Search Results (420)

Rare actinomycetes have emerged as important yet underexplored reservoirs for the discovery of novel bioactive compounds. Microbispora, a genus of rare actinomycetes, is widely distributed across diverse ecological niches, including terrestrial soils, marine-associated environments, plant-associated ecosystems, and insect-derived environments. To date, 81 secondary metabolites have been reported from this genus, encompassing quinones, chromones and chromanones, macrolides, other polyketides, alkaloids, peptides and diketopiperazines, and miscellaneous structural classes. These metabolites display antimicrobial, anticancer, neuroprotective, antiviral, plant growth-promoting, and enzyme inhibitory activities. Beyond systematically cataloging these compounds, this review provides an integrated analysis of their structure–activity relationships (SAR), biosynthetic origins, and biological significance. In addition, the biosynthetic potential of Microbispora is discussed based on reported genomic studies, highlighting the presence of numerous predicted and poorly characterized biosynthetic gene clusters. This review provides an integrative perspective on Microbispora as an underexplored but promising source of structurally diverse and bioactive natural products for drug discovery. Full article

Chalcones are naturally occurring open-chain flavonoids widely distributed in plants and recognized for their broad spectrum of pharmacological activities. Their versatile scaffold allows for extensive structural modifications, leading to a diverse range of natural and synthetic derivatives with notable biological potential. In the context of viral infections, chalcones have demonstrated remarkable efficacy against a variety of human pathogens, including dengue virus, HIV, HCV, influenza A, SARS-CoV-2, and other emerging viruses. Beyond human health, several chalcones have shown potent activity against plant viruses such as tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV), and animal viruses including porcine reproductive and respiratory syndrome virus (PRRSV) and mammalian reovirus (MRV), underscoring their broad antiviral spectrum. These compounds act through multiple mechanisms, including the inhibition of viral enzymes (e.g., proteases, polymerases, and integrases), interference with viral entry and replication, and the modulation of host-related pathways. Recent advances in molecular docking, structure–activity relationship (SAR) studies, and synthetic optimization have further highlighted chalcones as a promising scaffold for antiviral drug discovery. Accordingly, this review summarizes and categorizes antiviral chalcones reported over the last two decades, emphasizing and critically discussing their molecular targets, mechanisms of action, and pharmacological potential as lead compounds. It also provides a comparative perspective on their pharmacological relevance by correlating their activities against standard therapeutic agents and reference inhibitors. Furthermore, the most recurrent viral targets were critically discussed regarding their conservation, expected genetic barriers to resistance, and the global SAR trends identified for the corresponding antiviral chalcones. Finally, in silico ADMET profiling of the most promising naturally occurring chalcones was performed to evaluate their drug-likeness and pharmacokinetic properties, offering guidance for future structural optimization and translational development. Collectively, these findings highlight the chalcone scaffold as a versatile platform for the development of novel antiviral agents targeting diverse viral and host pathways. Full article

Background: The development of multitarget drugs capable of simultaneously inhibiting SARS-CoV-2 proteases—3CL^pro and PL^pro—may enhance therapeutic efficacy against COVID-19. Given the historical use of Traditional Chinese Medicine (TCM) in the management of respiratory diseases, phenylethanoid glycosides (PGs) represent an attractive and chemically diverse natural product scaffold for the discovery of antiviral agents. Objectives: This study aimed to identify promising candidates within this class capable of simultaneously inhibiting both target proteases. Methods: The PG structures described in the literature between 1950 and 2020 were gathered and curated to construct a dedicated database, which was subsequently subjected to virtual screening. In silico ADMETox predictions and 2D ligand–protein interaction analyses were then employed to evaluate the identified hit PGs. Ligand stability within the binding sites of the proteases was further assessed using free energy landscape (FEL) and MM/GBSA calculations, while enzymatic inhibition of the commercial PG was evaluated via FRET assays. Results: Virtual screening identified 22 PGs with multitarget potential, predominantly sourced from Asia, followed by the Americas and Europe. The hit compound magnoloside I is found in Magnolia officinalis, a species widely used in TCM for respiratory conditions and officially prescribed during the COVID-19 pandemic. A second hit, calceolarioside B, inhibited more than 90% of the enzymatic activity of both proteases in the FRET assay. Conclusions: Together, these findings highlight phenylethanoid glycosides as promising scaffolds for dual protease inhibition. Full article

