Viral-host molecular interactions and metabolic modulation: Strategies to inhibit flaviviruses pathogenesis

Abstract

Flaviviruses, which include globally impactful pathogens, such as West Nile virus, yellow fever virus, Zika virus, Japanese encephalitis virus, and dengue virus, contribute significantly to human infections. Despite the ongoing emergence and resurgence of flavivirus-mediated pathogenesis, the absence of specific therapeutic options remains a challenge in the prevention and treatment of flaviviral infections. Through the intricate processes of fusion, transcription, replication, and maturation, the complex interplay of viral and host metabolic interactions affects pathophysiology. Crucial interactions involve metabolic molecules, such as amino acids, glucose, fatty acids, and nucleotides, each playing a pivotal role in the replication and maturation of flaviviruses. These viral-host metabolic molecular interactions hijack and modulate the molecular mechanisms of host metabolism. A comprehensive understanding of these intricate metabolic pathways offers valuable insights, potentially unveiling novel targets for therapeutic interventions against flaviviral pathogenesis. This review emphasizes promising avenues for the development of therapeutic agents that target specific metabolic molecules, such as amino acids, glucose, fatty acids, and nucleotides, which interact with flavivirus replication and are closely linked to the modulation of host metabolism. The clinical limitations of current drugs have prompted the development of new inhibitory strategies for flaviviruses based on an understanding of the molecular interactions between the virus and the host.

Key Words: Flavivirus; Nonstructural proteins; Virus-host interaction; Metabolism; Inhibitors; Vaccines

Core Tip: Targeting host metabolic molecules and interactions shows promise for combating flavivirus infections but has limitations such as potential off-target effects, disruption of essential cellular functions, and virus resistance. A viral-host interactome can elucidate complex interactions, guiding anti-flavivirus drug and vaccine development. By inhibiting metabolic signaling, researchers can disrupt viral replication, entry, and assembly, increasing the likelihood of effective antiviral agents. This approach is key for developing treatments despite its challenges.

INTRODUCTION

Flavivirus, now designated as the genus Orthoflavivirus, exhibits global distribution, and its transmission over the past few decades has been remarkable[1]. The genus Flavivirus comprises more than 50 viruses, including West Nile virus (WNV), yellow fever virus (YFV), Zika virus (ZIKV), Japanese encephalitis virus, and dengue virus (DENV), all of which are highly infectious to humans[2]. According to the World Health Organization, half of the world’s population is at risk of DENV infection, which carries a higher mortality rate compared with that of other flaviviral infections[3]. Flaviviruses cause up to 400 million infections per year and lead to critical forms of disease, including fatal hemorrhage, encephalitis, and death[3]. Despite the considerable impact of flaviviral infections on human health, only a limited number of vaccines are available, and no specific antiviral therapies have been identified for any flavivirus[4]. Thus, there is an urgent need to understand host-virus interactions to develop specific anti-flavivirus therapeutics.

Typically, flaviviruses interact with host cells by manipulating cellular and molecular mechanisms to create a favorable environment for replication. Following infection, flaviviruses can significantly modulate all classes of host metabolic pathways[5]. They initially engage through protein-protein interactions, manipulating the host's crucial cellular and molecular metabolic pathways, especially those involved in carbohydrate (glucose and glutamine), lipid (fatty acids), and nucleotide metabolism, to enhance their replication and maturation[5-9]. Targeting the interface between flaviviruses and host cellular metabolic interactions represents a potential strategy for antiviral interventions, elucidating viral pathology and fostering the development of therapeutic agents. Specifically, the inactivation of targeted metabolites by inhibitors holds promise for the development of antiviral agents. Consequently, there is a pressing need to develop therapeutics that effectively target and inhibit the essential metabolic mechanisms underlying viral replication and maturation.

Here, we explore flavivirus-host interactions to highlight potential inhibitors targeting metabolic molecules at the cellular and molecular levels, aiming to advance flavivirus therapeutics. For this purpose, we discuss potential strategies targeting viral-host metabolic interactions to inhibit flavivirus pathogenesis.

