Binding of anti-prion agents to glycosaminoglycans: evidence from electronic absorption and circular dichroism spectroscopy.
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.
Zsila
Ferenc
F
Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, POB 17, Budapest, H-1525, Hungary. zsferi@chemres.hu
Gedeon
Gábor
G
D000042:Absorption; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D006025:Glycosaminoglycans / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology; D011328:Prions / Q000037:antagonists & inhibitors*; D011796:Quinacrine / Q000737:chemistry / Q000494:pharmacology
D006025:Glycosaminoglycans; D011328:Prions; D006493:Heparin; D002809:Chondroitin Sulfates; D011796:Quinacrine