NR ADGA
AU Demaimay,R.; Harper,J.; Gordon,H.; Weaver,D.; Chesebro,B.; Caughey,B.W.
TI Structural aspects of Congo red as an inhibitor of protease-resistant prion protein formation
QU Journal of Neurochemistry 1998 Dec; 71(6): 2534-41
PT journal article
AB Congo red (CR) has been shown to inhibit the accumulation in scrapie-infected cells of prion protein (PrP) in the abnormal protease-resistant form (PrPres). However, it was not clear if this effect was due to a direct interaction of CR with either PrPres or its protease-sensitive precursor (PrP-sen) or to a less direct effect on living cells. Here we show that CR inhibits PrPres formation in a simple cell-free reaction composed predominantly of purified PrPres and PrP-sen. Structurally modified CR analogues were also compared in both the cell-free conversion reaction and scrapie-infected neuroblastoma cells. Methylation of the central phenyl groups at the 2,2' positions diminished the inhibitory potency by > or = 10-fold. In contrast, there was little effect of 3,3' methylation of the phenyls, deletion of one phenyl, or addition of an amido group between the phenyls. The relative activities of these compounds were well correlated in both cellular and acellular systems. Molecular modeling indicated that CR and 3,3'-methyl-CR have little rotational restriction about the biphenyl bond and can readily adopt a planar conformation, as can phenyl-CR and amido-CR. In contrast, 2,2'-methyl-CR is restricted to a nonplanar conformation of the biphenyl group. Thus, planarity and/or torsional mobility of the central phenyl rings of CR and its analogues is probably important for inhibition of PrPres formation. On the other hand, variations in the intersulfonate distance in these molecules had little effect on PrPres inhibition. These results indicated a high degree of structural specificity in the inhibition of PrPres formation by CR and related compounds.
MH Animal; Biphenyl Compounds/metabolism; Cell-Free System/drug effects; Congo Red/*chemistry/metabolism/*pharmacology; Drug Resistance; Dyes/*chemistry/*pharmacology; Endopeptidases/*pharmacology; Hamsters; Methylation; Prions/*antagonists & inhibitors/metabolism; Protein Precursors/metabolism; Support, U.S. Gov't, P.H.S.; Tumor Cells, Cultured
AD Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA
SP englisch
PO USA