Production of Envelope Protein-Based Virus-like Particles of DENV‑2 in and Investigation of Their Binding Interactions with Gallic Acid Derivatives of Glucose as Potential Drug Candidates.

Perennial endemics of mosquito-borne dengue infection affect millions of lives across tropical and subtropical regions every year. Factors like the Earth's rising temperature, climate change, and lack of dengue-specific drugs and vaccines have led to a significant surge in these infections, warranting urgent efforts to develop new antidengue agents. The dengue virus (DENV) envelope exposes approximately 90 E (envelope) protein dimers on its surface, making it a potent target for drug discovery and vaccine development. E protein-based virus-like particles (VLPs) may serve as an ideal system to test the binding activity of compounds . Such VLPs have not been defined for DENV serotype 2 (DENV-2). The current study demonstrates the expression of the E protein-ectodomain in and VLP generation. Previously, chebulinic acid (CA), a tannin, was demonstrated as a strong DENV-2 inhibitor in Vero cells. However, the structural complexity of CA made its synthesis a challenging task, whereas toxicity at higher doses limited its therapeutic use. To investigate binding to E protein , simple analogues of CA (mono, di, tri, tetra, and pentagalloylglucose (PGG)) were selected and evaluated using molecular docking, molecular dynamics (MD) simulations, and electrostatic complementarity analysis. Herein, PGG-E-protein complex demonstrated higher docking scores, stable MD simulation patterns and electrostatics, equivalent to that of positive controls, CA, and epigallocatechin-3-gallate. Furthermore, the PGG interaction with VLP molecules was analyzed using biolayer interferometry, where nM-scale equilibrium constants were recorded. Therefore, a strong and E protein-binding profile of PGG supports its potential as a DENV-2 inhibitor, which may be developed as an anti-DENV-2 therapeutic.