Search Results (372)

Background/Objectives: Combination therapies using traditional Chinese medicine and Western drugs have gained attention for their enhanced therapeutic effects and reduced side effects. Toujie Quwen Granules (TQG), known for its antiviral properties, particularly against respiratory viruses, could offer new treatment strategies when combined with antiviral drugs like arbidol, especially for diseases such as Coronavirus disease. This study investigates the synergistic mechanisms between arbidol and components from TQG against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^pro). Methods: We identified compounds from TQG via existing data. Multi-ligand molecular docking, pharmacokinetic/toxicity screening, and preliminary simulations were performed to assess potential synergistic compounds with arbidol. UPLC-Q-Exactive Orbitrap-MS verified the presence of these compounds. Extended simulations and in vitro assays, including Luciferase and surface plasmon resonance, validated the findings. Results: Five compounds interacted with arbidol in synergy based on docking and preliminary dynamics simulation results. Only Baicalein (HQA004) could be identified in the herbal remedy by untargeted metabolomics, with ideal pharmacokinetic properties, and as a non-toxic compound. Extended simulations revealed that HQA004 enhanced arbidol’s antiviral activity via a “Far” Addition Mechanism #2, with an optimal 2:1 arbidol:HQA004 ratio. The movements of arbidol (diffusion and intramolecular conformational shifts) in the system were significantly reduced by HQA004, which may be the main reason for the synergism that occurred. In vitro experiments confirmed an increased inhibition of M^pro by the combination. Conclusions: HQA004 demonstrated synergistic potential with arbidol in inhibiting M^pro. The development of combination therapies integrating Western and herbal medicine is supported by these findings for effective antiviral treatments. Full article

The recent global coronavirus pandemic highlighted the ever-present threat of respiratory virus outbreaks and the consequent need for ongoing research into antiviral therapy. To this end, structural analogues of the guanidinium-based drug camostat mesylate have been synthesised to probe their potential inhibition of Transmembrane Serine Protease 2 (TMPRSS2), a human protease that is essential for infection by many respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Our in vitro fluorescence-based protease assays and supporting computational docking studies suggest that C-terminal camostat analogues retain TMPRSS2 inhibition potencies (IC₅₀ = 1–3 nM, BE = −6.6 to −7.0 kcal/mol) that match or exceed that of the parent drug. Analogues 1c and 1d emerge as lead candidates in this regard, thereby validating the rationale behind C-terminal structural modifications and highlighting these derivatives as promising scaffolds for the future development of targeted antiviral therapeutics. Replacement of camostat’s ester functionality with peptide linkages largely preserves non-covalent binding but disrupts in vitro protease inhibition, findings consistent with the parent drug’s known role as an acylating suicide inhibitor. Docking studies confirm that the replacement of aromatic residues with flexible, equivalent-length alkyl chains is detrimental to drug binding. These function and binding data offer new directions for the synthesis of further analogues of camostat and of other guanidinium-based protease inhibitors that have yet to be refined via structure–activity relationship studies. Further investigation will support tailoring this class of drugs for repurposing in antiviral therapy. Full article

The recent COVID-19 pandemic has prompted the scientific community to prioritize the discovery of preventive methods and new therapeutics, including the investigation of natural compounds with antiviral potential. Fungal secondary metabolites (SMs) represent a promising source of antiviral drugs due to their structural diversity and intrinsic biocompatibility. Herein, the antiviral activity of 6-pentyl-α-pyrone (6PP) against bovine coronavirus (BCoV) has been evaluated in vitro. Considering that BCoV and SARS-CoV-2 are both members of the Betacoronavirus genus and share several key features, BCoV represents a valuable reference model for human coronavirus research. A non-cytotoxic dose of 6PP was used on MDBK cells to evaluate its antiviral activity against BCoV. Different experimental conditions were employed to examine cell monolayer protection both pre- and post-infection, as well as the potential inhibition of viral internalization. Overall, post-infection 6PP treatment reduced viral load and decreased viral internalization. Results were analyzed using viral titration and quantitative PCR, while data interpretation was performed by statistical software tools. This study presents a novel fluorescence quantification approach with high confidence demonstrated by its significant concordance with RT-qPCR results. These data suggest that 6PP could be an effective antiviral agent for BCoV, warranting further investigation of its role in coronavirus inhibition. Full article

