Li Qiang, Dong Mingxin, Chen Pu
Department of Medicinal Chemistry, School of Pharmacy, Qingdao University Qingdao 266021 China
Research and Development Department, NanoPeptide (Qingdao) Biotechnology Ltd Qingdao China.
RSC Adv. 2024 May 30;14(25):17461-17466. doi: 10.1039/d4ra03023k. eCollection 2024 May 28.
GalNAc-conjugated siRNA has shown remarkable potential in liver-targeted delivery in recent years. In general, tetrahydroxymethylmethane or other branching clusters constitute the basis of GalNAc's structure, which yields trivalent or tetravalent ligands. A novel diamine-scaffold GalNAc conjugate was synthesized and evaluated for its efficiency in siRNA administration. It exhibits comparable siRNA delivery effectiveness to a GalNAc NAG37 phase II clinical drug candidate targeting ANGPTL3. In addition, it exhibits more powerful silencing activity when connected to the 3'-end of the sense strand with an additional PS-linkage instead of a PO linkage between the ligand and the oligomer compared to a GalNAc L96 standard targeting TTR. Taken together, the incorporation of a diamine-scaffold into the GalNAc conjugate structure has potential in the field of gene therapy.
近年来，N-乙酰半乳糖胺（GalNAc）缀合的小干扰RNA（siRNA）在肝脏靶向递送方面显示出巨大潜力。一般来说，四羟甲基甲烷或其他分支簇构成了GalNAc结构的基础，由此产生三价或四价配体。合成了一种新型的二胺支架GalNAc缀合物，并对其在siRNA给药中的效率进行了评估。它在siRNA递送效果方面与一种靶向血管生成素样蛋白3（ANGPTL3）的GalNAc NAG37 II期临床候选药物相当。此外，与靶向甲状腺素运载蛋白（TTR）的GalNAc L96标准物相比，当通过额外的硫代磷酸酯（PS）连接而非磷酸二酯（PO）连接连接到正义链的3'端时，它表现出更强的沉默活性。综上所述，将二胺支架引入GalNAc缀合物结构在基因治疗领域具有潜力。
