Interferon Control of Human Coronavirus Infection and Viral Evasion: Mechanistic Insights and Implications for Antiviral Drug and Vaccine Development

Zhao, Xiongyan; Danying, Chen; Li, Xinglin; Griffith, Lauren; Chang, Jinhong; An, Ping; Guo, Ju‐Tao

doi:10.1016/j.jmb.2021.167438

Cited by 9 publications

(7 citation statements)

References 240 publications

(259 reference statements)

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“…It was observed that several ISGs, like APOL2, RAB27A, FAM46A, and FAM46C that inhibited SCoV-2 replication, also inhibited HCoV-229E replication. However, other ISGs like SQLE, SLC1A1, and STARD5, which were found to potentially inhibit HCoV-229E, were not found to inhibit SCoV-2 (Zhao et al, 2022 ). These studies demonstrated overlap in ISG-mediated inhibition mechanisms of SCoV-2 and HCoV-229E replication.…”

Section: Resultsmentioning

confidence: 99%

“…We found a comparable level of similarity between the two genomes as well as in various pathways involved in pathogenesis and antiviral responses. Accordingly, the published literature suggests that the IFN-stimulated genes (ISGs) inhibit the infections with the two viruses in a similar fashion through overlapping pathways (Zhao et al, 2022 ). Supporting our hypothesis, some of the recent studies demonstrated the similarities in antiviral activities of pharmaceutical compounds against HCoV-229E and SCoV-2 (Siddell et al, 1983 ; Masters, 2006 ; Weiss and Leibowitz, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

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Repurposing of FDA Approved Drugs Against SARS-CoV-2 Papain-Like Protease: Computational, Biochemical, and in vitro Studies

et al. 2022

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The pandemic caused by SARS-CoV-2 (SCoV-2) has impacted the world in many ways and the virus continues to evolve and produce novel variants with the ability to cause frequent global outbreaks. Although the advent of the vaccines abated the global burden, they were not effective against all the variants of SCoV-2. This trend warrants shifting the focus on the development of small molecules targeting the crucial proteins of the viral replication machinery as effective therapeutic solutions. The PLpro is a crucial enzyme having multiple roles during the viral life cycle and is a well-established drug target. In this study, we identified 12 potential inhibitors of PLpro through virtual screening of the FDA-approved drug library. Docking and molecular dynamics simulation studies suggested that these molecules bind to the PLpro through multiple interactions. Further, IC50 values obtained from enzyme-inhibition assays affirm the stronger affinities of the identified molecules for the PLpro. Also, we demonstrated high structural conservation in the catalytic site of PLpro between SCoV-2 and Human Coronavirus 229E (HCoV-229E) through molecular modelling studies. Based on these similarities in PLpro structures and the resemblance in various signalling pathways for the two viruses, we propose that HCoV-229E is a suitable surrogate for SCoV-2 in drug-discovery studies. Validating our hypothesis, Mefloquine, which was effective against HCoV-229E, was found to be effective against SCoV-2 as well in cell-based assays. Overall, the present study demonstrated Mefloquine as a potential inhibitor of SCoV-2 PLpro and its antiviral activity against SCoV-2. Corroborating our findings, based on the in vitro virus inhibition assays, a recent study reported a prophylactic role for Mefloquine against SCoV-2. Accordingly, Mefloquine may further be investigated for its potential as a drug candidate for the treatment of COVID.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Repurposing of FDA Approved Drugs Against SARS-CoV-2 Papain-Like Protease: Computational, Biochemical, and in vitro Studies

et al. 2022

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“…These patients develop severe hypoxemia, which seems to be a trigger mechanism for damage in other organs, while for patients with sepsis, endothelial damage and coagulation activation are the classically well-described pathophysiological mechanisms related to the development of multiorgan failure. Cell populations of classical and non-classical monocytes have been demonstrated to be deeply involved in the immunopathogenesis of both systemic and organ (lung) hyper-inflammatory manifestations of severe COVID-19 [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Parallel Dysregulated Immune Response in Severe Forms of COVID-19 and Bacterial Sepsis via Single-Cell Transcriptome Sequencing

