Proefschrift
Puzzling pyrophosphates: synthetic methodologies for ADP-ribosylated biopolymers
This thesis focuses on developing new chemical synthesis strategies to produce native ADP‑ribosylated biomolecules with precise structural control.
- Auteur
- S. Wijngaarden
- Datum
- 20 februari 2026
- Links
- Thesis in Leiden Repository
The work presented here combines solution‑phase and solid‑phase methodologies to construct structurally defined ADP‑ribosylated peptides and oligo‑ADP‑ribose fragments. Key achievements include the synthesis of a doubly ADP‑ribosylated androgen‑receptor peptide to study DTX3L/PARP9 binding, the preparation and characterization of glutamate‑ and aspartate‑linked ADP‑ribosylated peptides, and the development of a strategy to convert labile acyl linkages into stable glutamine‑ADPr isosteres. A new solid‑phase method for assembling pyrophosphate‑linked biopolymers enabled the first synthesis of a decameric oligo‑ADP‑ribose fragment. Additionally, a convergent phosphorimidazolide‑based approach allowed the chemoselective introduction of pyrophosphate linkages into peptides, yielding both mono‑ and di‑ADP‑ribosylated constructs. The thesis concludes with an evaluation of these methodologies and their potential for generating increasingly complex ADP‑ribosylated biopolymers.