Author(s): Mendes, Maria ; Cova, Tânia ; Basso, João ; Ramos, M. Luísa ; Vitorino, Rui ; Sousa, João ; Pais, Alberto ; Vitorino, Carla
Date: 2020
Persistent ID: http://hdl.handle.net/10773/37254
Origin: RIA - Repositório Institucional da Universidade de Aveiro
Subject(s): Hyaluronic acid; C(RGDfK; H7k(R2)2; Polymer-peptide conjugates; Glioblastoma
The main bottleneck of glioblastoma still relies on the existence of the blood brain-blood brain tumor dual barrier, along with the lack of therapy specificity. The present work deals with the question of whether (and how) different targeting hyaluronic acid (HA)-peptide [c(RGDfK) and/or H7K(R2)2] moieties hierarchically interact with each other, to ensure a unique entity with specificity to glioblastoma. A dual experimental-computational approach, encompassing nuclear magnetic resonance and molecular dynamics simulations is enclosed. Relevant contact patterns based on the identification of the stabilizing/destabilizing noncovalent interactions within the constructs are detailed. The synthesis pathway requires the HA-c(RGDfK)-H7k(R2)2 association hierarchy, stemming from the size and amino acid residue rearrangement, in the 1:1 M ratio, to obtain a stable conjugate ultimately able to interact with the tumor cell membrane. To our knowledge, the structural and mechanistic rationale for the formation of hybrid polymer-peptide constructs, including HA-c(RGDfK)-H7k(R2)2, for glioblastoma has not been addressed so far.
