Michael Nguyen, Tanaya Walimbe, Andrew Woolley, John Paderi, Alyssa Panitch
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引用次数: 0
摘要
许多内皮并发症,无论是手术还是病理引起的,都会导致内皮层剥脱和胶原蛋白暴露。胶原蛋白的暴露会导致血小板活化,引发血栓和炎症级联反应,最终导致血管狭窄。我们以前曾报道过使用肽-GAG 化合物来靶向内皮损伤后暴露的胶原蛋白。在本文中,我们优化了胶原蛋白结合肽的间隔序列,以增加其与 GAG 骨架的连接,并通过增加肽 C 端阳离子电荷来提高肽-GAG 胶原蛋白结合亲和力。此外,我们还证明了这些分子可通过阻断胶原蛋白来抑制血小板活化,并可在全身给药后定位到暴露的血管胶原蛋白上。总之,肽序列和连接化学的优化可以提高共轭能力和功能,并对糖共轭物在其他临床应用中的使用产生影响。
Synthesis and Optimization of Collagen-targeting Peptide-Glycosaminoglycans for Inhibition of Platelets Following Endothelial Injury.
Many endothelial complications, whether from surgical or pathological origins, can result in the denudation of the endothelial layer and the exposure of collagen. Exposure of collagen results in the activation of platelets, leading to thrombotic and inflammatory cascades that ultimately result in vessel stenosis. We have previously reported the use of peptide-GAG compounds to target exposed collagen following endothelial injury. In this paper we optimize the spacer sequence of our collagen binding peptide to increase its conjugation to GAG backbones and increase the peptide-GAG collagen binding affinity by increasing peptide C-terminal cationic charge. Furthermore, we demonstrate the use of these molecules to inhibit platelet activation through collagen blocking, as well as their localization to exposed vascular collagen following systemic delivery. Altogether, optimization of peptide sequence and linkage chemistry can allow for increased conjugation and function, having implications for glycoconjugate use in other clinical applications.