Search Results (2,063)

Recently, there has been great interest in AI-based approaches for de novo design of novel drug candidates. However, the generation of useful lead drug candidate compounds requires more than predicting engagement with the desired protein target. Candidate molecules must also be anchored in the real world of medicinal chemistry for their synthesis and modification as well as satisfying multiple drug development-related criteria. Here, we present Nevermore, an AI target-conditioned, database-grounded workflow for prioritizing candidate ligands from large compound libraries. Nevermore uses a geometry-aware protein–ligand affinity oracle to score target-specific binding and perform sparse integer edits in count-based Morgan fingerprint space. Nevermore then retrieves the most structurally similar molecules from public chemical databases. This design enables multi-objective search over predicted affinity and absorption, distribution, metabolism, excretion, and toxicity (ADMET) proxies while keeping all candidates anchored to valid database compounds. We evaluated Nevermore’s performance across three biologically distinct targets: Menin, a protein-interaction target relevant to leukemia; SARS-CoV-2 M^pro, a viral cysteine protease relevant to antiviral discovery; and epidermal growth factor receptor (EGFR), a kinase-superfamily oncology target with extensive experimentally tested compounds. Nevermore retrieved candidate sets with favorable predicted affinity–property trade-offs. These results support database-grounded fingerprint steering as a practical computational strategy for lead prioritization and for generating testable molecular hypotheses, although the prioritized candidates remain predictions, requiring follow-up experimental validation. Full article

O’nyong-nyong virus (ONNV) is a mosquito-borne alphavirus responsible for large-scale epidemics in sub-Saharan Africa. As the closest evolutionary relative of Chikungunya virus (CHIKV), ONNV shares substantial genetic similarity and overlapping clinical manifestations with CHIKV. Mechanistic understanding of ONNV infection has therefore largely been extrapolated from CHIKV rather than directly established. However, ONNV exhibits distinct biological features, including predominant transmission by Anopheles mosquitoes and a clinical presentation characterized by prominent lymphadenopathy with limited acute joint edema. These distinctions underscore the need for an integrated synthesis of experimentally validated determinants of ONNV infection. In this review, we summarize current evidence on molecular and immunological factors regulating ONNV infection in mammalian hosts and mosquito vectors. We first discuss species-specific viral clearance, host dependency factors, intrinsic antiviral restriction mechanisms, protective innate immunity, inflammatory pathology, and mechanism-informed therapeutic strategies in mammalian hosts. We then examine stage-specific immune regulation in Anopheles mosquitoes, emphasizing mechanisms that constrain viral replication while permitting persistent infection and transmission. Finally, we discuss nsP3-dependent vector specificity and the potential contribution of alternative mosquito species to ONNV ecology. Together, this review provides an integrated framework for understanding how host factors, immune responses, and vector-specific adaptations shape ONNV infection, pathogenesis, and transmission. Full article

Honey bee populations face significant threats from viral pathogens, Nosema ceranae, Varroa destructor, and the small hive beetle (Aethina tumida), all of which contribute to colony losses worldwide. RNA interference (RNAi) has emerged as a promising molecular tool for controlling these pathogens and pests through sequence-specific gene silencing. This review summarizes current advances in RNAi applications against major honey bee diseases and parasites, including antiviral strategies, suppression of Nosema development, interference with Varroa reproduction, and RNAi-based control of small hive beetles. Particular attention is given to recent developments in delivery technologies, including oral administration, nanoparticle-assisted formulations, and symbiont-mediated RNAi systems. The opportunities, limitations, and future challenges associated with large-scale implementation, environmental safety, regulatory approval, and field deployment are also discussed. Collectively, these advances highlight the potential of RNAi as a valuable component of sustainable honey bee health management and integrated pest management programs. Full article