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its impact on public health continue to demand attention as the virus continues to evolve, demonstrating a remarkable ability to adapt to diverse selective pressures including immune responses, therapeutic treatments, and prophylactic interventions. The SARS-CoV-2 variant landscape remains dynamic, with new subvariants continuously emerging, many harboring spike protein mutations linked to immune evasion. In this study, we characterized a panel of live SARS-CoV-2 strains, including those key subvariants implicated in recent waves of infection. Our findings revealed a significant variability in mutation patterns in the spike protein across the strains analyzed. Commercial antibodies and human convalescent plasma (HCoP) samples from unvaccinated donors were ineffective in neutralizing the most recent Omicron subvariants, particularly after the emergence of JN.1 subvariant. Using human airway epithelial cells derived from healthy bronchiolar tissue (hBAEC), we established both monoinfections and coinfections involving SARS-CoV-2, Influenza A virus H1N1 (IFAV_H1N1) and Respiratory Syncytial Virus (RSV). Assessments were conducted to compare viral infectivity and the production and release of immune mediators in the apical and basolateral compartments. Notably, Omicron KP.3.1.1 subvariant induced a more pronounced cytopathic effect in hBAEC compared to its parental strain JN.1 and even surpassed the impact observed with the ancestral wild-type virus (WA1/2020, Washington strain). Furthermore, the coinfection of KP.3.1.1 subvariant with IFAV_H1N1 or RSV did not attenuate SARS-CoV-2 infectivity; instead, it significantly exacerbated the pathogenic synergy in the lung epithelium. Our study demonstrated that pro-inflammatory cytokines IL-6, IFN-β, and IL-10 were upregulated in hBAEC following SARS-CoV-2 monoinfection with recent Omicron subvariants as well as during coinfection with IFAV_H1N1 and RSV. Taken together, our findings offer new insights into the immune evasion strategies and pathogenic potential of evolving SARS-CoV-2 Omicron subvariants, as well as their interactions with other respiratory viruses, carrying important implications for therapeutic development and public health preparedness. Full article

During the early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, concerns arose regarding the susceptibility of asthmatic children, one of the most common chronic conditions in childhood and a major cause of hospitalization in pediatric settings. Unexpectedly, evidences showed milder clinical courses and fewer asthma exacerbations in these patients, even if cases of critical and fatal infection, often related to specific clinical features of the patient, are not negligible. In this regard, obesity is considered not only an important comorbidity in patients with difficult-to-treat asthma but also a risk factor for more severe forms of COVID-19. These observations are of even greater concern in the context of an increase in childhood obesity that began even before the SARS-CoV-2 pandemic and has continued also as a consequence of it. Given asthma’s heterogeneity, especially in children, an endotype-based approach is crucial. This is possible through a detailed analysis of the complex metabolic pathways that correlate asthma, COVID-19 infection and obesity thanks to new high-through-put technologies, especially metabolomics, which with minimally invasive sampling, including on exhaled breath condensate (EBC), can provide precise and unbiased evidence in support of existing endotypes, making it possible to identify not only the most vulnerable individuals and thus risk stratification through specific biomarkers, but also new molecular and therapeutic targets. This review explores asthma endotypes by highlighting their shared immunometabolic pathways with COVID-19. Findings suggest that metabolomics could enable more accurate risk stratification and guide personalized interventions during viral pandemics, especially in the presence of relevant comorbidities such as obesity. Full article

Background/Objectives: Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with far-reaching impacts on human activities. Moreover, direct viral damage and uncontrolled inflammation have been proposed as contributing factors to the severity of SARS-CoV-2 disease. Lipopolysaccharide binding protein (LBP) is also well recognized for its capability to trigger and modulate the host’s innate immune system by attaching to bacterial substances. Nevertheless, the pandemic has further emphasized the critical role of an effective host immune response in controlling viral infection and highlighted the detrimental effect of immune dysregulation. This study aimed to assess plasma levels of LBP and inflammatory biomarkers in SARS-CoV-2 patients with different malnutrition status and severity levels. Methods: This cross-sectional study was carried out in King Khalid University Hospital in Riyadh from December 2020 to December 2021. A total of 166 SARS-CoV-2 patients were recruited including 80 critical and 86 non-critical patients. Medical history, anthropometrical parameters, disease outcome information, and relevant biochemical parameters were extracted from medical records. Plasma samples were collected to test for LBP and inflammatory cytokines. Finally, nutritional risk was assessed by the Nutrition Risk Screening-2002 (NRS-2002) tool. Results: This cross-sectional study found no significant differences in LBP levels between critical and non-critical SARS-CoV-2 patients. However, LBP levels significantly correlated with IL-10, TNF-α and IL-6/IL-10 levels (Spearman’s rho = 0.430, 0.276 and −0.397 respectively; p < 0.001). Conclusions: This study confirmed the elevated inflammatory cytokines in hospitalized SARS-CoV-2 patients and their association with disease severity and malnutrition. These findings may support the mechanism of gut inflammation in order to develop new interventions that lower inflammatory biomarkers, disease severity, and aid in SARS-CoV-2 prevention and management. Full article

