Coronaviruses Pathogenesis, Immunity, and Antivirals

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

Deadline for manuscript submissions: closed (25 January 2025) | Viewed by 14537

Special Issue Editors


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Guest Editor
1. National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
2. The Cooperative Innovation Center for Sustainable Pig Production, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
Interests: virology; ASFV; viral entry; emerging viruses; virus discovery; infectious diseases; coronavirus
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Guest Editor
College of Life Sciences, Hebei Agricultural University, Baoding, China
Interests: influenza; COVID-19; HIV; antivirals
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Coronaviridae family includes a large number of viruses affecting humans, farm animals, pets, wildlife, and birds. Since coronaviruses have a broad host range and tropism, there is a continuous emergence of new coronaviruses, new serotypes, and new variants of the currently known coronaviruses. Some of them might cross the species barrier and infect humans, such as in the ongoing SARS-CoV-2 epidemic. Thus, it is important to study the pathogenesis and immunity of coronaviruses to better develop antiviral drugs and vaccines. In this Special Issue of Viruses, we invite the submission of original research papers and review articles spanning all aspects of coronaviruses, including molecular mechanisms mediating virus virulence, the molecular basis of virus replication, virus pathogenesis, virus diagnosis, animal models, host immune responses involved in protection against infection, the development of vaccines and antiviral drugs, and coronaviruses in wildlife.

Prof. Dr. Wentao Li
Prof. Dr. Fei Yu
Guest Editors

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Keywords

  • coronaviruses
  • virus pathogenesis
  • animal models
  • immune response
  • development of vaccines and antiviral drugs

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Published Papers (10 papers)