Type I interferons (IFN-I), including IFN-α, IFN-β, and IFN-ω, are central to antiviral defence and immune regulation. Autoantibodies targeting IFN-I (anti-IFN-I AAbs) have emerged as key pathogenic factors in severe coronavirus disease 2019 (COVID-19) and are detectable in systemic lupus erythematosus (SLE), a prototypic IFN-driven autoimmune disease. Here we compare the prevalence and clinical impact of anti-IFN-I autoantibodies (Aabs) in COVID-19 and SLE based on a structured review of 53 studies from 2014 to 2025 and highlight the clinical associations and therapeutic opportunities presented by these autoantibodies. In COVID-19, neutralising anti-IFN-α and/or anti-IFN-ω AAbs were consistently associated with severe disease and impaired antiviral responses, particularly in older male populations. In SLE, anti-IFN-α AAbs were variably detected; neutralising antibodies were associated with reduced interferon gene signatures in some cohorts but inconsistent correlations with disease activity. Therapeutically, anti-IFN-I AAbs in COVID-19 may inform risk stratification and early antiviral strategies, whereas in SLE, IFN-α blockade, including IFN-α kinoid vaccination, demonstrates modulation of IFN signatures but variable clinical benefit. Notably, these findings reveal an immunological paradox: the same neutralising mechanism that impairs antiviral defence in COVID-19 may attenuate chronic IFN-driven inflammation in SLE. Taken together, anti-IFN-I AAbs exert context-dependent effects: pathogenic in acute viral infection yet potentially modulatory in chronic IFN-driven autoimmunity. Prospective longitudinal studies are required to further clarify their translational utility and long-term clinical impact. Full article

Interferons (IFNs) are antiviral cytokines that serve as key mediators of the innate immune response, and their production is induced in the majority of cells within hours of pathogen entry. IFNs are predominantly produced by pathogen-infected cells; however, their antiviral effects extend to surrounding cells through autocrine and paracrine signaling mechanisms, inducing the transcription of hundreds of antiviral genes. Numerous gene products either interfere directly with viral replication or play regulatory roles that influence the progression and strength of the ensuing immune response. Viruses, on the other hand, have devised techniques to circumvent the host antiviral immune response and establish infection. This review focuses on the current state of evidence demonstrating how certain viral proteins block antiviral responses via immunomodulatory strategies and discusses how to overcome these immune evasion tactics. Full article

Flavonols are an important class of flavonoids widely distributed across various plant species. They have garnered significant attention from synthetic chemists due to their extensive biological activities and medicinal value. This review provides a systematic overview of five classical synthetic methods, including the Auwers reaction, the Allan–Robinson reaction, the Baker–Venkataraman rearrangement, the Algar–Flynn–Oyamada (AFO) reaction, and DMDO-mediated oxidation. Each methodology is comprehensively discussed in terms of its advantages, limitations, and potential optimization strategies. Additionally, the biological activities, including antioxidant, anticancer, anti-inflammatory, and antiviral properties, are summarized and discussed in the context of structure–activity relationships (SARs). Full article

Amaranthin is a major red-violet betacyanin of Amaranthaceae and an increasingly relevant natural pigment for food, cosmetic, nutraceutical, and biotechnological applications. This review integrates knowledge from over 100 studies, addressing amaranthin as a chemically defined betalain, distinguishing it from other scientific uses of the term, and evaluates its natural sources, analytical methods, extraction strategies, in vitro production systems, biosynthetic regulation, and biological activity. Cultivated Amaranthus species are among the richest plant sources, with total betacyanins of 46.1–199 mg/100 g fresh weight and amaranthin constituting up to 80.9% of the pigment fraction. Reliable identification and quantification rely on high performance liquid chromatography coupled with a diode array detector (HPLC-DAD), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and ultraviolet–visible (UV–Vis) spectrophotometry, while microwave-, ultrasound-, and green solvent-assisted extraction markedly improve pigment recovery and stability. While plant in vitro cultures, including callus, suspension, and shoot systems, have clarified biosynthetic regulation and offer controlled production platforms, engineered Yarrowia lipolytica CcAmaSy1 currently provides the highest reported yield, reaching 2.97 ± 0.029 g L⁻¹ in fed-batch fermentation. Amaranthin-rich extracts and purified pigments demonstrate antioxidant, anti-inflammatory, antimicrobial, and antiviral potential; however, mechanistic, bioavailability, and in vivo evidence remain limited. Standardized analytical protocols, further investigation of stable high-yield sources, physicochemical stability assessment, and structure–activity studies are identified as priorities for advancing future application-oriented research on this multipotential pigment. Full article

