Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(7), P. 3507 - 3507

Published: March 23, 2022

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of most devastating pandemics recent times. The lack potent novel antivirals had led to global health crises; however, emergence and approval inhibitors viral main protease (Mpro), such as Pfizer’s newly approved nirmatrelvir, offers hope not only in therapeutic front but also context prophylaxis against infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, lessons learnt from previous currently ongoing taught us that these can easily escape selection pressure through vital target amino acid residues monotherapeutic settings. In this paper, we review nirmatrelvir its binding SARS-CoV-2 Mpro draw a comparison HIV were rendered obsolete resistance mutations, emphasizing potential pitfalls design may be important relevance long-term use SARS-CoV-2.

Language: Английский

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SARS-CoV-2 virus NSP14 Impairs NRF2/HMOX1 activation by targeting Sirtuin 1

Cellular and Molecular Immunology, Journal Year: 2022, Volume and Issue: 19(8), P. 872 - 882

Published: June 23, 2022

Most deaths from the COVID-19 pandemic are due to acute respiratory distress syndrome (ARDS)-related failure. Cytokine storms and oxidative stress major players in ARDS development during virus infections. However, it is still unknown how regulated by viral host factors response SARS-CoV-2 infection. Here, we found that activation of NRF2/HMOX1 significantly suppressed replication multiple cell types producing metabolite biliverdin, whereas impaired axis through action nonstructural protein NSP14. Mechanistically, NSP14 interacts with catalytic domain NAD-dependent deacetylase Sirtuin 1 (SIRT1) inhibits its ability activate pathway. Furthermore, both genetic pharmaceutical evidence corroborated novel antiviral activity SIRT1 against SARS-CoV-2. Therefore, our findings reveal a mechanism which dysregulates antioxidant defense system emphasize vital role played SIRT1/NRF2

Language: Английский

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Interferon induction, evasion, and paradoxical roles during SARS‐CoV‐2 infection*

Immunological Reviews, Journal Year: 2022, Volume and Issue: 309(1), P. 12 - 24

Published: July 1, 2022

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative agent of disease 2019 (COVID‐19), has caused millions deaths in past two years. Although initially little was understood about this virus, recent research significantly advanced and landed interferons (IFNs) spotlight. While Type I III IFN have long been known as central to antiviral immunity, case COVID‐19 their role controversial. However, protective function is now well supported by identification human deficiencies responses a predictor severity. Here, we will review cell types pathways that lead production importance timing location for outcome. We further discuss mechanisms SARS‐CoV‐2 uses evade responses, current efforts implement IFNs therapeutics treatment COVID‐19. It essential understand relationships between better inform treatments exploit functions alleviate

Language: Английский

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The Role of Coinhibitory Receptors in B Cell Dysregulation in SARS-CoV-2–Infected Individuals with Severe Disease

The Journal of Immunology, Journal Year: 2024, Volume and Issue: 212(10), P. 1540 - 1552

Published: March 22, 2024

Abstract Severe SARS-CoV-2 infection is associated with significant immune dysregulation involving different cell subsets. In this study, when analyzing critically ill COVID-19 patients versus those mild disease, we observed a reduction in total and memory B subsets but an increase naive cells. Moreover, cells from displayed impaired effector functions, evidenced by diminished proliferative capacity, reduced cytokine, Ab production. This functional impairment was accompanied increased apoptotic potential upon stimulation severely patients. Our further studies revealed the expansion of expressing coinhibitory molecules (PD-1, PD-L1, TIM-1, VISTA, CTLA-4, Gal-9) intensive care unit (ICU)–admitted not disease. The receptor expression linked to altered IgA IgG capacity Also, found frequency CD24hiCD38hi regulatory IL-10 mechanistic that upregulation PD-L1 elevated plasma IL-6 levels implies connection between cytokine storm phenotype function. Finally, our metabolomic analysis showed tryptophan elevation kynurenine ICU-admitted We promotes cells, correlating IL-6R STAT1/STAT3 activation. observations provide novel insights into complex interplay dysregulation, implicating receptors, IL-6, potentially contributing pathogenesis COVID-19.

