Common Challenges to the Development of Novel Antivirals to Tackle Re-emerging Infections of Pandemic Potential

Yu Wu MD^1#, Shuo Hu MBA^2#, Feng Liu MD^3*

¹Department of Clinical Laboratory and Blood Transfusion, Chinese People's Liberation Army Joint Logistic Support Force 908 Hospital, Nanchang, Jiangxi, 330002, China

²Department of Innovation and Development, Shanghai SPSENS Technology Co., Ltd., Shanghai 200131, China

³Department of Scientific Research, Beijing Fresta Technologies Co, Ltd., Beijing 100176, China

*Corresponding Author: Feng Liu, Department of Scientific Research, Beijing Fresta Technologies Co, Ltd., Beijing 100176, China.

^#The authors contributed equally to this study.

Received: 26 February 2026; Accepted: 03 March 2026; Published: 11 March 2026

1. Introduction

Virus infections continue to emerge and evolve at an alarming rate [1]. They have huge capacity to cause widespread morbidity and mortality, exemplified by their high levels of transmissibility, zoonotic reservoirs, and ability to genetically adapt to therapy (Figure 1). All of which pose challenges to traditional containment and therapeutic strategies [2].

Figure 1: Current and largest know threats of a global pandemic. Exemplar Viruses related to those discussed in this review are highlighted.

The discovery of effective antiviral interventions is central to mitigating the imminent threat of a global pandemic. The most effective antiviral drugs have focussed on virus-specific processes, resulting in agents with a potent but narrow-spectrums of activity and vulnerability to resistance [3]. Recent advances in molecular techniques, structural biology approaches (crystallography and CryoEM), and computational drug design, have enabled more targeted strategies to combatting virus infections [4]. Herein, we use four exemplar viruses (Herpeviruses, DENV, Ebola virus and influenza virus) to discuss current problems, areas of promise and the next stages required for effective antiviral drug development.

Figure 2: Key stages of Global pandemic preparedness. These encompass effective surveillance and detection, accurate risk assessment to guide planning strategies, stockpiling of antiviral agents, preparation of health systems for larger patient numbers and clear and effective delivery of health care programs.

Significant challenges remain for antiviral drug development. High mutation rates in viruses, the complexity of host-virus interactions, and the balance between safety and efficacy underscore the importance of a multi-pronged approach. The unpredictability of viral emergence means that world-class genomic surveillance is needed, combined with rapid risk assessment and health system prepardness (outlined in Figure 2). This combined with global collaboration and scalable treatment/response platforms represents the most effective route to effective drug development [5].

In this review, we discuss current strategies in antiviral development for exemplar viruses (Herpesviruses, DENV, Ebola virus and Influenza virus), highlight key scientific and logistical challenges that remain with their treatment, and provide pan-viral recommendations for strengthening pandemic preparedness through collaborative research and drug discovery innovation.

2. Virus

2.1 Herpesviruses

Herpesviruses are a large family of enveloped, double-stranded DNA viruses with complex lifecycles (Figure 3). This includes persistence in hosts [6]. Importantly, Herpesviruses are considered a re-emerging pathogen due to the increase in prevalence of factors that trigger their reactivation from a latent (resting) to lytic (active) state [7]. Up to nine virus genotypes are known to infect humans. These include Alphaherpesvirinae (HSV-1, HSV-2, VZV), Betaherpesvirinae (CMV, HHV-6/7), and Gammaherpesvirinae (EBV, HHV-8) [8]. HSV-1 currently infects ~65% of individuals under 50; HSV-2 infects ~13% of adults aged 15–49 [9]. Both are epidemiologically correlated [10]. Regarding diseases spectrum, HSV-1 and HSV-2 are associated with genital lesions, cold sores, keratitis and encephalitis. This can be fatal in neonates [11]. VZV is associated with varicella (chickenpox) and reactivation as shingles, frequently with postherpetic neuralgia [12,13]. EBV and HHV-8 lead to Burkitt lymphoma (fast growing high grade non-Hodgkin lymphoma), nasopharyngeal carcinoma and Kaposi’s sarcoma [14]. HCMV in healthy adults shows limited symptoms but can cause congenital defects in immunocompromised patients [15]. Most infections are asymptomatic but virus shedding can still occur which facilitates transmission. During the lytic phase, virus replication occurs in epithelial cells resulting in virion production. During the latent phase, viruses persist but with restricted gene expression. Reactivation (and its associated disease pathology), can occur at any time [16].

