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1.
Arq. bras. oftalmol ; 88(1): e2023, 2025. graf
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1568849

RESUMEN

ABSTRACT Unvaccinated identical twins developed bilateral anterior uveitis soon after the onset of coronavirus disease 2019 symptoms. During follow-up, both patients developed choroiditis, and one twine developed posterior scleritis and serous retinal detachment. Prompt treatment with oral prednisone ameliorated the lesions, and no recurrence was observed at the 18-month follow-up. Choroiditis may rarely be associated with severe acute respiratory syndrome coronavirus 2 infection, and it responds well to corticosteroid therapy. Although the exact mechanism is unknown, we hypothesize that the virus may act as an immunological trigger for choroiditis.

2.
Ocul Surf ; 34: 296-308, 2024 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-39218301

RESUMEN

PURPOSE: Our aim was to evaluate a potential role for the lacrimal drainage system (LDS) as a portal of entry and conduit for SARS-CoV-2 in human infection. We also investigate the mucosal surface area. The relatively long tear contact time in a closed system raises the possibility that this pathway may contribute to the initiation of systemic infection. We looked for expression of ACE2, the main receptor for SARS-CoV-2, as well as cofactors such as TMPRSS2 and other enzymes such as cathepsinB, CD147, elastase1, furin, neuropilin1, neuropilin2, TMPRSS11D and trypsin which also play a role in SARS-CoV-2 infection, in this system. METHODS: Human tissue samples of the draining tear ducts from body donors were analyzed by RT-PCR, Western blot and immunohistochemistry. It is not known whether the respective body donors were Sars-Cov-2 positive at any time; they were negative when they entered the institute. Besides, the draining LDS of body donors were measured to determine the mucosal surface in the lacrimal system. RESULTS: The expression of the main receptor studied, ACE2, cofactors such as TMPRSS2 and other enzymes such as cathepsinB, CD147, elastase1, furin, neuropilin1, neuropilin2, TMPRSS11D and trypsin were all detected at the gene and protein level. The average mucosal surface area of the lacrimal sac and nasolacrimal duct was calculated to be 110 mm2. CONCLUSION: The results show the presence of all analyzed receptors in the efferent LDS. With an average tear passage time of 3 min and a relatively large mucosal surface area, the LDS could therefore be considered as a portal of entry and conduit for SARS-CoV-2. In addition, it represents a surface that should be taken into consideration in the administration of topically applied medication to the ocular surface.

3.
J Inflamm Res ; 17: 5633-5643, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39219813

RESUMEN

Purpose: Visceral adiposity is a significant risk factor for severe COVID-19. However, the impact of the Chinese visceral adiposity index (CVAI) on the efficacy of SARS-CoV-2 vaccines remains poorly understood. This study aims to explore the impact of CVAI on the production of neutralizing antibodies (NAb) in inactivated SARS-CoV-2 vaccines and the potential mechanism, thereby optimizing vaccination guidance. Methods: In this cross-sectional study, 206 health workers (completed two SARS-CoV-2 vaccination on February 8th and March 10th, 2021, respectively) were recruited. All baseline anthropometric parameters of the participants were collected, and venous blood samples were obtained 6 weeks later to measure peripheral innate immune cells, inflammatory cytokines, and NAb titers against SARS-CoV-2. CVAI were calculated according to the formula and divided participants into two groups depending on CVAI median. Results: The median NAb titer among healthcare workers was 12.94 AU/mL, with an efficacy of 87.86% for the SARS-CoV-2 vaccine. NAb titers were lower in the CVAI dysfunction group than in the CVAI reference group (median: 11.40 AU/mL vs 15.57 AU/mL), the hsCRP levels (median: 0.50 mg/L vs 0.30 mg/L) and peripheral monocyte count (mean: 0.47 × 109/L vs 0.42 × 109/L) in the CVAI dysfunction group were higher than in the CVAI reference group. Additionally, CVAI showed positive correlations with hsCRP, monocytes, lymphocytes, and B-lymphocytes, and a negative correlation with NAb titers. Conclusion: CVAI may inhibit SARS-CoV-2 neutralizing antibody expression through inducing immune dysfunction and chronic inflammation. Thus, more attention should be paid to the vaccination for high CVAI population to improve the effectiveness of vaccination, which could provide more robust support for COVID-19 epidemic prevention and control.

