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Since the infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China during December 2019, the coronavirus disease 2019 (COVID-19) has spread on a global scale, causing the World Health Organization (WHO) to issue a warning. While novel vaccines and drugs that target SARS-CoV-2 are under development, this review provides information on therapeutics which are under clinical trials or are proposed to antagonize SARS-CoV-2. Based on the information gained from the responses to other RNA coronaviruses, including the strains that cause severe acute respiratory syndrome (SARS)-coronaviruses and Middle East respiratory syndrome (MERS), drug repurposing might be a viable strategy. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Given that several currently marketed drugs may be efficient therapeutic agents for severe COVID-19 cases, they may be beneficial for future viral pandemics and other infections caused by RNA viruses when standard treatments are unavailable.

Currently, viral infection is the most serious health issue which causing unexpected higher rate of death globally. Many viruses are not yet curable, such as corona virus-2 (SARS-CoV-2), human immunodeficiency virus (HIV), hepatitis virus, human papilloma virus and so others. Furthermore, the toxicities and ineffective responses to resistant strains of synthetic antiviral drugs have reinforced the search of effective and alternative treatment options, such as plant-derived antiviral drug molecules. Therefore, in the present review, an attempt has been taken to summarize the medicinal plants reported for exhibiting antiviral activities available in Bangladesh along with discussing the mechanistic insights into their bioactive components against three most hazardous viruses, namely SARS-CoV-2, HIV, and HBV. The review covers 46 medicinal plants with antiviral activity from 25 families. Among the reported 79 bioactive compounds having antiviral activities isolated from these plants, about 37 of them have been reported for significant activities against varieties of viruses. Hesperidin, apigenin, luteolin, seselin, 6-gingerol, humulene epoxide, quercetin, kaempferol, curcumin, and epigallocatechin-3-gallate (EGCG) have been reported to inhibit multiple molecular targets of SARS-CoV-2 viral replication in a number of in silico investigations. Besides, numerous in silico , in vitro , and in vivo bioassays have been demonstrated that EGCG, anolignan-A, and B, ajoene, curcumin, and oleanolic acid exhibit anti-HIV activity while piperine, ursolic acid, oleanolic acid, (+)-cycloolivil-4′-O-β-d-glucopyranoside, quercetin, EGCG, kaempferol, aloin, apigenin, rosmarinic acid, andrographolide, and hesperidin possess anti-HBV activity. Thus, the antiviral medicinal plants and the isolated bioactive compounds may be considered for further advanced investigations with the aim of the development of effective and affordable antiviral drugs.

RNA viruses pose a persistent global threat due to their high mutation rates, zoonotic potential, and rapid adaptability. Emergence events have risen steadily, as demonstrated by major outbreaks caused by Influenza A, Ebola, Zika, and Chikungunya viruses, followed by the coronavirus epidemics of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-1) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and culminating in the COVID-19 pandemic. These characteristics frequently compromise the durability of existing vaccines and antiviral therapies, highlighting the urgent need for new antiviral agents. Alkaloids, a structurally diverse class of nitrogen-containing natural compounds, have gained attention for their ability to interfere with multiple stages of the viral life cycle, including entry, replication, protein synthesis, and host immune modulation. To our knowledge, this review compiles all currently reported alkaloids with antiviral activity against RNA viruses and summarizes their proposed mechanisms of action, distinguishing evidence from in vitro, in vivo, and in silico studies. Quaternary alkaloids are discussed separately because their permanent ionic charge enables distinctive interactions with membranes and host pathways. Although many findings are promising, clinical translation remains limited by incomplete mechanistic validation, scarce in vivo data, suboptimal bioavailability, narrow therapeutic windows, and inconsistent experimental methodologies. To advance the field, future research should prioritize RT-qPCR–based antiviral evaluation to accurately quantify viral replication, incorporate mechanistic assays to clarify modes of action, apply structure–activity relationship (SAR) approaches for rational optimization, and expand in vivo pharmacokinetic and efficacy studies to assess therapeutic feasibility. Overall, alkaloids represent a promising yet underdeveloped reservoir for next-generation antiviral discovery against rapidly evolving RNA viruses.

The COVID-19 pandemic showed that heterogeneous antiviral assay designs, endpoints and reporting practices can obscure which candidate drugs and combinations are genuinely promising. As antiviral discovery expands from acute infections to chronic and latent viral diseases, the field needs a compact, reproducible and biologically interpretable set of response metrics. In this Personal View, we argue that EC₅₀ and the selectivity index should be retained for pharmacological interpretation but systematically complemented by drug sensitivity scores (DSS), which integrate potency and efficacy across the tested concentration range, and by ΔDSS, calculated as DSS_antiviral minus DSS_toxicity from matched efficacy and viability curves. We propose standardized modules for resistance passaging, sequencing and host-side-effect profiling so that monotherapies are assessed not only for antiviral potency but also for durability and host-cell perturbation. For combinations, we discuss Bliss, ZIP, HSA and Loewe models as complementary tools for identifying additive or synergistic regimens while accounting for toxicity, resistance suppression and drug-drug interactions. Finally, we outline how harmonized metrics can support organoid, animal and clinical prioritization, improve machine-learning datasets and guide pandemic response, including rapid monotherapy testing for some DNA viruses and early combination testing for RNA and reverse-transcribing viruses.

