Mechanism of Receptor Recognition in Coronavirus

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Coronaviruses".

Deadline for manuscript submissions: 31 October 2024 | Viewed by 6462

Special Issue Editor

Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
Interests: virus; host; structure; biology; cells; biochemistry; protein; gene; vaccines; immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent decades, the scientific community has made remarkable advancements in unraveling the mechanisms of receptor recognition in coronaviruses, a critical facet in the field of virology. Early research delineated the pivotal role of spike (S) proteins in facilitating virus entry into host cells, laying a solid foundation for subsequent, more detailed investigations. A significant breakthrough came in the early 2000s with the identification of the ACE2 receptor as a key entry point for SARS-CoV. This was followed by the discovery of DPP4 as the receptor for MERS-CoV, further underscoring the receptor diversity among different coronaviruses. More recently, during the COVID-19 pandemic, the critical role of the ACE2 receptor in SARS-CoV-2 entry was elucidated, marking a pivotal moment in contemporary research. The rapid response to the COVID-19 outbreak saw an unprecedented focus in this field, with researchers swiftly pinpointing the involvement of proteases like TMPRSS2 in virus entry, thereby opening new avenues for therapeutic interventions. Complementing these efforts, advancements in structural biology have facilitated high-resolution mapping of virus–receptor interactions, offering a molecular blueprint for the development of targeted therapeutics.

As the field of coronavirus receptor recognition advances, it is confronted with a myriad of intricate challenges, each holding significant importance and necessitating a multifaceted approach for effective navigation. Among these challenges is the burgeoning exploration into the roles of alternative receptors and co-receptors, which highlights the complex virus–host dynamics that define these pathogens. This is exacerbated by the rapid mutation rates observed in the spike proteins of certain coronaviruses, a phenomenon that continually threatens to undermine the efficacy of existing vaccines and therapeutics. Adding to this complexity is the broad host range that coronaviruses exhibit, encompassing various animal species, which introduces additional layers of complexity to the study of receptor recognition mechanisms. As we navigate this critical juncture, it becomes increasingly clear that a comprehensive understanding of these dynamics is pivotal in crafting strategies that can effectively curb the spread and mitigate the impact of these viruses, marking significant strides in contemporary virological research. This evolving landscape sets the stage for future endeavors aimed at mitigating the repercussions of coronavirus outbreaks, underscoring the intricate and multifaceted nature of virus–host interactions.

This Special Issue invites contributions that offer a panoramic view of the current state of research in this field, encouraging submissions that not only delve into the molecular intricacies of receptor recognition across the diverse coronavirus family but also address the pressing challenges that impede progress in this critical area of study. We welcome original research articles, comprehensive reviews, and short communications that resonate with the evolving trends and prospective directions in this dynamic field.

We eagerly anticipate your invaluable contributions.

Sincerely,
Dr. Qibin Geng
Guest Editor

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Keywords

  • coronavirus family (alpha, beta, gamma, delta)
  • receptor recognition mechanisms
  • spike protein mutations
  • host range diversity
  • emerging coronaviruses
  • vaccine and therapeutic challenges
  • molecular interaction complexity
  • viral evolution and zoonotic transmission
  • host–pathogen interactions
  • cellular entry factors

Published Papers (3 papers)

