1 Introduction

Mosquito-borne viral infections, caused by pathogens such as dengue, Zika, chikungunya, and West Nile viruses, represent a significant global health challenge. These viruses are transmitted primarily through the bites of infected Aedes mosquitoes and can lead to severe health outcomes, including neurological disorders, congenital defects, and even death (Jackman et al., 2018; Baz and Boivin, 2019). The widespread prevalence of these infections, affecting hundreds of millions of people annually, underscores the urgent need for effective therapeutic interventions (Dong and Dimopoulos, 2021; Qian and Qi, 2022).

Despite the high morbidity and mortality associated with mosquito-borne viral infections, there are currently no clinically approved antiviral therapies available for their treatment. The development of antiviral drugs is crucial not only to alleviate the symptoms and reduce the severity of these infections but also to prevent their spread and reduce the economic burden on affected regions (Bouma et al., 2020; Celegato et al., 2023). Innovative therapeutic strategies, including the targeting of viral replication mechanisms and host factors, have shown promise in preclinical studies and offer hope for the development of broad-spectrum antiviral agents (Taguwa et al., 2019; Chen et al., 2020).

This study provides a comprehensive overview of the current status of antiviral drug development for mosquito borne virus infections, covering various strategies used in antiviral drug discovery and development, including virus protein targeting, host directed therapy, and the use of small molecule inhibitors. It focuses on the latest developments in this field, discusses the challenges faced in developing effective antiviral drugs, and proposes future research directions. This study aims to provide information and guidance for ongoing efforts to combat mosquito borne viral infections through the development of novel antiviral therapies.

2 Mechanisms of Mosquito-Borne Virus Infection

2.1 Virus entry and host cell tropism

Mosquito-borne viruses, such as dengue, Zika, and chikungunya, initiate infection by entering host cells through specific interactions with cellular receptors (Samuel et al., 2018). For instance, Zika virus (ZIKV) utilizes host Hsp70 isoforms to facilitate its entry and replication within human and mosquito cells, including neural stem cells and placental trophoblasts (Taguwa et al., 2019). Similarly, chikungunya virus (CHIKV) entry is influenced by serotonergic drugs, which inhibit the virus at early stages of the replication cycle, prior to RNA translation and genome replication. The blood-brain barrier (BBB) disruption is a common route for ZIKV to invade the central nervous system (CNS), leading to severe neurological manifestations (Figure 1) (Tan et al., 2022a).

Figure 1 The proposed mechanisms of ZIKV invasion into the central nervous system (CNS)  (Adopted from Tan et al., 2022a) Image caption: (1) Transcellular transport within endothelial cells of the BBB through infection or transcytosis mediated by ZIKV-induced degradation of Mfsd2a. (2) Paracellular trafficking of ZIKV across the blood–brain barrier (BBB) occurs through the upregulation of proinflammatory cytokines, chemokines, adhesion molecules and growth factors, and downregulation of tight junction proteins leading to alteration of the endothelial barrier integrity and permeability. (3) ZIKV-infected monocytes cross the BBB via the Trojan horse strategy. Once reach the CNS, ZIKV infects the brain cells, including astrocytes and microglial cells producing cytokines and chemokines leading to inflammation (Adopted from Tan et al., 2022a)

2.2 Replication and immune evasion

Once inside the host cell, mosquito-borne viruses replicate by hijacking the host's cellular machinery. ZIKV, for example, recruits Hsp70 isoforms to establish active replication complexes and assemble capsids, making it resistant to drug-resistant mutations. These viruses also employ various strategies to evade the host's immune response. Flaviviruses, including ZIKV and dengue virus (DENV), interfere with the type I interferon (IFN) response, a critical antiviral defense mechanism. They delay or prevent the establishment of an antiviral state by inhibiting IFN signaling pathways and the synthesis of interferon-stimulated genes (ISGs) (Zoladek and Nisole, 2023). ZIKV further antagonizes antiviral innate immune signaling pathways and modulates intrinsic antiviral responses such as nonsense-mediated mRNA decay and stress granule formation (Serman and Gack, 2019).

