# Dengue and Flavivirus Co-Infections: Challenges in Diagnosis, Treatment, and Disease Management
## 5 Implications of Better Understanding Flaviviral Co-Infections
### Improved Disease Management and Treatment  
Co-infections of flaviviruses produce unspecific disease symptoms, and disrupt immune response that in turn leads to damaging complications [103,104]. Therefore, identifying the etiological agents in a co-infection is crucial for a few reasons: (i) it prevents the disease progression to severe and life-threatening forms; (ii) it helps curb the occurrence of adverse complications particularly in immunocompromised individuals such as pregnant women so intensive monitoring and counselling can be provided to them in follow-ups; (iii) it ensures better disease surveillance and outbreak controls, and implementation of effective public health interventions. To achieve those aims, a comprehensive understanding of fluavirial life cycle is crucial. Furthermore, it also provides insights into the specific stages for therapeutic interventions. Figure 2 briefly illustrates the life cycle of fluiviruses and highlights the targeted stages for therapeutic interventions. The key therapeutic targets of fluavirial life cycle include enzymes involved in the (i) viral genome replication: the viral replicase (NS5), helicase (NS3), methyltransferase (NS5); and (ii) splicing of polyprotein: NS3-NS4 complex [106; 107]. Interruptions to these viral molecules undermine the formation of mature virion, thus lowering viral load in the host. Interestingly, similar targets are found in a wide range of fluavirises, thereby making it possible to invent universal therapeutics for fluivirus infections especially in fighting fluavirial co-infections [106; 107]. Effective therapeutics are equally important as control and preventive measures. [PERSON] et al. [108] developed a mathematical model to simulate the prevention of dengue fever and Zika in the absence of treatment controls and found that relying purely on  
Figure 2: Life cycle of fluiviruses. The key therapeutic targets include the viral genome replicative enzymes (RdRp, helicase, and methyltransferase) and proteases (NS3–NS4 complex). (+)ssRNA indicates positive-sense single-stranded RNA. Adapted from [PERSON] et al. [105]. control measures did not significantly reduce the occurrence of DENV-ZIKV co-infections. This is further supported by several lines of evidence demonstrating the potential use of antiviral peptides to disrupt the replication of DENV [109]. The inhibitory peptides selectively targeted diverse biological mechanisms, including molecular signalling [110]. Recently, various peptide-based drugs have become available for treating virus infections, for instance, Fuzeon used in the treatment of HIV [110]. Peptide-based inhibitors can disrupt the viral life cycle [111]. They serve as binding partners of viral antigens, thereby blocking the activation of the antigens and viral life cycle [112]. Besides, owing to their small molecular sizes, they can penetrate and cross cell membranes, thereby showing high target specificity and strong binding affinity [113]. [PERSON] et al. [114] synthesised a few peptide candidates to inhibit DENV replication. The peptides disturbed the intramolecular interactions between the stem region and other parts of the class II viral fusion protein, preventing viral fusion and entry. Other peptide molecules such as N-sulfonyl peptide-hybrids exhibited anti-dengue potential through binding to the DENV-2 protease [115]. Interestingly, these peptide candidates were metabolically stable in the rat liver microsomes and pancreatic enzymes, emphasizing their potential as therapeutic anti-dengue agents. Besides peptide inhibitors, the anti-dengue properties of several synthetic molecular inhibitors were investigated. For example, DV-B-120 and JNJ-A07 that inhibit the DENV NS2B-NS3 protease [116] and disrupt the formation of the NS3-NS4B complex [112], respectively.