Nsp1 facilitates SARS-CoV-2 replication through calcineurin-NFAT signaling

mBio, Journal Year: 2024, Volume and Issue: 15(4)

Published: Feb. 27, 2024

SARS-CoV-2, the causative agent of COVID-19, has been intensely studied in search effective antiviral treatments. The immunosuppressant cyclosporine A (CsA) suggested to be a pan-coronavirus inhibitor, yet its underlying mechanism remained largely unknown. Here, we found that non-structural protein 1 (Nsp1) SARS-CoV-2 usurped CsA-suppressed nuclear factor activated T cells (NFAT) signaling drive expression cellular DEAD-box helicase 5 (DDX5), which facilitates viral replication. Nsp1 interacted with calcineurin (CnA) displace regulatory regulator 3 (RCAN3) CnA for NFAT activation. influence activation on replication was also validated by using Nsp1-deficient mutant virus. Calcineurin inhibitors, such as CsA and VIVIT, inhibited exhibited synergistic effects when used combination nirmatrelvir. Our study delineated molecular CsA-mediated inhibition anti-SARS-CoV-2 action inhibitors. Cyclosporine (CsA), commonly inhibit immune responses, is known have activity, but mode remains elusive. provide model explain how antagonizes through three critical proteins: DDX5, NFAT1, Nsp1. DDX5 facilitator replication, NFAT1 controls production DDX5. absent from mature particle capable activating function similar agents suppress Nsp1, exert their activity either alone or Paxlovid.

Language: Английский

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Network-based Multi-omics Disease–Drug Associations Reveal Drug Repurposing Candidates for Covid-19 Disease Phases

Drug repurposing, Journal Year: 2024, Volume and Issue: 1(1)

Published: July 3, 2024

Background The development and rollout of vaccines the use various drugs have contributed to controlling coronavirus disease 2019 (Covid-19) pandemic. Nevertheless, challenges such as inequitable distribution vaccines, influence emerging viral lineages immunoevasive variants on vaccine efficacy, inadequate immune defense in subgroups population continue motivate new combat disease. Aim In this study, we sought identify, prioritize, characterize drug repurposing candidates appropriate for treating mild, moderate, or severe Covid-19 using a network-based integrative approach that systematically integrates drug-related data multi-omics datasets. Methods We leveraged used random walk with restart algorithm explore an integrated knowledge graph comprising three subgraphs: (i) graph, (ii) (iii) state-specific omics graph. Results prioritized 20 US Food Drug Administration-approved agents potential candidate phases. Specifically, could stimulate cell recruitment activation including histamine, curcumin, paclitaxel utility mild states mitigate progression. Drugs like omacetaxine, crizotinib, vorinostat exhibit antiviral properties inhibit replication can be considered moderate states. Also, given association between antioxidant deficiency high inflammatory factors trigger cytokine storms, antioxidants glutathione potent anti-inflammatory effects (sarilumab tocilizumab), corticosteroids (dexamethasone hydrocortisone), immunosuppressives (sirolimus cyclosporine) are hyperinflammatory cascade Covid-19. Conclusion Our study demonstrates data-driven analysis within enables prioritizing phases, offering comprehensive basis therapeutic strategies brought market quickly their established safety profiles. Importantly, implemented here prioritize other diseases.

Language: Английский

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Cyclosporine may reduce the risk of symptomatic COVID-19 in patients with systemic lupus erythematosus: a retrospective cohort study

Microbiology Spectrum, Journal Year: 2024, Volume and Issue: 12(11)

Published: Oct. 15, 2024

ABSTRACT This study aimed to explore the effect of cyclosporine (CsA) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in systemic lupus erythematosus (SLE) patients provide a valuable reference for clinical treatment strategies context long-term risk SARS-CoV-2 infection. SLE who visited Rheumatology Outpatient Department Fujian Medical University Union Hospital between 1 May and 31 October 2022 were included. Data November July 2023 obtained by telephone follow-up. Patients divided into two groups according whether CsA was used during observation period: glucocorticoid or hydroxychloroquine group group. To assess robustness results, sets established be analyzed independently. Multivariate logistic regression estimate odds ratios (ORs) 95% confidence intervals (CIs) symptomatic disease (COVID-19). A total 184 included, among whom 129 definite COVID-19 patients; 29 presumptive 4 had signs symptoms COVID-19, but tested negative virological test. According multivariable-adjusted models, associated with lower ( P = 0.042, OR 0.316, CI: 0.104–0.959 set 0.021, 0.257, 0.081–0.812 2). is contracting COVID-19. The use may considered an appropriate therapeutic option management rheumatic diseases have activity persistent IMPORTANCE Our indicated that reduce spite its immunosuppressive effects. provides AIIRD