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV), members of the family Pneumoviridae, represent a foremost global cause of acute lower respiratory tract infection in infants, young children, the elderly, and immunocompromised individuals. Despite the recent approval of preventive vaccines and monoclonal antibody prophylactics targeting the viral fusion protein, no widely adopted, RSV-specific direct-acting antiviral is currently approved for routine post-infection treatment. The large (L) protein of the viral RNA polymerase complex, which catalyzes genome replication and mRNA transcription in concert with its obligate cofactor, the phosphoprotein (P), constitutes an ideal drug target owing to its essential and multifunctional enzymatic activities and its absence from host cells. Over the past decade, Cryo-electron microscopy (Cryo-EM) has yielded a series of landmark structures of Pneumoviridae L–P complexes, including apo forms of RSV (at 3.2–3.67 Å) and hMPV (at 3.7 Å) polymerases, among the first promoter-bound non-segmented negative-sense (nsNSV) RNA virus polymerase structures (at 3.40–3.41 Å), and inhibitor-bound complexes that illuminate the molecular basis of non-nucleoside inhibitor (NNI) action at sub-nanomolar potency. This review synthesizes the structural biology of Pneumoviridae RNA polymerases from a chronological and mechanistic perspective, compares RSV and hMPV L protein active sites at near-atomic resolution, and critically evaluates how structural insights are being translated into next-generation antiviral drug candidates, including nucleoside analog inhibitors, allosteric non-nucleoside inhibitors, and emerging candidates at various stages of preclinical and clinical investigation. Full article

The Oropouche virus (OROV), an orthobunyavirus primarily transmitted by the biting midge Culicoides paraensis, is the causative agent of Oropouche fever, a re-emerging arboviral disease associated with significant morbidity in Central and South America. The increasing frequency of outbreaks, including cases of sustained transmission in non-endemic regions and reports of vertical transmission, highlights the growing public health concern posed by OROV. Currently, there are no specific antiviral therapies or licensed vaccines available, underscoring the urgent need for effective therapeutic and preventive strategies. Recent advances in antiviral research have identified promising candidates, including repurposed drugs and bioactive compounds that target key stages of the viral replication cycle. In parallel, vaccine development has progressed through modern platforms, including viral vector-based and nucleic-acid-based technologies, enabling rapid responses to emerging outbreaks. However, major challenges remain, particularly due to the limited understanding of OROV pathogenesis, virus–host interactions, and the correlates of protective immunity. Furthermore, the ongoing evolution of OROV, including the genetic diversity and potential genomic rearrangements observed among circulating strains, represents an additional challenge that may influence viral characteristics and potentially affect the long-term efficacy of antiviral interventions and vaccine-induced protection. This review summarizes recent advances in the discovery of antiviral candidates and the development of vaccine approaches against OROV, both of which are essential for reducing the impact of OROV infections and strengthening preparedness for future outbreaks. Full article

The amide functional group remains a cornerstone of medicinal chemistry, serving as an indispensable scaffold in the design of modern therapeutics. This review presents an analysis of FDA-approved drugs (small molecules and peptides with MW < 1300 Da) containing amide functionality between 2021 and 2025, highlighting its continued and evolving role in addressing contemporary medical challenges. An analysis of these novel therapeutics reveals the remarkable functional versatility of the amide bond. In antiviral agents like nirmatrelvir (Paxlovid^®), amides form the structural backbone of peptidomimetics, enabling high-affinity binding to a viral protease. In precision oncology, as seen with adagrasib (Krazati^®), the amide acts as a critical, metabolically stable linker that positions a covalent warhead for selective inhibition of a mutant kinase. This analysis underscores that amide’s unique combination of planarity, resonance stabilization, and capacity for robust hydrogen bonding continues to make it an essential element in the medicinal chemist’s toolkit, underpinning the development of next-generation therapeutics across oncology, infectious diseases, and neurology. To provide a practical framework for drug discovery, the synthetic routes for each drug are detailed, with particular emphasis placed on the key amide-forming strategies employed. Full article