4.
Cureus ; 16(7): e65837, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39219954

RESUMEN

This case report presents a posterior circulation infarction in a previously healthy 39-year-old male, three months post-severe COVID-19. He presented with right-sided homonymous hemianopia and elevated inflammatory markers and D-dimer levels. Imaging revealed an acute left occipital infarct. Such post-COVID-19 posterior circulation strokes are rare. This report discusses the pathophysiology, optimal anticoagulation therapy for COVID-19-related thrombotic complications, and early predictor models. This case underscores the need to recognize thromboembolic events as potential late sequelae in severe COVID-19 cases.

5.
Front Pediatr ; 12: 1414023, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39220151

RESUMEN

Objective: To analyze the clinical characteristics, treatment, and prognosis of children infected with SARS-CoV-2 following the adjustment of COVID-19 prevention and control policies in China in December 2022. Methods: A retrospective study was conducted on 9 cases of severe neurological dysfunction caused by SARS-CoV-2 infection in children admitted to Foshan First People's Hospital from December 17 to 31, 2022. Results: Among the 9 cases, 7 (71.43%) were under 3 years old, and 2 (22.2%) were over 3 years old with underlying diseases. All patients presented with fever and neurological symptoms such as consciousness disturbance and/or convulsions, and their conditions deteriorated rapidly within 24 h after the onset of fever, without respiratory symptoms. Levels of IL-6, LDH, and d-dimer were significantly elevated. Five cases died within 48 h of admission, one case died after 7 days of treatment due to secondary bacterial infection, and three cases survived for more than 48 h after the initial rescue. All patients developed rapid shock, and five cases experienced multi-organ failure within a short period. In terms of treatment, glucocorticoids were used in 5 cases, intravenous immunoglobulin (IVIG) in 3 cases, and blood purification and tocilizumab in 2 cases. Conclusion: SARS-CoV-2 infection in children can lead to severe neurological damage. High fever, convulsions, and inflammatory factors serve as early warning indicators. Glucocorticoids, immunoglobulins, blood purification, and tocilizumab may have some therapeutic effects, but further research is needed to confirm the efficacy.

6.
Mol Ther Nucleic Acids ; 35(3): 102278, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39220269

RESUMEN

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas13d system was adapted as a powerful tool for targeting viral RNA sequences, making it a promising approach for antiviral strategies. Understanding the influence of template RNA structure on Cas13d binding and cleavage efficiency is crucial for optimizing its therapeutic potential. In this study, we investigated the effect of local RNA secondary structure on Cas13d activity. To do so, we varied the stability of a hairpin structure containing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target sequence, allowing us to determine the threshold RNA stability at which Cas13d activity is affected. Our results demonstrate that Cas13d possesses the ability to effectively bind and cleave highly stable RNA structures. Notably, we only observed a decrease in Cas13d activity in the case of exceptionally stable RNA hairpins with completely base-paired stems, which are rarely encountered in natural RNA molecules. A comparison of Cas13d and RNA interference (RNAi)-mediated cleavage of the same RNA targets demonstrated that RNAi is more sensitive for local target RNA structures than Cas13d. These results underscore the suitability of the CRISPR-Cas13d system for targeting viruses with highly structured RNA genomes.

7.
Health Care Sci ; 3(4): 211-214, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39220429

RESUMEN

SARS-CoV-2 continues to evolve and circulate globally. In recent weeks, variants such as KP.2 and KP.3 have been rapidly increasing in many countries. Prevention strategies such as receiving updated COVID-19 vaccines, wearing masks when recommended, washing hands frequently, getting tested if symptoms appear, and staying home when sick can help protect individuals and others from COVID-19.

