Aug 2026· Viruses· Vol 18· 0 citations· 161 references
Medicine
TL;DR
This review discusses selected RNA viruses, focusing on the structure of their RNA polymerases and interactions with host factors during the different stages of the viral lifecycle, as well as the traditional antivirals targeting these structures and pathways.
Abstract
Highly pathogenic RNA viruses, such as Ebola, SARS-CoV-2, and influenza, cause severe disease in humans. High mutation rates, which enable RNA viruses to evade immunity and escape antivirals, and their ability to spread from animals to humans and cause pandemics and outbreaks, make RNA viruses significant threats to public health. Diseases caused by Ebola, SARS-CoV-2, and influenza are prevented and treated with only a limited number of approved antiviral drugs, the effectiveness of which is limited by mutations in the viral targets. It is crucial to understand the structural determinants, molecular mechanisms, and host interactions of pathogenic RNA viruses to develop effective antiviral strategies. In this review, we discuss selected RNA viruses, focusing on the structure of their RNA polymerases and interactions with host factors during the different stages of the viral lifecycle, as well as the traditional antivirals targeting these structures and pathways. Furthermore, emerging concepts such as liquid–liquid phase separation and biomolecular condensates, and novel promising antiviral strategies are discussed. Understanding shared and distinct structures, molecular mechanisms, and host interactions across highly pathogenic RNA viruses enables the discovery of new and more effective antiviral strategies, ultimately improving clinical outcomes against evolving RNA viruses.
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.
Xinru Zhang, Heng Jia, Xianglong Wang et al.· ACS Infectious Diseases· 0 citations
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.
S. Samrat, Gauri Srivastava, Ran Zhang et al.· Pathogens· 0 citations
Respiratory viral infections caused by seasonal influenza, respiratory syncytial virus (RSV), and pandemic-potential coronaviruses are responsible for several million hospitalisations and an estimated several hundred thousand deaths each year, a burden underscored by the severe 2024–2025 influenza season and the continued emergence of zoonotic threats such as clade 2.3.4.4b H5N1. This review critically examines the pharmacological basis for targeting host cell-surface receptors as a strategy for the treatment and prophylaxis of respiratory viral infections, evaluates the current evidence for each major receptor axis, and identifies the key translational gaps that must be addressed. Respiratory viruses, including influenza, RSV, SARS-CoV-2, and MERS-CoV, collectively cause millions of hospitalisations annually, and the persistent challenges of antigenic drift, zoonotic emergence, and antiviral resistance highlight the need for mechanistically distinct strategies. Host-directed therapies (HDTs) targeting conserved receptors (ACE2, DPP4, sialic acids, TMPRSS2) exploit genetically stable host factors required for viral entry. Across the receptor axes reviewed here, we appraise more than a dozen candidate agents spanning preclinical development through Phase III evaluation, including TMPRSS2 inhibitors, soluble ACE2 decoys, anti-CD147 and receptor-blocking monoclonal antibodies, the sialidase fusion protein DAS181, and avian IgY preparations. This evidence reveals a consistent gap between robust preclinical activity and as-yet-limited clinical efficacy. We conclude that host receptor targeting is a mechanistically rational but still clinically unproven component of the respiratory antiviral landscape; its value is most plausibly realised in defined niches—prophylaxis, early outpatient treatment, and combination with direct-acting antivirals—and within pandemic preparedness frameworks, provided that the safety, delivery, and trial-design challenges identified here are resolved.
Sherif A. El-Kafrawy, Norah A. Othman, M. Zeyadi et al.· Frontiers in Cellular and In...· 0 citations
A programmable RNA-targeting antiviral platform based on RfxCas13d is developed and its activity in avian cells is evaluated, establishing RfxCas13d as a versatile RNA-guided antiviral platform and providing a foundation for cross-strain influenza control through conserved RNA targeting.
Sudip Dhakal, Aaron J. Smith, Emiliana Weiss et al.· npj Antimicrobials and Resis...· 0 citations
Hantaviruses are zoonotic RNA viruses belonging to the family Hantaviridae, primarily transmitted to humans through rodent reservoirs. These viruses cause two major clinical syndromes in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). Due to their high mortality rates, potential for global spread, and the lack of specific antiviral therapies, hantaviruses are regarded as significant public health threats. In recent years, advances in molecular virology, immunology, structural biology, and vaccine technologies have provided important insights into hantavirus pathogenesis and host–virus interactions. Current research has increasingly focused on host-targeted antiviral strategies, TFEB-mediated lysosomal degradation mechanisms, monoclonal antibody therapies, and mRNA-based vaccine platforms. In addition, advanced molecular diagnostic methods and metagenomic surveillance systems have improved opportunities for early diagnosis. This review comprehensively summarizes the current literature regarding the epidemiology, virology, pathogenesis, immune responses, clinical manifestations
Çağnur Elpen Kodaz· Eurasian Journal of Medical...· 0 citations
Human norovirus (HuNoV) is a leading cause of acute viral gastroenteritis worldwide and represents a major unmet challenge in antiviral drug and vaccine development. HuNoV is a non-enveloped, positive-sense RNA virus characterized by extensive genetic diversity and rapid evolution, which contribute to recurrent outbreaks in the absence of effective licensed therapeutics. Despite substantial progress in understanding HuNoV molecular biology, effective antiviral strategies remain limited, in part due to historical limitations in experimental model systems and the virus’s ability to evade host antiviral responses. Recent advances in HuNoV in vitro culture systems, particularly human intestinal enteroids, and inhibitor screening platforms have improved the identification of antiviral candidates, while parallel efforts in vaccine development have yielded immunogenicity data in preclinical and early-stage clinical studies. However, significant challenges persist, including antigenic diversity, strain-specific immunity, and limited correlates of protection. This review provides a critical analysis of the molecular mechanisms governing HuNoV infection, immune evasion, and replication, with a focused emphasis on key antiviral targets, inhibitory strategies, and therapeutic development. Moreover, this review outlines key limitations and future directions for the development of effective therapeutic and preventive measures against HuNoV infection.
Sadia Islam, Sabbir Zia, Simonto Mirza et al.· Therapeutic Advances in Infe...· 0 citations
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