Shiono H, Shibukawa A, Kuroda Y, Nakagawa T
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Chirality. 1997;9(3):291-6. doi: 10.1002/(SICI)1520-636X(1997)9:3<291::AID-CHIR15>3.0.CO;2-I.
The function of sialic acid groups at the terminal of sugar chains of human alpha 1-acid glycoprotein (AGP) was investigated with respect to chiral discrimination between optical isomers of basic drugs, using high-performance capillary electrophoresis/frontal analysis (HPCE/FA), a novel analytical method developed for the determination of unbound drug concentration with ultramicrosample volume (100-200 nl). Native human AGP and desialylated AGP were used as test proteins, and propranolol (PRO) and verapamil (VER) were used as model drugs. The unbound concentration of (S)-VER was 1.31 times higher than that of (R)-VER in native AGP solution. This selectivity was not affected by desialylation. Further, enzymatic elimination of galactose residues, which neighbored sialic acid groups, did not change the binding of either isomer of VER. On the other hand, the unbound concentration of (R)-PRO was 1.27 times higher than that of (S)-PRO in native AGP solution. Desialylation caused the unbound concentration of (S)-PRO to rise to the same level of (R)-PRO, resulting in loss of enantioselectivity. Thus, it follows that sialic acid groups of AGP, as a whole, are not responsible for chiral recognition between enantiomers of VER but are involved in enantioselectivity toward the isomers of PRO.
利用高效毛细管电泳/前沿分析法（HPCE/FA）这一为超微量样品体积（100 - 200 nl）测定游离药物浓度而开发的新型分析方法，研究了人α1 - 酸性糖蛋白（AGP）糖链末端唾液酸基团在碱性药物光学异构体之间的手性识别功能。天然人AGP和去唾液酸AGP用作测试蛋白，普萘洛尔（PRO）和维拉帕米（VER）用作模型药物。在天然AGP溶液中，（S）-VER的游离浓度比（R）-VER高1.31倍。这种选择性不受去唾液酸化的影响。此外，与唾液酸基团相邻的半乳糖残基的酶促去除并未改变VER任何一种异构体的结合。另一方面，在天然AGP溶液中，（R）-PRO的游离浓度比（S）-PRO高1.27倍。去唾液酸化导致（S）-PRO的游离浓度升至与（R）-PRO相同水平，导致对映体选择性丧失。因此，由此可见，AGP的唾液酸基团总体上不负责VER对映体之间的手性识别，但参与了对PRO异构体的对映体选择性。