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Research

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24 pages, 6076 KiB  
Article
Betacoronaviruses Differentially Activate the Integrated Stress Response to Optimize Viral Replication in Lung-Derived Cell Lines
by David M. Renner, Nicholas A. Parenti, Nicole Bracci and Susan R. Weiss
Viruses 2025, 17(1), 120; https://doi.org/10.3390/v17010120 - 16 Jan 2025
Viewed by 673
Abstract
The betacoronavirus genus contains five of the seven human coronaviruses, making it a particularly critical area of research to prepare for future viral emergence. We utilized three human betacoronaviruses, one from each subgenus—HCoV-OC43 (embecovirus), SARS-CoV-2 (sarbecovirus), and MERS-CoV (merbecovirus)—, to study betacoronavirus interactions [...] Read more.
The betacoronavirus genus contains five of the seven human coronaviruses, making it a particularly critical area of research to prepare for future viral emergence. We utilized three human betacoronaviruses, one from each subgenus—HCoV-OC43 (embecovirus), SARS-CoV-2 (sarbecovirus), and MERS-CoV (merbecovirus)—, to study betacoronavirus interactions with the PKR-like ER kinase (PERK) pathway of the integrated stress response (ISR)/unfolded protein response (UPR). The PERK pathway becomes activated by an abundance of unfolded proteins within the endoplasmic reticulum (ER), leading to phosphorylation of eIF2α and translational attenuation. We demonstrate that MERS-CoV, HCoV-OC43, and SARS-CoV-2 all activate PERK and induce responses downstream of p-eIF2α, while only SARS-CoV-2 induces detectable p-eIF2α during infection. Using a small molecule inhibitor of eIF2α dephosphorylation, we provide evidence that MERS-CoV and HCoV-OC43 maximize viral replication through p-eIF2α dephosphorylation. Interestingly, genetic ablation of growth arrest and DNA damage-inducible protein (GADD34) expression, an inducible protein phosphatase 1 (PP1)-interacting partner targeting eIF2α for dephosphorylation, did not significantly alter HCoV-OC43 or SARS-CoV-2 replication, while siRNA knockdown of the constitutive PP1 partner, constitutive repressor of eIF2α phosphorylation (CReP), dramatically reduced HCoV-OC43 replication. Combining GADD34 knockout with CReP knockdown had the maximum impact on HCoV-OC43 replication, while SARS-CoV-2 replication was unaffected. Overall, we conclude that eIF2α dephosphorylation is critical for efficient protein production and replication during MERS-CoV and HCoV-OC43 infection. SARS-CoV-2, however, appears to be insensitive to p-eIF2α and, during infection, may even downregulate dephosphorylation to limit host translation. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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18 pages, 2609 KiB  
Article
Effect of Fusion to the LTB Carrier Protein on Coronavirus Spike Protein Vaccine Candidates Produced in Maize
by Erin Egelkrout, Magdalena Maj, Rodrigo Manjarin, Gina Fake, Muneaki Watanabe, Jenna Williams, Nate Blanchard, John Walker, Celine Hayden and John Howard
Viruses 2025, 17(1), 7; https://doi.org/10.3390/v17010007 - 24 Dec 2024
Viewed by 770
Abstract
Coronaviruses continue to disrupt health and economic productivity worldwide. Porcine epidemic diarrhea virus (PEDV) is a devastating swine disease and SARS-CoV-2 is the latest coronavirus to infect the human population. Both viruses display a similar spike protein on the surface that is a [...] Read more.
Coronaviruses continue to disrupt health and economic productivity worldwide. Porcine epidemic diarrhea virus (PEDV) is a devastating swine disease and SARS-CoV-2 is the latest coronavirus to infect the human population. Both viruses display a similar spike protein on the surface that is a target of vaccine development. Despite the availability of commercial vaccines for both viruses, there is still a high occurrence of infections and a great need for enhanced efficacy and lower costs. We previously produced the PEDV spike protein (S) using transgenic maize, enabling a low-cost supply of the vaccine candidate. In this study, we (1) test orally delivered PEDV vaccine candidates in pigs to optimize the mucosal immune response; (2) generate the SARS-CoV-2 S1 protein in maize; and (3) perform structural characterization of the S1 protein for PEDV and SARS-CoV-2. We demonstrated high expression levels in maize of the S1 subunit of the SARS-CoV-2 spike protein, both with and without fusion to the heat-labile enterotoxin B (LTB) subunit. We found that the LTB fusion protein from both coronaviruses preferentially assembles into higher molecular weight multimers, consistent with the formation of trimers. For PEDV, administering the spike protein fused to LTB to young pigs elicited a higher level of mucosal IgAs compared to maize grain containing the S1 protein alone or controls. This suggests that fusing the coronavirus spike protein with LTB may provide better protection. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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15 pages, 471 KiB  
Article
Azelastine Nasal Spray in Non-Hospitalized Subjects with Mild COVID-19 Infection: A Randomized Placebo-Controlled, Parallel-Group, Multicentric, Phase II Clinical Trial
by Peter Meiser, Michael Flegel, Frank Holzer, Dorothea Groß, Charlotte Steinmetz, Barbara Scherer, Rajesh Jain and CARVIN-II Study Group
Viruses 2024, 16(12), 1914; https://doi.org/10.3390/v16121914 - 13 Dec 2024
Viewed by 1160
Abstract
