Zsila Ferenc, Gedeon Gábor
Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, POB 17, Budapest, H-1525, Hungary.
Biochem Biophys Res Commun. 2006 Aug 11;346(4):1267-74. doi: 10.1016/j.bbrc.2006.06.033. Epub 2006 Jun 14.
The polyanionic glycosaminoglycans (GAGs) are intimately involved in the pathogenesis of protein conformational disorders such as amyloidosis and prion diseases. Several cationic agents are known to exhibit anti-prion activity but their mechanism of action is poorly understood. In this study, UV absorption and circular dichroism (CD) spectroscopic techniques were used to investigate the interaction between heparin and chondroitin-6-sulfate and anti-prion drugs including acridine, quinoline, and phenothiazine derivatives. UV band hypochromism of (+/-)-quinacrine, (+/-)-primaquine, tacrine, quinidine, chlorpromazine, and induced CD spectra of (+/-)-quinacrine upon addition of GAGs provided evidence for the GAG binding of these compounds. The association constants (approximately 10(6)-10(7)M(-1)) estimated from the UV titration curves show high-affinity drug-heparin interactions. Ionic strength-dependence of the absorption spectra suggested that the interaction between GAGs and the cationic drugs is principally electrostatic in nature. Drug binding differences of heparin and chondroitin-6-sulfate were attributed to their different negative charge density. These results call the attention to the alteration of GAG-prion/GAG-amyloid interactions by which these compounds might exert their anti-prion/anti-amyloidogenic activities.
聚阴离子糖胺聚糖（GAGs）与蛋白质构象紊乱（如淀粉样变性和朊病毒疾病）的发病机制密切相关。已知几种阳离子药物具有抗朊病毒活性，但其作用机制尚不清楚。在本研究中，采用紫外吸收和圆二色性（CD）光谱技术研究了肝素与硫酸软骨素-6-硫酸盐以及包括吖啶、喹啉和吩噻嗪衍生物在内的抗朊病毒药物之间的相互作用。（±）-奎纳克林、（±）-伯氨喹、他克林、奎尼丁、氯丙嗪的紫外吸收带减色以及加入GAGs后（±）-奎纳克林的诱导CD光谱为这些化合物与GAGs的结合提供了证据。从紫外滴定曲线估计的缔合常数（约10⁶ - 10⁷ M⁻¹）显示了药物与肝素的高亲和力相互作用。吸收光谱对离子强度的依赖性表明，GAGs与阳离子药物之间的相互作用主要是静电性质的。肝素和硫酸软骨素-6-硫酸盐的药物结合差异归因于它们不同的负电荷密度。这些结果提醒人们注意GAG-朊病毒/GAG-淀粉样蛋白相互作用的改变，这些化合物可能通过这种改变发挥其抗朊病毒/抗淀粉样蛋白生成活性。