The Chinese bahaba (Bahaba taipingensis), an endangered marine fish, is highly vulnerable to infectious spleen and kidney necrosis virus (ISKNV). In this work, we developed a gill filament-derived cell line, designated BTG, to investigate how these cells respond to ISKNV over time, specifically from 3 to 24 h post-infection (hpi). BTG cells grew steadily, displayed a diploid chromosome number of 2n = 48, demonstrated high transfection efficiency, and were highly susceptible to viral infection. Characteristic cytopathic effects (CPEs) became noticeable as early as 6 hpi at 27 °C. RNA-seq profiling showed that the number of differentially expressed genes (DEGs) steadily increased with time. Standard enrichment analysis at individual time points (3, 6, 12, and 24 hpi) highlighted pathways mainly involved in DNA replication, cell cycle control, ribosome assembly, transcription and translation, mismatch repair, and cell adhesion. Temporal clustering analysis, however, revealed hidden patterns in immune gene expression. Genes that were consistently downregulated were enriched in immune-related pathways, including ECM–receptor interaction, cytokine–receptor signaling, PI3K–AKT, and Wnt signaling, indicating prolonged suppression of host defense mechanisms. In contrast, clusters of genes transiently upregulated during the first 6 h post-infection were associated with antiviral and innate immune pathways, such as NF-κB, JNK, IRF3, IRF7, caspases, JAK, MHC I, and lysosome-related functions, suggesting a rapid but short-lived antiviral response. Genes that were continuously upregulated were primarily involved in nucleic acid replication and protein synthesis, reflecting a gradual host cell reprogramming to support viral replication. Taken together, these findings reveal a temporal shift in BTG cells from an initial burst of immune activity to immune suppression, accompanied by enhanced viral replication. The BTG cell line thus represents a valuable in vitro model for dissecting ISKNV–host interactions and offers new perspectives on the molecular strategies employed by megalocytiviruses in B. taipingensis. Full article

Porcine coronavirus is one of the prevalent enteric coronaviruses in pigs, causing watery diarrhea and even death in suckling piglets and resulting in giant losses to the pig industry. However, effective antiviral strategies against PDCoV remain limited. Notoginsenoside R1 (NG-R1), a saponin extracted from Panax notoginseng, exhibits diverse bioactivities, but its antiviral potential has not been fully characterized. Herein, we systematically investigated the anti-PDCoV effect of NG-R1 and its underlying mechanism. NG-R1 showed no cytotoxic effect on LLC-PK1 cells and exerted antiviral ability against PDCoV infection through targeting the whole life cycle of the virus. In addition, network pharmacology analysis identified calcium signaling as a potentially relevant pathway involved in the antiviral activity of NG-R1. Further data demonstrated that PDCoV infection disrupted intracellular calcium homeostasis, whereas NG-R1 treatment partially restored calcium balance and attenuated endoplasmic reticulum (ER) stress. Moreover, NG-R1 modulated the expression of SERCA2, a key regulator of ER calcium transport. Thapsigargin, an inhibitor of SERCA2, showed similar antiviral capacity to NG-R1. Collectively, our findings suggest that NG-R1 exerts antiviral activity against PDCoV, potentially through regulation of calcium homeostasis mediated by SERCA2. This study provides a theoretical basis for the development of novel antiviral agents targeting calcium signaling pathways. Full article