Language: Английский

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An Enhanced Dissolving Cyclosporin-A Inhalable Powder Efficiently Reduces SARS-CoV-2 Infection In Vitro

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(3), P. 1023 - 1023

Published: March 22, 2023

This work illustrates the development of a dry inhalation powder cyclosporine-A for prevention rejection after lung transplantation and treatment COVID-19. The influence excipients on spray-dried powder's critical quality attributes was explored. best-performing in terms dissolution time respirability obtained starting from concentration ethanol 45% (v/v) feedstock solution 20% (w/w) mannitol. showed faster profile (Weibull 59.5 min) than poorly soluble raw material (169.0 min). exhibited fine particle fraction 66.5% an MMAD 2.97 µm. inhalable powder, when tested A549 THP-1, did not show cytotoxic effects up to 10 µg/mL. Furthermore, CsA efficiency reducing IL-6 A549/THP-1 co-culture. A reduction replication SARS-CoV-2 Vero E6 cells observed adopting post-infection or simultaneous treatment. formulation could represent therapeutic strategy rejection, but is also viable approach inhibition COVID-19 pulmonary inflammatory process.

Language: Английский

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SARS‐CoV‐2 in digital era: Diagnostic techniques and importance of nucleic acid quantification with digital PCRs

Reviews in Medical Virology, Journal Year: 2023, Volume and Issue: 33(5)

Published: Aug. 2, 2023

Studies related to clinical diagnosis and research of SARS-CoV-2 are important in the current pandemic era. Although molecular biology has emphasised importance qualitative analysis, quantitative analysis with nucleic acids relation needs be clearly emphasised, which can provide perspective for viral dynamic studies SARS-CoV-2. In this regard, requirement utilization digital PCR COVID-19 substantially increased during pandemic, necessitating aggregation its cardinal applications future scopes. Hence, meta-review comprehensively addresses emphasises acid quantification RNA (dPCR). Various techniques significance like immunological, proteomic acid-based quantification, have been comparatively discussed. Furthermore, core part article focusses on working principle advantages PCR, along research. Several load quantitation, environmental surveillance assay validation extensively investigated Certain key scopes importance, mortality prediction, viral/variant-symbiosis, antiviral were also identified, suggesting several possible

Language: Английский

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SARS-CoV-2 hampers dopamine production in iPSC-derived dopaminergic neurons

Experimental and Molecular Pathology, Journal Year: 2023, Volume and Issue: 134, P. 104874 - 104874

Published: Sept. 30, 2023

An increasing number of patients experiences prolonged symptoms, whose profile and timeline remain uncertain, a condition that has been defined as post COVID. The majority recovered hospitalized manifests at least one persistent symptom even sixty days after the first clinical manifestation's onset. Particularly, in light COVID-19-related symptomatology, it hypothesized SARS-CoV-2 might affect dopamine pathway. However, no scientific evidence produced so far. To this end, human iPSC-derived dopaminergic neurons were infected with EU, Delta Omicron variants. infection EU variants, but not Omicron, results reduced intracellular content extracellular release dopamine. Indeed, tyrosine hydroxylase was found to be significantly upregulated mRNA level, while being greatly protein level. major downstream synthetic enzyme DOPA-decarboxylase transporter downregulated both Notably, vitro also associated an altered MAP2 TAU expression increased presence neuronal stress markers. These preliminary observations suggest metabolism production are affected by SARS-CoV-2, partially explaining some neurological symptoms manifested.

Language: Английский

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Targeting Cyclophilin A and CD147 to Inhibit Replication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and SARS-CoV-2–Induced Inflammation

Molecular Pharmacology, Journal Year: 2023, Volume and Issue: 104(6), P. 239 - 254