Nasal spray treatments that inhibit the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) entry into nose and nasopharynx at early stages can be an appropriate approach to stop or delay the progression of the disease. We performed a prospective, randomized, double-blind, placebo-controlled, parallel-group, [...] Read more.
Nasal spray treatments that inhibit the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) entry into nose and nasopharynx at early stages can be an appropriate approach to stop or delay the progression of the disease. We performed a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicentric, phase II clinical trial comparing the rate of hospitalization due to COVID-19 infection between azelastine 0.1% nasal spray and placebo nasal spray treatment groups. The study furthermore assessed the reduction in virus load in SARS-CoV-2-infected subjects estimated via quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using nasopharyngeal swabs in both groups during the treatment period. A total of 294 subjects with mild COVID-19 infection were screened and randomized in a 1:1 ratio. There was no incidence of COVID-19-related hospitalization in either treatment group. Mean virus load was significantly reduced in both groups during the 11 treatment days as compared with baseline viral load values. The reduction in virus load in the azelastine 0.1% nasal spray group was significantly higher than the reduction in the placebo group at day 11 (log10 5.93 vs. log10 5.85 copies/mL, respectively, p = 0.0041). A total of 39 (32.0%) subjects in the azelastine 0.1% treatment group and 40 (31.0%) subjects in the placebo group reported 48 and 51 adverse events, respectively. It is therefore concluded that azelastine 0.1% nasal spray is an efficacious, safe, and well-tolerated treatment of mild COVID-19 infection. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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11 pages, 898 KiB  
Article
Epithelial Antimicrobial Peptide/Protein and Cytokine Expression Profiles Obtained from Nasopharyngeal Swabs of SARS-CoV-2-Infected and Non-Infected Subjects
by Thilo Gambichler, Silke Goesmann, Marina Skrygan, Laura Susok, Christian Schütte, Nahza Hamdani and Wolfgang Schmidt
Viruses 2024, 16(9), 1471; https://doi.org/10.3390/v16091471 - 15 Sep 2024
Viewed by 1287
Abstract
Immune responses of the epithelia of the upper respiratory tract are likely crucial in early inhibition of the viral replication and finally clearance of SARS-CoV-2. We aimed to compare the expression profiles of antimicrobial peptides/proteins (AMPs) and related cytokines observed in the nasopharynx [...] Read more.
Immune responses of the epithelia of the upper respiratory tract are likely crucial in early inhibition of the viral replication and finally clearance of SARS-CoV-2. We aimed to compare the expression profiles of antimicrobial peptides/proteins (AMPs) and related cytokines observed in the nasopharynx of SARS-CoV-2-infected patients and non-infected controls and to assess the associations between these parameters and COVID-19 patients’ outcomes. We included 45 subjects who had tested positive for SARS-CoV-2 and 22 control subjects who had tested negative for SARS-CoV-2. Biomaterial for SARS-CoV-2 detection, as well as gene and protein expression studies, was obtained from all subjects using nasopharyngeal swabs which were performed a maximum of 7 days before inclusion in the study. Univariable and multivariable statistics were performed. When compared to the controls, the mRNA expression levels of human β-defensin 1 (hBD-1), LL-37, and trappin-2 were significantly higher in specimens of nasopharyngeal swabs from COVID-19 patients. Protein expression of hBD-1 was also increased in the COVID-19 group. mRNA expression levels of interferon-ɣ (IFN-ɣ), tumor necrosis factor- ɑ (TNF-ɑ), and interleukin-6 (IL-6) measured in SARS-CoV-2-infected patients were significantly higher than those observed in the controls, which could also be confirmed in the protein levels of IFN-ɣ and IL-6. A significant correlation between mRNA and protein levels could be observed only for IL-6. Univariable analysis revealed that low IFN-ɣ mRNA levels were associated with severe/fatal outcomes. The occurrence of COVID-19 pneumonia was significantly associated with lower expression levels of IL-6 mRNA, IFN-ɣ mRNA, and TNF-ɑ mRNA. Concerning the severe/fatal outcomes, the multivariable logistic regression model revealed that none of the aforementioned parameters remained significant in the model. However, the logistic regression model revealed that higher TNF-ɑ mRNA expression was a significant independent predictor of absence of pneumonia [odds ratio: 0.35 (95% CI 0.14 to 0.88, p = 0.024)]. In conclusion, nasopharyngeal expression of AMPs (hBD-1, LL-37, and trappin-2) and cytokines (IL-6, IFN-ɣ, and TNF-ɑ) is upregulated in response to early SARS-CoV-2 infection, indicating that these AMPs and cytokines play a role in the local host defense against the virus. Upregulated nasopharyngeal TNF-ɑ mRNA expression during the early phase of SARS-CoV-2 infection was a significant independent predictor of the absence of COVID-19 pneumonia. Hence, high TNF-ɑ mRNA expression in the nasopharynx appears to be a protective factor for lung complications in COVID-19 patients. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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22 pages, 13602 KiB  
Article
An ISG15-Based High-Throughput Screening Assay for Identification and Characterization of SARS-CoV-2 Inhibitors Targeting Papain-like Protease
by Subodh Kumar Samrat, Prashant Kumar, Yuchen Liu, Ke Chen, Hyun Lee, Zhong Li, Yin Chen and Hongmin Li
Viruses 2024, 16(8), 1239; https://doi.org/10.3390/v16081239 - 1 Aug 2024