Emerging viral diseases continue to pose major challenges to global health, creating demand for materials that can support pathogen control, diagnosis, and therapy. Owing to their tunable structures and versatile biointerfaces, metal–organic frameworks (MOFs) have attracted increasing attention in anti-pathogen applications. While previous studies have often focused on individual functions such as catalysis, biosensing, or drug delivery, a broader perspective on the functional development of MOF-based systems remains limited. In this Review, we summarize recent advances in MOF-enabled pathogen inactivation, diagnostic biosensing, host-directed intervention, and virus-inspired therapeutic platforms. Emerging opportunities in antiviral drug discovery and artificial intelligence-assisted materials design are also discussed. In addition, key challenges associated with structural stability, biosafety, scalable fabrication, and clinical translation are highlighted. This Review provides an overview of current progress and outlines perspectives for the future development of MOF-based anti-pathogen technologies. Full article

For nearly a century, since the discovery of penicillin by Alexander Fleming, we have used covalent inhibitors as antimicrobial drugs. The success of penicillin in treating microbial infections led to numerous other antibiotics containing β-lactam, the reactive warhead that forms the covalent adduct, exemplified by later-generation cephalosporins with approvals into 2020. In parallel, early non-β-lactam covalent agents also emerged, extending covalent mechanisms beyond β-lactam antibacterials to antifungal, antiparasitic, and antiviral applications. Despite the successes of covalent mechanisms of action, there are still considerable safety concerns due to the possibility of off-target covalent adducts which may lead to significant side effects. This review provides an overview of non-β-lactam covalent antimicrobials across all major pathogen classes, organized by their warhead class, covalency, and resistance mechanisms, and outlines design and clinical-level mitigation strategies. We trace the field from the serendipitous discovery of penicillin to the intentional design of new drugs, with a discussion of changes in perception and evolution of technology that enable modern covalent drug design. Full article

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

The SARS-CoV-2 non-structural proteome remains the most clinically validated and strategically important landscape for direct-acting small-molecule antiviral drug discovery. The success of inhibitors targeting the main protease (M^pro, Nsp5) and RNA-dependent RNA polymerase (RdRp, Nsp12) has firmly established viral replication enzymes as tractable, druggable, and therapeutically relevant targets, while setting clear benchmarks for translational antiviral development. Building on this foundation, a second wave of non-structural protein (Nsp) targets has emerged with increasing translational promise, including the papain-like protease (PL^pro), the bifunctional Nsp14 proofreading and capping machinery, Nsp16 2′-O-methyltransferase, Nsp13 helicase, and Nsp15 endoribonuclease. In parallel, additional components such as Nsp1 and the Mac1 domain of Nsp3 continue to expand the antiviral design space, although they remain at earlier stages of chemical validation. In this review, we comprehensively assess SARS-CoV-2 non-structural proteins through a medicinal chemistry and translational lens, with an emphasis on structural tractability, mechanism of action, quality of chemical matter, cellular and in vivo antiviral evidence, evolutionary conservation, resistance liabilities, and developability. Particular attention is given to the features that distinguish tool compounds from genuinely actionable leads and to the opportunities for rational combination regimens that extend beyond first-generation protease- and polymerase-centred therapy. Collectively, the non-structural proteome offers the strongest foundation for next-generation and potentially broader-spectrum coronavirus antivirals with improved resilience to viral evolution. Full article