Figure 3: Summary of the proposed therapeutic solutions for Ebola Virus, Influenza Virus, Dengue Virus and Herpesviruses.

Current diagnostics include RT-PCR of blood, cerebrospinal fluid, and mucocutaneous swabs. Multiplexed platforms that detect HSV-1, HSV-2, VZV, CMV, and EBV are also available [17]. Triplex and multiplex PCR panels also show utility for cases where the clinical presentation overlaps among HSV, VZV, and related viruses, allowing tailored antiviral therapy and infection-control [18].

2.1.1 Current treatment regimens and emerging antiviral resistance

Standard antiviral regimens for herpesvirus include (but are not limited to) the nucleoside analogues acyclovir, valacyclovir (prodrug of acyclovir), and famciclovir [19]. Helicase-primase inhibitors including pritelivir can disrupt the unwinding/priming process crucial for HSV replication and are showing promise as a potential therapeutic. Whilst all improve symptoms, they fail to clear persistent and latent infections. A major problem is the emergence of resistant strains. These are common in immunocompromised populations, particularly transplant recipients, HIV-positive patients and those undergoing extended treatment/therapy. Resistance primarily maps to both DNA polymerases and/or virus encoded kinases [20], exerting structural changes that reduce drug efficacy. Ongoing public health concerns due to virus-associated stigma and increased HIV risk, particularly with genital herpes also remain significant hurdles for successful antiviral campaigns [21].

2.1.2 Limitation of treatments and gaps in current approaches

Treatment limitations, latency, resistance, and the lack of an effective vaccine underscore the complexity of treating herpesvirus infections [22]. Acyclovir targets the DNA polymerase but face resistance issues as a monotherapy. Recent structural studies have begun to add important information into the 3D design of novel antiviral agents. Approaches of interest include knowledge of the assembly pathway (scaffold proteins and procapsid intermediates) that may be amenable to disruption with small molecules; the heterogeneity in capsid structures which may limit pan-viral approaches, glycoprotein structures that can reveal druggable opportunities to perturb virus-host cell engagement and fusion and high-resolution structures of the helicase-primase complex (UL52, UL8) that continue to shed light on the mechanisms controlling the initiation of replication [23].

Research into vaccine development has been extensive and prolonged, but with limited success due to failures in clinical trials. Current advances in this area focus on the induction of polyfunctional antibody responses, enhancing T-cell immunity and the delivery of antiviral agents via AAV approaches (Figure 4). The next stages for anti-herpesvirus therapies should aim to target both latency and resistance. This can be supported by further clinical trials for more effective prophylactic and therapeutic vaccines, increased epidemiological surveillance to track evolving transmission trends and high-risk demographics and a specific focus on patient genetics and at-risk individuals, most notably on resistant infections in immunocompromised and neonatal populations.

Figure 4: Advantages and limitations of current and emerging antiviral drug strategies.

2.2 Dengue Virus

Dengue virus (DENV) is a single-stranded, +ve-sense RNA virus in the Flaviviridae family. It circulates as 4 serotypes (DENV-1 to DENV-4) that are transmitted by Aedes aegypti and Aedes albopictus mosquitoes (Figure 3). These vectors drive is emergence due to a complex interplay of climate change, urbanization, and increased global travel that has extended their global habitat and ability to transmit disease. DENV is endemic in ≥ 100 countries with a total of ~390 million infections occurring annually, causing a massive disease burden [24]. The virus is the major cause of Dengue fever, typically presenting as fever, headache and myalgia [25]. DENV causes haemorrhagic fever and dengue shock syndrome in severe cases, both of which can be fatal. A continual problem is DENV-mediated antibody-dependent enhancement, caused by previous infections with another DENV serotype that leads to more severe disease upon the second round of infection with another serotype [26]. The economic impact of DENV is also significant due to high rates of hospitalization and a loss of productivity due to DENV-mediated illness in endemic regions [27].

