scholarly journals Alpha-Soluble NSF Attachment Protein Prevents the Cleavage of the SARS-CoV-2 Spike Protein by Functioning as an Interferon-Upregulated Furin Inhibitor

mBio ◽  
2022 ◽  
Author(s):  
Jinliang Wang ◽  
Jie Luo ◽  
Zhiyuan Wen ◽  
Xinxin Wang ◽  
Lei Shuai ◽  
...  
Keyword(s):  
Drug Target ◽  
Antiviral Drug ◽  
Spike Protein ◽  
Attachment Protein ◽  
Furin Cleavage ◽  
Cleavage Motif

Some key mutations of SARS-CoV-2 spike protein, such as D614G and P681R mutations, increase the transmission or pathogenicity by enhancing the cleavage efficacy of spike protein by furin. Loss of the furin cleavage motif of SARS-CoV-2 spike protein reduces the virulence and transmission, suggesting that furin is an attractive antiviral drug target.

scholarly journals Murine Coronavirus with an Extended Host Range Uses Heparan Sulfate as an Entry Receptor

2005 ◽  
Vol 79 (22) ◽  
pp. 14451-14456 ◽  
Author(s):  
Cornelis A. M. de Haan ◽  
Zhen Li ◽  
Eddie te Lintelo ◽  
Berend Jan Bosch ◽  
Bert Jan Haijema ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Host Range ◽  
Binding Sites ◽  
Spike Protein ◽  
Heparin Binding ◽  
Furin Cleavage ◽  
Cleavage Motif ◽  
Entry Receptor ◽  
Murine Coronavirus

ABSTRACT Only a relatively few mutations in its spike protein allow the murine coronavirus to switch from a murine-restricted tropism to an extended host range by being passaged in vitro. One such virus that we studied had acquired two putative heparan sulfate-binding sites while preserving another site in the furin-cleavage motif. The adaptation of the virus through the use of heparan sulfate as an attachment/entry receptor was demonstrated by increased heparin binding as well as by inhibition of infection through treatment of cells and the virus with heparinase and heparin, respectively.

scholarly journals The Functional Consequences of the Novel Ribosomal Pausing Site in SARS-CoV-2 Spike Glycoprotein RNA

2021 ◽  
Vol 22 (12) ◽  
pp. 6490
Author(s):  
Olga A. Postnikova ◽  
Sheetal Uppal ◽  
Weiliang Huang ◽  
Maureen A. Kane ◽  
Rafael Villasmil ◽  
...  
Keyword(s):  
Amino Acid ◽  
Insertion Sequence ◽  
Experimental Studies ◽  
Spike Protein ◽  
Spike Glycoprotein ◽  
Furin Cleavage ◽  
New Host ◽  
S Protein ◽  
Furin Cleavage Site ◽  
Ribosome Pausing

The SARS-CoV-2 Spike glycoprotein (S protein) acquired a unique new 4 amino acid -PRRA- insertion sequence at amino acid residues (aa) 681–684 that forms a new furin cleavage site in S protein as well as several new glycosylation sites. We studied various statistical properties of the -PRRA- insertion at the RNA level (CCUCGGCGGGCA). The nucleotide composition and codon usage of this sequence are different from the rest of the SARS-CoV-2 genome. One of such features is two tandem CGG codons, although the CGG codon is the rarest codon in the SARS-CoV-2 genome. This suggests that the insertion sequence could cause ribosome pausing as the result of these rare codons. Due to population variants, the Nextstrain divergence measure of the CCU codon is extremely large. We cannot exclude that this divergence might affect host immune responses/effectiveness of SARS-CoV-2 vaccines, possibilities awaiting further investigation. Our experimental studies show that the expression level of original RNA sequence “wildtype” spike protein is much lower than for codon-optimized spike protein in all studied cell lines. Interestingly, the original spike sequence produces a higher titer of pseudoviral particles and a higher level of infection. Further mutagenesis experiments suggest that this dual-effect insert, comprised of a combination of overlapping translation pausing and furin sites, has allowed SARS-CoV-2 to infect its new host (human) more readily. This underlines the importance of ribosome pausing to allow efficient regulation of protein expression and also of cotranslational subdomain folding.