Cited by 1 | Viewed by 1653
Abstract
Emergence of newer variants of SARS-CoV-2 underscores the need for effective antivirals to complement the vaccination program in managing COVID-19. The multi-functional papain-like protease (PLpro) of SARS-CoV-2 is an essential viral protein that not only regulates the viral replication but also modulates the [...] Read more.
Emergence of newer variants of SARS-CoV-2 underscores the need for effective antivirals to complement the vaccination program in managing COVID-19. The multi-functional papain-like protease (PLpro) of SARS-CoV-2 is an essential viral protein that not only regulates the viral replication but also modulates the host immune system, making it a promising therapeutic target. To this end, we developed an in vitro interferon stimulating gene 15 (ISG15)-based Förster resonance energy transfer (FRET) assay and screened the National Cancer Institute (NCI) Diversity Set VI compound library, which comprises 1584 small molecules. Subsequently, we assessed the PLpro enzymatic activity in the presence of screened molecules. We identified three potential PLpro inhibitors, namely, NSC338106, 651084, and 679525, with IC50 values in the range from 3.3 to 6.0 µM. These molecules demonstrated in vitro inhibition of the enzyme activity and exhibited antiviral activity against SARS-CoV-2, with EC50 values ranging from 0.4 to 4.6 µM. The molecular docking of all three small molecules to PLpro suggested their specificity towards the enzyme’s active site. Overall, our study contributes promising prospects for further developing potential antivirals to combat SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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15 pages, 945 KiB  
Article
Elucidating the Immune Response to SARS-CoV-2: Natural Infection versus Covaxin/Covishield Vaccination in a South Indian Population
by Agalya Vanamudhu, Renuka Devi Arumugam, Arul Nancy, Nandhini Selvaraj, Kadar Moiden, Syed Hissar, Uma Devi Ranganathan, Ramalingam Bethunaickan, Subash Babu and Nathella Pavan Kumar
Viruses 2024, 16(8), 1178; https://doi.org/10.3390/v16081178 - 23 Jul 2024
Viewed by 1265
Abstract
A natural infection or a vaccination can initially prime the immune system to form immunological memory. The immunity engendered by vaccination against COVID-19 versus natural infection with SARS-CoV-2 has not been well studied in the Indian population. In this study, we compared the [...] Read more.
A natural infection or a vaccination can initially prime the immune system to form immunological memory. The immunity engendered by vaccination against COVID-19 versus natural infection with SARS-CoV-2 has not been well studied in the Indian population. In this study, we compared the immunity conferred by COVID-19 vaccines to naturally acquired immunity to SARS-CoV-2 in a South Indian population. We examined binding and neutralizing antibody (NAb) levels against the ancestral and variant lineages and assessed the ex vivo cellular parameters of memory T cells, memory B cells, and monocytes and finally measured the circulating cytokine response. COVID-19 vaccination stimulates heightened levels of IgG antibodies against the original strain of SARS-CoV-2, as well as increased binding to the spike protein and neutralizing antibody levels. This enhanced response extends to variant lineages such as B.1.617.2 (Delta, India), B.1.1.529 (Omicron, India), B.1.351 (Beta, South Africa), and B.1.1.7 (Alpha, UK). COVID-19 vaccination differs from SARS-CoV-2 infection by having increased frequencies of classical memory B cells, activated memory B and plasma cells, CD4/CD8 T cells of effector memory, effector cells, stem cell-like memory T cells, and classical and intermediate monocytes and diminished frequencies of CD4/CD8 T cells of central memory and non-classical monocytes in vaccinated individuals in comparison to those with natural infection. Thus, COVID-19 vaccination is characterized by enhanced humoral responses and robust activation of innate and memory T cell responses in comparison to natural infection in a South Indian population. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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17 pages, 3087 KiB  
Article
Protein C Pretreatment Protects Endothelial Cells from SARS-CoV-2-Induced Activation
by Bruna Rafaela dos Santos Silva, Davi Sidarta-Oliveira, Joseane Morari, Bruna Bombassaro, Carlos Poblete Jara, Camila Lopes Simeoni, Pierina Lorencini Parise, José Luiz Proenca-Modena, Licio A. Velloso, William H. Velander and Eliana P. Araújo
Viruses 2024, 16(7), 1049; https://doi.org/10.3390/v16071049 - 28 Jun 2024
Viewed by 1318
Abstract
SARS-CoV-2 can induce vascular dysfunction and thrombotic events in patients with severe COVID-19; however, the cellular and molecular mechanisms behind these effects remain largely unknown. In this study, we used a combination of experimental and in silico approaches to investigate the role of [...] Read more.
