Hierarchical design of hyaluronic acid-peptide constructs for glioblastoma targeting: Combining insights from NMR and molecular dynamics simulations

• Autor(a) principal: Mendes, Maria
• Data de Publicação: 2020
• Outros Autores: Cova, Tânia, Basso, João, Ramos, M. Luísa, Vitorino, Rui, Sousa, João, Pais, Alberto, Vitorino, Carla
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• DOI: 10.1016/j.molliq.2020.113774
• Texto Completo: http://hdl.handle.net/10316/90813; https://doi.org/10.1016/j.molliq.2020.113774
• topic: 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.