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首页> 外文期刊>Drug design and discovery >Inhibition of beta 2glycoprotein I binding to anionic phospholipids: a strategy for the development of antiphospholipid syndrome-specific drugs.
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Inhibition of beta 2glycoprotein I binding to anionic phospholipids: a strategy for the development of antiphospholipid syndrome-specific drugs.

机译：抑制β2糖蛋白I与阴离子磷脂的结合：开发抗磷脂综合征特异性药物的策略。

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摘要

The binding of beta 2glycoprotein I (beta 2GPI) to anionic phospholipids (PL) leads to the presentation of one or more epitopes recognized by autoantibodies from patients with antiphospholipid syndrome (APS). The inhibition of beta 2GPI binding to PL mixtures coated on polystyrene microtiter wells (MTW) and to large, multilamellar PL vesicles (LMV) was examined. Inhibitors included phosphorylated monosaccharide metabolites, myo-inositol monophosphate (IMP), hexaphosphate (IHP) and hexasulfate (IHS), pyrophosphate (PPi), methyl bisphosphonate (MBP) and phenyl phosphonate, and a series of carboxylic and aromatic sulfonic acids. Inhibitors were incubated with beta 2GPI at 37 degrees C for 2 hr either with dimyristoylphosphatidic acid, 80%/dimyristoylphosphatidyl choline, 20% (DMPA/DMPC) coated on MTW or in a suspension of LMV. Phospholipid-bound beta 2GPI to PA/PC on MTW was detected using an immunoassay based on rabbit anti-beta 2GPI; free beta 2GPI (not bound to LMV) was detected by fluorescence spectroscopy. Inhibition was studied over the range 0.01-9.0 mumoles/10(-4)L (0.1-90 mM). Inhibition at maximum concentration in the MTW system ranged from 0.1% (for ADP) to > 94% (for IHP). IHP also provided the greatest inhibition in the LMV system (76%) and was also effective in displacing beta 2GPI already bound to PL surfaces (approximately 50% displaced at 0.25 mM). These data suggest that a strategy for development of therapeutic agents for APS may be based on the use of small cyclic, organic oligoanions such as inositol derivatives to act as ligands for lysine residues at the PL binding site of beta 2GPI.
机译：β2糖蛋白I（β2 GPI）与阴离子磷脂（PL）的结合导致呈现一种或多种抗原表位，这些抗原表位被抗磷脂综合症（APS）患者的自身抗体识别。测试了β2GPI与包被在聚苯乙烯微量滴定孔（MTW）上的PL混合物以及大的多层PL囊泡（LMV）结合的抑制作用。抑制剂包括磷酸化的单糖代谢产物，肌醇单磷酸酯（IMP），六磷酸酯（IHP）和六硫酸酯（IHS），焦磷酸酯（PPi），双膦酸甲酯（MBP）和苯基膦酸酯，以及一系列羧酸和芳族磺酸。将抑制剂与β2GPI在37℃下与涂在MTW上的二豆蔻酰基磷脂酸，80％/二肉豆蔻酰基磷脂酰胆碱，20％（DMPA / DMPC）或LMV悬浮液中孵育2小时。使用基于兔抗β2GPI的免疫测定法检测MTW上与PA / PC结合的磷脂β2GPI。通过荧光光谱法检测到游离β2GPI（不与LMV结合）。在0.01-9.0摩尔/ 10（-4）L（0.1-90 mM）的范围内研究了抑制作用。在MTW系统中，最大浓度时的抑制作用范围为0.1％（对于ADP）到> 94％（对于IHP）。 IHP在LMV系统中也提供了最大的抑制作用（76％），并且还可以有效取代已经与PL表面结合的β2GPI（在0.25 mM处位移约50％）。这些数据表明，开发APS治疗剂的策略可能基于使用小的环状有机低聚阴离子（如肌醇衍生物）充当β2GPI的PL结合位点赖氨酸残基的配体。

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