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Wijngaarden, S. (2026)

Puzzling pyrophosphates: synthetic methodologies for ADP-ribosylated biopolymers

Doctoral Thesis
This thesis focuses on developing new chemical synthesis strategies to produce native ADP‑ribosylated biomolecules with precise structural control. 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...Show moreThis thesis focuses on developing new chemical synthesis strategies to produce native ADP‑ribosylated biomolecules with precise structural control. 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.
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ADP-ribosylation
Chemical synthesis
Pyrophosphate
Solid-phase synthesis
Oligo-ADP-ribose
ADP-ribosylated peptides
All authors
Wijngaarden, S.
Supervisor
Filippov, D.V.; Overkleeft, H.S.
Committee
Ubbink, M.; Codée, J.D.C.; Kasteren, S.I. van; Vermeulen, M.; Höfer, K.
Qualification
Doctor (dr.)
Awarding Institution
Leiden Institute of Chemistry (LIC), Faculty of Science, Leiden University
Date
2026-02-20