8.
Heliyon ; 10(16): e35790, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39220928

RESUMEN

The global SARS-CoV-2 monitoring effort has been extensive, resulting in many states and countries establishing wastewater-based epidemiology programs to address the spread of the virus during the pandemic. Challenges for programs include concurrently optimizing methods, training new laboratories, and implementing successful surveillance programs that can rapidly translate results for public health, and policy making. Surveillance in Michigan early in the pandemic in 2020 highlights the importance of quality-controlled data and explores correlations with wastewater and clinical case data aggregated at the state level. The lessons learned and potential measures to improve public utilization of results are discussed. The Michigan Network for Environmental Health and Technology (MiNET) established a network of laboratories that partnered with local health departments, universities, wastewater treatment plants (WWTPs) and other stakeholders to monitor SARS-CoV-2 in wastewater at 214 sites in Michigan. MiNET consisted of nineteen laboratories, twenty-nine local health departments, 6 Native American tribes, and 60 WWTPs monitoring sites representing 45 % of Michigan's population from April 6 and December 29, 2020. Three result datasets were created based on quality control criteria. Wastewater results that met all quality assurance criteria (Dataset Mp) produced strongest correlations with reported clinical cases at 16 days lag (rho = 0.866, p < 0.05). The project demonstrated the ability to successfully track SARS-CoV-2 on a large, state-wide scale, particularly data that met the outlined quality criteria and provided an early warning of increasing COVID-19 cases. MiNET is currently poised to leverage its competency to complement public health surveillance networks through environmental monitoring for new and emerging pathogens of concern and provides a valuable resource to state and federal agencies to support future responses.

9.
Int J Cardiol Heart Vasc ; 54: 101483, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39221116

RESUMEN

Background: Monoclonal antibodies (mAbs) are currently under investigation as a potential therapeutic option for COVID-19. Clinical trials are examining their efficacy in lowering mortality rates and the requirement for mechanical ventilation (MV). It is necessary to conduct a thorough examination of current randomized controlled trials (RCTs) in order to provide more definitive evidence on their effectiveness for COVID-19 patients. This meta-analysis aims to analyze RCT results on the impact of three mAbs (Anakinra, Sarilumab, Tocilizumab) on COVID-19 patient outcomes. Method: The meta-analysis was conducted in accordance with the PRISMA guidelines. Eligible RCTs were conducted to evaluate the effectiveness of three mAbs in treating patients with COVID-19. These trials were identified by searching various databases up to April 1, 2024. In total, this meta-analysis incorporated 19 trials with a total of 8097 patients. Pooled relative risk and studies' heterogeneity were assessed by statistical analysis, which involved the use of fixed effects models and subgroup analysis. Result: The administration of mAbs (Tocilizumab, Sarilumab, and Anakinra) showed various results in the management of COVID-19 patients. While the overall pooled data did not reveal a significant reduction in the need for MV, the study found that the use of mAbs was associated with a decreased risk of clinical worsening (pooled relative risk: 0.75, 95 % CI [0.59, 0.94], p = 0.01) and an increased probability of discharging COVID-19 patients by day 28 or 29 (pooled relative risk: 1.17, 95 % CI [1.10, 1.26]). Notably, the subgroup analysis revealed that Tocilizumab had a significant effect in reducing the risk of clinical worsening compared to Sarilumab. Additionally, the analysis of mortality outcomes indicated that the administration of mAbs had the potential to decrease the overall risk of mortality over time (pooled RR: 0.90, 95 % CI [0.83, 0.97], p = 0.01). Conclusion: In summary, our meta-analysis suggests that mAbs, particularly Tocilizumab, may play a valuable role in managing COVID-19 by reducing the risk of clinical worsening, improving hospital discharge rates, and decreasing mortality.

