ◽  
Topological Constraints ◽  
Exit Mechanism ◽  
Neuropilin 1 ◽  
Host Membrane ◽  
Surface Receptor

The cell surface receptor Neuropilin-1 (Nrp1) was recently identified as a host factor for SARS-CoV-2 entry. As the Spike protein of SARS-Cov-2 is cleaved into the S1 and the S2 domain by furin protease, Nrp1 binds to the newly created C-terminal RRAR amino acid sequence of the S1 domain. In this study, we model the association of a Nrp1 (a2-b1-b2) protein with the Spike protein computationally and analyze the topological constraints in the SARS-CoV-2 Spike protein for binding with Nrp1 and ACE2. Importantly, we study the exit mechanism of S2 from the S1 domain with the assistance of ACE2 as well as Nrp1 by molecular dynamics pulling simulations. In the presence of Nrp1, by binding the S1 more strongly to the host membrane, there is a high probability of S2 being pulled out, rather than S1 being stretched. Thus, Nrp1 binding could stimulate the exit of S2 from the S1 domain, which will likely increase virus infectivity as the liberated S2 domain mediates the fusion of virus and host membranes. Understanding of such a Nrp1-assisted viral infection opens the gate for the generation of protein-protein inhibitors, such as antibodies, which could attenuate the infection mechanism and protect certain cells in a future combination therapy.

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

scholarly journals The role of Neuropilin-1 in COVID-19

2021 ◽  
Vol 17 (1) ◽  
pp. e1009153
Author(s):  
Bindu S. Mayi ◽  
Jillian A. Leibowitz ◽  
Arden T. Woods ◽  
Katherine A. Ammon ◽  
Alphonse E. Liu ◽  
...  
Keyword(s):  
Immune Function ◽  
Viral Entry ◽  
Axonal Guidance ◽  
Cell Surface Receptor ◽  
Neuropilin 1 ◽  
Surface Receptor ◽  
The Central Nervous System

Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in vitro. This cell surface receptor with its disseminated expression is important in angiogenesis, tumor progression, viral entry, axonal guidance, and immune function. NRP-1 is implicated in several aspects of a SARS-CoV-2 infection including possible spread through the olfactory bulb and into the central nervous system and increased NRP-1 RNA expression in lungs of severe Coronavirus Disease 2019 (COVID-19). Up-regulation of NRP-1 protein in diabetic kidney cells hint at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction. It is prudent to further research NRP-1 and its possibility of serving as a therapeutic target in SARS-CoV-2 infections. We anticipate that widespread expression, abundance in the respiratory and olfactory epithelium, and the functionalities of NRP-1 factor into the multiple systemic effects of COVID-19 and challenges we face in management of disease and potential long-term sequelae.

scholarly journals Neuropilin-1 and heparan sulfate proteoglycans cooperate in cellular uptake of nanoparticles functionalized by cationic cell-penetrating peptides

2015 ◽  
Vol 1 (10) ◽  
pp. e1500821 ◽  
Author(s):  
Hong-Bo Pang ◽  
Gary B. Braun ◽  
Erkki Ruoslahti
Keyword(s):  
Cell Surface ◽  
Heparan Sulfate ◽  
Vascular Permeability ◽  
Mammalian Cells ◽  
Cell Penetrating Peptides ◽  
Proteolytic Processing ◽  
Cell Surface Receptor ◽  
Neuropilin 1 ◽  
Cell Penetrating ◽  
Surface Receptor

Cell-penetrating peptides (CPPs) have been widely used to deliver nanomaterials and other types of macromolecules into mammalian cells for therapeutic and diagnostic use. Cationic CPPs that bind to heparan sulfate (HS) proteoglycans on the cell surface induce potent endocytosis; however, the role of other surface receptors in this process is unclear. We describe the convergence of an HS-dependent pathway with the C-end rule (CendR) mechanism that enables peptide ligation with neuropilin-1 (NRP1), a cell surface receptor known to be involved in angiogenesis and vascular permeability. NRP1 binds peptides carrying a positive residue at the carboxyl terminus, a feature that is compatible with cationic CPPs, either intact or after proteolytic processing. We used CPP and CendR peptides, as well as HS- and NRP1-binding motifs from semaphorins, to explore the commonalities and differences of the HS and NRP1 pathways. We show that the CendR-NRP1 interaction determines the ability of CPPs to induce vascular permeability. We also show at the ultrastructural level, using a novel cell entry synchronization method, that both the HS and NRP1 pathways can initiate a macropinocytosis-like process and visualize these CPP-cargo complexes going through various endosomal compartments. Our results provide new insights into how CPPs exploit multiple surface receptor pathways for intracellular delivery.

scholarly journals Conformational Dynamics of Nonenveloped Circovirus Capsid to the Host Cell Receptor