DENV lacks an effective vaccine. Dengvaxia was licensed but its use is limited to seropositive individuals as the risk of severe disease is high in seronegative recipients [25]. Cross-serotype immunity also remains a significant hurdle to DENV treatment. The picture for antivirals is similarly limited. Current patient management in DENV infected individuals involves hydration and monitoring [28]. Antivirals can be administered but often from an experimental standpoint. Mosnodenvir is an exemplar of a drug that shows some promise, but is not effective enough for widespread treatment [29]. Human challenge studies have reported a dose-dependent reduction in infection rates of ~60% with accompanying decreases in circulating DENV RNA [24]. Its mechanism of action involves inhibition of the viral NS3–NS4B interaction that is essential for virus replication. Diagnosis and rapid treatment also remains an issue as early symptoms present as febrile illness. Scalable and deployable diagnostics that accurately detect DENV infection remain lacking in many endemic regions. Current diagnostics include a combination of RT-PCR, NS1 detection, and serological assays for IgM/IgG antibodies. The selected test can vary dependent on the stage of infection [30]. During acute infection (up to 10 days), DENV RNA is detectable in the serum and NS1 can be identified via ELISA. At later stages of infection, IgM and IgG antibodies increase and their detection forms part of the diagnostic arm. Cross-reactivity with other flaviviruses can however complicate interpretation. Multiplexed platforms, biosensors and NGS all represent emerging technologies that offer hope for early detection during any future outbreak [31].

The next stages for DENV includes the advancement of NS3 protease and NS5 polymerase targeting therapeutics, by analogy to the success of these approaches for other flaviviruses (Figure 4). Combination therapy involving pairing host-targeted therapies with DAAs would also offer hope for resistance and improve outcomes. Exemplars include UV-4B (32), endosome acidification (chloroquine), and intracellular lipids (lovastatin, prednisolone).

Broad-Spectrum antivirals that target conserved processes of flavivirus replication such as fusion inhibitors and glycan-binding molecules also offer attractive treatment options. RNA-based therapeutics including oligonucleotides that target DENV genomes are also emerging, however these require improvements in delivery systems (nanoparticles and lipids) to ensure stability and tissue targeting. Immune pathway modulators and the use of cyclophilins to target the host factors required for DENV replication also offer hope for combination approaches.

2.2.1 Remaining challenges for DENV

• • Safety and mitigating ADE mitigation.
• • Rapid diagnostics for timely therapeutic intervention.
• • Global collaboration: Clinical trials, surveillance, and further focus on resistant infections in immunocompromised and neonatal populations.

2.3 Influenza virus

Influenza viruses remain the most persistent global pandemic threat due to the high prevalence of zoonotic reservoirs, high mutation rates, and capacity for rapid global transmission (Figure 3) [33,34].

Pandemic preparedness for influenza relies on vaccine readiness and antiviral stockpiling. The WHO plays a central role in monitoring circulating strains in both humans and animals, enabling early detection of those with pandemic potential (35). Surveillance is complemented by preparedness at a national level.

Despite advances in both the treatment of control of Influenza virus, preparedness remains challenging due to limited manufacture of vaccines, antigenic shift, and low access to antiviral countermeasures [34]. This highlights the importance of non-vaccine interventions as first-line tools in pandemic response (Figure 4).

Current antiviral strategies include Neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, and laninamivir) that inhibit viral assembly and release. All have been used to combat seasonal and pandemic influenza cases [36]. If administered early after infection, all can reduce disease severity, but resistance has emerged, most notably for seasonal H1N1 [37].

Polymerase-targeting antivirals have expanded the treatment landscape. These include Baloxavir marboxil, a cap-dependent endonuclease inhibitor that targets PA and effectively reduces viral loads [38]. Resistance-associated PA substitutions are however emerging [39]. Current priorities are for pan-spectrum antivirals that retain activity across influenza subtypes. The Influenza RDRP is highly conserved across strains, making it an attractive target for next-generation nucleoside and non-nucleoside inhibitors [40]. Pan-strain activity is desirable as it can provide protection against antigenic drift and shift compared with virion targeted agents.

As for DENV, combination therapy has also been explored. Whilst clinical studies combining baloxavir with NAIs have failed to show improvements for severe influenza, this remains an approach of interest for patients with high viral loads and resistant strains [41]. Vaccination remains the main method for influenza prevention, but their production early in a pandemic is challenging. Stockpiling a range of antiviral agents all with novel mechanisms of action to widen efficacy and reduce the likelihood of the emergence of resistance remains a key strategic priority [34,42].

Current influenza virus diagnostics rely on rapid influenza diagnostic tests (RIDTs), molecular assays and RT-PCR. RIDTs can detect influenza A and B as a fast point-of-care diagnostic. Sensitivity and false negatives remain common issues. Emerging platforms such as the cobas® Liat multiplex PCR assay can simultaneously detect influenza A, influenza B, SARS-CoV-2, and RSV. Microfluidic assays that detect viral proteins at zeptomolar concentrations can further enhance early detection and hold promise for point-of-care influenza diagnostics [43].