The COVID-19 infection, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has evoked a worldwide pandemic. Even though vaccines have been developed on an enormous scale, but due to regular mutations in the viral gene and the emergence of new strains could pose a more significant problem for the population. Therefore, new treatments are always necessary to combat future pandemics. Utilizing an antiviral peptide as a model biomolecule, we trained a generative deep learning algorithm on a database of known antiviral peptides to design novel peptide sequences with antiviral activity. Using artificial intelligence (AI), specifically variational autoencoders (VAE) and Wasserstein autoencoders (WAE), we were able to generate a latent space plot that can be surveyed for peptides with known properties and interpolated across a predictive vector between two defined points to identify novel peptides that exhibit dose-responsive antiviral activity. Two hundred peptide sequences were generated from the trained latent space and the top peptides were subjected to a molecular docking study. The docking analysis revealed that the top four peptides (MSK-1, MSK-2, MSK-3, and MSK-4) exhibited the strongest binding affinity, with docking scores of −106.4, −126.2, −125.7, and −127.8, respectively. Molecular dynamics simulations lasting 500 ns were performed to assess their stability and binding interactions. Further analyses, including MMGBSA, RMSD, RMSF, and hydrogen bond analysis, confirmed the stability and strong binding interactions of the peptide–protein complexes, suggesting that MSK-4 is a promising therapeutic agent for further development. We believe that the peptides generated through AI and MD simulations in the current study could be potential inhibitors in natural systems that can be utilized in designing therapeutic strategies against SARS-CoV-2. Full article

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the zoonotic virus responsible for the COVID-19 pandemic, has caused global health and economic disruption. American mink (Neovison vison) are highly susceptible to SARS-CoV-2 and capable of transmitting it to both mink and humans. We previously reported the first detection of SARS-CoV-2 in feral mink, with two positive cases among 13 animals in the upper courses of two rivers in the Valencian Community, eastern Spain. Here, we expand that study with 60 additional feral mink sampled from November 2020 to May 2022. Four new positives were identified by two-step RT-PCR assay on necropsy samples, including nasal and rectal swabs, lung tissue, lymph nodes, and fetuses from three pregnant females. In total, six of 73 mink tested positive, all with low viral loads. Sanger sequencing confirmed infection and revealed clustering with the B.1.177 and Alpha variants. Body weight and reproductive status analyses indicated seasonal breeding and high population turnover, consistent with other wild mink populations. Our findings reveal that SARS-CoV-2 circulation is limited in feral mink, at least in this region. They underscore the key importance of wildlife surveillance as an element of the One Health strategy, which encompasses humans, animals, and the environment. Full article

With the emergence of the SARS-CoV-2 pandemic the process of coronavirus replication has been under increasing scrutiny. During the replication of their genomic RNA, coronaviruses produce a range of other RNAs in addition to the negative-sense replicative intermediates of the genome, which includes a set of subgenomic RNAs. These subgenomic RNAs are nested within the sequence of the complete genome and can be both replicated further and act as templates for protein production. Alongside these functional products of discontinuous replication, coronaviruses produce defective viral genomes that can potentially impact both the virus and infected host cells. These interactions can arise from the ability of these defective viral genomes to impact the production of new infectious virions, through either competition with the wild-type genome for replication or by stimulating an antiviral response. Examining the behaviour of defective viral genomes can also help to elucidate the functional elements of the genome involved in the processes of replication and packaging. This review covers the process of intracellular replication by coronaviruses describing the mechanisms by which the different RNA species are produced. Of particular focus are factors involved in discontinuous replication that produces defective viral genomes, and the behaviour of coronavirus defective viral genomes. Full article

