Wijngaarden Sven, van der Heijden Femke L A M, Bogaart Cindy J, Siskou Maria, Tsoumani Ioanna, Robinson Daisy J, van der Marel Gijsbert A, Codée Jeroen D C, Overkleeft Herman S, Filippov Dmitri V
Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden, 2333 CC, The Netherlands.
Chemistry. 2025 Jul 8;31(38):e202501383. doi: 10.1002/chem.202501383. Epub 2025 Jun 16.
The preparation of well-defined ADP-ribosylated peptides is essential for studying the functional implications of this post-translational modification. While methodologies exist for the chemical synthesis of short oligo-ADPr fragments and mono-ADP-ribosylated peptides separately, combining the two distinct chemistries, required to assemble them, has remained challenging. In this research, we employ a methodology for the regio- and chemoselective condensation of two phosphomonoesters to convergently install the pyrophosphate bond in ADP-ribosylated constructs. A diverse set of phosphoribosylated peptides, varying in the amino acid acceptor, was prepared and condensed with adenosine monophosphate to yield mono-ADP-ribosylated peptides. Furthermore, a solid-phase approach was developed to access a phosphoadenosyl-ADPr fragment, which was used to prepare a di-ADPr-peptide as the first example of a synthetic oligo-ADP-ribosylated peptide. Overall, the work presented here extends synthetic methodology for the preparation of well-defined ADP-ribosylated peptides.
制备结构明确的ADP-核糖基化肽对于研究这种翻译后修饰的功能意义至关重要。虽然存在分别化学合成短寡聚ADP-核糖片段和单ADP-核糖基化肽的方法，但将组装它们所需的两种不同化学方法结合起来仍然具有挑战性。在本研究中，我们采用了一种使两种磷酸单酯进行区域和化学选择性缩合的方法，以在ADP-核糖基化构建体中汇聚式地安装焦磷酸键。制备了一组多样的磷酸核糖基化肽，其氨基酸受体各不相同，并与单磷酸腺苷缩合以产生单ADP-核糖基化肽。此外，还开发了一种固相方法来获得磷酸腺苷基-ADP-核糖片段，该片段被用于制备二ADP-核糖基化肽，这是合成寡聚ADP-核糖基化肽的首个实例。总体而言，本文介绍的工作扩展了用于制备结构明确的ADP-核糖基化肽的合成方法。