SARS-CoV-2 can induce vascular dysfunction and thrombotic events in patients with severe COVID-19; however, the cellular and molecular mechanisms behind these effects remain largely unknown. In this study, we used a combination of experimental and in silico approaches to investigate the role of PC in vascular and thrombotic events in COVID-19. Single-cell RNA-sequencing data from patients with COVID-19 and healthy subjects were obtained from the publicly available Gene Expression Omnibus (GEO) repository. In addition, HUVECs were treated with inactive protein C before exposure to SARS-CoV-2 infection or a severe COVID-19 serum. An RT-qPCR array containing 84 related genes was used, and the candidate genes obtained were evaluated. Activated protein C levels were measured using an ELISA kit. We identified at the single-cell level the expression of several pro-inflammatory and pro-coagulation genes in endothelial cells from the patients with COVID-19. Furthermore, we demonstrated that exposure to SARS-CoV-2 promoted transcriptional changes in HUVECs that were partly reversed by the activated protein C pretreatment. We also observed that the serum of severe COVID-19 had a significant amount of activated protein C that could protect endothelial cells from serum-induced activation. In conclusion, activated protein C protects endothelial cells from pro-inflammatory and pro-coagulant effects during exposure to the SARS-CoV-2 virus. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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16 pages, 7293 KiB  
Article
SARS-CoV-2 Accessory Protein ORF8 Targets the Dimeric IgA Receptor pIgR
by Frederique Laprise, Ariana Arduini, Mathew Duguay, Qinghua Pan and Chen Liang
Viruses 2024, 16(7), 1008; https://doi.org/10.3390/v16071008 - 22 Jun 2024
Viewed by 1846
Abstract
SARS-CoV-2 is a highly pathogenic respiratory virus that successfully initiates and establishes its infection at the respiratory mucosa. However, little is known about how SARS-CoV-2 antagonizes the host’s mucosal immunity. Recent findings have shown a marked reduction in the expression of the polymeric [...] Read more.
SARS-CoV-2 is a highly pathogenic respiratory virus that successfully initiates and establishes its infection at the respiratory mucosa. However, little is known about how SARS-CoV-2 antagonizes the host’s mucosal immunity. Recent findings have shown a marked reduction in the expression of the polymeric Ig receptor (pIgR) in COVID-19 patients. This receptor maintains mucosal homeostasis by transporting the dimeric IgA (dIgA) and pentameric IgM (pIgM) across mucosal epithelial cells to neutralize the invading respiratory pathogens. By studying the interaction between pIgR and SARS-CoV-2 proteins, we discovered that the viral accessory protein Open Reading Frame 8 (ORF8) potently downregulates pIgR expression and that this downregulation activity of ORF8 correlates with its ability to interact with pIgR. Importantly, the ORF8-mediated downregulation of pIgR diminishes the binding of dIgA or pIgM, and the ORF8 proteins of the variants of concern of SARS-CoV-2 preserve the function of downregulating pIgR, indicating the importance of this conserved activity of ORF8 in SARS-CoV-2 pathogenesis. We further observed that the secreted ORF8 binds to cell surface pIgR, but that this interaction does not trigger the cellular internalization of ORF8, which requires the binding of dIgA to pIgR. These findings suggest the role of ORF8 in SARS-CoV-2 mucosal immune evasion. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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21 pages, 1658 KiB  
Article
T-Cell Epitope Mapping of SARS-CoV-2 Reveals Coordinated IFN-γ Production and Clonal Expansion of T Cells Facilitates Recovery from COVID-19
by Xing Fan, Jin-Wen Song, Wen-Jing Cao, Ming-Ju Zhou, Tao Yang, Jing Wang, Fan-Ping Meng, Ming Shi, Chao Zhang and Fu-Sheng Wang
Viruses 2024, 16(7), 1006; https://doi.org/10.3390/v16071006 - 22 Jun 2024
Cited by 2 | Viewed by 1330
Abstract
Background: T-cell responses can be protective or detrimental during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, the underlying mechanism is poorly understood. Methods: In this study, we screened 144 15-mer peptides spanning the SARS-CoV-2 spike, nucleocapsid (NP), M, ORF8, ORF10, and [...] Read more.
Background: T-cell responses can be protective or detrimental during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, the underlying mechanism is poorly understood. Methods: In this study, we screened 144 15-mer peptides spanning the SARS-CoV-2 spike, nucleocapsid (NP), M, ORF8, ORF10, and ORF3a proteins and 39 reported SARS-CoV-1 peptides in peripheral blood mononuclear cells (PBMCs) from nine laboratory-confirmed coronavirus disease 2019 (COVID-19) patients (five moderate and four severe cases) and nine healthy donors (HDs) collected before the COVID-19 pandemic. T-cell responses were monitored by IFN-γ and IL-17A production using ELISA, and the positive samples were sequenced for the T cell receptor (TCR) β chain. The positive T-cell responses to individual SARS-CoV-2 peptides were validated by flow cytometry. Results: COVID-19 patients with moderate disease produced more IFN-γ than HDs and patients with severe disease (moderate vs. HDs, p < 0.0001; moderate vs. severe, p < 0.0001) but less IL-17A than those with severe disease (p < 0.0001). A positive correlation was observed between IFN-γ production and T-cell clonal expansion in patients with moderate COVID-19 (r = 0.3370, p = 0.0214) but not in those with severe COVID-19 (r = −0.1700, p = 0.2480). Using flow cytometry, we identified that a conserved peptide of the M protein (Peptide-120, P120) was a dominant epitope recognized by CD8+ T cells in patients with moderate disease. Conclusion: Coordinated IFN-γ production and clonal expansion of SARS-CoV-2-specific T cells are associated with disease resolution in COVID-19. Our findings contribute to a better understanding of T-cell-mediated immunity in COVID-19 and may inform future strategies for managing and preventing severe outcomes of SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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Review

