The Dengue Virus Capsid Protein Inhibitor Peptide Pep14-23 becomes Alpha-Helical upon Binding to Negative Lipids

Dengue virus (DENV) causes a mosquito-borne disease affecting millions of people, which is spreading to temperate regions, including North America and Europe. Currently, there is no effective treatment for DENV infection. The interaction in the host liver of the viral capsid (C) protein with host intracellular lipid droplets (LDs) is crucial for virus formation [1], being previously studied in our labs [2, 3]. DENV C-LDs interaction involves a conserved segment of DENV C intrinsically disordered N-terminus [3], which led to the design of pep14-23, a novel peptide inhibitor of this critical interaction [3].Here, we used bioinformatics tools, combined with circular dichroism (CD) and zeta-potential analysis, to determine the structural parameters and the tendency of DENV C and pep14-23 to interact and bind lipid vesicles. Bioinformatics suggests that the Flavivirus capsid protein N-terminus region, roughly corresponding to pep14-23, has a high α-helical tendency and is likely to interact with lipid systems. CD shows a conversion of pep14-23 to α-helix conformation in the presence of negative phospholipids. Zeta-potential light scattering spectroscopy supports the CD data, showing that the peptide binds strongly to negative lipid vesicles.pep14-23 inhibition mechanism may therefore involve its binding to negative LDs phospholipids and the conversion to an α-helical peptide. This finding contributes to the design of pep14-23 based treatments of DENV and similar Flavivirus infections.References1. Samsa et al., PLoS Pathog, 2009, 5:e1000632.2. Carvalho et al., J Virol 2012, 86:2096-2108.3. Martins et al., Biochem J, 2012, 444:405-415.