Language: Английский

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Pyroptotic cell death in SARS-CoV-2 infection: revealing its roles during the immunopathogenesis of COVID-19

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(15), P. 5827 - 5848

Published: Jan. 1, 2022

The rapid dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent disease 2019 , remains a global public health emergency.The host immune response to SARS-CoV-2 plays key role in COVID-19 pathogenesis.SARS-CoV-2 can induce aberrant and excessive responses, leading cytokine storm syndrome, autoimmunity, lymphopenia, neutrophilia dysfunction monocytes macrophages.Pyroptosis, proinflammatory form programmed cell death, acts as defense mechanism against infections.Pyroptosis deprives replicative niche by inducing lysis infected cells exposing virus extracellular attack.Notably, has evolved sophisticated mechanisms hijack this death mode for its own survival, propagation shedding.SARS-CoV-2-encoded viral products act modulate various components pyroptosis pathways, including inflammasomes, caspases gasdermins.SARS-CoV-2-induced contriubtes development COVID-19-associated immunopathologies through leakage intracellular contents, disruption system homeostasis or exacerbation inflammation.Therefore, emerged an important involved immunopathogenesis.However, entangled links between pathogenesis lack systematic clarification.In review, we briefly summarize characteristics COVID-19-related immunopathologies.Moreover, present overview interplay infection highlight recent research advances understanding responsible implication pathways pathogenesis, which will provide informative inspirations new directions further investigation clinical practice.Finally, discuss potential value therapeutic target COVID-19.An in-depth discussion underlying be conducive identification targets exploration effective treatment measures aimed at conquering SARS-CoV-2-induced COVID-19.

Language: Английский

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Role of interferons in the antiviral battle: from virus-host crosstalk to prophylactic and therapeutic potential in SARS-CoV-2 infection

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 15, 2024

Mammalians sense antigenic messages from infectious agents that penetrate the respiratory and digestive epithelium, as well signals damaged host cells through membrane cytosolic receptors. The transduction of these triggers a personalized response, depending on nature stimulus host’s genetics, physiological condition, comorbidities. Interferons (IFNs) are primary effectors innate immune their synthesis is activated in most within few hours after pathogen invasion. IFNs primarily synthesized infected cells, but anti-infective effect extended to neighboring by autocrine paracrine action. emergence severe acute syndrome coronavirus 2 (SARS‐CoV‐2) pandemic 2019 was stark reminder potential threat posed newly emerging viruses. This has also triggered an overwhelming influx research studies aiming unveil mechanisms protective versus pathogenic responses induced SARS‐CoV‐2. purpose this review describe role vital players battle against SARS‐CoV-2 infection. We will briefly characterize classify IFNs, present inductors IFN synthesis, sensors, signaling pathways, then discuss controlling evolution SARS-CoV-2 infection its clinical outcome. Finally, we perspectives controversies regarding prophylactic therapeutic

Language: Английский

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SARS-CoV-2 infection and immune responses

AIMS Microbiology, Journal Year: 2023, Volume and Issue: 9(2), P. 245 - 276

Published: Jan. 1, 2023

<abstract> <p>The recent pandemic caused by the SARS-CoV-2 virus continues to be an enormous global challenge faced healthcare sector. Availability of new vaccines and drugs targeting sequelae COVID-19 has given world hope in ending pandemic. However, emergence mutations viral genome every couple months different parts is a persistent danger public health. Currently there no single treatment eradicate risk COVID-19. The widespread transmission due Omicron variant necessitates continued work on development implementation effective vaccines. Moreover, evidence that receptor domain spike glycoprotein led decrease current vaccine efficacy escaping antibody recognition. Therefore, it essential actively identify mechanisms which evades host immune system, study long-lasting effects develop therapeutics infections humans preclinical models. In this review, we describe pathogenic infection as well innate adaptive responses infection. We address ongoing need provide protection against variants SARS-CoV-2, validated endpoint assays evaluate immunogenicity pipeline, medications, anti-viral drug therapies health measures, will required successfully end pandemic.</p> </abstract>