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20 pages, 6148 KiB  
Review
3-Chymotrypsin-like Protease (3CLpro) of SARS-CoV-2: Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials
by Vitor Martins de Freitas Amorim, Eduardo Pereira Soares, Anielle Salviano de Almeida Ferrari, Davi Gabriel Salustiano Merighi, Robson Francisco de Souza, Cristiane Rodrigues Guzzo and Anacleto Silva de Souza
Viruses 2024, 16(6), 844; https://doi.org/10.3390/v16060844 - 24 May 2024
Cited by 3 | Viewed by 2334
Abstract
Proteases represent common targets in combating infectious diseases, including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19, and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural [...] Read more.
Proteases represent common targets in combating infectious diseases, including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19, and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships and diverse subsites of 3CLpro, shedding light on the pivotal role of dimerization and active site architecture in substrate recognition and catalysis. Our analysis of bioinformatics and other published studies motivated us to investigate a novel catalytic mechanism for the SARS-CoV-2 polyprotein cleavage by 3CLpro, centering on the triad mechanism involving His41-Cys145-Asp187 and its indispensable role in viral replication. Our hypothesis is that Asp187 may participate in modulating the pKa of the His41, in which catalytic histidine may act as an acid and/or a base in the catalytic mechanism. Recognizing Asp187 as a crucial component in the catalytic process underscores its significance as a fundamental pharmacophoric element in drug design. Next, we provide an overview of both covalent and non-covalent inhibitors, elucidating advancements in drug development observed in preclinical and clinical trials. By highlighting various chemical classes and their pharmacokinetic profiles, our review aims to guide future research directions toward the development of highly selective inhibitors, underscore the significance of 3CLpro as a validated therapeutic target, and propel the progression of drug candidates through preclinical and clinical phases. Full article
(This article belongs to the Special Issue Coronaviruses Pathogenesis, Immunity, and Antivirals)
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