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Inhibition of L-selectin binding by polyacrylamide-based conjugates under defined flow conditions

机译:在规定的流动条件下,基于聚丙烯酰胺的结合物对L-选择蛋白的结合抑制

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Selectins mediate tethering and rolling of leukocytes along the endothelium in a shear force-dependent manner. This key step in the cellular immune response is a target for experimental anti-inflammatory therapies. In the present paper we have examined the inhibitory activity of the minimal selectin ligand sialyl Lewis x (SiaLe(x)), its isomer sialyl Lewis a (SiaLe(a)) and sulfated tyrosine (sTyr) residues under dynamic flow reflecting the rheological conditions in the blood stream. The monomeric ligands were compared to multivalent polyacrylamide (PAA)-based conjugates under defined flow conditions on the molecular level, using surface plasmon resonance (SPR) technology, and on the cellular level, using a parallel-plate flow chamber. SPR measurements showed that a spatial arrangement of binding epitopes mimicking the selectin binding motif of the natural ligand PSGL-1 inhibits L-selectin binding successfully with IC50 values in the nanomolar range. Using a flow chamber adhesion assay it could be shown that the multivalent inhibitors efficiently blocked rolling and tethering of NALM-6 pre-B cells transfected with human L-selectin to activated endothelium and that the inhibitory activity increased with rising shear stress. While PAA-conjugates were almost not inhibitory at low shear stress, NALM-6 cell rolling was nearly completely inhibited at high shear stress. The results indicate that multimeric conjugates of SiaLe(x), SiaLea and sTyr are highly effective inhibitors of L-selectin-mediated cell adhesion particularly Linder flow conditions. Consequently, SiaLe(x), SiaLe(x) and/or sTyr on macromolecular carriers may be promising candidates for anti-inflammatory therapy. (c) 2007 Elsevier B.V. All rights reserved.
机译:选择素介导以剪切力依赖的方式沿内皮细胞束缚和滚动白细胞。细胞免疫应答中的这一关键步骤是实验性抗炎疗法的目标。在本文中,我们研究了最小选择素配体唾液酸化路易斯(x)(SiaLe(x)),其异构体唾液酸化路易斯(aia)(siaLe(a))和硫酸化酪氨酸(sTyr)残基在反映流变条件的动态流动下的抑制活性。在血液中。使用表面等离振子共振(SPR)技术,在限定的流动条件下,将单体配体与基于多价聚丙烯酰胺(PAA)的缀合物进行比较,使用表面等离振子共振(SPR)技术,在细胞水平上,使用平行板流动室。 SPR测量显示,模拟天然配体PSGL-1的选择素结合基序的结合表位的空间排列可成功抑制L-选择素结合,其IC50值在纳摩尔范围内。使用流动室粘附测定法,可以表明多价抑制剂有效地阻断了用人L-选择素转染的NALM-6 pre-B细胞的滚动和束缚,并且其抑制活性随着剪切应力的增加而增加。虽然PAA偶联物在低剪切应力下几乎不受抑制,但在高剪切应力下NALM-6细胞的滚动几乎被完全抑制。结果表明,SiaLe(x),SiaLea和sTyr的多聚体共轭物是L-选择蛋白介导的细胞粘附(尤其是Linder流动条件)的高效抑制剂。因此,大分子载体上的SiaLe(x),SiaLe(x)和/或sTyr可能是抗炎治疗的有希望的候选人。 (c)2007 Elsevier B.V.保留所有权利。

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