10.
Vaccine X ; 20: 100543, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39221180

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), rapidly spread across the globe in 2019. With the emergence of the Omicron variant, COVID-19 shifted into an endemic phase. Given the anticipated rise in cases during the fall and winter seasons, the strategy of implementing seasonal booster vaccines for COVID-19 is becoming increasingly valuable to protect public health. This practice already exists for seasonal influenza vaccines to combat annual influenza seasons. Our goal was to investigate an easily modifiable vaccine platform for seasonal use against SARS-CoV-2. In this study, we evaluated the genetically modified influenza virus ΔNA(RBD) as an intranasal vaccine candidate for COVID-19. This modified virus was engineered to replace the coding sequence for the neuraminidase (NA) protein with a membrane-anchored form of the receptor binding domain (RBD) protein of SARS-CoV-2. We designed experiments to assess the protection of ΔNA(RBD) in K18-hACE2 mice using lethal (Delta) and non-lethal (Omicron) challenge models. Controls of COVID-19 mRNA vaccine and our lab's previously described intranasal virus like particle vaccine were used as comparisons. Immunization with ΔNA(RBD) expressing ancestral RBD elicited high anti-RBD IgG levels in the serum of mice, high anti-RBD IgA in lung tissue, and improved survival after Delta variant challenge. Modifying ΔNA(RBD) to express Omicron variant RBD shifted variant-specific antibody responses and limited viral burden in the lungs of mice after Omicron variant challenge. Overall, this data suggests that ΔNA(RBD) could be an effective intranasal vaccine platform that generates mucosal and systemic immunity towards SARS-CoV-2.

11.
Vaccine X ; 20: 100545, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39221182

RESUMEN

The coronavirus disease 2019 (COVID-19) emerged as a major global health crisis, posing significant health, economic, and social challenges. Vaccine development has been a crucial response to the severe-acute-respiratory-syndrome-related coronavirus-2 pandemic owing to the critical role of immunization in controlling infectious diseases, leading to the expedited development of several effective vaccines. Although mRNA platform-based COVID-19 vaccines authorized under emergency-use authorization have been administered globally, concerns regarding the vaccines have increased owing to the occurrence of various side effects. The present study aimed to evaluate the safety of a non-replicating recombinant baculovirus expressing the human endogenous retrovirus envelope gene (AcHERV) vaccine encoding SARS-CoV-2 antigens. Owing to the limited number of existing safety pharmacology studies on AcHERV as a viral vector vaccine, we conducted neurobehavior (Modified Irwin's Test), body temperature, and respiratory function studies in rats and cardiovascular system studies in male beagle dogs, which were administered the AcHERV-COVID-19 vaccine using telemetry. The safety assessment revealed no significant toxicological alterations. However, in rats, both sexes administered with the AcHERV-COVID-19 vaccine exhibited a temporary increase in body temperature, which normalized or showed signs of recovery. In conclusion, AcHERV-COVID-19 demonstrates a sufficient safety profile that supports its potential evaluation in future clinical trials.

12.
Vaccine X ; 20: 100546, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39221179

RESUMEN

Introduction: Health care workers (HCWs) have been at increased risk of infection during the SARS-CoV-2 pandemic and as essential workers have been prioritised for vaccination. Due to increased exposure HCW are considered a predictor of what might happen in the general population, particularly working age adults. This study aims to summarise effect of vaccination in this 'at risk' cohort. Methods: Ovid MEDLINE and Embase were searched, and 358 individual articles were identified. Of these 49 met the inclusion criteria for review and 14 were included in a meta-analysis. Results: Participants included were predominantly female and working age. Median time to infection was 51 days. Reported vaccine effectiveness against infection, symptomatic infection, and infection requiring hospitalisation were between 5 and 100 %, 34 and 100 %, and 65 and 100 % (respectively). No vaccinated HCW deaths were recorded in any study. Pooled estimates of protection against infection, symptomatic infection, and hospitalisation were, respectively, 84.7 % (95 % CI 72.6-91.5 %, p < 0.0001), 86.0 % (95 % CI 67.2 %-94.0 %; p < 0.0001), and 96.1 % (95 % CI 90.4 %-98.4 %). Waning protection against infection was reported by four studies, although protection against hospitalisation for severe infection persists for at least 6 months post vaccination. Conclusions: Vaccination against SARS-CoV2 in HCWs is protective against infection, symptomatic infection, and hospitalisation. Waning protection is reported but this awaits more mature studies to understand durability more clearly. This study is limited by varying non-pharmacological responses to COVID-19 between included studies, a predominantly female and working age population, and limited information on asymptomatic transmission or long COVID protection.

