期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 143, 期 9, 页码 3416-3429出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c12043
关键词
-
资金
- Structure Analysis and Separation Science group of AstraZeneca Gothenburg
The study demonstrates the potential of GLP1R agonist conjugation to improve the delivery efficiency of ASOs in diabetes treatment, particularly for pancreatic beta cells. Optimization of linker chemistry and exploration of GLP1R agonist ligands can effectively enhance the in vivo efficacy of ASOs.
The extra hepatic delivery of antisense oligonucleotides (ASOs) remains a challenge and hampers the widespread application of this powerful class of therapeutic agents. In that regard, pancreatic beta cells are a particularly attractive but challenging cell type because of their pivotal role in diabetes and the fact that they are refractory to uptake of unconjugated ASOs. To circumvent this, we have expanded our understanding of the structure activity relationship of ASOs conjugated to Glucagon Like Peptide 1 Receptor (GLP1R) agonist peptide ligands. We demonstrate the key role of the linker chemistry and its optimization to design maleimide based conjugates with improved in vivo efficacy. In addition, truncation studies and scoping of a diverse set of GLP1R agonists proved fruitful to identify additional targeting ligands efficacious in vivo including native hGLP1(7-36)NH2. Variation of the carrier peptide also shed some light on the dramatic impact of subtle sequence differences on the corresponding ASO conjugate performance in vivo, an area which clearly warrant further investigations. We have confirmed the remarkable potential of GLP1R agonist conjugation for the delivery of ASOs to pancreatic beta cell by effectively knocking down islet amyloid polypeptide (IAPP) mRNA, a potential proapoptotic target, in mice.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据