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Research

16 pages, 12030 KiB  
Article
Stabilization of the Metastable Pre-Fusion Conformation of the SARS-CoV-2 Spike Glycoprotein through N-Linked Glycosylation of the S2 Subunit
by Fuwen Zan, Yao Zhou, Ting Chen, Yahan Chen, Zhixia Mu, Zhaohui Qian and Xiuyuan Ou
Viruses 2024, 16(2), 223; https://doi.org/10.3390/v16020223 - 31 Jan 2024
Viewed by 1181
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic, represents a serious threat to public health. The spike (S) glycoprotein of SARS-CoV-2 mediates viral entry into host cells and is heavily glycosylated. In this [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic, represents a serious threat to public health. The spike (S) glycoprotein of SARS-CoV-2 mediates viral entry into host cells and is heavily glycosylated. In this study, we systemically analyzed the roles of 22 putative N-linked glycans in SARS-CoV-2 S protein expression, membrane fusion, viral entry, and stability. Using the α-glycosidase inhibitors castanospermine and NB-DNJ, we confirmed that disruption of N-linked glycosylation blocked the maturation of the S protein, leading to the impairment of S protein-mediated membrane fusion. Single-amino-acid substitution of each of the 22 N-linked glycosylation sites with glutamine revealed that 9 out of the 22 N-linked glycosylation sites were critical for S protein folding and maturation. Thus, substitution at these sites resulted in reduced S protein-mediated cell–cell fusion and viral entry. Notably, the N1074Q mutation markedly affected S protein stability and induced significant receptor-independent syncytium (RIS) formation in HEK293T/hACE2-KO cells. Additionally, the removal of the furin cleavage site partially compensated for the instability induced by the N1074Q mutation. Although the corresponding mutation in the SARS-CoV S protein (N1056Q) did not induce RIS in HEK293T cells, the N669Q and N1080Q mutants exhibited increased fusogenic activity and did induce syncytium formation in HEK293T cells. Therefore, N-glycans on the SARS-CoV and SARS-CoV-2 S2 subunits are highly important for maintaining the pre-fusion state of the S protein. This study revealed the critical roles of N-glycans in S protein maturation and stability, information that has implications for the design of vaccines and antiviral strategies. Full article
(This article belongs to the Special Issue Mechanism of Receptor Recognition in Coronavirus)
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20 pages, 6788 KiB  
Article
The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses
by Olga I. Yarovaya, Aleksandr S. Filimonov, Dmitriy S. Baev, Sophia S. Borisevich, Anna V. Zaykovskaya, Varvara Yu. Chirkova, Mariya K. Marenina, Yulia V. Meshkova, Svetlana V. Belenkaya, Dmitriy N. Shcherbakov, Maxim A. Gureev, Olga A. Luzina, Oleg V. Pyankov, Nariman F. Salakhutdinov and Mikhail V. Khvostov
Viruses 2024, 16(2), 215; https://doi.org/10.3390/v16020215 - 31 Jan 2024
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Abstract
Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on [...] Read more.
Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (−)-usnic acid and studied their ability to inhibit the main protease of SARS-CoV-2. Substances containing unsubstituted thiophene groups or methyl- or bromo-substituted thiophene moieties showed moderate activity. Derivatives containing nitro substituents in the thiophene heterocycle—just as pure (+)- and (−)-usnic acids—showed no anti-3CLpro activity. Kinetic parameters of the most active compound, (+)-3e, were investigated, and molecular modeling of the possible interaction of the new thiazolo-thiophenes with the active site of the main protease was carried out. We evaluated the binding energies of the ligand and protein in a ligand–protein complex. Active compound (+)-3e was found to bind with minimum free energy; the binding of inactive compound (+)-3g is characterized by higher values of minimum free energy; the positioning of pure (+)-usnic acid proved to be unstable and is accompanied by the formation of intermolecular contacts with many amino acids of the catalytic binding site. Thus, the molecular dynamics results were consistent with the experimental data. In an in vitro antiviral assay against six strains (Wuhan, Delta, and four Omicron sublineages) of SARS-CoV-2, (+)-3e demonstrated pronounced antiviral activity against all the strains. Full article
(This article belongs to the Special Issue Mechanism of Receptor Recognition in Coronavirus)
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26 pages, 5876 KiB  
Article
Investigating the Potential Shared Molecular Mechanisms between COVID-19 and Alzheimer’s Disease via Transcriptomic Analysis
by Yixian Fan, Xiaozhao Liu, Fei Guan, Xiaoyi Hang, Ximiao He and Jing Jin
Viruses 2024, 16(1), 100; https://doi.org/10.3390/v16010100 - 9 Jan 2024
Viewed by 1501
Abstract
SARS-CoV-2 caused the COVID-19 pandemic. COVID-19 may elevate the risk of cognitive impairment and even cause dementia in infected individuals; it may accelerate cognitive decline in elderly patients with dementia, possibly in Alzheimer’s disease (AD) patients. However, the mechanisms underlying the interplay between [...] Read more.
SARS-CoV-2 caused the COVID-19 pandemic. COVID-19 may elevate the risk of cognitive impairment and even cause dementia in infected individuals; it may accelerate cognitive decline in elderly patients with dementia, possibly in Alzheimer’s disease (AD) patients. However, the mechanisms underlying the interplay between AD and COVID-19 are still unclear. To investigate the underlying mechanisms and associations between AD progression and SARS-CoV-2 infection, we conducted a series of bioinformatics research into SARS-CoV-2-infected cells, COVID-19 patients, AD patients, and SARS-CoV-2-infected AD patients. We identified the common differentially expressed genes (DEGs) in COVID-19 patients, AD patients, and SARS-CoV-2-infected cells, and these DEGs are enriched in certain pathways, such as immune responses and cytokine storms. We constructed the gene interaction network with the signaling transduction module in the center and identified IRF7, STAT1, STAT2, and OAS1 as the hub genes. We also checked the correlations between several key transcription factors and the SARS-CoV-2 and COVID-19 pathway-related genes. We observed that ACE2 expression is positively correlated with IRF7 expression in AD and coronavirus infections, and interestingly, IRF7 is significantly upregulated in response to different RNA virus infections. Further snRNA-seq analysis indicates that NRGN neurons or endothelial cells may be responsible for the increase in ACE2 and IRF7 expression after SARS-CoV-2 infection. The positive correlation between ACE2 and IRF7 expressions is confirmed in the hippocampal formation (HF) of SARS-CoV-2-infected AD patients. Our findings could contribute to the investigation of the molecular mechanisms underlying the interplay between AD and COVID-19 and to the development of effective therapeutic strategies for AD patients with COVID-19. Full article
(This article belongs to the Special Issue Mechanism of Receptor Recognition in Coronavirus)
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