Language: Английский

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VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

Science Advances, Journal Year: 2023, Volume and Issue: 9(25)

Published: June 23, 2023

Stringent control of type I interferon (IFN-I) signaling is critical to potent innate immune responses against viral infection, yet the underlying molecular mechanisms are still elusive. Here, we found that Van Gogh–like 2 (VANGL2) acts as an IFN-inducible negative feedback regulator suppress IFN-I during vesicular stomatitis virus (VSV) infection. Mechanistically, VANGL2 interacted with TBK1 and promoted selective autophagic degradation via K48-linked polyubiquitination at Lys 372 by E3 ligase TRIP, which serves a recognition signal for cargo receptor OPTN. Furthermore, myeloid-specific deletion in mice showed enhanced production VSV infection improved survival. In general, these findings revealed loop through VANGL2-TRIP-TBK1-OPTN axis highlighted cross-talk between autophagy preventing could be potential clinical therapeutic target infectious diseases, including COVID-19.

Language: Английский

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Broad antagonism of coronaviruses nsp5 to evade the host antiviral responses by cleaving POLDIP3

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(10), P. e1011702 - e1011702

Published: Oct. 6, 2023

Coronaviruses (CoVs) are a family of the largest RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals humans, imposing great threats to public safety animal health. Porcine deltacoronavirus (PDCoV), newly emerging enteropathogenic coronavirus, causes severe diarrhea suckling piglets all over world poses potential risks cross-species transmission. Here, we use PDCoV as model CoVs illustrate reciprocal regulation between infection host antiviral responses. In this study, downregulation DNA polymerase delta interacting protein 3 (POLDIP3) was confirmed infected IPEC-J2 cells by isobaric tags for relative absolute quantification (iTRAQ) Western blotting analysis. Overexpression POLDIP3 inhibits infection, whereas knockout (POLDIP3-/-) CRISPR-Cas9 editing significantly promotes indicating novel regulator against infection. Surprisingly, an antagonistic strategy revealed encoded nonstructural 5 (nsp5) responsible reduction via its 3C-like protease cleavage at glutamine acid 176 (Q176), facilitating due loss effects cleaved fragments. Consistent with obtained data cell vitro, also corroborated infected-SPF vivo. Collectively, unveiled new evolved counteract innate immunity nsp5-mediated cleavage, eventually ensuring productive virus replication. Importantly, further demonstrated nsp5s from PEDV TGEV harbor conserved function cleave porcine Q176 despair POLDIP3-mediated effects. addition, nsp5 SARS-CoV-2 cleaves human POLDIP3. Therefore, speculate coronaviruses employ similar mechanisms mediated antagonize responses sustain efficient

Language: Английский

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Developing Next-Generation Live Attenuated Vaccines for Porcine Epidemic Diarrhea Using Reverse Genetic Techniques

Vaccines, Journal Year: 2024, Volume and Issue: 12(5), P. 557 - 557

Published: May 19, 2024

Porcine epidemic diarrhea virus (PEDV) is the etiology of porcine (PED), a highly contagious digestive disease in pigs and especially neonatal piglets, which mortality rate up to 100% will be induced. Immunizing pregnant sows remains most promising effective strategy for protecting their offspring from PEDV. Although half century has passed since its first report Europe several prophylactic vaccines (inactivated or live attenuated) have been developed, PED still poses significant economic concern swine industry worldwide. Hence, there an urgent need novel clinical practice, attenuated (LAVs) that can induce strong protective lactogenic immune response sows. Reverse genetic techniques provide robust tool virological research function viral proteins generation rationally designed vaccines. In this review, after systematically summarizing progress on virulence-related proteins, we reviewed reverse genetics PEDV application development LAVs. Then, probed into potential methods generating safe, effective, genetically stable LAV candidates, aiming new ideas rational design

Language: Английский

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