There is provided inter alia a conjugate for inhibiting expression of a target gene in a cell, said conjugate comprising a nucleic acid portion and ligand portions, said nucleic acid portion comprising at least one duplex region that comprises at least a portion of a first RNA strand and at least a portion of a second RNA strand that is at least partially complementary to the first strand, wherein said first strand is at least partially complementary to at least a portion of RNA transcribed from said target gene, said ligand portions comprising a linker moiety and a targeting ligand for in vivo targeting of cells and being conjugated exclusively to the 3' and/or 5' ends of one or both RNA strands, wherein the 5' end of the first RNA strand is not conjugated, wherein: (i) the second RNA strand is conjugated at the 5' end to the targeting ligand, and wherein (a) the second RNA strand is also conjugated at the 3' end to the targeting ligand and the 3' end of the first RNA strand is not conjugated; or (b) the first RNA strand is conjugated at the 3' end to the targeting ligand and the 3' end of the second RNA strand is not conjugated; or (c) both the second RNA strand and the first RNA strand are also conjugated at the 3' ends to the targeting ligand; or (ii) both the second RNA strand and the first RNA strand are conjugated at the 3' ends to the targeting ligand and the 5' end of the second RNA strand is not conjugated.
提供了一种用于抑制细胞中靶
基因表达的共轭物,该共轭物包括
核酸部分和
配体部分,所述
核酸部分包括至少一个双链区域,该区域包括至少部分第一RNA链和至少部分第二RNA链,该第二RNA链至少部分与第一链互补,其中所述第一链至少部分与从所述靶
基因转录的RNA的至少部分互补,所述
配体部分包括连接子基团和用于体内细胞靶向的靶向
配体,并且仅连接到一个或两个RNA链的3'和/或5'末端,其中第一RNA链的5'末端未连接,其中:(i) 第二RNA链在5'末端连接到靶向
配体,其中(a) 第二RNA链还在3'末端连接到靶向
配体,且第一RNA链的3'末端未连接;或(b) 第一RNA链在3'末端连接到靶向
配体,且第二RNA链的3'末端未连接;或(c) 第二RNA链和第一RNA链的3'末端均连接到靶向
配体;或(ii) 第二RNA链和第一RNA链的3'末端均连接到靶向
配体,且第二RNA链的5'末端未连接。