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

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.

• Authors: André F Faustino, Gabriela M Guerra, Roland G Huber, Axel Hollmann, Marco M Domingues, Glauce M Barbosa, Francisco J Enguita, Peter J Bond, Miguel A R B Castanho, Andrea T Da Poian, Fabio C L Almeida, Nuno C Santos, Ivo C Martins
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 10 Issue 2 Pg. 517-26 (Feb 20 2015) ISSN: 1554-8937 [Electronic] United States
• PMID: 25412346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Capsid Proteins
• Peptide Fragments
• Peptides

Topics

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