School of Chemistry & Biochemistry, Georgia Institute of Technology , 901 Atlantic Avenue, Atlanta, Georgia 30332, United States.
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
J Am Chem Soc. 2017 Mar 8;139(9):3528-3536. doi: 10.1021/jacs.6b12964. Epub 2017 Feb 23.
A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo. Assessment of the biodistribution in rodents of a prototypical Alexa647-labeled trivalent conjugate showed selective hepatocyte targeting with no detectable distribution in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed hepatocellular uptake and prolonged retention compared to a similar GalNAc derived trimer conjugate. Selective release in the liver of a passively permeable small-molecule cargo was achieved by retro-Diels-Alder cleavage of an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, the multicomponent construct described here represents a highly efficient delivery vehicle to hepatocytes.
开发了一种紧凑稳定的双环桥接缩酮作为去唾液酸糖蛋白受体（ASGPR）的配体。该化合物表现出优异的配体效率，并且通过 ASGPR 配体结合的首次 X 射线晶体结构揭示了结合的分子细节。该类似物被用于制备 ASGPR 的有效二价和三价结合物。对这些化合物功能的广泛表征表明，它们在体外具有快速的 ASGPR 依赖性细胞摄取作用，并且在体内具有高的肝脏/血浆选择性。对啮齿动物中原型 Alexa647 标记的三价缀合物的生物分布评估表明，具有选择性的肝细胞靶向作用，在非实质细胞中没有检测到分布。与类似的 GalNAc 衍生的三聚体缀合物相比，该分子还表现出增加的 ASGPR 定向肝细胞摄取和延长的保留。通过反-Diels-Alder 断裂 oxanorbornadiene 键，小分子货物的被动渗透在肝脏中实现选择性释放，推测是在遇到细胞内硫醇时。因此，这里描述的多组分构建物代表了一种高效的肝细胞递药载体。