2.3 Pathogenesis and disease progression

The pathogenesis of mosquito-borne viral infections involves complex interactions between the virus and the host's immune system, leading to disease progression. For instance, ZIKV infection can result in neurological disorders and microcephaly due to its ability to invade neuronal cells and trigger neurotoxic mechanisms, leading to neurogenesis dysfunction and cell death. CHIKV causes acute febrile illness characterized by headache, rash, and debilitating polyarthralgia, which can persist for months to years (Bouma et al., 2020). The immune response to these infections often involves the production of antimicrobial peptides and the activation of RNA interference pathways, as seen in mosquito cells infected with insect-specific chimeric viruses (Tan et al., 2022b). These responses can inhibit subsequent pathogenic alphavirus replication, highlighting the potential for biological control measures against mosquito-borne viruses.

3 Strategies for Antiviral Drug Development

3.1 Targeting viral entry and replication

One of the primary strategies in antiviral drug development is to inhibit the entry and replication of viruses within host cells. This approach often involves targeting specific viral proteins or host cell pathways that are essential for the viral life cycle. For instance, small-molecule inhibitors targeting the interaction between flaviviral NS3 and NS5 proteins have shown broad-spectrum antiviral potential against dengue, Zika, and West Nile viruses by disrupting viral replication (Figure 2) (Celegato et al., 2023). Additionally, targeting viral entry mechanisms, such as clathrin-mediated endocytosis, has been effective in identifying compounds that block viral internalization and fusion, thereby reducing viral replication in vivo (Mazzon et al., 2019). Another promising approach involves the use of Lipid Envelope Antiviral Disruption (LEAD) molecules, which target the lipid membranes of virions, demonstrating broad antiviral activities against various mosquito-borne viruses (Jackman et al., 2018).

Figure 2  Structure-guided virtual screening of inhibitors of NS3-NS5 interaction (Adopted from Celegato et al., 2023) Image caption: (A) Analysis of NS3-NS5 interaction surface on NS5 of DENV, ZIKV, and WNV (PDB accession numbers are in panel B). The residues of NS5 involved in the interaction with NS3 are indicated. (B) Analysis of the similarity between flavivirus NS5 cavity B in terms of residue conservation (% of sequence identity) and the average distance between the atoms (RMSD, expressed in angstrom, Å) for both NS5 and the NS3-NS5 interface. Conserved residues are highlighted in bold. (C) Schematic workflow of the experimental approach followed for the virtual screening. (MM-GBSA, molecular mechanics energies combined with generalized Born and surface area continuum solvation, i.e., the method used to estimate the free energy of the binding of small molecules to NS5) (Adopted from Celegato et al., 2023)

3.2 Enhancing host immune responses

Enhancing the host's immune response is another critical strategy in antiviral drug development. This can be achieved by modulating host proteins and pathways that are involved in the immune response to viral infections. For example, drugs targeting host Hsp70 proteins have been shown to significantly reduce Zika virus replication by interfering with multiple stages of the viral life cycle, including entry and capsid assembly, without causing toxicity to host cells (Taguwa et al., 2019). Additionally, host-targeted therapies that optimize immune responses can be used in combination with virus-targeted therapies to provide a more comprehensive treatment approach (Rocha et al., 2017). Serotonergic drugs, which modulate host serotonin receptors, have also been identified as potential antivirals for chikungunya virus by inhibiting early stages of the viral replication cycle (Bouma et al., 2020).

3.3 Broad-spectrum antiviral approaches

Broad-spectrum antiviral approaches aim to develop drugs that are effective against a wide range of viruses, particularly those that share common features or utilize similar host pathways. One such approach involves targeting lipid metabolism, which is crucial for the replication of many flaviviruses, including Zika and dengue viruses (Foo et al., 2021). Inhibitors of lipid metabolism pathways, such as sterol regulatory element-binding proteins (SREBP) and acetyl-Coenzyme A carboxylase (ACC), have shown efficacy against multiple flaviviruses, highlighting their potential as broad-spectrum antivirals (Martín-Acebes et al., 2019). Another promising strategy is the use of host-targeting antivirals (HTAs) that inhibit universal host factors necessary for viral replication. For instance, inhibitors of human dihydroorotate dehydrogenase (DHODH) have demonstrated broad-spectrum antiviral activity by targeting a key enzyme in pyrimidine synthesis, which is essential for viral replication (Zheng et al., 2022). Additionally, natural products have been explored for their broad-spectrum antiviral properties, with some compounds showing the ability to block host factors critical for the replication of various viruses (Martinez et al., 2015).

