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A solid-phase approach for the synthesis of muramyl dipeptide conjugates for detection of NOD2
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2021-09-15 , DOI: 10.1016/j.bioorg.2021.105360
Ivy Kekessie 1 , Tatiana Goncharov 1 , László G Kőműves 2 , Domagoj Vucic 1 , Aimin Song 1
Affiliation  

Proper recognition of invading pathogens and prompt initiation of host defense mechanisms are instrumental for the maintenance of organismal homeostasis. Nucleotide–binding oligomerization domain-containing (NOD)-like receptors (NLRs) serve as pathogen-recognition receptors that specifically recognize bacterial peptidoglycans. NOD2 detects muramyl dipeptide (MDP) through its carboxy-terminal leucine rich repeats (LRRs), which enables the activation of downstream inflammatory signaling. Synthesis of MDP conjugates based on solution phase chemistry have been previously reported. Our solid phase approach synthetically provides a facile approach for the conjugation of biological probes to MDP, with the advantage of minimal functional/protecting group manipulation, and reduction in the laborious process of intermediate purification and isolation. MDP conjugates that we generated using solid phase synthesis allow detection of NOD2 is cell lysates and NOD2 subcellular localization by immunofluorescence microscopy. MDP-PEG6-Cyanine5.5 conjugate selectively colocalized with WT NOD2 but not NOD2 variant found in Crohn’s disease, which lacks carboxy-terminal end and cannot bind MDP. Overall, these data indicate that distinct solid phase-produced MDP conjugates can be used to examine biological properties of NOD2 and could potentially facilitate further development of NOD2 targeting agents.



中文翻译:

用于合成胞壁酰二肽偶联物以检测 NOD2 的固相方法

正确识别入侵病原体和迅速启动宿主防御机制有助于维持机体稳态。含有核苷酸结合寡聚化结构域 (NOD) 的受体 (NLR) 作为病原体识别受体,可特异性识别细菌肽聚糖。NOD2 通过其羧基末端富含亮氨酸的重复序列 (LRR) 检测胞壁酰二肽 (MDP),从而激活下游炎症信号。先前已经报道了基于溶液相化学的 MDP 缀合物的合成。我们的固相方法综合地为生物探针与 MDP 的结合提供了一种简便的方法,其优点是功能/保护基团操作最少,并减少了中间纯化和分离的繁琐过程。我们使用固相合成生成的 MDP 缀合物允许通过免疫荧光显微镜检测 NOD2 是细胞裂解物和 NOD2 亚细胞定位。MDP-PEG6-Cyanine5.5 偶联物选择性地与 WT NOD2 共定位,但不与克罗恩病中发现的 NOD2 变体共定位,克罗恩病缺乏羧基末端且不能结合 MDP。总体而言,这些数据表明,不同的固相产生的 MDP 缀合物可用于检查 NOD2 的生物学特性,并有可能促进 NOD2 靶向剂的进一步开发。它缺乏羧基末端,不能结合 MDP。总体而言,这些数据表明,不同的固相产生的 MDP 缀合物可用于检查 NOD2 的生物学特性,并有可能促进 NOD2 靶向剂的进一步开发。它缺乏羧基末端,不能结合 MDP。总体而言,这些数据表明,不同的固相产生的 MDP 缀合物可用于检查 NOD2 的生物学特性,并有可能促进 NOD2 靶向剂的进一步开发。

更新日期:2021-09-23
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