The shortage of effective chemotherapeutic agents poses a significant challenge to the global public health system. Cancer is among the leading diseases affecting the human population worldwide. Issues such as drug resistance, toxicity, lack of specificity, poor bioavailability and water solubility, and severe side effects reduce the effectiveness of many existing anticancer drugs. As a result, there is growing interest in discovering a new generation of therapeutic agents to overcome these limitations. Phenolic acids, including ferulic and caffeic acids, are cinnamic acid derivatives with numerous biological effects, including anti-inflammatory, antibacterial, antifungal, antioxidant, antiviral, cytotoxic, and antiproliferative effects. In recent years, drug repurposing and hybridization strategies have emerged as attractive approaches in medicinal chemistry because they may reduce both the cost and time associated with conventional drug discovery. As a result, several researchers have combined ferulic acid and caffeic acid scaffolds with different pharmacophores to generate hybrid compounds with enhanced anticancer potential. This review summarizes recent in vitro and in silico studies published between 2022 and 2025 on ferulic and caffeic acid hybrid compounds that exhibit cytotoxic and antiproliferative effects. Furthermore, the review discusses structure–activity relationship trends, synthetic approaches, and structural modifications associated with improved biological activity. Collectively, the findings highlight the significant potential of ferulic acid and caffeic acid scaffolds in the development of multifunctional anticancer agents. Full article

Protein–protein interactions (PPIs) are fundamental to viral replication, regulating processes such as assembly, genome packaging, and virion maturation. Despite their biological importance, these interactions remain challenging to study and are relatively underexploited as therapeutic targets. Split reporter systems, based on protein-fragment complementation, provide quantitative platforms to measure PPIs by reconstituting reporter activity when interacting protein partners are brought into proximity. These systems can be applied in vitro and in live cells which enables detection of dynamic and multimeric interactions in physiologically relevant contexts. Major classes of split reporter systems include β-lactamase, alkaline phosphatase, luciferase-based platforms, green fluorescent protein, and horseradish peroxidase. Assay performance depends on factors such as fusion protein stability, expression levels, and reporter kinetics, which influence sensitivity, dynamic range, and reliability. These approaches have been applied to study viral protein interactions across diverse systems, including HIV-1 matrix and nucleocapsid proteins, flaviviral capsid proteins, hepatitis B virus core protein, and chikungunya virus capsid. Split reporter assays also enable high-throughput screening for small-molecule inhibitors that disrupt viral PPIs and multimerization. This provides a functional readout linked to viral replication. Despite the challenges that exist in assay optimization and protein stability, the sensitivity and versatility of these systems provide a framework to interrogate viral protein interactions and support the development of antiviral therapeutics.: Full article

Enteroviruses are positive-sense single-stranded RNA viruses and common pathogens that are responsible for diverse public health diseases. To facilitate the study of the virus biology and pathogenesis of enterovirus, we developed a rapid method for construction of the enteroviral cDNA clones including enterovirus A71 (EV-A71) and coxsackievirus B5 (CVB5). As described for EV-A71, the full-length cDNA of CVB5 was amplified by long-distance PCR and cloned into a T7 promoter-containing plasmid using directional seamless cloning technology. The virus was successfully rescued by single transfection into cells stably expressing T7 polymerase and exhibited characteristics similar to the parental virus. Next, through systematic construction and the optimization of the EV-A71 and CVB5 reporter viruses, we successfully generated two novel reporter virus panels with high virus titers, rapid replication, and relatively stable genetic inheritance across passages using the new fluorescence proteins mScarlet3-H and the smallest miRFP670nano3. Analysis of critical determinants for the reporter virus construction revealed that reporter gene sizes, genomic insertion sites, and the usage of protease recognition sites are crucial parameters. The EV-A71 and CVB5 reporter viruses enable antiviral drug evaluation, as demonstrated by our identification of gemcitabine as a broad-spectrum inhibitor of both viruses. These systems also facilitate the functional interrogation of host factors, exemplified by our discovery that METTL3 promotes EV-A71 and CVB5 replication. These reverse genetic tools, including infectious cDNA clones and reporter viruses, will advance basic enterovirus biology and accelerate antiviral drug discovery. Full article

Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b continues to circulate globally across wild birds, poultry, and an expanding range of mammalian hosts, highlighting the need for antiviral strategies that address the animal–environment–human interface. The influenza A polymerase acidic (PA) endonuclease, a key enzyme in viral transcription, represents a conserved antiviral target across host species. In this study, we present a computational prioritization framework integrating homology modeling, molecular docking, molecular dynamics simulations, and physicochemical filtering to identify candidate PA endonuclease inhibitors relevant to a One Health context. Homology models of contemporary H5N1 clade 2.3.4.4b PA sequences were constructed based on the crystallographic template 6FS8 and used for cross-host docking against a targeted ligand library. Docking analysis identified baloxavir, a reference inhibitor, and entecavir, a nucleoside analog, as compounds of interest, with entecavir demonstrating favorable binding behavior, particularly in the poultry-associated model. Molecular dynamics simulations of the poultry PA–entecavir complex indicated stable interaction over 170 ns, supported by low structural deviation and favorable binding free energy (ΔG ≈ −85 kJ/mol). Physicochemical profiling suggested that entecavir possesses properties such as high polarity and predicted aqueous solubility, which were considered within the translational filtering step of this computational workflow. However, these properties do not establish antiviral efficacy or practical suitability for field use. The study provides a structured framework for integrating cross-host structural analysis with basic translational considerations, supporting the identification of candidate compounds for further biochemical and virological evaluation within the context of H5N1 control. Full article

Background: Hepatitis B virus (HBV) infection continues to be a major public health concern, especially in sub-Saharan Africa, where widespread epidemics and restricted availability of long-term antiviral therapies result in higher mortality and morbidity rates. Drug repurposing represents a strategic approach to accelerate the discovery of effective therapies by leveraging agents with demonstrated antiviral and immunomodulatory activity. Product Nkabinde (PN) is a patented African polyherbal formulation initially developed for the treatment of HIV. Recent experimental studies demonstrate PN’s potent anti-HIV activity and significant immunomodulatory effects in human immune cells, implicating host-directed mechanisms relevant to chronic viral infections. This study combines an integrative application of network pharmacology and molecular docking to evaluate the repurposing potential of PN as a multi-target agent in HBV. Method: Bioactive components of PN were screened, and compound-associated targets were intersected with HBV-associated genes (proteins) to construct a protein–protein interaction (PPI) network. Topological analysis identified 10 hub targets (STAT1, STAT3, SRC, HCK, EGFR, SYK, PIK3CA, PIK3CB, PIK3R1, and PTPN11). Gene Ontology and KEGG pathway enrichment were performed with an FDR cut-off < 0.05. Significantly enriched pathways included JAK–STAT signaling, chemokine signaling, EGFR-TKI resistance, PI3K complex signaling, and viral infection pathways, particularly those related to Kaposi sarcoma virus and HSV-1, indicating immunoregulatory and antiviral roles. Molecular docking was performed using AutoDock Vina 1.1.2 to evaluate binding affinity and interaction mode of key PN phytochemicals against the hub proteins, and results were compared to their respective co-crystallized ligands. Results: Molecular docking indicated that major phytochemicals from PN exhibited significant binding affinities across all 10 hub host targets, typically outperforming or closely matching their respective co-crystallized ligands. The strongest contacts were observed for β-sitosterol–PIK3CB (−14.2 kcal/mol) and oleanolic acid–SYK (−14.0 kcal/mol), which were significantly stronger than the co-crystallized ligands (−7.9 and −8.3 kcal/mol, respectively), indicating robust stabilization within catalytic and regulatory pockets. Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol) and PIK3CA (−9.5 vs. −7.3 kcal/mol), quercetin toward PIK3R1 (−10.6 vs. −8.2 kcal/mol) and PTPN11 (−9.2 vs. −7.5 kcal/mol), rutin toward SRC (−10.5 vs. 7.8 kcal/mol), and diosgenin toward EGFR (−9.4 vs. 8.4 kcal/mol). Procyanidin B2 maintained robust multi-hydrogen bonding networks, demonstrating significant binding, despite STAT1 and STAT3 docking showing identical affinities to co-crystals. Conserved hydrogen bonds, π–cation interactions, and significant hydrophobic packing at ATP-binding clefts and regulatory domains supported these interaction patterns, indicating competitive suppression of host signaling nodes taken over by HBV. Conclusions: Together, these results demonstrate that the components of PN possess strong multitarget binding capabilities across the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways, supporting their potential repurposing as host-directed HBV therapeutics with the ability to impede immune evasion, viral persistence, and HBV-associated oncogenic progression. Full article