4 Challenges in Antiviral Drug Development

4.1 Resistance to antiviral agents

One of the primary challenges in developing antiviral drugs for mosquito-borne viral infections is the emergence of resistance (Dong et al., 2018; Liu et al., 2024). Viruses such as dengue and Zika can rapidly mutate, leading to the development of drug-resistant strains. For instance, while targeting viral enzymes like NS3 and NS5 has shown promise, the propensity for these viruses to develop resistance remains a significant hurdle (Song et al., 2020; Celegato et al., 2023). Additionally, drugs targeting host factors, such as Hsp70 inhibitors, have shown reduced likelihood of resistance, but this approach is still under investigation (Taguwa et al., 2019).

4.2 Pharmacological and toxicological limitations

Pharmacological and toxicological limitations also pose significant challenges. Many potential antiviral compounds exhibit toxicity at effective doses, limiting their therapeutic window. For example, while Hsp70 inhibitors have shown efficacy in reducing Zika virus replication, their safety profile needs thorough evaluation to ensure minimal toxicity to host cells. Similarly, benzenesulfonamide derivatives targeting CaMKII have demonstrated antiviral activity against dengue and Zika viruses, but their pharmacokinetic properties and potential side effects require further optimization (Chen et al., 2020). The balance between efficacy and safety is crucial, and achieving this balance is often a complex and time-consuming process.

4.3 Economic and regulatory barriers

Economic and regulatory barriers further complicate the development of antiviral drugs. The high cost of drug development, coupled with stringent regulatory requirements, can delay the availability of effective treatments. The lack of specific antiviral agents for mosquito-borne diseases like dengue and Zika underscores the economic challenges faced by pharmaceutical companies (Baz and Boivin, 2019; Qian and Qi, 2022). Additionally, the need for extensive clinical trials to ensure safety and efficacy adds to the financial burden. Regulatory hurdles, including the approval process for new drugs, can also be lengthy and complex, further delaying the introduction of new antiviral therapies to the market (Saiz et al., 2018).

5 Case Study: Antiviral Drug Development for Dengue Virus

5.1 Overview of dengue virus and existing therapeutics

Dengue virus (DENV) is the most prevalent mosquito-borne viral disease globally, affecting approximately 2.5 billion people across over 100 countries (Obi et al., 2021). The virus is transmitted primarily by Aedes aegypti mosquitoes, leading to significant public health concerns due to its widespread geographic expansion. (Ashraf-Uz-Zaman et al., 2023) Despite the high incidence of dengue infections, there are currently no approved antiviral drugs specifically for treating dengue. The only available vaccine is limited to seropositive patients, making supportive care the primary treatment option. Research efforts have focused on targeting nonstructural proteins, particularly NS3 and NS5, due to their critical roles in viral replication. However, these efforts have yet to yield a successful antiviral drug.

5.2 A promising drug candidate

One promising candidate in the development of antiviral drugs for dengue is celgosivir, an α-glucosidase inhibitor. A phase 1b, randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of celgosivir in patients with acute dengue fever (Low et al., 2014). The study involved 50 patients who were randomly assigned to receive either celgosivir or a placebo. The primary endpoints were the mean virological log reduction (VLR) and the area under the fever curve (AUC). Although celgosivir was generally safe and well-tolerated, it did not significantly reduce viral load or fever burden compared to the placebo.

Another notable candidate is ivermectin, an antiparasitic drug that has shown efficacy in inhibiting the replication of all four dengue virus serotypes in vitro. A combined phase 2/3 randomized, double-blind, placebo-controlled trial demonstrated that a 3-day regimen of ivermectin accelerated the clearance of nonstructural protein 1 (NS1) antigenemia in dengue patients, although it did not significantly impact clinical outcomes (Figure 3) (Suputtamongkol et al., 2021).

Figure 3 Kaplan-Meier plots of fever clearance (A, B, C), dengue viremia clearance (D, E, F) and dengue NS1 antigenemia clearance (G, H, I) after enrollment compared between placebo (blue) and 3-day IVM (red) groups. Data were analyzed for all intention-to-treat participants (A, D, G). Subgroup analyses were done for patients who received the treatment within 72 hours after fever onset (B, E, H) and later than 72 hours after fever onset (C, F, I). P-values were calculated by log-rank tests. Abbreviations: IVM, ivermectin; NS1, nonstructural protein 1 (Adopted from Suputtamongkol et al., 2021)

5.3 Implications for other mosquito-borne viral infections

The development of antiviral drugs for dengue virus has broader implications for other mosquito-borne viral infections. For instance, the strategies and insights gained from targeting dengue virus can be applied to other flaviviruses such as Zika and West Nile viruses (Chuang et al., 2020). The discovery of small molecules that inhibit the interaction between flaviviral NS3 and NS5 proteins has shown potential for broad-spectrum antiviral activity against multiple flaviviruses (Celegato et al., 2023). Additionally, the use of Lipid Envelope Antiviral Disruption (LEAD) molecules has emerged as a promising approach to achieve broad antiviral activities against various mosquito-borne viruses (Jackman et al., 2018).

