Schultis H W, von Baeyer H, Neitzel H, Riedel E
Institut für Biochemie, Freie Universität Berlin, Germany.
Eur J Clin Chem Clin Biochem. 1991 Oct;29(10):665-74. doi: 10.1515/cclm.1991.29.10.665.
Antiviral therapy of human immunodeficiency virus (HIV) infection is currently based on inhibition of reverse transcriptase by dideoxynucleosides, such as azidothymidine. Because of widespread toxicity it is reasonable to selectively target these drugs to infected cells. This may be accomplished utilizing drug-LDL conjugates, which are internalized via cell specific receptor pathways. With respect to HIV infection, scavenger receptors of the macrophage system seems to offer a hopeful perspective. This pathway requires chemical modification of surface polarity of the LDL. Cell experiments were conducted in HepG2 hepatocytes, which express apolipoprotein B receptors, and in P388 macrophages, which express scavenger receptors. LDL particles to be conjugated were isolated from blood donor plasma and from LDL-apheresis waste material. Non-covalent LDL conjugation with amphiphilic nucleoside derivatives produced only an unspecific nucleoside transfer to cell membranes, due to instability of the LDL conjugates. An experimental method (coincubation test) was developed to identify those conjugates that are stable in the presence of other lipophilic compartments. Covalent coupling of nucleosides to the apolipoprotein B moiety of LDL particles resulted in stable conjugates. As a consequence, the surface charge became negative, and the LDL displayed scavenger receptor affinity rather than apolipoprotein B receptor affinity. Selective targeting of nucleosides to macrophages can be accomplished by covalent coupling to LDL.
目前，人类免疫缺陷病毒（HIV）感染的抗病毒治疗是基于双脱氧核苷（如叠氮胸苷）对逆转录酶的抑制作用。由于其广泛的毒性，将这些药物选择性地靶向感染细胞是合理的。这可以通过利用药物-LDL偶联物来实现，药物-LDL偶联物通过细胞特异性受体途径被内化。就HIV感染而言，巨噬细胞系统的清道夫受体似乎提供了一个有希望的前景。该途径需要对LDL的表面极性进行化学修饰。在表达载脂蛋白B受体的HepG2肝细胞和表达清道夫受体的P388巨噬细胞中进行了细胞实验。用于偶联的LDL颗粒从献血者血浆和LDL血液成分分离废料中分离出来。由于LDL偶联物的不稳定性，两亲性核苷衍生物与LDL的非共价偶联仅产生非特异性的核苷转移到细胞膜上。开发了一种实验方法（共孵育试验）来鉴定那些在其他亲脂性区室存在下稳定的偶联物。核苷与LDL颗粒的载脂蛋白B部分的共价偶联产生了稳定的偶联物。结果，表面电荷变为阴性，并且LDL表现出清道夫受体亲和力而不是载脂蛋白B受体亲和力。通过与LDL共价偶联可以实现核苷对巨噬细胞的选择性靶向。