13.
Mater Today Bio ; 28: 101165, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39221218

RESUMEN

The antiviral effect of four porphyrin-based Metal-Organic Frameworks (PMOFs) with Al and Zr, namely Al-TCPP, PCN-222, PCN-223 and PCN-224 was assessed for the first time against HCoV-229E, two highly pathogenic coronaviruses (SARS-CoV-2 and MERS-CoV) and hepatitis C virus (HCV). Infection tests in vitro were done under dark or light exposure for different contact times, and it was found that 15 min of light exposure were enough to give antiviral properties to the materials, therefore inactivating HCoV-229E by 99.98 % and 99.96 % for Al-TCPP and PCN-222. Al-TCPP diminished the viral titer of SARS-CoV-2 greater than PCN-222 in the same duration of light exposure, having an effect of 99.95 % and 93.48 % respectively. Next, Al-TCPP was chosen as the best candidate possessing antiviral properties and was tested against MERS-CoV and HCV, showcasing a reduction of infectivity of 99.28 % and 98.15 % respectively for each virus. The mechanism of the antiviral activity of the four PMOFs was found to be the production of singlet oxygen 1O2 from the porphyrin ligand TCPP when exposed to visible light, by using sodium azide (NaN3) as a scavenger, that can later attack the phospholipids on the envelope of the viruses, thus preventing their entry into the cells.

14.
PeerJ ; 12: e17956, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39221275

RESUMEN

Background: Fecal shedding of SARS-CoV-2 occurs during infection, particularly in pediatric populations. The gut microbiota are associated with resistance to enteric pathogens. COVID-19 is associated with alterations to the gut microbiome. We hypothesized that the gut microbiome of infants born to SARS-CoV-2+ mothers differs between infants with and without fecal shedding of the virus. Methods: We enrolled 10 infants born to SARS-CoV-2+ mothers. We used qPCR on fecal RNA to test for SARS-CoV-2 and 16S rRNA gene sequencing of the V4 region to assess the gut microbiome. Infant SARS-CoV-2 status from nasal swabs was abstracted from medical records. Results: Of the 10 included infants, nine were tested for SARS-CoV-2 by nasal swab with 1 testing positive. Four infants, including the nasal swab positive infant, had at least one sample with detectable levels of SARS-CoV-2 fecal shedding. Detection of both SARS-CoV-2 genes in feces was associated with increased gut alpha diversity compared to no detection by a linear mixed effects model (p < 0.001). Detection of both SARS-CoV-2 genes was associated with increased levels Erysipelotrichaceae, Lactobacillaceae, and Ruminococceae by MaAsLin2. Conclusion: Fecal shedding of SARS-CoV-2 occurs in infants who test negative on nasal swabs and is associated with differences in the gut microbiome.


Asunto(s)
COVID-19 , Heces , Microbioma Gastrointestinal , SARS-CoV-2 , Esparcimiento de Virus , Humanos , Heces/virología , Heces/microbiología , COVID-19/virología , COVID-19/transmisión , COVID-19/diagnóstico , Proyectos Piloto , Femenino , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , Microbioma Gastrointestinal/genética , Embarazo , Recién Nacido , Lactante , Masculino , Adulto , ARN Ribosómico 16S/genética , Complicaciones Infecciosas del Embarazo/microbiología , Complicaciones Infecciosas del Embarazo/virología , Transmisión Vertical de Enfermedad Infecciosa , Madres
15.
J Med Microbiol ; 73(9)2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39222071

RESUMEN

Background. The COVID-19 pandemic demonstrated a need for robust SARS-CoV-2 test evaluation infrastructure to underpin biosecurity and protect the population during a pandemic health emergency.Gap statement. The first generation of rapid antigen tests was less accurate than molecular methods due to their inherent sensitivity and specificity shortfalls, compounded by the consequences of self-testing. This created a need for more accurate point-of-care SARS-CoV-2 detection methods.Aim. Here we present the lessons-learned during the COVID-19 emergency response in Western Australia including the detailed set-up, evaluation and operation of rapid antigen test in a state-run drive-through sample collection service during the COVID-19 pandemic after the strict border shutdown ended.Methods. We report a conformity assessment of a novel, second-generation rapid antigen test (Virulizer) comprising a technician-operated rapid lateral flow immunoassay with fluorescence-based detection.Results. The Virulizer rapid antigen test demonstrated up to 100% sensitivity (95% CI: 61.0-100%), 91.94% specificity (95% CI: 82.5-96.5%) and 92.65% accuracy when compared to a commercial PCR assay method. Wide confidence intervals in our series reflect the limits of small sample size. Nevertheless, the Virulizer assay performance was well-suited to point-of-care screening for SARS-CoV-2 in a drive-through clinic setting.Conclusion. The adaptive evaluation process necessary under changing pandemic conditions enabled assessment of a simple sample collection and point-of-care testing process, and showed how this system could be rapidly deployed for SARS-CoV-2 testing, including to regional and remote settings.