VIRUS-HOST MOLECULAR INTERACTIONS AND METABOLISM

Flavivirus structural features

Flaviviruses are icosahedral and characterized by a positive-sense, single-stranded RNA (approximately 11 kb), enclosed within a nucleocapsid. The nucleocapsid is further surrounded by the envelope glycoprotein E (53 kDa) and membrane protein M (8 kDa). The M protein is a small proteolytic fragment of its precursor form, prM (approximately 21 kDa), which is anchored to the viral membrane via two transmembrane helices. The genome contains a 5′ untranslated region and a singular open reading frame, which includes signals necessary for viral translation and replication, and concludes with a type 1 cap structure. Notably, the 3′ untranslated region harbors signals for replication and RNA synthesis but lacks a poly(A) tail. The single open reading frame undergoes translation into a polyprotein, which is subsequently cleaved to generate 10 viral proteins. The capsid, pre-membrane, and envelope proteins constitute the viral capsid shell that encapsulates the viral RNA genome, while seven nonstructural (NS) proteins-NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5—play critical roles in viral genome replication and polyprotein processing (Figure 1).

Figure 1 Flavivirus structural features. NS: Nonstructural.

NS1 exists in diverse oligomeric forms, including an endoplasmic reticulum (ER) membrane-bound form within the larger viral replication complex, and a soluble secreted hexametric form implicated in viral immune evasion[10]. Membrane-associated proteins, such as NS2A, NS2B, NS4A, and NS4B, likely serve as scaffolds for assembling the viral replication complex on the ER membrane. NS2A contributes to the assembly of infectious virions, whereas NS2B acts as a cofactor for NS3 protease activity[11]. NS4A participates in membrane rearrangement during viral replication, and NS4B modulates host responses to facilitate viral replication. Notably, NS3 and NS5, which exist in a free form, exhibit enzymatic activities that are crucial for viral RNA synthesis. NS3, a multifunctional protein, comprises an N-terminal protease and a C-terminal helicase domain with 5′ RNA triphosphatase, nucleoside triphosphatase, and helicase activities[12]. NS5, the largest flaviviral protein, contains an RNA-dependent RNA polymerase, which is vital for viral replication and transcription[13]. NS1 has the highest number of interactions with host proteins, followed by NS3 and NS5, making them promising candidates for anti-flaviviral therapies. The aldehyde form of the tripeptide phenacetyl-Lys-Lys-Arg-CHO has demonstrated inhibitory activity against the WNV NS2B-NS3 protease[14]. Flaviviruses can significantly modulate all classes of host metabolites, including proteins, carbohydrates, lipids, and nucleotides, during entry, transcription, replication, and maturation, as discussed in the upcoming section[15].

Lifecycle of flavivirus

The flaviviral lifecycle begins when the virus enters cells through receptor-mediated endocytosis. Inside the cell, in a slightly acidic environment, the viral membrane fuses with the cell membrane, releasing its genetic material. This genetic material is then utilized by the cells to produce various viral proteins through a series of steps (Figure 2).

Figure 2 Flavivirus mechanism of infection to host cell. PH: Pondus hydrogenii; DC-Sign: Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin.

In the cytoplasm, the viral genetic material is translated into a polyprotein, which is then inserted into the cell membrane. Both host and viral proteases cleave this polyprotein into structural and NS proteins. The NS proteins form a complex responsible for viral replication. As the virus replicates, it creates structures called replication organelles (ROs) and vesicle packets (VPs) within the ER[13]. These structures shield the virus from the cytoplasm. The viral genetic material is then transported to an assembly site, where the viral capsid protein accumulates on lipid droplets and combines with the genetic material. Other viral proteins are recruited to the assembly site, where the entire structure buds into the ER, forming an immature virion. These virions accumulate in the ER before being transported through the host secretory pathway[16]. Mature viruses can be released as free virions or enclosed within membranes derived from cellular structures called autophagosomes. These membrane-enclosed forms may contain a lipid bilayer derived from the host cell and represent variations in the virus.

Following fusion, the positive-stranded RNA genome is released into the cytoplasm and used to produce a viral polyprotein[17]. This polyprotein is then cleaved into structural and NS proteins by both host and viral proteases. The polyprotein is synthesized in the ER and relies on the ER membrane protein complex for proper folding and stable expression[4]. NS viral proteins, along with host proteins, cause significant changes in the ER, forming ROs and VPs. Within these ROs, the positive-sense RNA serves as a template for the viral polymerase NS5 to generate an intermediate negative-sense RNA. This negative-sense RNA is then used to produce positive-sense progeny RNA, either for incorporation into new viral particles or for further translation. Progeny viral RNA is encapsulated in immature virions that form within VPs in the rough ER, adjacent to the ROs. Recent findings suggest that specific ER proteins, known as atlastins, play a central role in inducing membrane remodeling for RO formation, viral replication, and viral assembly. The newly synthesized capsid protein, along with the structural prM and E proteins, is recruited to VPs. These proteins assist in the budding of the nucleocapsid into the ER, and viral NS3 recruits host endosomal sorting complexes required for transport machinery to release immature virions into the ER[4]. These immature virions are then transported and secreted into the extracellular space (Figure 2).

