Targeted Delivery of Antisense Oligonucleotides Using Neurotensin Peptides

被引：31

作者：

Nikan, Mehran ^{[1
]}

Tanowitz, Michael ^{[1
]}

Dwyer, Chrissa A. ^{[1
]}

Jackson, Michaela ^{[1
]}

Gaus, Hans J. ^{[1
]}

Swayze, Eric E. ^{[1
]}

Rigo, Frank ^{[1
]}

Seth, Punit P. ^{[1
]}

Prakash, Thazha P. ^{[1
]}

机构：

[1] Ionis Pharmaceut Inc, Carlsbad, CA 92010 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 15期

关键词：

MOLECULAR-MECHANISMS; SORTILIN; ANALOGS; BINDING;

D O I：

10.1021/acs.jmedchem.0c00840

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Despite recent advances, targeted delivery of therapeutic oligonucleotide to extra-hepatic tissues continues to be a challenging endeavor and efficient ligand-receptor systems need to be identified. To determine the feasibility of using neurotensin to improve the productive uptake of antisense oligonucleotides (ASO), we synthesized neurotensin-ASO conjugates and evaluated their cellular uptake and activity in cells and in mice. We performed a comprehensive structure-activity relationship study of the conjugates and determined the influence of ASO charge, ASO length, peptide charge, linker chemistry and ligand identity on receptor binding and internalization. We identified a modified neurotensin peptide capable of improving the cellular uptake and activity of gapmer ASOs in sortilin expressing cells (sixfold) and in spinal cord in mice (twofold). Neurotensin conjugation also improved the potency of morpholino ASO designed to correct splicing of survival motor neuron pre-mRNA in the cortex and striatum after intracerebroventricular injection. Neurotensin-mediated targeted delivery represents a possible approach for enhancing the potency of ASOs with diverse nucleic acid modifications.

引用

页码：8471 / 8484

页数：14

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