Understanding dengue virus capsid protein disordered N-Terminus and pep14-23-based inhibition

ACS Chem Biol. 2015 Feb 20;10(2):517-26. doi: 10.1021/cb500640t. Epub 2014 Nov 20.

Abstract

Dengue virus (DENV) infection affects millions of people and is becoming a major global disease for which there is no specific available treatment. pep14-23 is a recently designed peptide, based on a conserved segment of DENV capsid (C) protein. It inhibits the interaction of DENV C with host intracellular lipid droplets (LDs), which is crucial for viral replication. Combining bioinformatics and biophysics, here, we analyzed pep14-23 structure and ability to bind different phospholipids, relating that information with the full-length DENV C. We show that pep14-23 acquires α-helical conformation upon binding to negatively charged phospholipid membranes, displaying an asymmetric charge distribution structural arrangement. Structure prediction for the N-terminal segment reveals four viable homodimer orientations that alternatively shield or expose the DENV C hydrophobic pocket. Taken together, these findings suggest a new biological role for the disordered N-terminal region, which may function as an autoinhibitory domain mediating DENV C interaction with its biological targets. The results fit with our current understanding of DENV C and pep14-23 structure and function, paving the way for similar approaches to understanding disordered proteins and improved peptidomimetics drug development strategies against DENV and similar Flavivirus infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Capsid Proteins / antagonists & inhibitors*
  • Capsid Proteins / chemistry
  • Capsid Proteins / metabolism*
  • Circular Dichroism
  • Dengue Virus / metabolism*
  • Models, Molecular
  • Peptide Fragments
  • Peptides / pharmacology*
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Virus Replication

Substances

  • Capsid Proteins
  • Peptide Fragments
  • Peptides