Beta-o-glicosilación de péptidos que incorporan aminoácidos no naturales

  1. Alberto Fernández Tejada
Supervised by:
  1. Jesús Manuel Peregrina García Director
  2. Francisco Corzana López Director

Defence university: Universidad de La Rioja

Year of defence: 2009

Committee:
  1. Rafael Pedrosa Sáez Chair
  2. Jesús Héctor Busto Sancirián Secretary
  3. Juan Luis Asensio Alvarez Committee member
  4. David Andreu Martínez Committee member
  5. Sonsoles Martín-Santamaría Committee member
Department:
  1. Chemistry

Type: Thesis

Abstract

Firstly, in this Doctoral Thesis, the synthesis and conformational analysis in aqueous solution of different alpha-methyl-alpha-amino acid diamides, derived from serine (Ser), threonine (Thr), beta-hydroxyciclobutane-alpha-amino acids and their corresponding model beta-O-glycopeptides, are reported. From this study, it can be concluded that the incorporation of non-natural amino acids allows us to modulate as desired the conformational space of the model glycopeptides. The different conformations exhibited by these molecules could be a useful tool to obtain systems with conformational preferences "à la carte". With the intention of expanding our novel small systems, we have synthesized larger glycopeptides similar to the previous ones. Their conformational analysis shows that the elongation of the backbone does not drastically affect the conformational preferences of these glycopeptides. Moreover, the synthesis of the first glycopeptide with a non natural amino acid at the underlying residue has been achieved. It is worth noting that the beta-O-glycosylation has a remarkable and completely different effect on the backbone of the peptides derived from natural and non-natural amino acids, respectively. To go one step further, the synthesis of a glycopeptide incorporating the consensus sequence for O-glucose modification is reported. In addition, we have synthesized a novel glycopeptide and its corresponding peptide, in which the underlying serine residue has been replaced by the non-natural amino acid alpha-methylserine. Finally, despite the importance of beta-O-GlcNAc glycosylation in fundamental biological processes, sparse structural information is known about beta-O-GlcNAc-Ser/Thr motifs. For this reason, we report the synthesis and conformational analysis of the simplest model glycopeptides derived from Ser and Thr glycosylated with beta-O-GlcNAc, as well as of the non-natural analogues incorporating alpha-methylserine and alfa-methylthreonine. The results demonstrate a distinct behavior of the glycosidic linkage (alternate conformations for the serine derivatives and eclipsed ones for the Thr-derived glycopeptides) allowing the carbohydrate moiety to adopt a completely different orientation. As a consequence, water pockets at key sites are responsible for modulating sugar-peptide interactions in these beta-O-GlcNAc glycopeptides. It is likely that these solvent pockets have important biological implications, providing the required presentation of the GlcNAc moieties to interact with their biological receptors.