The biogenesis of ROs and VPs is tightly regulated by NS viral proteins to prevent innate immune activation and ER stress while securing the necessary energy and membrane resources. Viruses exploit cellular lipid metabolism, with viral proteins influencing processes, such as fatty acid and cholesterol synthesis. These pathways are crucial for efficient viral replication. The final steps of flaviviral assembly and secretion involve multiple exit strategies. Immature viral progeny accumulate in the ER cisternae before undergoing maturation, which includes the cleavage of prM, glycosylation, and ubiquitylation of the E protein. Mature viral progeny exit the cell through various routes, including the host secretory pathway and the secretory arm of autophagy. Although the exact mechanisms are not fully understood, recent studies have provided insights into alternative exit routes and their potential implications for tissue tropism and immune evasion[2,4,17]. Several questions regarding the viral lifecycle remain unanswered, such as the mechanisms of RO biogenesis. In vitro reconstitution using liposomes and a combination of host and viral factors is needed to gain further insights into the lifecycle of other positive-sense RNA viruses.

Resistance mechanisms of flaviviruses

Flaviviruses exhibit several resistance mechanisms that enable them to evade the effects of antiviral drugs and vaccines, thereby complicating their treatment. One primary mechanism is the mutation of viral targets, such as RNA polymerase, which reduces the efficacy of antiviral drugs, including ribavirin and favipiravir[18]. Alterations in viral entry mechanisms due to mutations in viral proteins can render entry inhibitors less effective, thereby challenging the prevention of viral infection in its initial stages[19]. Flaviviruses can also upregulate their replication pathways by increasing the expression or activity of proteins involved in replication to counteract the inhibitory effects of antiviral drugs. Evasion of the host immune response is another critical resistance mechanism. Flaviviruses can evolve to avoid detection and destruction by immune cells, thereby diminishing the effectiveness of immunomodulatory therapies. Furthermore, continuous exposure to antiviral agents can lead to the selection of viral strains that evade adaptive immune responses, such as those induced by vaccines[20]. These adaptive immune escape mechanisms highlight the dynamic nature of flaviviral evolution and the ongoing challenges in developing effective, long-lasting therapeutic and preventive measures.

STRATEGIES TO INHIBIT FLAVIVIRUSES PATHOGENESIS

Flavivirus-host protein-protein metabolism interactions and associated therapeutics targets

Flaviviral infection begins with receptor-mediated interactions with host cells. The interaction between the flavivirus and the host involves protein-protein interactions, which facilitate the fusion of the viral envelope with the host cell membrane. For instance, WNV and ZIKV interact through the heparan sulfate proteoglycan (HSP) receptor, YFV interacts with the dendritic cell (DC)-specific intercellular adhesion molecule-3-grabbing non-integrin receptor, and DENV interacts with both DC-specific intercellular adhesion molecule-3-grabbing non-integrin and HSP receptors[21]. In addition, each flavivirus interacts with specific host cells, allowing it to enter and replicate. WNV, ZIKV, and Japanese encephalitis virus interact with neuronal cells, YFV interacts with macrophages and DC, and DENV interacts with monocytes, macrophages, and DC[15]. Understanding cellular tropism—the affinity for specific cell types and receptor interactions of flaviviruses—is a crucial step in developing antiviral therapies.

The molecular mechanisms underlying viral fusion triggers are not yet fully understood, but it is known that histidine residues on the E glycoprotein interact with host cell protein receptors and have been proposed as prime candidates to act as pondus hydrogenii (pH) sensors (at pH 6.0) to initiate the fusion process[6,15]. The E protein contains five histidine residues that are conserved among all flaviviruses: two in domain I, H146 and H323; two in domain II, H248 and H287; and one in the stem region, H438[22]. At low pH, these histidine residues trigger conformational changes that expose the amino acid residue of the E protein, allowing fusion of the virus with the host cell. This fusion permits the viral genome to enter the cytoplasm of the host cell and initiate infection. Mutational analysis of the conserved histidine residues in domains I and III among all flavivirus E proteins has provided evidence that H323 is an important residue for initiating the low-pH-dependent multistep fusion process[17]. In addition, the host receptor HSP, identified as an attachment factor for several flaviviruses, has been shown to inhibit flavivirus replication (Figure 3)[21].