et al. 2023

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Critically ill COVID-19 patients start developing single respiratory organ failure that often evolves into multiorgan failure. Understanding the immune mechanisms in severe forms of an infectious disease (either critical COVID-19 or bacterial septic shock) would help to achieve a better understanding of the patient’s clinical trajectories and the success of potential therapies. We hypothesized that a dysregulated immune response manifested by the abnormal activation of innate and adaptive immunity might be present depending on the severity of the clinical presentation in both COVID-19 and bacterial sepsis. We found that critically ill COVID-19 patients demonstrated a different clinical endotype that resulted in an inflammatory dysregulation in mild forms of the disease. Mild cases (COVID-19 and bacterial non severe sepsis) showed significant differences in the expression levels of CD8 naïve T cells, CD4 naïve T cells, and CD4 memory T cells. On the other hand, in the severe forms of infection (critical COVID-19 and bacterial septic shock), patients shared immune patterns with upregulated single-cell transcriptome sequencing at the following levels: B cells, monocyte classical, CD4 and CD8 naïve T cells, and natural killers. In conclusion, we identified significant gene expression differences according to the etiology of the infection (COVID-19 or bacterial sepsis) in the mild forms; however, in the severe forms (critical COVID-19 and bacterial septic shock), patients tended to share some of the same immune profiles related to adaptive and innate immune response. Severe forms of the infections were similar independent of the etiology. Our findings might promote the implementation of co-adjuvant therapies and interventions to avoid the development of severe forms of disease that are associated with high mortality rates worldwide.

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“…A SARS-CoV-2 egyik legfontosabb "fegyvere" tehát az, hogy eredményesen képes gátolni vagy legalábbis lassítani az I-es és III-as típusú IFN-válaszokat. A vírus patológiájának alapja jórészt ezen a "trükkön" alapul [7,8].…”

Section: öSszefoglaló Közleményunclassified

A súlyos akut légzőszervi szindrómát okozó koronavírus-2 elleni immunválasz

Uher¹,

Matula²,

Gönczi³

et al. 2022

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A koronavírus-betegség (COVID–19) lefolyása rendkívül sokféle lehet. Az érintettek egy része gyakorlatilag tünetmentes marad, míg másoknál súlyos, esetenként halálos kimenetelű komplikációk alakulnak ki. Ennek a variabilitásnak a hátterében – bár kétségtelenül szükség van további kutatásokra is – minden jel szerint az immunrendszer egyes alkotóelemeinek eltérő, néha kifejezetten kóros működése áll. Összefoglalónkban azt szeretnénk bemutatni, hogy milyen kölcsönhatás alakul ki a természetes és az adaptív immunrendszer, valamint a súlyos akut légzőszervi szindrómát okozó koronavírus-2 (SARS-CoV-2) között az emberi szervezetben. Megvizsgáljuk, hogyan befolyásolja a betegség lefolyását az I-es típusú interferonoknak a genetikai hibákra vagy az antiinterferon-autoantitestek jelenlétére visszavezethető elégtelen aktivitása, a myeloid rendszer zavara, a hipergyulladásos állapot kialakulása, a lymphopenia és az adaptív immunrendszer egyénenként eltérő működése. Kitérünk azokra a kulcsfontosságú megfigyelésekre is, amelyek segítettek körvonalazni a SARS-CoV-2-specifikus humorális és sejtközvetített immunmemória legfontosabb jellemzőit. Orv Hetil. 2022; 163(20): 774–787.

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Interferon Control of Human Coronavirus Infection and Viral Evasion: Mechanistic Insights and Implications for Antiviral Drug and Vaccine Development

Abstract: Graphical abstract

Cited by 9 publications

References 240 publications

Repurposing of FDA Approved Drugs Against SARS-CoV-2 Papain-Like Protease: Computational, Biochemical, and in vitro Studies

Repurposing of FDA Approved Drugs Against SARS-CoV-2 Papain-Like Protease: Computational, Biochemical, and in vitro Studies

Parallel Dysregulated Immune Response in Severe Forms of COVID-19 and Bacterial Sepsis via Single-Cell Transcriptome Sequencing

A súlyos akut légzőszervi szindrómát okozó koronavírus-2 elleni immunválasz

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