DENV-DERIVED PEPTIDES AND METHODS FOR THE INHIBITION OF THE FLAVIVIRUS REPLICATION

摘要

Dengue virus (DENV) is a Flavivirus that causes the major human arbovirosis, for which no specific treatment exists. The C protein, the viral capsid protein, is a symmetric homodimeric a-helical protein that interacts with intracellular lipid droplets (LDs) during viral replication, possibly via a a2-a2' non-polar central patch that has been hypothesized to interact with lipids. The C protein binding sites to LD were identified, revealing a new function for a conserved segment in the N- terminal disordered region, and indicating that conformational selection is involved in recognition. The obtained results showed that C protein positively-charged N-terminal region prompts the interaction with negatively- charged LDs, after which a conformational rearrangement enables the access of the central hydrophobic patch to LD surface. Altogether, the results allowed the design of a peptide with inhibitory activity of C protein-LD binding, paving the way for new drug development approaches against dengue. The ability of this peptide to bind to LDs in a similar fashion to that of the C protein was demonstrated employing different techniques, such as, but not limited to, nuclear magnetic resonance, zeta potential analysis and atomic force microscopy. Moreover, the de novo designed peptides were tested regarding their ability to inhibit DENV C protein binding to LDs, having been shown that it effectively inhibits the DENV C interaction with LDs, a finding of direct applicability for dengue and related Flavivirus originated pathologies.