Viral and Host Attributes Underlying the Origins of Zoonotic Coronaviruses in Bats

2021 ◽  
Author(s):  
Alison E Stout ◽  
Qinghua Guo ◽  
Jean K Millet ◽  
Gary R Whittaker
Keyword(s):  
Viral Pathogenesis ◽  
Spike Protein ◽  
Future Research ◽  
Receptor Binding Domain ◽  
Viral Reservoirs ◽  
Furin Cleavage ◽  
Proteolytic Activation ◽  
Furin Cleavage Site ◽  
Unique Aspect ◽  
Genome Level

With a presumed origin in bats, the COVID-19 pandemic has been a major source of morbidity and mortality in the humanpopulation, and the causative agent, SARS-CoV-2, aligns most closely at the genome level with the bat coronavirusesRaBtCoV4991/RaTG13 and RmYN02. The ability of bats to provide reservoirs of numerous viruses in addition to coronavirusesremains an active area of research. Unique aspects of the physiology of the chiropteran immune system may contributeto the ability of bats to serve as viral reservoirs. The coronavirus spike protein plays important roles in viral pathogenesis and the immune response. Although much attention has focused on the spike receptor-binding domain, a unique aspect of SARS-CoV-2 as compared with its closest relatives is the presence of a furin cleavage site in the S1–S2 region of the spike protein. Proteolytic activation is likely an important feature that allows SARS-CoV-2—and other coronaviruses—to overcome the species barriers and thus cause human disease. The diversity of bat species limits the ability to draw broad conclusions about viral pathogenesis, but comparisons across species and with reference to humans and other susceptible mammals may guide future research in this regard.

Characterization of the furin cleavage motif for HIV-1 trimeric envelope glycoprotein by intact LC-MS analysis

The Analyst ◽  
2020 ◽  
Vol 145 (5) ◽  
pp. 1636-1640 ◽  
Author(s):  
Nicole A. Schneck ◽  
Vera B. Ivleva ◽  
Cindy X. Cai ◽  
Jonathan W. Cooper ◽  
Q. Paula Lei
Keyword(s):  
Envelope Glycoprotein ◽  
Mass Measurement ◽  
Furin Cleavage ◽  
Ms Analysis ◽  
Cleavage Motif ◽  
Hiv 1 ◽  
Trimeric Envelope

We demonstrate a rapid deglycosylation strategy for recombinant HIV-1 envelope glycoprotein, enabling intact LC-MS mass measurement and furin cleavage monitoring.

scholarly journals Xanthohumol Is a Potent Pan-Inhibitor of Coronaviruses Targeting Main Protease

2021 ◽  
Vol 22 (22) ◽  
pp. 12134
Author(s):  
Yuxi Lin ◽  
Ruochen Zang ◽  
Yanlong Ma ◽  
Zhuoya Wang ◽  
Li Li ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Small Molecule ◽  
Drug Target ◽  
Antiviral Drug ◽  
High Morbidity ◽  
Lead Compound ◽  
Human Beings ◽  
Main Protease ◽  
Ic50 Value

Coronaviruses cause diseases in humans and livestock. The SARS-CoV-2 is infecting millions of human beings, with high morbidity and mortality worldwide. The main protease (Mpro) of coronavirus plays a pivotal role in viral replication and transcription, which, in theory, is an attractive drug target for antiviral drug development. It has been extensively discussed whether Xanthohumol is able to help COVID-19 patients. Here, we report that Xanthohumol, a small molecule in clinical trials from hops (Humulus lupulus), was a potent pan-inhibitor for various coronaviruses by targeting Mpro, for example, betacoronavirus SARS-CoV-2 (IC50 value of 1.53 μM), and alphacoronavirus PEDV (IC50 value of 7.51 μM). Xanthohumol inhibited Mpro activities in the enzymatical assays, while pretreatment with Xanthohumol restricted the SARS-CoV-2 and PEDV replication in Vero-E6 cells. Therefore, Xanthohumol is a potent pan-inhibitor of coronaviruses and an excellent lead compound for further drug development.

scholarly journals A Dual Controllability Analysis of Influenza Virus-Host Protein-Protein Interaction Networks for Antiviral Drug Target Discovery

2018 ◽  
Author(s):  
Emily E. Ackerman ◽  
John F. Alcorn ◽  
Takeshi Hase ◽  
Jason E. Shoemaker
Keyword(s):  
Influenza Virus ◽  
Protein Interaction ◽  
Drug Target ◽  
Influenza A ◽  
Antiviral Drug ◽  
Host Factors ◽  
Host Protein ◽  
Drug Target Discovery ◽  
Protein Protein Interaction ◽  
Protein Protein Interaction Networks