Background/Objectives: Although influenza A viruses with partially truncated NS1 proteins are substantially attenuated and immunogenic due to enhanced innate immune activation; residual NS1-mediated antagonism of antiviral innate responses may support viral replication in the lower respiratory tract and constrain optimal immune responses. Strategies to further improve their immunogenicity and protective efficacy by incorporating immunomodulatory cytokines, such as IL-2, have been successfully explored. Methods: Here, we extended this approach to chemokine expression by engineering an NS1-truncated PR8-based virus (PR8/NS124) to express the immunomodulatory chemokine CXCL10 from the NS segment and compared it with the parental vector. Results: The recombinant NS124_SS_CXCL10 virus replicated to high titers in embryonated chicken eggs and MDCK cells. In vivo, however, CXCL10 expression reduced viral replication in mouse lungs by ~10⁴-fold, resulting in a near-non-replicating phenotype. In contrast to the parental virus, the vector did not induce weight loss and exhibited a strongly attenuated phenotype. This effect was associated with altered innate immune signaling, including increased IRF7 expression and early induction of IFN-α responses in the lungs, together with modulation of TLR-dependent sensing pathways in the upper respiratory tract. Despite severely impaired replication, intranasal immunization induced antigen-specific T-cell responses comparable to those elicited by the parental vector. Following intraperitoneal immunization, when replication of both vectors was minimal, the CXCL10-expressing vector induced significantly higher frequencies of antigen-specific CD8⁺ and CD4⁺ effector-memory T cells. This was accompanied by enhanced antigen-specific T-cell recall responses in the lungs following intranasal challenge. Importantly, the CXCL10-expressing vector demonstrated protective efficacy comparable to that of the parental NS124 vector against heterologous H3N2 challenge while exhibiting an improved safety profile. Conclusions: These findings support the incorporation of CXCL10 as a strategy to improve the safety and T-cell immunogenicity of NS1-truncated influenza vectors. Full article

Hantaviruses (HTVs) are lethal zoonotic pathogens responsible for hemorrhagic fever with renal syndrome and HTV cardiopulmonary syndrome; however, no specific antiviral treatments or vaccines have been approved. Bee products, such as propolis, honey, royal jelly, bee venom, and bee pollen, demonstrate extensive antiviral, anti-inflammatory, antioxidant, and immunomodulatory properties against various RNA and DNA viruses. No published research has directly evaluated bee products in relation to HTV infection. This review proposes a hypothesis-driven mechanistic framework suggesting that bioactive compounds from bee products may concurrently inhibit HTV replication, alleviate the cytokine storm, diminish oxidative stress, and maintain endothelial barrier integrity. We explicitly recognize the lack of direct experimental evidence regarding bee products’ efficacy against HTVs. Considering the mechanistic similarities with other enveloped viral infections and the recognized functions of NF-κB, Nrf2, and endothelial signaling pathways in HTV pathogenesis, we present a scientifically substantiated rationale for forthcoming research endeavors. The diverse bioactive compounds present in bee products including bee pollen, bee venom, honey, propolis, and royal jelly could provide a multifaceted strategy for inhibiting HTV pathology. We propose systematic in vitro, in silico, and in vivo investigations to assess the potential of bee-derived flavonoids, peptides, and fatty acids as adjunctive therapeutic strategies for HTV disease. Full article

Pediatric respiratory infections remain among the leading causes of emergency department visits, hospitalization and pediatric intensive care unit (PICU) admission. Although most acute respiratory infections in children are viral, clinical manifestations overlap substantially among viral, bacterial and atypical pathogens, creating diagnostic uncertainty and promoting empirical antimicrobial use. Rapid antigen tests, nucleic acid amplification tests, multiplex respiratory panels and metagenomic sequencing have expanded the ability to detect pathogens within clinically actionable timeframes. However, evidence from pediatric emergency trials indicates that rapid pathogen detection alone does not necessarily reduce antibiotic prescribing or healthcare costs. These findings suggest that the value of rapid diagnostics depends less on analytical breadth than on whether testing is applied to the right child, in the right clinical scenario and within a predefined decision pathway. This narrative review reorganizes the evidence around a scenario-driven top-pathogen framework. Top pathogens are defined as organisms that, in a specific age group, syndrome, season or care setting, have high prevalence, severe disease potential, transmissibility, treatment implications, antimicrobial resistance relevance or infection-control value. We discuss how top-pathogen testing should differ across emergency triage, inpatient ward management, severe pneumonia, PICU care, hospital-acquired pneumonia, ventilator-associated pneumonia and outbreak settings. We further examine the economic mechanisms through which rapid testing may generate value, including reduced unnecessary antibiotics, timely antiviral therapy, optimized isolation, shorter length of stay, reduced repeated testing and prevention of healthcare-associated transmission. Finally, we propose implementation principles centered on diagnostic stewardship, antimicrobial stewardship, local epidemiology and real-world cost-effectiveness evaluation. A scenario-driven top-pathogen strategy may provide a practical bridge between broad syndromic testing and precision infectious disease management in children. Full article