Human Metapneumovirus (HMPV) is a major contributor to acute respiratory tract infections, particularly affecting children, the elderly, and immunocompromised individuals. Despite its global prevalence, no specific antiviral treatments or vaccines are available, highlighting the urgent need for effective therapeutic interventions. This study utilized a comprehensive computational drug discovery approach to identify potential inhibitors targeting the highly conserved nucleocapsid (N) protein of HMPV, a crucial component in viral replication and transcription. A virtual screening of 1,227 natural compounds from the NP-lib database was performed, identifying MOLPORT-001-742-110, MOLPORT-001-812-855, and MOLPORT-001-740-100 as the top candidates based on their docking scores and binding energies. The initial results were validated through re-docking, molecular interaction analysis, and molecular dynamics (MD) simulations. MOLPORT-001-742-110 demonstrated the highest stability with minimal deviations in Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) analyses, as well as a well-defined low-energy conformation in the Free Energy Landscape (FEL). Key hydrogen bonds and hydrophobic interactions were retained, reinforcing its strong binding affinity. Principal Component Analysis (PCA) and superimposition studies further supported the stability and adaptability of these compounds within the binding site. Comparative analyses with the control compound confirmed the superior inhibitory potential of the selected ligands, particularly MOLPORT-001-742-110. This study underscores the utility of computational approaches in identifying natural product-based inhibitors and provides a foundation for experimental validation and development of antiviral therapies against HMPV.

The constant emergence of new viral pathogens underscores the need for continually evolving, effective antiviral drugs. A key challenge is identifying compounds that are both efficacious and safe, as many candidates fail during development due to unforeseen toxicity. To address this, the embryonic zebrafish morphology, mortality, and behavior (ZBE) screen and the SYSTEMETRIC® Cell Health Screen (CHS) were employed to evaluate the safety of 403 compounds from the Cayman Antiviral Screening Library. Of these compounds, 114 were FDA-approved, 17 were discontinued, and 97 remained on the market. CHS identified 25% (104 compounds) as toxic, with a Cell Health Index™ (CHI) > 0.5. The embryonic zebrafish model identified an additional 20% as toxic (79), bringing the total to 183. ZBEscreen flagged 19 toxic hits among compounds still on the market, seven of which were also identified by CHS. The combined use of CHS and zebrafish models enhanced hazard detection. Together, CHS and ZBEscreen identified 45.5% of the library as potentially hazardous. Notably, the zebrafish non-hazardous compounds correlated strongly with over-the-counter or prescribed antiviral drugs, confirming their known safety profile. Over 130 hazard-associated compounds warranted further investigation. Using self-organizing maps, six distinct neighborhoods of compound similarity were identified. This dual approach streamlined the early detection of hazards associated with promising leads and is expected to facilitate faster, safer antiviral discovery.

The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for antivirals that are resilient to resistance. Current Food and Drug Administration (FDA)-approved therapies primarily target single viral mechanisms, leaving gaps in efficacy. Here, we developed a Deep Learning-based Activity Screening Model (DLASM), which integrates graph convolutional network with machine learning to identify SARS-CoV-2 inhibitors, using experimental 3-chymotrypsin-like (3CL) main protease assay data. The optimized DLASMs virtually screened ~170,000 compounds from diverse in-house collections and yielded novel hits, several of which not only inhibited the 3CL protease but also blocked viral entry by interfering with heparan sulfate-mediated host interactions. These activities were validated through multiple assays, including 3CL enzymatic inhibition, SARS-CoV-2 pseudotyped particle entry, α-synuclein fibril uptake as a proxy for endocytosis, live virus cytopathic effect, heparan sulfate-dependent entry assay, and a 3D human lung mucociliary tissue model. Molecular docking studies elucidated binding modes at the 3CL protease active site, while molecular dynamics simulations provided insights into compound–heparan sulfate interactions. The identified compounds represent early-stage hits with moderate potency that demonstrate dual-mechanism antiviral activity. Together, these findings establish dual-target inhibition as a promising antiviral strategy, offering not only enhanced potency but also reduced risk of resistance. Moreover, our DLASM framework provides a generalizable pipeline for identifying chemically diverse scaffolds and for broader applications beyond SARS-CoV-2.