Background/Objectives: Highly pathogenic coronaviruses (CoVs), including SARS-CoV, MERS-CoV, and SARS-CoV-2, continue to pose a significant threat to global public health. Therefore, this situation highlights the urgent need for effective broad-spectrum antiviral agents. Curcumin, a naturally occurring polyphenol known for its antiviral and anti-inflammatory properties, faces limitations such as poor bioavailability and rapid metabolic degradation, restricting its practical therapeutic application. Methods: To address these limitations, this study introduces a novel design strategy aimed at 42 new curcumin derivatives with improved pharmacokinetic profiles, specifically targeting the conserved coronavirus enzyme papain-like protease (PLpro). A comprehensive in silico evaluation was performed, including ADMET (Absorption, Distribution, Metabolism, Elimination, and Toxicity) analysis, molecular docking, molecular dynamics (MD) simulations, and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) calculations. Results: Extensive pharmacokinetic and toxicological assessments (ADMET analyses) identified 19 derivatives exhibiting optimal drug-like characteristics according to Lipinski’s Rule of Five (Ro5). Molecular docking analyses demonstrated that these novel derivatives possess significantly enhanced binding affinities to PLpro enzymes from SARS-CoV, MERS-CoV, and SARS-CoV-2 compared to standard antiviral agents and natural curcumin. Further validation through MD simulations and MM/PBSA calculations confirmed the structural stability and robust interactions of the most promising derivatives within the SARS-CoV PLpro active site. Conclusions: The results of this study provide essential structural and functional insights, reinforcing the potential of these newly developed curcumin derivatives as potent, broad-spectrum antiviral agents effective against current and future coronavirus threats. Full article

The novel coronavirus pandemic, SARS-CoV-2, has a variable clinical spectrum, ranging from asymptomatic to critical forms. High mortality and morbidity rates have been associated with risk factors such as comorbidities, age, sex, and virulence factors specific to viral variants. Material and Methods: We retrospectively evaluated imaging characteristics using the Brixia radiological score in relation to favorable or unfavorable outcomes in adult patients. We included COVID-19 cases, admitted between 2020 and 2022, in a specialized pulmonology hospital with no intensive care unit. We analyzed 380 virologically confirmed COVID-19 cases, with a mean age of 52.8 ± 13.02 years. The mean Brixia radiological score at admission was 5.13 ± 3.56, reflecting predominantly mild-to-moderate pulmonary involvement. Multivariate analysis highlighted the utility of this score as a predictive marker for COVID-19 prognosis, with values >5 correlating with other severity biomarkers, NEWS-2 scores, and a lack of vaccination and hospitalization delay of more than 6 days from symptom onset. Summarizing, the Brixia score is itself an effective tool for screening COVID-19 cases at risk of death for early recognition of clinical deterioration and for decisions regarding appropriate care settings. Promoting vaccination can reduce the severity of radiological lesions, thereby decreasing the risk of death. Technologies based on artificial intelligence could optimize diagnosis and management decisions. Full article

The Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), disproportionately affects individuals with diabetes mellitus (DM) by exacerbating cardiovascular and renal complications. This increased risk is mediated through immune dysfunction, chronic inflammation, hyperglycemia, dysregulation of renin-angiotensin system dysregulation, endothelial dysfunction, and hypercoagulability. Epidemiological studies indicate a two-fold increased risk of stroke and end-stage renal disease in SARS-CoV-2-infected individuals with diabetes, along with a 60% higher risk of cardiovascular disease. While antidiabetic therapies like sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists show potential protective effects, insulin use in hospitalized patients is linked to higher mortality. Vaccination is crucial in reducing severe COVID-19 outcomes and mitigating post-infection complications, including new-onset diabetes. While concerns exist regarding vaccine-associated nephropathy and thromboembolic events, these risks are thought to be minimal compared to the benefits. As COVID-19 shifts to an endemic phase, the long-term renal and cardiovascular outcomes in patients with DM remain uncertain, highlighting the urgent need for continued research and targeted management strategies. Full article