2019 ◽  
Author(s):  
Jiarong Li ◽  
Jinyan Gu ◽  
Shengnan Wang ◽  
Cui Lin ◽  
Jianwei Zhou ◽  
...  
Keyword(s):  
Cell Surface ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Dynamic Equilibrium ◽  
Conformational Dynamics ◽  
Cell Surface Receptor ◽  
Virus Infectivity ◽  
Surface Receptor ◽  
Nonenveloped Virus

AbstractCircovirus, comprising one capsid protein, is the smallest nonenveloped virus and induces lymphopenia. Circovirus can be used to explore the cell adhesion mechanism of nonenveloped viruses. We developed a single-molecule fluorescence resonance energy transfer (smFRET) assay to directly visualize the capsid’s conformational feature. The capsid underwent reversible dynamic transformation between three conformations. The cell surface receptor heparan sulfate (HS) altered the dynamic equilibrium of the capsid to the high-FRET state, revealing the HS binding region. Neutralizing antibodies restricted capsid transition to a low-FRET state, masking the HS binding domain. The lack of positively charged amino acids in the HS binding site reduced cell surface affinity and attenuated virus infectivity via conformational changes. These intrinsic characteristics of the capsid suggested that conformational dynamics is critical for the structural changes occurring upon cell surface receptor binding, supporting a dynamics-based mechanism of receptor binding.ImportanceViral proteins were commom working as ligand to interacte with cell surface glycosaminoglycan receptors to achieve the virus attachment, during which the conformational dynamics of the protein ligand are also vital for the binding properties. In this study, PCV2 capsid and heparin sulfate were used to study the protein conformational dynamics of nonenveloped and icosahedral circovirus capsid during triggering to cell surface receptor. we demonstrated the PCV2 capsid could acts as a dynamic machine, spontaneously adopting multiple conformations with reversible interconversion and intrinsic conformational features could be regulated by glycosaminoglycan receptors and neutralizing antibodies. These increased our understanding of the mechanism by which nonenveloped virus attach to cells.

scholarly journals Hydroxyzine inhibits SARS-CoV-2 Spike protein binding to ACE2 in a qualitative in vitro assay

2021 ◽  
Author(s):  
Maria Dolores Rivas ◽  
Jose Maria Rafael Saponi-Cortes ◽  
Jose Zamorano
Keyword(s):  
Public Health Problem ◽  
In Vitro Assay ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Major Public Health Problem ◽  
Receptor Binding Domain ◽  
Vitro Assay ◽  
Surface Receptor

AbstractCOVID-19 currently represents a major public health problem. Multiple efforts are being performed to control this disease. Vaccinations are already in progress. However, no effective treatments have been found so far. The disease is caused by the SARS-CoV-2 coronavirus that through the Spike protein interacts with its cell surface receptor ACE2 to enter into the host cells. Therefore, compounds able to block this interaction may help to stop disease progression. In this study, we have analyzed the effect of compounds reported to interact and modify the activity of ACE2 on the binding of the Spike protein. Among the compounds tested, we found that hydroxyzine could inhibit the binding of the receptor-binding domain of Spike protein to ACE2 in a qualitative in vitro assay. This finding supports the reported clinical data showing the benefits of hydroxyzine on COVID-19 patients, raising the need for further investigation into its effectiveness in the treatment of COVID-19 given its well-characterized medical properties and affordable cost.

scholarly journals In Vitro Effect of Taraxacum officinale Leaf Aqueous Extract on the Interaction between ACE2 Cell Surface Receptor and SARS-CoV-2 Spike Protein D614 and Four Mutants

2021 ◽  
Vol 14 (10) ◽  
pp. 1055
Author(s):  
Hoai Thi Thu Tran ◽  
Michael Gigl ◽  
Nguyen Phan Khoi Le ◽  
Corinna Dawid ◽  
Evelyn Lamy
Keyword(s):  
Immune Escape ◽  
Taraxacum Officinale ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Post Exposure Prophylaxis ◽  
Lung Cells ◽  
Surface Receptor ◽  
Exposure Prophylaxis ◽  
Vitro Effect

To date, there have been rapidly spreading new SARS-CoV-2 “variants of concern”. They all contain multiple mutations in the ACE2 receptor recognition site of the spike protein, compared to the original Wuhan sequence, which is of great concern, because of their potential for immune escape. Here we report on the efficacy of common dandelion (Taraxacum officinale) to block protein–protein interaction of SARS-COV-2 spike to the human ACE2 receptor. This could be shown for the wild type and mutant forms (D614G, N501Y, and a mix of K417N, E484K, and N501Y) in human HEK293-hACE2 kidney and A549-hACE2-TMPRSS2 lung cells. High-molecular-weight compounds in the water-based extract account for this effect. Infection of the lung cells using SARS-CoV-2 spike D614 and spike Delta (B.1.617.2) variant pseudotyped lentivirus particles was efficiently prevented by the extract and so was virus-triggered pro-inflammatory interleukin 6 secretion. Modern herbal monographs consider the usage of this medicinal plant as safe. Thus, the in vitro results reported here should encourage further research on the clinical relevance and applicability of the extract as prevention strategy for SARS-CoV-2 infection in terms of a non-invasive, oral post-exposure prophylaxis.