Asunto(s)
COVID-19 , Pruebas en el Punto de Atención , SARS-CoV-2 , Sensibilidad y Especificidad , Humanos , COVID-19/diagnóstico , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificación , Inmunoensayo/métodos , Australia Occidental/epidemiología , Antígenos Virales/análisis , Prueba Serológica para COVID-19/métodos , Prueba de COVID-19/métodos , Fluorescencia , Sistemas de Atención de Punto
16.
Biochem Soc Trans ; 2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-39222407

RESUMEN

E3 ubiquitin ligases regulate the composition of the proteome. These enzymes mono- or poly-ubiquitinate their substrates, directly altering protein function or targeting proteins for degradation by the proteasome. In this review, we discuss the opposing roles of human E3 ligases as effectors and targets in the evolutionary battle between host and pathogen, specifically in the context of SARS-CoV-2 infection. Through complex effects on transcription, translation, and protein trafficking, human E3 ligases can either attenuate SARS-CoV-2 infection or become vulnerabilities that are exploited by the virus to suppress the host's antiviral defenses. For example, the human E3 ligase RNF185 regulates the stability of SARS-CoV-2 envelope protein through the ubiquitin-proteasome pathway, and depletion of RNF185 significantly increases SARS-CoV-2 viral titer (iScience (2023) 26, 106601). We highlight recent advances that identify functions for numerous human E3 ligases in the SARS-CoV-2 life cycle and we assess their potential as novel antiviral agents.

17.
J Med Virol ; 96(9): e29891, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39223933

RESUMEN

The ubiquitin-proteasome system is frequently employed to degrade viral proteins, thereby inhibiting viral replication and pathogenicity. Through an analysis of the degradation kinetics of all the SARS-CoV-2 proteins, our study revealed rapid degradation of several proteins, particularly NSP5. Additionally, we identified FBXO22, an E3 ubiquitin ligase, as the primary regulator of NSP5 ubiquitination. Moreover, we validated the interaction between FBXO22 and NSP5, demonstrating that FBXO22-mediated ubiquitination of NSP5 facilitated its recognition by the proteasome, leading to subsequent degradation. Specifically, FBXO22 catalyzed the formation of K48-linked polyubiquitin chains on NSP5 at lysine residues 5 and 90. Knockdown of FBXO22 resulted in decreased NSP5 ubiquitination levels, increased stability, and enhanced ability to evade the host innate immune response. Notably, the protein level of FBXO22 were negatively correlated with SARS-CoV-2 load, highlighting its importance in inhibiting viral replication. This study elucidates the molecular mechanism by which FBXO22 mediates the degradation of NSP5 and underscores its critical role in limiting viral replication. The identification of FBXO22 as a regulator of NSP5 stability provides new insights and potential avenues for targeting NSP5 in antiviral strategies.


Asunto(s)
Complejo de la Endopetidasa Proteasomal , SARS-CoV-2 , Ubiquitinación , Replicación Viral , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , SARS-CoV-2/fisiología , SARS-CoV-2/metabolismo , COVID-19/virología , COVID-19/metabolismo , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Células HEK293 , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteolisis , Proteasas Similares a la Papaína de Coronavirus/metabolismo , Receptores Citoplasmáticos y Nucleares
18.
J Biomater Sci Polym Ed ; : 1-18, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39225011

