Precision repurposing of clinically characterized molecules targeting dengue virus RNA-dependent RNA polymerase: an in silico identification and in vitro validation.

Repurposing of DrugBank small molecules against Dengue virus capsid protein: an in silico study

Inhibitors of the Influenza Virus Polymerase Basic 2 (PB2): Recent Advances and Future Perspectives.

Influenza, an acute respiratory infectious disease caused by influenza viruses, poses a serious public health threat with high infectivity and virulence. Existing antivirals suffer from numerous limitations, such as the frequent emergence of drug resistance and inconvenient administration, highlighting the urgent need for the development of next-generation anti-influenza agents. As a core component of the RNA-dependent RNA polymerase (RdRp) complex, the PB2 subunit mediates cap binding in the cap-snatching process, a prerequisite for viral mRNA transcription. Owing to its indispensable biological roles, high sequence conservation, and distinct structural differences from host proteins, PB2 serves as an attractive therapeutic target for antiviral drug development. Recently, the approval of onradivir, the first-in-class PB2 inhibitor, has not only validated the scientific rationale and feasibility of drug discovery targeting the PB2 subunit but also underscored the considerable clinical potential of this novel class of agents. In this review, we systematically summarize the research advances in PB2 inhibitors and discuss the challenges and prospects for their broader clinical application, with the aim of providing new insights into the development of novel anti-influenza drugs.

Targeting Dengue Viral Proteins with Eco-Friendly Nanotechnology: A Promising Path for Antiviral Research

Dengue virus (DENV), a mosquito-borne pathogen belonging to the Flaviviridae family, continues to be a major global public health concern, causing millions of infections annually across tropical and subtropical regions. The virus encodes both structural and non-structural proteins that play critical roles in its replication, assembly, and immune evasion. Despite substantial research progress, there is still no specific antiviral drug available, and current treatment remains primarily supportive. This review highlights the significance of DENV structural proteins (C, prM/M, and E) and non-structural proteins (NS1–NS5) as potential molecular targets for antiviral interventions. Green-synthesized silver, gold, and iron oxide nanoparticles have demonstrated strong inhibitory activity against DENV by targeting key viral proteins such as the envelope (E), NS3 protease/helicase, and NS5 RNA-dependent RNA polymerase. These nanoparticles interfere with viral entry, replication, and protein synthesis while exhibiting high biocompatibility and minimal cytotoxicity. Collectively, the findings discussed in this review underscore the promise of eco-friendly nanotechnology as a sustainable and effective platform for developing next-generation antiviral therapies against dengue virus.

Target-Based Antiviral Drug Development Against Human Respiratory Viruses

Human respiratory viruses represent a major global health burden, causing millions of severe infections and deaths annually. Despite the central role of vaccines in prevention, their limitations, such as incomplete coverage, waning immunity, and vulnerability to viral evolution, underscore the urgent need for effective antiviral therapeutics. This review examines the principles and applications of target-based antiviral drug development against human respiratory viruses, emphasizing the identification and exploitation of conserved viral and host targets. Key viral proteins, including RNA-dependent RNA polymerases, proteases, and fusion glycoproteins, are analyzed across major virus families such as coronaviruses, paramyxoviruses, and adenoviruses, highlighting their structural features, functional constraints, and therapeutic potential. We further explore the integration of high-throughput screening and rational drug design, supported by advances in structural biology, cryo-electron microscopy, and computational approaches, including artificial intelligence-driven drug discovery. These methodologies collectively enhance the precision and efficiency of antiviral development. However, significant challenges remain, particularly the conflict between viral mutation and target conservation, the rapid emergence of drug resistance, and the safety limitations of host-targeted therapies. Finally, we discuss emerging strategies to overcome these barriers, including combination therapies and the development of broad-spectrum antivirals targeting conserved molecular mechanisms. This paper highlights a framework for the rational design of durable antiviral interventions capable of addressing both existing and emerging respiratory viral threats.

Structural biology of the dengue virus NS2B-NS3 protease as a target for antiviral drug development.

Dengue is the most common global problem in recent times, particularly in tropical and subtropical areas, yet antivirals for therapy or prophylaxis are lacking. Millions of people are affected by this dengue virus, but no proper medication is available yet to cure this disease. One polyprotein that is encoded by the DENV genome is converted into structural and non-structural proteins that are necessary for viral pathogenesis and replication. Among these, the non-structural protein complex NS2B-NS3 is essential for viral polyprotein processing, replication, and host innate immune response control. It acts as a trypsin-like serine protease. The NS2B/NS3 protease is a key enzyme involved in viral replication and serves as a major target for drug development against the dengue virus. The NS3 protease has a conserved catalytic triad (His-Asp-Ser), whereas NS2B serves as an essential cofactor that stabilizes the active conformation of the enzyme and aids in substrate recognition. By disrupting interferon signalling pathways, the NS2B-NS3 protease not only aids in viral replication but also makes immune evasion easier. The compound that inhibits the action of this enzyme could be pioneering in the antiviral drug discovery process. This article provides a comprehensive overview of the detailed structural information of the viral protease (NS2B/NS3) enzyme with the mechanistic role of this enzyme, and highlights various inhibitors related to the NS2B/NS3 protease. A more thorough comprehension of this protease could facilitate the logical development of potent antiviral medications to prevent dengue infection.

Dengue Virus Molecular Targets and Antiviral Drug Development: Advances, Challenges and Therapeutic Perspectives

Dengue is the most prevalent arboviral disease in tropical and subtropical regions, with over 13 million cases recorded in the Americas in 2024. Despite its enormous public health impact, no specific antiviral therapy is currently approved for dengue virus (DENV). In this context, this narrative review critically analyses the principal molecular targets of DENV, including structural proteins (C, prM/M and E), nonstructural proteins (NS1–NS5) and host factors, with emphasis on the development of small‐molecule antivirals and an evaluation of their progress in pre‐clinical and clinical studies. The NS2B–NS3 protease complex and NS5 (both RdRp and MTase domains) remain the most extensively explored targets, owing to the availability of high‐resolution crystal structures and higher inter‐serotype conservation. NS4B has emerged as the most clinically advanced target. Among direct‐acting antivirals, AT‐752 was also discontinued due to low viraemia at enrolment, while NITD‐688 remains among the most advanced pipeline molecules. Host‐directed therapies including anakinra and baricitinib are under clinical investigation for severe dengue. Key translational challenges include viral serotype diversity, pharmacokinetic limitations, cytotoxicity, and the timing of treatment initiation relative to viral kinetics. Advances in rational drug design, drug repurposing, allosteric inhibition, and targeted protein degradation (PROTACs) offer renewed perspectives for effective dengue therapeutics.