title: 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.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal.
authors.forename: André F
authors.initials: AF
authors.lastname: Faustino
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Guerra
authors.forename: Roland G
authors.initials: RG
authors.lastname: Huber
authors.forename: Axel
authors.initials: A
authors.lastname: Hollmann
authors.forename: Marco M
authors.initials: MM
authors.lastname: Domingues
authors.forename: Glauce M
authors.initials: GM
authors.lastname: Barbosa
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Enguita
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
authors.forename: Miguel A R B
authors.initials: MA
authors.lastname: Castanho
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Da Poian
authors.forename: Fabio C L
authors.initials: FC
authors.lastname: Almeida
authors.forename: Nuno C
authors.initials: NC
authors.lastname: Santos
authors.forename: Ivo C
authors.initials: IC
authors.lastname: Martins
mesh_terms: D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D002942:Circular Dichroism; D003716:Dengue Virus / Q000378:metabolism*; D008958:Models, Molecular; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D014779:Virus Replication
chemical_list: D036022:Capsid Proteins; D010446:Peptide Fragments; D010455:Peptides