6 Future Directions in Antiviral Drug Development

6.1 Advances in drug discovery technologies

Recent advancements in drug discovery technologies have significantly accelerated the development of antiviral agents for mosquito-borne viral infections. High-throughput screening (HTS) methods have been pivotal in identifying numerous small-molecule inhibitors with potential antiviral activity against various mosquito-borne viruses, including dengue, Zika, and chikungunya viruses (Dong and Dimopoulos, 2021). Structure-guided drug design and virtual screening have also emerged as powerful tools, enabling the identification of compounds that target critical viral components, such as the NS3-NS5 interaction in flaviviruses (Celegato et al., 2023). Additionally, innovative approaches like Lipid Envelope Antiviral Disruption (LEAD) molecules have shown promise in broadly inhibiting mosquito-borne viruses by targeting viral membranes (Jackman et al., 2018).

6.2 Integration of multi-omics approaches

The integration of multi-omics approaches, including genomics, proteomics, and metabolomics, has opened new avenues for antiviral drug development (Xuan, 2024). These approaches facilitate a comprehensive understanding of the molecular mechanisms underlying viral infections and host-pathogen interactions. For instance, computational drug repositioning methods have been applied to identify potential antiviral compounds by analyzing omics data and projecting signature molecules onto human protein-protein interaction networks (Amemiya et al., 2021). This strategy has led to the identification of numerous drug candidates and target proteins for mosquito-borne viral infections, providing a robust framework for the development of novel antiviral therapies.

6.3 Collaboration and policy initiatives

Collaboration and policy initiatives play a crucial role in advancing antiviral drug development. Public-private partnerships, such as the Novartis Institute of Tropical Diseases (NITD), have been instrumental in driving research and development efforts for neglected tropical diseases, including dengue (Lim et al., 2013). These collaborations facilitate the sharing of resources, expertise, and data, thereby accelerating the discovery and development of effective antiviral agents. Additionally, policy initiatives aimed at fostering international cooperation and funding for research on mosquito-borne viral infections are essential for addressing the global health threat posed by these diseases. Enhanced regulatory frameworks and streamlined approval processes for antiviral drugs can further expedite the availability of new treatments.

7 Conclusion

The development of antiviral drugs for mosquito-borne viral infections has seen significant advancements, yet challenges remain. Current research highlights the global impact of mosquito-borne flaviviruses, such as dengue, Zika, and West Nile viruses, which affect millions annually and pose severe health risks. Despite the absence of commercially available specific antiviral agents, various strategies have been explored, including targeting viral components and essential host factors. Innovative approaches, such as Lipid Envelope Antiviral Disruption (LEAD) molecules and small-molecule inhibitors targeting viral protein interactions, have shown promise in preclinical studies. Additionally, host-directed therapies, including the use of serotonergic drugs and Hsp70 inhibitors, offer potential broad-spectrum antiviral effects.

Future research should focus on the continued exploration and optimization of broad-spectrum antiviral agents that can target multiple mosquito-borne viruses simultaneously. This includes further development of LEAD molecules and small-molecule inhibitors that disrupt critical viral protein interactions, as these have shown efficacy in both in vitro and in vivo models Additionally, the potential of host-directed therapies, such as those targeting Hsp70 and serotonergic pathways, should be further investigated to understand their mechanisms and improve their therapeutic indices. High-throughput screening methods and computational approaches should be leveraged to identify new antiviral candidates and optimize existing ones. Collaborative efforts between virologists, pharmacologists, and computational biologists will be crucial in accelerating the discovery and development of effective antiviral therapies.

The fight against mosquito-borne viral infections is far from over, but the progress made in recent years provides a solid foundation for future advancements. The integration of innovative therapeutic strategies, such as broad-spectrum antivirals and host-directed therapies, holds promise for the development of effective treatments. Continued research and collaboration are essential to overcome the challenges and ultimately reduce the global burden of these debilitating diseases.

Acknowledgments

We thank Mr. Jiang for helpful discussion and giving thoughtful and invaluable comments and feedback of this manuscript.

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

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