Figure 3 Flavivirus-host metabolic interaction and associated therapeutics targets. Protein-protein metabolic interaction, carbohydrate metabolic interaction, lipid metabolic interaction, nucleotide metabolic interaction associated therapeutic strategy. PH: Pondus hydrogenii; DC-Sign: Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; FASN: Fatty acid synthase; ATP: Adenosine triphosphate; COA: Coenzyme A; TCA: Tricarboxylic acid; SCD: Sperm chromatin dispersion; SFA: Saturated fatty acid; MUFA: Monounsaturated fatty acid; CPT: Camptothecin; HMG: 3-hydroxy-3-methylglutaryl.

Flavivirus-host carbohydrate metabolism interactions and associated therapeutic targets

Flaviviral infection modulates carbohydrate metabolism, particularly glucose and glutamine utilization, to meet the increased energy demands required for optimal viral replication. Following successful entry into host cells, viruses raise their energy requirements. Infection leads to elevated cellular glucose concentrations, likely resulting in increased expression of glucose transporter 1 and hexokinase 2, the initial enzymes involved in glycolysis[22]. Limited glucose availability significantly impedes viral replication, whereas restricted glutamine exerts only a modest effect on viral replication, and glutaminase inhibition disrupts glutamine conversion. Glycolytic stimulation induced by flaviviruses may enhance various processes, including the production of glutamine, to increase adenosine triphosphate and nucleotide pools. Additionally, the production of citrate, a precursor of fatty acid synthesis, is enhanced. Inhibiting the key enzymes involved in glycolysis or disrupting glucose uptake by virus-infected cells can hinder viral replication.

Many viruses utilize host cell-surface carbohydrates as receptors for entry, where viral envelope proteins interact with specific carbohydrates on the cell surface to initiate the infection process. Carbohydrate inhibitors disrupt various stages of the viral lifecycle, including entry, attachment, and fusion. Carbohydrate-receptor interactions often play a crucial role in the docking of viruses to host cells, representing a necessary step in the viral lifecycle that precedes infection and, ultimately, replication. Understanding these interactions provides insight into druggable targets. In this context, the role of carbohydrate-receptor interactions in flavivirus entry and their potential to prevent viral infection should be investigated. To date, several molecules have been identified as potential targets for therapeutic intervention at carbohydrate receptors in flaviviruses, including the mannose receptor[23], glucose-regulating protein 78[24], heparan sulfate[25], and glycosphingolipids[26]. The mannose receptor is a type 1 transmembrane protein that recognizes and binds to pathogens, particularly glycoproteins containing mannose. This recognition initiates phagocytosis by immune cells, including macrophages and DC. These carbohydrate-receptor interactions provide potential targets for intervention in the flavivirus lifecycle, making them promising candidates for developing antiviral strategies. Flaviviruses often interact with cell surface glycosaminoglycans during the initial stages of infection[27]. Carbohydrate moieties on the surfaces of viral glycoproteins can disrupt viral entry and infection[28]. Inhibitors that interfere with this interaction may hinder viral entry (Figure 3).

Flavivirus-host lipid metabolism interaction and associated therapeutic targets

Flaviviruses manipulate host lipid metabolism by hijacking viral replication complexes during their assembly and maturation. Flaviviruses have been observed to strategically alter the composition of lipid rafts to evade host immune responses. Lipid rafts, which are specialized, cholesterol-rich microdomains in cellular membranes, play a pivotal role in signaling pathways that are crucial for antiviral immune responses. These microdomains are integral to the efficient assembly of viruses. During the assembly phase, the lipid composition of the viral envelope is influenced by the host ER membrane from which the virus buds. The orchestrated modulation of lipid rafts by flaviviruses highlights the intricate strategies employed by these pathogens to navigate the host immune system and ensure successful viral assembly. Cholesterol plays a pivotal role in the viral envelope, influencing membrane fluidity and stability and profoundly impacting flaviviral infectivity. Disruption of the formation of these complexes, which are crucial for viral replication, can be achieved by inhibiting enzymes involved in lipid synthesis or transport. Viruses manipulate host cell lipid metabolism to create an optimal replication environment. This manipulation may entail modifications to the lipid composition of cellular membranes or the induction of specialized membrane structures. Fatty acid synthesis begins with the carboxylation of acetyl-coenzyme A (CoA) to malonyl-CoA, catalyzed by the enzymatic activity of acetyl-CoA carboxylase (ACC). ACC is a rate-limiting enzyme in the intricate process of lipid biosynthesis. Notably, cells infected with flaviviruses exhibit pronounced upregulation of fatty acid synthesis, as documented by Heaton et al[29] in 2010. Flaviviral infection exhibits heightened sensitivity to the inhibition of fatty acid synthesis, particularly through the targeted inhibition of ACC or fatty acid synthase (FASN)[30]. Understanding the intricate interplay between flaviviruses and lipids is pivotal for the formulation of antiviral strategies. Targeting lipid-centric processes, including membrane fusion, lipid raft formation, and viral envelope biogenesis, is a promising approach for the development of antiviral drugs. Viruses may modulate fatty acid synthesis and oxidation in host cells to meet their lipid requirements. This modulation can affect the lipid composition of cellular membranes and viral replication. Notably, hypolipidemic drugs, such as 5-(tetradecyloxyl)-2-furoic acid and MEDICA, which are designed to target ACC, have demonstrated efficacy in inhibiting fatty acid synthesis during WNV infection[31]. Furthermore, compounds, such as C75 and cerulenin, act as inhibitors of DENV and YFV, thereby contributing to the inhibition of fatty acid synthesis.