Imaging of infections has the potential to improve clinical outcomes, but pathogen-specific imaging strategies are currently unavailable. Given their target specificity, antimicrobials may be useful as molecular imaging ligands to target infections. Despite substantial development efforts, no antimicrobial-based ligands are approved for clinical use. This scoping review comprehensively surveys radiolabeled antimicrobials across antibacterial, antimycobacterial, antiviral, and antifungal drug classes, examining their progression through the translational pipeline. The review utilized PubMed and Google Scholar databases (1970–2025), following PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines. Two reviewers independently screened titles, abstracts, and full-text articles; data were extracted, and content duplicates were removed. In total, 143 preclinical and 25 clinical articles met the selection criteria. In clinical studies, most tracers showed suboptimal specificity for infections, while some proved useful for pharmacokinetic characterization. Among preclinical studies, radiolabeled plazomicin and echinocandins (caspofungin and anidulafungin) exhibited the greatest number of preferred characteristics. In conclusion, ideal antimicrobial pharmacologic properties can be counterproductive for imaging, where rapid background clearance and a high target-to-non-target ratio (T/NT) are essential. Many radioligands demonstrate good tissue penetration but suboptimal washout, limiting their diagnostic value. In vivo pharmacokinetic applications during active infections are promising, though significant challenges remain for infection imaging. Full article

Avian influenza virus (AIV), a zoonotic pathogen capable of cross-species transmission, poses a significant global health threat due to its rapid evolutionary adaptation. This review consolidates evidence from the past decade on AIV-autophagy interactions, emphasizing mechanistic insights and therapeutic potential. Research indicates that various AIV strains can trigger autophagosome formation via viral components, although the completeness of autophagic flux is not fully understood. These virus–host interactions are notably influenced by viral genotypes (e.g., H5N1 vs. H9N2) and host species (avian vs. mammalian). Current studies suggest that modulating autophagy may reduce AIV-induced acute lung injury, with pharmacological agents showing potential in mitigating inflammatory responses. We systematically explore three research areas: (1) strain-specific mechanisms of autophagy induction, (2) host-specific autophagic responses in poultry and human models, and (3) the therapeutic potential of stage-specific autophagy manipulation. This synthesis clarifies critical knowledge gaps, particularly the need for standardized autophagic flux assessment in avian cells, while providing a conceptual framework for developing autophagy-targeted strategies against AIV pathogenesis. Full article

DNA viruses rely extensively on host cellular machinery, including replication factors and transcriptional systems, to persist after infection. These mechanisms make studying and targeting DNA viral proteins challenging, as they also play key roles in mammalian processes. Traditional strategies include CRISPR-mediated gene disruption and small interfering RNA (siRNA) to target host proteins. However, Proteolysis Targeting Chimeras (PROTACs) offer a novel strategy by enabling the selective and rapid degradation of specific viral or host proteins involved in the DNA viral lifecycle. PROTACs are heterobifunctional molecules composed of three key components: a ligand that binds the target protein, a chemical linker, and a ligand that recruits an E3 ubiquitin ligase. By simultaneously binding both the target protein and the E3 ligase, PROTACs form a ternary complex. This proximity enables the E3 ligase to ubiquitinate the target protein, marking it for recognition and subsequent degradation by the intracellular proteasome. This approach represents a promising avenue for targeting previously undruggable proteins and improving therapeutic outcomes in virus-associated malignancies. In this perspective, we describe studies that use PROTACs as tools to modulate host proteins to investigate DNA viral processes with temporal control of host protein expression, as well as the use of PROTACs as antivirals to directly target DNA viral proteins. We also provide a detailed chart summarizing known host-targeting PROTACs and their potential applications across different stages of DNA viral lifecycles, highlighting opportunities for future DNA virus research. Full article