Rapid clinical trial networks to evaluate therapeutics during outbreaks and global equity frameworks for access to antivirals and vaccines early in a pandemic remain the key approaches for Influenza virus. Together, these aim to build a resilient and flexible antiviral arsenal of drugs and vaccines capable of mitigating the impact of future influenza pandemics.

2.4 Ebola Virus

Ebola virus (EBOV) part of the Filoviridae family, genus Ebolavirus, is a non-segmented, negative-sense RNA virus for which six species are known; namely Zaire ebolavirus (lethal), Sudan ebolavirus, Bundibugyo ebolavirus, Taï Forest ebolavirus, Reston ebolavirus, and Bombali ebolavirus [44]. It is spread through direct contact with blood, or contaminated surfaces [45]. Key reservoirs include fruit bats. Clinically, EBOV causes severe haemorrhagic fever leading to multi-organ failure and high rates of death (Figure 3). This can be as high as a 90% fatality rate for some outbreaks [46]. Challenges with EBOV include outbreaks frequently occurring in resource-limited settings that makes containment challenging. Current treatments include cocktails of monoclonal antibodies (Ebanga and Inmazeb), but these are expensive and access is limited [47]. Remdesivir has shown some efficacy (though limited) in clinical trials. Regarding vaccine development, rVSV-ZEBOV is effective but cold-chain issues present a logistical challenge with coverage during outbreaks remaining sporadic. Delayed detection due to outbreaks in remote locations and the lack of rapid, point-of-care diagnostics are further issues. Current diagnostics include RT-PCR as the gold standard due to its ability to detect viral RNA within the first few days of infection [48]. The Xpert Ebola Test and FilmArray Biothreat-E can inform infection status within 2 hours, supporting rapid clinical decision in the advent of an outbreak. Lateral flow antigen assays are increasingly used for point-of-care screening and can detect EBOV proteins within 15–30 minutes, though their sensitivity is lower than PCR. Serological assays to detect IgM/IgG antibodies can be complementary for surveillance and are detectable approximately 7 days post-symptom onset. Used together, these diagnostics provide a layered strategy for outbreak control, but RT-PCR remains essential for definitive diagnosis [49].

Socioeconomic and cultural factors including a lack of trust in healthcare systems and cultural burial practices that enhance virus spread also hinder containment. Emerging political instability and conflict zones are now further complicating EBOV response efforts [50].

Other issues include virus persistent virus in survivors (immune-privileged sites such as the eyes and testes and genetic variability that can affect vaccine and therapeutic efficacy.

3. Broad-Spectrum Antivirals and their Associated Challenges

3.1 Production of Synthetic Carbohydrate Receptors

Synthetic Carbohydrate Receptors bind to viral surface glycans and can block virus entry and replication, including SARS-CoV-1/2, MERS, Nipah, Hendra and Ebola viruses. In recent in vivo studies, mouse models of COVID-19 showed ~90% survival with a single-dose of Synthetic Carbohydrate Receptor treatment.

3.2 Virus Polymerase Inhibitors (DNA and RNA viruses)

Broad-acting antiviral agents that target viral RNA-dependent RNA polymerases (RdRp) and viral DNA polymerases remain a therapeutic strategy to combat numerous viral infections. Polymerases offer an attractive broad acting target as they are highly conserved across viral families and are essential for viral genome replication. They are also sufficiently distinct from host polymerases that therapeutics can be selective, thereby avoiding host toxicity [51].

For RNA viruses, including human respiratory syncytial virus (RSV), influenza virus, and coronaviruses, the RdRp is central to virus replication. Due to the structural conservation of the catalytic core, inhibitors of RdRps often show cross-family activity, making them candidates for broad-spectrum antiviral development [51,52]

Examples include Nucleoside and non-nucleoside inhibitors such as remdesivir, favipiravir, ribavirin, and baloxavir marboxil, all of which inhibit viral RNA synthesis through chain termination, delayed termination, or disruption of polymerase complex assembly [40,53]. All show antiviral activity against RSV, influenza A and B viruses, and multiple coronaviruses, including SARS-CoV-2 and MERS-CoV [40,53].

An additional feature that make RdRp inhibitors attractive antiviral targets are their ability to evade immune-based interventions, highlighting their use in pandemic preparedness and as a front line therapeutic to limit virus spread in the face of a potential outbreak [54]. Structural and mechanistic studies further demonstrate that both active-site and allosteric RdRp inhibitors can suppress replication across phylogenetically diverse RNA viruses [52].

