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Novel Cluster and Monomer-Based GalNAc Structures Induce Effective Uptake of siRNAs in Vitro and in Vivo
Bioconjugate Chemistry ( IF 4.7 ) Pub Date : 2018-06-13 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00365
Vivek K. Sharma , Maire F. Osborn , Matthew R. Hassler , Dimas Echeverria , Socheata Ly , Egor A. Ulashchik 1 , Yury V. Martynenko-Makaev 1 , Vadim V. Shmanai 1 , Timofei S. Zatsepin 2, 3 , Anastasia Khvorova , Jonathan K. Watts
Affiliation  

GalNAc conjugation is emerging as a dominant strategy for delivery of therapeutic oligonucleotides to hepatocytes. The structure and valency of the GalNAc ligand contributes to the potency of the conjugates. Here we present a panel of multivalent GalNAc variants using two different synthetic strategies. Specifically, we present a novel conjugate based on a support-bound trivalent GalNAc cluster, and four others using a GalNAc phosphoramidite monomer that was readily assembled into tri- or tetravalent designs during solid phase oligonucleotide synthesis. We compared these compounds to a clinically used trivalent GalNAc cluster both in vitro and in vivo. In vitro, cluster-based and phosphoramidite-based scaffolds show a similar rate of internalization in primary hepatocytes, with membrane binding observed as early as 5 min. All tested compounds provided potent, dose-dependent silencing, with 2–4% of injected dose recoverable from liver after 1 week. The two preassembled trivalent GalNAc clusters showed higher tissue accumulation and gene silencing relative to di-, tri-, or tetravalent GalNAc conjugates assembled via phosphoramidite chemistry.

中文翻译:

新型的基于簇和单体的GalNAc结构可诱导体内和体外有效摄取siRNA。

GalNAc偶联正在成为将治疗性寡核苷酸递送至肝细胞的主要策略。GalNAc配体的结构和化合价有助于缀合物的效价。在这里,我们展示了使用两种不同合成策略的一组多价GalNAc变体。具体而言,我们提出了一种基于结合有载体的三价GalNAc簇的新型共轭物,以及使用固相寡核苷酸合成过程中很容易组装成三价或四价设计的GalNAc亚磷酰胺单体的其他四个共轭物。我们在体外和体内将这些化合物与临床使用的三价GalNAc簇进行了比较。在体外,基于簇和基于亚磷酰胺的支架在原代肝细胞中显示出相似的内在化速率,最早在5分钟时就观察到了膜结合。所有测试的化合物均具有有效的剂量依赖性沉默作用,1周后可从肝中回收2–4%的注射剂量。相对于通过亚磷酰胺化学组装的二价,三价或四价GalNAc缀合物,两个预组装的三价GalNAc簇显示出更高的组织积累和基因沉默。
更新日期:2018-06-13
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