Nanoscale self-assembled multivalent (SAMul) heparin binders in highly competitive, biologically relevant, aqueous media
Nanoscale self-assembled multivalent (SAMul) heparin binders in highly competitive, biologically relevant, aqueous media
复制标题
DOI：
10.1039/c4sc00298a
复制
发表时间：
2014-01-01
期刊：
影响因子：
8.4
通讯作者：
Smith, David K.
中科院分区：
文献类型：
--
作者：
Bromfield, Stephen M.;Posocco, Paola;Smith, David K.
这篇论文研究了小分子自组装展示多价配体阵列与肝素结合。在水中，自组装多价(SAMUL)肝素结合剂与当前临床肝素逆转剂鱼精蛋白具有很强的竞争力。随着盐的加入，自组装纳米结构的尺寸增大。这一独特的特征是由于组装的动态、响应的性质，使用多尺度建模预测并在实验中证明，相对于固定的共价多价纳米结构，增强SAMUL系统的肝素结合。相反，由于组件的部分不稳定，血清的存在对SAMUL系统相对于共价纳米结构的肝素结合产生不利影响。尽管如此，人体血浆中的凝血试验表明SAMUL系统起到了肝素功能逆转剂的作用。化合物的降解会导致纳米结构的解体和SAMUL结合的丧失，由于酯类的水解会在24小时内发生--但当与肝素结合时，稳定性会增强。肝素在血浆中的逆转，以及治疗上有用的降解谱，使这种SAMUL方法在取代鱼精蛋白方面具有潜在的治疗价值，鱼精蛋白在临床上使用时会产生一些不良反应。
This paper investigates small molecules that self-assemble to display multivalent ligand arrays for heparin binding. In water, the self-assembled multivalent (SAMul) heparin binder is highly competitive with the current clinical heparin reversal agent, protamine. On addition of salt, the dimensions of the self-assembled nanostructure increase. This unique feature is due to the dynamic, responsive nature of assembly, predicted using multiscale modelling and proven experimentally, enhancing heparin binding of SAMul systems relative to fixed covalent multivalent nanostructures. Conversely, the presence of serum adversely affects the heparin binding of SAMul systems relative to covalent nanostructures due to partial destabilisation of the assemblies. Nonetheless, clotting assays in human plasma demonstrate that the SAMul system acts as a functional heparin reversal agent. Compound degradation, inducing nanostructure disassembly and loss of SAMul binding, takes place over 24 hours due to ester hydrolysis - but when bound to heparin, stability is enhanced. Heparin reversal in plasma, and the therapeutically useful degradation profile, make this SAMul approach of potential therapeutic value in replacing protamine, which has a number of adverse effects when used in the clinic.