ABSTRACTHost factors of influenza virus replication are often found in key topological positions within protein-protein interaction networks. This work explores how protein states can be manipulated through controllability analysis: the determination of the minimum manipulation needed to drive the cell system to any desired state. Here, we complete a two-part controllability analysis of two protein networks: a host network representing the healthy cell state and an influenza A virus-host network representing the infected cell state. This knowledge can be utilized to understand disease dynamics and isolate proteins for study as drug target candidates. Both topological and controllability analyses provide evidence of wide-reaching network effects stemming from the addition of viral-host protein interactions. Virus interacting and driver host proteins are significant both topologically and in controllability, therefore playing important roles in cell behavior during infection. 24 proteins are identified as holding regulatory roles specific to the infected cell by measures of topology, controllability, and functional role. These proteins are recommended for further study as potential antiviral drug targets.ImportanceSeasonal outbreaks of influenza A virus are a major cause of illness and death around the world each year, with a constant threat of pandemic infection. Even so, the FDA has only approved four treatments, two of which are unsuited for at risk groups such as children and those with breathing complications. This research aims to increase the efficiency of antiviral drug target discovery using existing protein-protein interaction data and network analysis methods. Controllability analyses identify key regulating host factors of the infected cell’s progression, findings which are supported by biological context. These results are beneficial to future studies of influenza virus, both experimental and computational.

scholarly journals Sequence Analysis Indicates that 2019-nCoV Virus Contains a Putative Furin Cleavage Site at the Boundary of S1 and S2 Domains of Spike Protein

2020 ◽  
Author(s):  
Z. Galen WO
Keyword(s):  
Amino Acid ◽  
Cleavage Site ◽  
Spike Protein ◽  
Sequence Motif ◽  
Furin Cleavage ◽  
Host Cell Membrane ◽  
Virus Family ◽  
Prediction Program ◽  
Furin Cleavage Site ◽  
Novel Coronavirus

The infectious 2019-nCoV virus, which caused the current novel coronavirus pneumonia epidemic outbreak, possesses a unique 4-Amino Acid insert at the boundary of the two subdomains (S1 and S2) of Spike protein based on multiple protein sequence alignment with the large SARS and SARS-related virus family. Using Bat CoV_RaTG13 Spike protein as reference (sharing 97% aa identity) the 4-amino acid insert can be identified as PRRA (AA position 681-684). The effect of the 4-AA insertion is the presence of a furin signature sequence motif (PRRARSV) at the boundary of S1 and S2 domains of spike protein. This sequence motif consists the required Arg residue for P1 and P4 position of Furin site. In addition, it contains Arg at P3 site as well as Ser at P1’ site of furin motif. This sequence motif matches Aerolysin furin site in FurinDB and was predicted to be moderately strong (score 0.62) by ProP, a protease cleavage site prediction program. This finding suggests that the infectious 2019-nCoV virus, unlike SARS viruses, may be processed via cellular furin recognition and cleavage of the spike protein before host cell membrane fusion and entry. This putative furin site in spike protein of 2019-nCoV virus, if proven to be functional, suggests the potential of looking into agents inhibiting furin as therapeutic mean for the treatment of the novel coronavirus pneumonia.

scholarly journals Profiling B cell immune responses to identify neutralizing antibodies from convalescent COVID-19 patients

2020 ◽  
Author(s):  
Lisu Huang ◽  
Bingqing Shen ◽  
Yu Guo ◽  
Shu Shen ◽  
Heyu Huang ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Therapeutic Option ◽  
Antiviral Drug ◽  
Cell Receptor ◽  
High Serum ◽  
Spike Protein ◽  
Live Virus ◽  
Angiotensin Converting Enzyme 2 ◽  
Humoral Responses

Abstract The pandemic Coronavirus Disease 2019 (COVID-19) causes noticeable morbidity and mortality worldwide. In addition to vaccine and antiviral drug therapy, the use of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) neutralizing antibodies for treatment purposes is a viable alternative. In this study, we aimed to profile the humoral responses and identify neutralizing antibodies against SARS-CoV-2 using high-throughput single-cell sequencing that tailored to B cell receptor sequencing. From two convalescent patients with high serum titer against SARS-COV-2, we identified seven antibodies specifically binding to SARS-CoV-2. Among these, the most potent antibody, P4A1 was demonstrated to block the binding of spike protein to its receptor angiotensin-converting enzyme 2 (ACE2), and prevent the viral infection in neutralization assays with pseudovirus as well as live virus at nM to sub-nM range. Moreover, antibody P4A1 can also bind strongly to spike protein with N354D/D364Y, R408I, W436R, V367F or D614G mutations respectively, suggesting that the antibody alone or in combination with other antibodies that recognize different variations of SARS-CoV-2, may provide a broad spectrum therapeutic option for COVID-19 patients. Authors Lisu Huang, Bingqing Shen, Yu Guo, and Shu Shen contributed equally to this work.

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