The DENV NS3 protein establishes a direct link between fatty acid synthesis and flaviviral infection. Through its interaction with FASN, DENV NS3 redirects the enzymatic complex to the viral replication sites, thereby stimulating its functional activity. Intriguingly, NS1 is secreted and associates with the cholesterol transporter caveolin chaperone complex within cells, highlighting a unique aspect of flavivirus biology and suggesting potential implications for viral pathogenesis and host-cell interactions. In patients with dengue, NS1 is detected in complex with high-density and low-density lipoproteins and accumulates over time[32]. Current in-depth protein interaction studies have revealed that NS1 is a focal point in flaviviral protein research for therapeutic endeavors[33]. Researchers continue to investigate the specific mechanisms and pathways through which flaviviruses manipulate host lipids, shedding light on potential targets for therapeutic interventions (Figure 3).

Flavivirus-host nucleotide metabolism interaction and associated therapeutic targets

Flaviviruses, similar to other viruses, exhibit a pronounced reliance on host cell nucleotide pools to facilitate their replication, making targeting this intricate process a promising strategy for antiviral interventions. Disruption of enzymes integral to nucleotide biosynthesis is a potent means of impeding viral RNA and DNA synthesis. The modulation of nucleotide metabolism by viruses is carefully orchestrated to ensure an ample supply for the replication of their genomic material. Pathogenic organisms possess a genomic architecture characterized by an ordered sequence of nucleotides. This sequence not only contains essential information for synthesizing and expressing proteins necessary for growth and survival, but also holds critical details that shape the organism's evolutionary trajectory. Changes in the precise arrangement of nucleotides can lead to the emergence of novel species or strains, thereby underscoring the pivotal role of genetic variation in evolutionary processes. Nucleosides can be integrated into cellular RNA. Interestingly, nucleoside analogs, particularly adenosine derivatives with methyl substitutions at the 2´-C position, exhibit potent inhibitory effects against DENV, WNV, and YFV. This inhibition occurs through the disruption of RNA synthesis via chain termination, indicating their potential as effective antiviral compounds[34]. Notably, a single point mutation within the active site of hepatitis C virus NS5B polymerase confers resistance to the antiviral effects of these nucleosides[35]. These approaches affect flaviviral replication at the nucleoside level (Figure 3).

Ribavirin, initially approved for treating other viral infections, targets RNA polymerase inhibition and is currently in combination trials for flavivirus infections, with results expected within 1–2 years[36]. Favipiravir, originally developed for influenza, has shown promising results in preclinical studies for dengue and Zika and is now undergoing multiple phase II/III trials, with results anticipated within the next 2 years[37]. Interferons, long used to treat various viral infections, work by modulating the immune response and are being tested in combination therapies for their efficacy against flaviviruses. Tilorone, an experimental antiviral agent that induces interferon production, is in the early phase of clinical trials for flaviviral infections, with preliminary results expected within 1–2 years. NITD008, a preclinical-stage drug, inhibits viral RNA synthesis but faces significant toxicity concerns that must be addressed before further development can proceed[38]. Balapiravir, another investigational drug, has shown mixed results in early trials for flaviviral infections, leading to a temporary hold on future trials pending further data and analysis[39]. Remdesivir, initially approved for the coronavirus disease treatment, targets RNA polymerase and is currently in phase II/III trials for dengue and Zika, with results expected within 1–2 years[40]. Ivermectin, a repurposed antiparasitic drug, inhibits viral replication and is undergoing multiple phase II trials for dengue and Zika, with results anticipated in the coming years[41]. These therapeutic options reflect a multifaceted approach to tackling flaviviral infections by targeting various metabolic pathways to inhibit viral replication and pathogenesis. The following Table 1 highlights the diverse treatment options currently under investigation and provides a snapshot of the therapeutic landscape and future directions. Ongoing trials and research efforts have underscored the complexity of developing effective therapies against flaviviruses, emphasizing the need for continued innovation and clinical testing to bring these potential treatments to fruition[18,38,42,43].