RESUMEN

This study utilized small molecular characterization and docking study to evaluate the binding affinity of seven antiviral phytocompounds with the SARS CoV-2 variants (SARS-CoV-2 Spike Glycoprotein, SARS-CoV-2 Spike Protein Variant in 1-RBD, Alpha Variant SARS-CoV2- Spike Protein). The results revealed that five of seven compounds, possesses excellent drug lead property reveled through in-silico ADMET analysis. In addition, six of seven except D-Glucosamine, exhibited excellent binding affinity. Six ligands possess significant binding affinity towards SARS-CoV-2 variants 6VXX, 7LWV and 7R13, which is certainly greater than Remdesivir. Fagaronine found to be the best drug candidate against SARS-CoV-2 variants, It was found that -7.4, -5.6 and -6.3 is the docking score respectively. Aranotin, Beta aescin, Gliotoxin, and Fagaronine formed hydrogen bonds with specific amino acids and exhibited significant binding interactions. These findings suggest that these phytocompounds could be promising candidates for developing antiviral therapies against SARS-CoV-2. Moreover, the study underscores the importance of molecular docking in understanding protein-ligand interactions and its role in drug discovery. The documented pharmacological properties of these compounds in the literature further support their potential therapeutic relevance in various diseases.

19.
Antimicrob Agents Chemother ; : e0056224, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39225484

RESUMEN

We have synthesized a novel and highly selective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease peptide mimetic inhibitor mimicking the replicase 1ab recognition sequence -Val-Leu-Gln- and utilizing a cysteine selective acyloxymethyl ketone as the electrophilic warhead to target the active site Cys145. Utilizing a constrained cyclic peptide that locks the conformation between the P3 (Val) and P2 (Leu) residues, we identified a highly selective inhibitor that fills the P2 pocket occupied by the leucine residue sidechain of PF-00835231 and the dimethyl-3-azabicyclo-hexane motif in nirmatrelvir (PF-07321332). This strategy resulted in potent and highly selective Mpro inhibitors without inhibiting essential host cathepsin cysteine or serine proteases. The lead prototype compound 1 (MPro IC50 = 230 ± 18 nM) also inhibits the replication of multiple SARS-CoV-2 variants in vitro, including SARS-CoV-2 variants of concern, and can synergize at lower concentrations with the viral RNA polymerase inhibitor, remdesivir, to inhibit replication. It also reduces SARS-CoV-2 replication in SARS-CoV-2 Omicron-infected Syrian golden hamsters without obvious toxicities, demonstrating in vivo efficacy. This novel lead structure provides the basis for optimization of improved agents targeting evolving SARS-CoV-2 drug resistance that can selectively act on Mpro versus host proteases and are less likely to have off-target effects due to non-specific targeting. Developing inhibitors against the active site of the main protease (Mpro), which is highly conserved across coronaviruses, is expected to impart a higher genetic barrier to evolving SARS-CoV-2 drug resistance. Drugs that selectively inhibit the viral Mpro are less likely to have off-target effects warranting efforts to improve this therapy.

20.
Carbohydr Polym ; 346: 122605, 2024 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-39245521

RESUMEN

With the global spread of COVID-19 posing ongoing challenges to public health systems, there is an ever-increasing demand for effective therapeutics that can mitigate both viral transmission and disease severity. This review surveys the landscape of polysaccharides derived from traditional Chinese medicine, acclaimed for their medicinal properties and potential to contribute to the COVID-19 response. We specifically focus on the capability of these polysaccharides to thwart SARS-CoV-2 entry into host cells, a pivotal step in the viral life cycle that informs transmission and pathogenicity. Moreover, we delve into the concept of trained immunity, an innate immune system feature that polysaccharides may potentiate, offering an avenue for a more moderated yet efficacious immune response against various pathogens, including SARS-CoV-2. Our comprehensive overview aims to bolster understanding of the possible integration of these substances within anti-COVID-19 measures, emphasizing the need for rigorous investigation into their potential applications and underlying mechanisms. The insights provided here strongly support ongoing investigations into the adjunctive use of polysaccharides in the management of COVID-19, with the anticipation that such findings could lead to a deeper appreciation and clearer elucidation of the antiviral potentials inherent in complex Chinese herbal remedies.


Asunto(s)
Medicina Tradicional China , Polisacáridos , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , COVID-19/inmunología , COVID-19/virología , Integración Viral , SARS-CoV-2/fisiología , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Antivirales/farmacología , Antivirales/uso terapéutico , Humanos
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