Published: Oct. 12, 2023

Identification and development of effective therapeutics for coronavirus disease 2019 (COVID-19) are still urgently needed. The CD147-spike interaction is involved in the severe acute respiratory syndrome (SARS-CoV)-2 invasion process addition to angiotensin-converting enzyme 2 (ACE2). Cyclophilin A (CyPA), extracellular ligand CD147, has been found play a role infection replication coronaviruses. In this study, our results show that CyPA inhibitors such as cyclosporine (CsA) STG-175 can suppress intracellular SARS-CoV-2 by inhibiting binding nucleocapsid C-terminal domain (N-CTD), IC50 0.23 μM 0.17 μM, respectively. Due high homology, CsA also had inhibitory effects on SARS-CoV Middle East (MERS-CoV), 3.2 2.8 Finally, we generated formulation phosphatidylserine (PS)-liposome-CsA pulmonary drug delivery. These findings provide scientific basis identifying potential target treatment COVID-19 well broad-spectrum via targeting CyPA. Highlights: 1) infects cells its S protein CD147; 2) N essential viral replication; 3) CD147 therapeutic targets SARS-CoV-2; 4) strategy interrupting CD147/CyPA interactions. SIGNIFICANCE STATEMENT: New variants other pathogenic coronaviruses (CoVs) continually emerging, new anti-CoV therapy We sites cyclophilin A/cyclosporin (CyPA/CsA) overlap with CyPA/N-CTD (nucleocapsid domain), which shows during infection. Here, evidence developing inhibition CoVs.

Language: Английский

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Antiviral Activity of a Cyclic Pro-Pro-β3-HoPhe-Phe Tetrapeptide against HSV-1 and HAdV-5

Molecules, Journal Year: 2022, Volume and Issue: 27(11), P. 3552 - 3552

Published: May 31, 2022

The core of Cyclolinopeptide A (CLA, cyclo(LIILVPPFF)), responsible for its high immunosuppressive activity, contains a Pro-Pro-Phe-Phe sequence. newly synthesized cyclic tetrapeptide, cyclo(Pro-Pro-β3-HoPhe-Phe) (denoted as 4B8M) bearing the active sequence CLA, was recently shown to exhibit wide array anti-inflammatory properties in mouse models. In this investigation, we demonstrate that peptide significantly inhibits replication human adenovirus C serotype 5 (HAdV-5) and Herpes simplex virus type-1 (HSV-1) epithelial lung cell line A-549, applying Cidofovir Acyclovir reference drugs. Based on previously established mechanism action, propose may inhibit by induction PGE2 acting via EP2/EP4 receptors cells. summary, reveal new, antiviral property peptide.

Language: Английский

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A Review of Potential Therapeutic Strategies for COVID-19

Viruses, Journal Year: 2022, Volume and Issue: 14(11), P. 2346 - 2346

Published: Oct. 25, 2022

Coronavirus disease 2019 is a rather heterogeneous caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing pandemic global threat with increasing death tolls worldwide. SARS-CoV-2 belongs to lineage B β-CoV, subgroup of Sarbecovirus. These enveloped, large, positive-sense single-stranded RNA viruses are easily spread among individuals, mainly via the system and droplets. Although has been gradually controlled in many countries, once social restrictions relaxed virus may rebound, leading more uncontrollable situation again, as occurred Shanghai, China, 2022. current health calls for urgent development effective therapeutic options treatment prevention infection. This systematic overview possible strategies from 2022 indicates three potential targets: entry, replication, immune system. information provided this review will aid potent specific antiviral compounds.

Language: Английский

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Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases

Published: April 16, 2024

Background: The development and roll-out of vaccines, the use various drugs have contributed to controlling COVID-19 pandemic. Nevertheless, challenges such as inequitable distribution influence emerging viral lineages immune evasive variants on vaccine efficacy, inadequate defense in subgroups population continue motivate new combat disease. Aim: In this study, we sought identify, prioritize, characterize drug repurposing candidates appropriate for treating mild, moderate, or severe using a network-based integrative approach that systematically integrates drug-related data multi-omics datasets. Methods : We leveraged data, used random walk restart algorithm explore an integrated knowledge graph comprised three sub-graphs: (i) graph, (ii) (iii) disease-state specific omics graph. Results: prioritized twenty FDA-approved agents potential candidate disease phases. Specifically, could stimulate cell recruitment activation including histamine, curcumin, paclitaxel utility mild states mitigate progression. Drugs like omacetaxine, crizotinib, vorinostat exhibit antiviral properties inhibit replication can be considered moderate states. Also, given association between antioxidant deficiency high inflammatory factors trigger cytokine storms, antioxidants glutathione potent anti-inflammatory effects (sarilumab tocilizumab), corticosteroids (dexamethasone hydrocortisone), immunosuppressives (sirolimus cyclosporine) are hyperinflammatory cascade COVID-19. Conclusion: Our study demonstrates data-driven analysis within enables prioritizing phases, offering comprehensive basis therapeutic strategies brought market quickly their established safety profiles. Importantly, implemented here prioritize other diseases.

Language: Английский

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