ST-148

Dengue is a prominent viral disease transmitted by mosquitoes to humans that affects mainly tropical and subtropical countries worldwide. The global spread of dengue virus (DENV) is mainly occurred by Aedes aegypti and Aedes albopictus mosquitoes. The dengue virus serotypes‐2 (DENV‐2) is a widely prevalent serotype of DENV, that causes the hemorrhagic fever and bleeding in the mucosa, which can be fatal. In the life cycle of DENV‐2, a structural capsid (DENV‐2 C) protein forms the nucleocapsid assembly and bind to the viral progeny RNA. For DENV‐2 maturation, the nucleocapsid is a vital component. We used virtual ligand screening to filter out the best in‐house synthesized acridinedione analogs (DSPD molecules) that could efficiently bind to DENV‐2 C protein. The molecular docking and dynamics simulations studies were performed to analyze the effect of DSPD molecules on DENV‐2 C protein after binding. Our findings showed that DSPD molecules strongly interacted with DENV‐2 C protein, as evident from molecular interactions and several time‐dependent molecular dynamics‐driven analyses. Moreover, this study was also supported by the thermodynamic binding free energy and steered molecular dynamics simulations. Therefore, we intend to suggest that the DSPD3 molecule could be used as a potential therapeutic molecule against dengue complications as compared to the cocrystallized inhibitor ST‐148. However, further studies are required to demonstrate the ability of DSPD3 to induce DENV‐2 C tetramer formation.

Dengue virus (DENV) was designated as a top 10 public health threat by the World Health Organization in 2019. No clinically approved anti-DENV drug is currently available. Here we report the high-resolution cocrystal structure (1.5 Å) of the DENV-2 capsid protein in complex with an inhibitor that potently suppresses DENV-2 but not other DENV serotypes. The inhibitor induces a "kissing" interaction between two capsid dimers. The inhibitor-bound capsid tetramers are assembled inside virions, resulting in defective uncoating of nucleocapsid when infecting new cells. Resistant DENV-2 emerges through one mutation that abolishes hydrogen bonds in the capsid structure, leading to a loss of compound binding. Structure-based analysis has defined the amino acids responsible for the inhibitor's inefficacy against other DENV serotypes. The results have uncovered an antiviral mechanism through inhibitor-induced tetramerization of the viral capsid and provided essential structural and functional knowledge for rational design of panserotype DENV capsid inhibitors.