Solid-Phase Synthesis and Biological Evaluation of Peptides ADP-Ribosylated at Histidine
Solid-Phase Synthesis and Biological Evaluation of Peptides ADP-Ribosylated at Histidine
复制标题
组氨酸 ADP 核糖基化肽的固相合成和生物学评价
DOI：
10.1002/ange.202313317
复制
发表时间：
2023
影响因子：
--
通讯作者：
Minnee H
中科院分区：
文献类型：
--
作者：
Minnee H
通过消耗烟酰胺腺嘌呤二核苷酸将腺苷二磷酸 (ADP) 核糖部分转移到亲核侧链被称为 ADP-核糖基化，它可以对细胞凋亡和 DNA 修复等重要过程进行时空调节。最近基于质谱的“ADP-核糖基体”分析已确定组氨酸为 ADP-核糖受体位点。为了研究这种修饰，开发了一种针对 α 配置的 N(τ)- 和 N(π)-ADP-核糖基化含组氨酸肽的完全合成策略。通过 Mukaiyama 型糖基化获得呋喃核糖基化组氨酸结构单元，并使用基于芴甲氧羰基 (Fmoc) 的固相肽合成将结构单元整合到 ADP-核糖基组衍生的肽序列中。 ADP 部分的树脂安装是使用亚磷酰胺化学实现的，并且整体脱保护提供了所需的 ADP 核糖基化寡肽。对各种化学条件下的稳定性和对（ADP-核糖基）水解酶介导的降解的抵抗力进行了研究，结果表明该构建体在各种化学条件下都是稳定的，并且不会被任何已知的 ADP-核糖基水解酶降解。
The transfer of an adenosine diphosphate (ADP) ribose moiety to a nucleophilic side chain by consumption of nicotinamide adenine dinucleotide is referred to as ADP‐ribosylation, which allows for the spatiotemporal regulation of vital processes such as apoptosis and DNA repair. Recent mass‐spectrometry based analyses of the “ADP‐ribosylome” have identified histidine as ADP‐ribose acceptor site. In order to study this modification, a fully synthetic strategy towards α‐configured N(τ)‐ and N(π)‐ADP‐ribosylated histidine‐containing peptides has been developed. Ribofuranosylated histidine building blocks were obtained via Mukaiyama‐type glycosylation and the building blocks were integrated into an ADP‐ribosylome derived peptide sequence using fluorenylmethyloxycarbonyl (Fmoc)‐based solid‐phase peptide synthesis. On‐resin installation of the ADP moiety was achieved using phosphoramidite chemistry, and global deprotection provided the desired ADP‐ribosylated oligopeptides. The stability under various chemical conditions and resistance against (ADP‐ribosyl) hydrolase‐mediated degradation has been investigated to reveal that the constructs are stable under various chemical conditions and non‐degradable by any of the known ADP‐ribosylhydrolases.