Role of quercetin as a promising antiviral, therapeutic and immunomodulatory mediator against dengue virus induced robust infection in in-vivo Balb/C mice model

Currently, there are no clinically approved antiviral agents against dengue-virus (DENV). This study aimed to determine the prophylactic, antiviral, and therapeutic potential of quercetin by its pre-treatment, co-treatment, and post-treatment [24, 48, and 72 h-post-infection (HPI)] of DENV-infected Balb/C mice through both oral and intraperitoneal (I.P) route, respectively. 80 mg/kg/day and 16 mg/kg/day of quercetin were non-toxic for oral and I.P administration, respectively. I.P. was found to be more effective than oral administration which significantly reduced DENV copy-number in co-treatment group (from day 1, p < 0.01); post-treatment (24hpi),and pretreatment groups (day 3 onwards, p < 0.05). Molecular-docking experiments indicated quercetin could act as a double-edged sword by strongly interacting with DENV envelope-glycoprotein (-8.1 kcal/mol) and NS5-RdRp domain (-8.0 kcal/mol), which are crucial for viral-attachment and replication. MD-simulation of docked complexes indicated their stability defined by low RMSD, RMSF, and stable H-bond with active-site residues. Significant reduction (p < 0.001) in TNF-α, IL-6, ROS-production, and vascular leakage was observed among pre-, co-, and post-treatment (24 and 48 HPI) groups with promising hepatic and renal-protective effects. Pharmacological and functional-molecular interaction networks indicate a significant effect of quercetin on vascular integrity byVEGF-KDR signaling pathway (via PI3K-Akt and Ras signalling), oxygen homeostasis through HIF-1 signalling, and the anti-inflammatory response via PI3K-Akt, IL-6 and its receptor signalling (PPI enrichment P = 3.19e-10).Thus, it can be concluded that I.P. co- and post-treatment (24hpi) of quercetin to DENV-infected mice could effectively reduce viral-titer, pro-inflammatory cytokines, ROS-response, and vascular permeability. Taken together this demonstrates quercetin as an important antiviral candidate against dengue.