Viral DNA polymerases are similarly well-validated antiviral targets for DNA viruses and contain conserved catalytic motifs that support targeted development of inhibitors with a broad range of activity [52].

Non-Nucleoside and nucleoside analogues show efficacy against a range of DNA viruses through targeting the DNA polymerase, most notably in immunocompromised populations for which resistance is a common theme [42]. Recent structural enablement of viral polymerases (CyroEM approaches most notably) have provided mechanistic insight into polymerase inhibition and resistance mechanisms. It is hoped that this information can inform the design of next-generation broad-acting therapies [55].

Viral polymerases offers multiple strategic advantages for therapies including their broad-spectrum antiviral coverage, low levels of resistance and utility as combination therapies. Polymerase complexes in RNA viruses cap their mRNAs to enhance translation and evade host innate immune sensors. The inhibition of viral MTases prevents both translational efficiency and immune masking, impacting virus fitness and highlighting the attractiveness of this approach. Structural studies have shown for coronaviruses nsp14 and nsp16 (both MTases) perform the latter stages of capping, using S-adenosyl-L-methionine (SAM) as the methyl donor. Nsp10 acts as an essential co-factor for nsp16 and can modulate nsp14 activity, highlighting further potential for druggability. For Ebola virus, the L protein possesses capping and MTase domains with emerging high-resolution structural information revealing a series of novel features for replication competence and immune escape.

3.3 RNA-Based Therapies & Biologics

RNA-based therapies and biologics are attractive as they can be programmed against novel sequences, can act intra- and extracellularly and can modulate host defences. As priorities shift towards platforms that can be adapted across pathogens, they may be central to anti- pandemic strategies [56].

Neutralizing mAbs engage viruses to prevent attachment/fusion and can recruit Fc-mediated effector functions. These hold value as post-exposure prophylaxis and early treatment regimens, particularly for those who are immunocompromised and respond poorly to vaccines [42,57]. For EBOV, a randomized PALM trial showed that survival could be enhanced with mAb114 and REGN-EB3, establishing mAbs as life-saving therapy in high-risk areas [58]. A key limitation of antibody therapies is antigenic drift, highlighting the need for cocktails, careful and conserved epitope selection, and Fc-engineering for improved functionality [57].

3.4 Small interfering RNAs and CRISPR-based Approaches

siRNAs harness endogenous RNA interference to degrade target viral RNAs with sequence precision. A key advantage is their ability to be rapidly re-designed against conserved virus regions [42,59]. Although approved for non-infectious indications, RNAi use for viruses is limited [56]. The major obstacle is delivery to the site of infection whilst evading immune sensing. Advances in delivery mechanisms (lipid nanoparticles, conjugates, and chemical modifications) offer hope for improved tolerability and pharmacology [56].

RNA-targeting CRISPR systems can be programmed to directly cleave viral RNA genomes even in the face of virus mutation and evolution [60]. This can enable rapid retargeting to new viral variants and/or latent reservoirs, a major problem with current HIV therapeutics. Challenges however remain, including targeted in vivo delivery, stability, and limiting off-targets effects. All encompass active areas of research [60].

4. Summary of Challenges and Future Outlook

The ability of viruses to adapt and evolve often outpaces a single-target antiviral therapeutic. The variability is driven by high mutation rates due to error-prone polymerases, large viral population sizes and reservoirs that “bounce back” following treatment and selective pressure under treatment. Numerous examples of this evolution are evident, including influenza (NA inhibitors), HIV monotherapies, HCV and SARS-CoV-2 monoclonal antibodies. For all examples, resistance-associated mutations have arisen within months of widespread useage.

Resistance can be mitigated through structure-based drug design and combination regimens that targets variable virus processes. The ability to identify conserved catalytic or allosteric domains that impose high fitness costs on resistance mutations, e.g. polymerase and cap-methyltransferases for RNA viruses, offer a therapeutic avenue for pan-viral approaches [61]. HIV is an example of successful combination therapy whereby the likelihood of virus escape is minimised through synergistic or additive antiviral agents (6, 41). This combined with host-directed agents likely offers the most rationale path to the maintenance of clinical efficacy against evolving and newly emerging pathogens.

Acknowledgments

None.

Funding

None.

Conflicts of Interest

None.

Highlights:

• • We highlight a roadmap of the current challenges with antiviral drug discovery.
• • We discuss current shared approaches, novel and emerging strategies.
• • We provide recommendations to strengthen global health resilience.

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