Table 1 Summary of therapeutic options for flaviviruses and vaccines.

Antiviral drug	Therapy name	Development stage	Target action site	Available data	Ongoing trials	Classification	Ref.
Favipiravir	Avigan	Clinical trials	Viral RNA polymerase	Some efficacies in clinical trials; used in Japan for influenza and Ebola	Ongoing trials for dengue and Zika	RNA-based therapy	[18]
Ribavirin	Virazole	Completed/discontinued	Viral RNA polymerase	Mixed results; used for HCV, not widely effective for flaviviruses	Not actively pursued for flavivirus	RNA-based therapy	[18]
Sofosbuvir	Sovaldi	Completed/discontinued	Viral RNA polymerase	Highly effective for HCV; no data for flavivirus	No ongoing trials for flavivirus	RNA-based therapy	[42]
Interferon-alpha	Intron A	Clinical trials	Immune modulation	Used for hepatitis B and C; some efficacy in flavivirus treatment	Trials for dengue and West Nile	Immunotherapy	[38]
Dengvaxia	Dengue vaccine	Approved	Immune response	Approved for dengue; mixed safety and efficacy profiles	Post-marketing surveillance ongoing	Immunotherapy	[50]
Chimeric yellow fever 17D-tetravalent dengue vaccine	Dengue vaccine	Approved	Immune response	Approved for dengue; mixed safety and efficacy profiles	Post-marketing surveillance ongoing	Immunotherapy	[50]

HCV: Hepatitis C virus.

Side effects of drugs and vaccines targeting host metabolic pathways

The therapeutic options and vaccines developed to combat flavivirus pathogenesis comes with a range of potential side effects, reflecting the complexity of targeting host metabolic pathways. For example, ribavirin can induce anemia and has teratogenic effects, limiting its use, particularly in pregnant individuals[44]. Favipiravir, while promising, also presents a risk of teratogenicity and mild gastrointestinal symptoms[45]. Drugs, such as sofosbuvir, are generally well-tolerated but can cause fatigue and headaches[42]. Chloroquine, although initially promising, has been associated with retinal toxicity and gastrointestinal issues[46]. Balapiravir has shown potential hepatotoxicity, adding a layer of caution to its application[47]. Remdesivir, a widely used antiviral agent, can lead to kidney and liver function abnormalities alongside gastrointestinal symptoms[48]. NITD008, though effective in preclinical studies, poses long-term toxicity risks[38]. Immunomodulators, such as tilorone and seliciclib, may cause mild gastrointestinal symptoms and potential hepatotoxicity, respectively. Ivermectin is usually well-tolerated but can cause mild gastrointestinal disturbances[49]. Mycophenolic acid, an inhibitor of nucleotide synthesis, can lead to immunosuppression and gastrointestinal symptoms[50]. Vaccines, such as Dengvaxia and YF-VAX, have shown efficacy but come with risks, such as severe dengue in seronegative individuals and rare severe reactions, respectively[50]. These side effects highlight the need for careful monitoring and tailored treatment strategies.

CONCLUSION

Targeting host metabolic molecules and their interactions to inhibit flaviviral pathogenesis presents several challenges. These include potential off-target effects, disruption of essential host functions, and the risk of unintended side effects during antiviral drug or vaccine development. The dynamic virus-host interactions and the potential for viral resistance complicate the sustained effectiveness of this approach. Despite these challenges, manipulating host metabolic pathways remains a promising strategy owing to its impact on viral replication and pathogenesis.

Developing a detailed viral-host interactome is crucial for understanding the virus-host interplay, identifying key targets for intervention, and designing effective antiviral agents. Targeting the metabolic signaling pathways that the virus exploits can disrupt multiple stages of the viral lifecycle, including entry, replication, and assembly. This approach has the potential to hinder the ability of the virus to establish and propagate infections, making it a valuable avenue for anti-flavivirus drug and vaccine development.