Vaccination has been instrumental in curbing the transmission of SARS-CoV-2 and mitigating the severity of clinical manifestations associated with COVID-19. Numerous COVID-19 vaccines have been developed to this effect, including BioNTech-Pfizer and Moderna’s mRNA vaccines, as well as adenovirus vector-based vaccines such as Oxford–AstraZeneca. However, the emergence of new variants and subvariants of SARS-CoV-2, characterized by enhanced transmissibility and immune evasion, poses significant challenges to the efficacy of current vaccination strategies. In this review, we aim to comprehensively outline the landscape of emerging SARS-CoV-2 variants of concern (VOCs) and sub-lineages that have recently surfaced in the post-pandemic years. We assess the effectiveness of existing vaccines, including their booster doses, against these emerging variants and subvariants, such as BA.2-derived sub-lineages, XBB sub-lineages, and BA.2.86 (Pirola). Furthermore, we discuss the latest advancements in vaccine technology, including multivalent and pan-coronavirus approaches, along with the development of several next-generation coronavirus vaccines, such as exosome-based, virus-like particle (VLP), mucosal, and nanomaterial-based vaccines. Finally, we highlight the key challenges and critical areas for future research to address the evolving threat of SARS-CoV-2 subvariants and to develop strategies for combating the emergence of new viral threats, thereby improving preparedness for future pandemics. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense RNA virus with an unusually large genome of approximately 30 kb. It is highly transmissible and exhibits broad tissue tropism. The third most pathogenic of all known coronaviruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the clinical manifestation known as coronavirus disease 2019 (COVID-19), which has resulted in the loss of millions of lives on a global scale. This pandemic has prompted significant efforts to develop therapeutic strategies that target the virus and/or human proteins to control viral infection. These efforts include the testing of hundreds of potential drugs and thousands of patients in clinical trials. Although the global pandemic caused by the SARS-CoV-2 virus is approaching its end, the emergence of new variants and drug-resistant mutants highlights the need for additional oral antivirals. The appearance of variants and the declining effectiveness of booster shots are resulting in breakthrough infections, which continue to impose a significant burden on healthcare systems. Computer-aided drug design (CADD) has been widely utilized for predicting drug–target interactions and evaluating drug safety; it is regarded as an effective tool for identifying promising drug candidates to combat SARS-CoV-2. The CADD approach aids in the discovery of new drugs or the repurposing of United States Food and Drug Administration (FDA)-approved drugs, whose safety and side effects are already well established, thus making the process more viable. This review summarizes potential therapeutic agents that target SARS-CoV-2 or host proteins critical for viral pathogenesis, as identified using CADD approaches. Additionally, this study provides insights into the common in silico methods used in CADD and their current applications in the SARS-CoV-2 drug discovery process. Full article

Background and Objectives: The interplay of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and Clostridioides difficile infection (CDI) poses a critical clinical challenge. The resultant inflammatory milieu and its impact on outcomes remain incompletely understood, especially among vulnerable subgroups such as elderly patients, those with diabetes, and individuals with cancer. This study aimed to characterize inflammatory markers and composite inflammatory severity scores—such as Acute Physiology and Chronic Health Evaluation II (APACHE II), Confusion, Urea, Respiratory rate, Blood pressure, and age ≥ 65 years (CURB-65), National Early Warning Score (NEWS), and the Systemic Immune-Inflammation Index (SII)—in hospitalized Coronavirus Disease 2019 (COVID-19) patients with and without CDI, and to evaluate their prognostic implications across key clinical subgroups. Methods: We conducted a retrospective, single-center study of 240 hospitalized adults with Reverse Transcription Polymerase Chain Reaction (RT-PCR)-confirmed COVID-19 between February 2021 and March 2023. Of these, 98 had concurrent CDI. We collected baseline demographics, comorbidities, and laboratory parameters including C-reactive protein (CRP), Interleukin-6 (IL-6), ferritin, neutrophil and lymphocyte counts, albumin, platelet counts, and calculated indices (C-reactive protein to Albumin Ratio (CAR), Neutrophil-to-Lymphocyte Ratio (NLR), Prognostic Nutritional Index (PNI), SII). Patients were stratified by CDI status and analyzed for inflammatory marker distributions, severity scores (APACHE II, CURB-65, NEWS), and outcomes (Intensive Care Unit (ICU) admission, mechanical ventilation, mortality). Subgroup analyses included diabetes, elderly (≥65 years), and cancer patients. Statistical comparisons employed t-tests, chi-square tests, and logistic regression models. Results: Patients with CDI demonstrated significantly higher CRP, IL-6, SII, and CAR, coupled with lower albumin and PNI (p < 0.05). They also had elevated APACHE II, CURB-65, and NEWS scores. CDI-positive patients experienced increased ICU admission (38.8% vs. 20.5%), mechanical ventilation (24.5% vs. 12.9%), and mortality (22.4% vs. 10.6%, all p < 0.05). Subgroup analyses revealed more pronounced inflammatory derangements and worse outcomes in elderly, diabetic, and cancer patients with CDI. Conclusions: Concurrent CDI intensifies systemic inflammation and adverse clinical trajectories in hospitalized COVID-19 patients. Elevations in inflammatory markers and severity scores predict worse outcomes, especially in high-risk subgroups. Early recognition and targeted interventions, including infection control and supportive measures, may attenuate disease severity and improve patient survival. Full article