scholarly journals COVID-19: Probing the Possibility of Transmission in Animal Kingdom

2020 ◽  
Author(s):  
Tawsif Ahmed Kazi ◽  
Suranjita Mitra ◽  
Bidhan Chandra Mukhopadhyay ◽  
Rajarshi Bhattacharya ◽  
Sukhendu Mandal ◽  
...  
Keyword(s):  
Global Economy ◽  
Comparative Sequence Analysis ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Broad Host Range ◽  
The Public ◽  
Molecular Events ◽  
Surface Receptor ◽  
Rats And Mice ◽  
Aquatic Mammals

The recent 2019-nCoV outbreak, spreading infection around the globe is jeopardizing the public health and global economy. The virus was reported to have emerged from an animal market in Wuhan, China at the end of 2019 and presumed to have originated from bats and eventually transmitted in humans. The entry of the virus into human cells is triggered by a series of molecular events initiated with the binding of a receptor-binding domain of viral spike protein to human Ace2 cell surface receptor. Based on the comparative sequence analysis of the well-known binding hotspots of human Ace2, cross-interacting potential of 2019-nCoV was predicted, which suggests Ace2 of wild animals like tiger, bear, orangutan, etc.; aquatic mammals like whale and dolphins; and domestic animals like cat, horse, goat, sheep, dog etc. as potential target. However, the recognition of Ace2 of bats, rats and mice by the 2019-nCoV spike protein remains under question. The study indicates that 2019-nCoV might have broad host range and may thus intensify the gravity of 2019-nCoV outbreak

scholarly journals N and O glycosylation of the SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Miloslav Sanda ◽  
Lindsay Morrison ◽  
Radoslav Goldman
Keyword(s):  
Current Knowledge ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
World Health ◽  
Furin Cleavage ◽  
Proteolytic Activation ◽  
Health Crisis ◽  
Antiviral Compounds ◽  
Furin Cleavage Site ◽  
Surface Receptor

ABSTRACTCovid-19 pandemic outbreak is the reason of the current world health crisis. The development of effective antiviral compounds and vaccines requires detailed descriptive studies of the SARS-CoV-2 proteins. The SARS-CoV-2 spike (S) protein mediates virion binding to the human cells through its interaction with the ACE2 cell surface receptor and is one of the prime immunization targets. A functional virion is composed of three S1 and three S2 subunits created by furin cleavage of the spike protein at R682, a polybasic cleavage sites that differs from the SARS-CoV spike protein of 2002. We observe that the spike protein is O-glycosylated on a threonine (T678) near the furin cleavage site occupied by core-1 and core-2 structures. In addition, we have identified eight additional O-glycopeptides on the spike glycoprotein and we confirmed that the spike protein is heavily N-glycosylated. Our recently developed LC-MS/MS methodology allowed us to identify LacdiNAc structural motives on all occupied N-glycopeptides and polyLacNAc structures on six glycopeptides of the spike protein. In conclusion, our study substantially expands the current knowledge of the spike protein’s glycosylation and enables the investigation of the influence of the O-glycosylation on its proteolytic activation.

scholarly journals Perspectives and potential approaches for targeting neuropilin 1 in SARS-CoV-2 infection

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Svetlana P. Chapoval ◽  
Achsah D. Keegan
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Virus Entry ◽  
Severe Disease ◽  
Spike Protein ◽  
Virus Infectivity ◽  
Human Response ◽  
Type B ◽  
Pathogenetic Mechanisms ◽  
Neuropilin 1 ◽  
Entry Receptor

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel type b coronavirus responsible for the COVID-19 pandemic. With over 224 million confirmed infections with this virus and more than 4.6 million people dead because of it, it is critically important to define the immunological processes occurring in the human response to this virus and pathogenetic mechanisms of its deadly manifestation. This perspective focuses on the contribution of the recently discovered interaction of SARS-CoV-2 Spike protein with neuropilin 1 (NRP1) receptor, NRP1 as a virus entry receptor for SARS-CoV-2, its role in different physiologic and pathologic conditions, and the potential to target the Spike–NRP1 interaction to combat virus infectivity and severe disease manifestations.

Sign in / Sign up

Export Citation Format

Share Document