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Comprehensive Structure–Activity Relationship of Triantennary N-Acetylgalactosamine Conjugated Antisense Oligonucleotides for Targeted Delivery to Hepatocytes
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-03-09 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01948 Thazha P. Prakash 1 , Jinghua Yu 1 , Michael T. Migawa 1 , Garth A. Kinberger 1 , W. Brad Wan 1 , Michael E. Østergaard 1 , Recaldo L. Carty 1 , Guillermo Vasquez 1 , Audrey Low 1 , Alfred Chappell 1 , Karsten Schmidt 1 , Mariam Aghajan 1 , Jeff Crosby 1 , Heather M. Murray 1 , Sheri L. Booten 1 , Jill Hsiao 1 , Armand Soriano 1 , Todd Machemer 1 , Patrick Cauntay 1 , Sebastien A. Burel 1 , Susan F. Murray 1 , Hans Gaus 1 , Mark J. Graham 1 , Eric E. Swayze 1 , Punit P. Seth 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-03-09 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01948 Thazha P. Prakash 1 , Jinghua Yu 1 , Michael T. Migawa 1 , Garth A. Kinberger 1 , W. Brad Wan 1 , Michael E. Østergaard 1 , Recaldo L. Carty 1 , Guillermo Vasquez 1 , Audrey Low 1 , Alfred Chappell 1 , Karsten Schmidt 1 , Mariam Aghajan 1 , Jeff Crosby 1 , Heather M. Murray 1 , Sheri L. Booten 1 , Jill Hsiao 1 , Armand Soriano 1 , Todd Machemer 1 , Patrick Cauntay 1 , Sebastien A. Burel 1 , Susan F. Murray 1 , Hans Gaus 1 , Mark J. Graham 1 , Eric E. Swayze 1 , Punit P. Seth 1
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The comprehensive structure–activity relationships of triantennary GalNAc conjugated ASOs for enhancing potency via ASGR mediated delivery to hepatocytes is reported. Seventeen GalNAc clusters were assembled from six distinct scaffolds and attached to ASOs. The resulting ASO conjugates were evaluated in ASGR binding assays, in primary hepatocytes, and in mice. Five structurally distinct GalNAc clusters were chosen for more extensive evaluation using ASOs targeting SRB-1, A1AT, FXI, TTR, and ApoC III mRNAs. GalNAc–ASO conjugates exhibited excellent potencies (ED50 0.5–2 mg/kg) for reducing the targeted mRNAs and proteins. This work culminated in the identification of a simplified tris-based GalNAc cluster (THA-GN3), which can be efficiently assembled using readily available starting materials and conjugated to ASOs using a solution phase conjugation strategy. GalNAc–ASO conjugates thus represent a viable approach for enhancing potency of ASO drugs in the clinic without adding significant complexity or cost to existing protocols for manufacturing oligonucleotide drugs.
中文翻译：
三天线N-乙酰半乳糖胺共轭反义寡核苷酸针对肝细胞的靶向递送的全面结构-活性关系。
报道了三天线GalNAc共轭ASO通过ASGR介导的向肝细胞的传递增强效力的全面的构效关系。用六个不同的支架组装了十七个GalNAc簇，并与ASO相连。在ASGR结合试验，原代肝细胞和小鼠中评估所得的ASO缀合物。选择了五个结构不同的GalNAc簇，以针对SRB-1，A1AT，FXI，TTR和ApoC III mRNA的ASO进行更广泛的评估。GalNAc-ASO共轭物表现出出色的效能（ED 500.5–2 mg / kg），以减少目标mRNA和蛋白质。这项工作最终确定了简化的基于tris的GalNAc簇（THA-GN3），可以使用容易获得的起始材料有效地组装它们，并使用溶液相偶联策略将其与ASO偶联。因此，GalNAc-ASO偶联物代表了一种在临床中增强ASO药物效力的可行方法，而不会增加现有的寡核苷酸药物生产流程的复杂性或成本。
更新日期：2016-03-09
中文翻译：
三天线N-乙酰半乳糖胺共轭反义寡核苷酸针对肝细胞的靶向递送的全面结构-活性关系。
报道了三天线GalNAc共轭ASO通过ASGR介导的向肝细胞的传递增强效力的全面的构效关系。用六个不同的支架组装了十七个GalNAc簇，并与ASO相连。在ASGR结合试验，原代肝细胞和小鼠中评估所得的ASO缀合物。选择了五个结构不同的GalNAc簇，以针对SRB-1，A1AT，FXI，TTR和ApoC III mRNA的ASO进行更广泛的评估。GalNAc-ASO共轭物表现出出色的效能（ED 500.5–2 mg / kg），以减少目标mRNA和蛋白质。这项工作最终确定了简化的基于tris的GalNAc簇（THA-GN3），可以使用容易获得的起始材料有效地组装它们，并使用溶液相偶联策略将其与ASO偶联。因此，GalNAc-ASO偶联物代表了一种在临床中增强ASO药物效力的可行方法，而不会增加现有的寡核苷酸药物生产流程的复杂性或成本。
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