A General Approach Towards Triazole‐Linked Adenosine Diphosphate Ribosylated Peptides and Proteins

• Published in: Angewandte Chemie International Edition 2018-02, Vol.57 (6), p.1659-1662
• Main Authors: Liu, Qiang, Kistemaker, Hans A. V., Bhogaraju, Sagar, Dikic, Ivan, Overkleeft, Herman S., van der Marel, Gijsbert A., Ovaa, Huib, van der Heden van Noort, Gerbrand J., Filippov, Dmitri V.
• Format: Article
• Language: English
• Subjects: Adenosine; Adenosine diphosphate; ADP-ribosylation; Alkynes; Biological effects; Chemical reactions; click chemistry; Incompatibility; Peptide synthesis; Peptides; Post-translation; post-translational modification; protein modification; Proteins; Ubiquitin; ubiquitination
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201710527

Current methods to prepare adenosine diphosphate ribosylated (ADPr) peptides are not generally applicable due to the labile nature of this post‐translational modification and its incompatibility with strong acidic conditions used in standard solid‐phase peptide synthesis. A general strategy is presented to prepare ADPr peptide analogues based on a copper‐catalyzed click reaction between an azide‐modified peptide and an alkyne‐modified ADPr counterpart. The scope of this approach was expanded to proteins by preparing two ubiquitin ADPr analogues carrying the biological relevant α‐glycosidic linkage. Biochemical validation using Legionella effector enzyme SdeA shows that clicked ubiquitin ADPr is well‐tolerated and highlights the potential of this strategy to prepare ADPr proteins. ADPr‐Ub‐date: A general strategy to prepare ADPr peptide and protein analogues based on a copper‐catalyzed click reaction between an azide‐modified peptide or protein and an alkyne‐modified ADPr counterpart is presented. Fully synthetic ADPribosylated protein analogues carrying the biological relevant α‐glycosidic linkage were prepared. Biochemical validation shows that clicked ADPr ubiquitin is tolerated.