West Nile virus (WNV) is an emerging mosquito-borne pathogen and is posing significant global health challenge through climate change. WNV, transmitted between birds and Culex mosquitoes, has significantly expanded northward in recent years, leading to outbreaks across Europe and North America. This review explores the recent advancements and therapeutic strategies targeting WNV’s structural and non-structural (NS) proteins, which play critical roles in viral replication and pathogenesis. Promising candidates include peptide-based inhibitors, monoclonal antibodies, and small molecules that disrupt protein-protein interactions. Most of current findings are derived from in silico methods or in vitro assays, with limited validation through in vivo studies. Although no vaccines are currently available for humans, several have been approved for horses, and development efforts are ongoing. The growing threat of WNV underscores the urgent need for validated antiviral therapies and scalable vaccines, especially considering its increasing geographic range and public health impact.

Background. To date, a number of human pathogenic viruses are still unaddressed by the current repertoire of approved antiviral drugs. In order to widen this spectrum of preventive measures against virus infections, we have focused on additional host targets that exert interesting virus-supportive functions. Inhibitors of cyclin-dependent kinase 8 (CDK8) have been found to exhibit highly pronounced and relatively broad antiviral activity. Objectives. The current research question concerning the potential for broad-spectrum antiviral drug activity should be addressed in detail to understand the mechanistic basis of the antiviral target function of CDK8. Materials and Methods. We established and specifically customized six assay systems, three of these newly developed for the present study, to corroborate the range of CDK8 inhibitors’ antiviral activity against four α-, β-, and γ-herpesviruses as well as two non-herpesviruses. Results. Similar to our earlier analysis of CDK7 and CDK9 inhibitors, the clinically relevant CDK8 inhibitors currently in use demonstrated antiherpesviral activity in cell-culture-based infection models. Interestingly, the antiviral efficacy against various human and animal cytomegaloviruses was particularly strong at nanomolar concentrations, whereas other herpesviruses or non-herpesviruses showed an intermediate or low sensitivity to CDK8 inhibitors. Thus, this approach provided novel insights into the inhibitory potential of the CDK8 inhibitors, such as CCT-251921, MSC-2530818, and BI-1347, when analyzed against equine herpesvirus 1 (EHV-1, α-herpesvirus), human herpesvirus 6A (HHV-6A, β), Epstein–Barr virus (EBV, γ), murine herpesvirus 68 (MHV-68, γ), vaccinia virus (VV, non-herpes DNA virus), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, non-herpes RNA virus). Conclusions. Our results confirm that drug sensitivity to CDK8 inhibitors, on the one hand, is very strong for certain viruses and, on the other hand, varies widely within the spectrum of viruses and host cell types analyzed. This suggests that CDK8 may play several different roles in viral replication. The option of a refined CDK8-specific antiviral drug targeting is discussed.

Dengue virus is one of the most significant emerging viruses that cause dengue fever, dengue hemorrhagic disease and dengue shock syndrome, threatening one-third of the world’s population. There are currently no vaccinations or antiviral therapies available for this disease. Dengue virus protease (NS2B-NS3pro) is a therapeutic target since it is essential for viral processing and replication. The study aimed to describe an in-silico analysis to uncover efficient Dengue virus inhibitors. In this work, we used computer-assisted virtual screening, ADMET and molecular dynamics-based analysis focus using the NS2B-NS3 protease to find effective Dengue virus inhibitors. Through literature mining, forty-seven phytochemicals from Artocarpus heterophyllus (Jackfruit) were retrieved and screened against the targeted protein. According to their binding free energy in MM-GBSA, Oxidihydroartocarpesin (-36.19 kcal/mole), Cyanomaclurin (-34.09 kcal/mole) and Dihydromorin (-32.44 kcal/mole) were expected to be potent inhibitors of the NS2B-NS3 protease. These ligands showed several noncovalent interactions with the catalytic triad (His51-Asp75-Ser135), required for the target protein inhibition. Notably, the ligand-bound complexes exhibited lower RMSD values (≈ 0.18–0.25 nm) compared to the apo protein (≈ 0.30 nm), indicating enhanced structural stability upon ligand binding. RMSF analysis further demonstrated reduced flexibility around the catalytic residues His51, Asp75, and Ser135 in the presence of the selected phytochemicals, while stable radius of gyration and solvent-accessible surface area profiles confirmed compact and well maintained protein-ligand conformations throughout the simulation period. Additionally, the ligand-bound systems maintained a consistent radius of gyration (~ 1.85–1.90 nm) and sustained an average of 3–6 intermolecular hydrogen bonds throughout the simulation, further supporting the structural integrity and dynamic stability of the complexes relative to the apo form. As a consequence, our computational analysis may be useful in the future development of Dengue Virus inhibitors.