Screening Congo Red and its analogues for their ability to prevent the formation of PrP-res in scrapie-infected cells

Abstract

Transmissible spongiform encephalopathies (TSEs) are incurable, fatal diseases. The dye Congo Red (CR) can cure cells infected with agents of the sheep TSE, scrapie, but is not used as a therapeutic or prophylactic agent in vivo, as its effects are small, possibly due to low blood-brain barrier permeability, and complicated by its intrinsic carcinogenicity. In this paper, the development is described of a structure-activity profile for CR by testing a series of analogues of this dye for their ability to inhibit the formation of the protease-resistant prion protein, PrP-res, a molecular marker for the infectious agent, in the scrapie-infected, SMB cell line. It was found that the central benzidine unit in CR, which gives the molecule potential carcinogenicity, can be replaced by other, less toxic moieties and that the sulphonate groups on the core molecule can be replaced by carboxylic acids, which should improve the brain permeability of these compounds. However, detailed dose-response curves were generated for several derivatives and they revealed that, while some compounds showed inhibition of PrP-res accumulation at high concentrations, at low concentrations they actually stimulated levels of PrP-res above control values.

Oligomeric-Induced Activity by Thienyl Pyrimidine Compounds Traps Prion Infectivity

“…Targeting amyloid fibrils was also explored using amyloid dyes (Adjou et al, 1999;Beringue et al, 2000), but in vivo effects were disappointing because of their low ability to cross the blood-brain barrier. Other studies showed that targeting fibrils could result in an unexpected increase in infectivity (Beringue et al, 2000;Rudyk et al, 2000), which was also observed using the protein misfolding cyclic am-plification (PMCA) technique, when large amyloid aggregates were broken up into smaller ones (Saborio et al, 2001;Wang et al, 2010). Altogether, these works led to the emerging concept that amyloid fibrils, rather than being a pathological entity, might be the result of a protective process to sequester more dangerous soluble oligomers (Caughey and Lansbury, 2003;Silveira et al, 2005;Simoneau et al, 2007).…”

Kinetics and Energetics of Assembly, Nucleation, and Growth of Aggregates and Fibrils for an Amyloidogenic Protein

“…Similarly, ⌬V* growth in the presence of CR is about half that in the absence of CR, suggesting that the CR⅐SMA complex must undergo a smaller conformational change to reach N* than that for SMA alone. The effects of CR on both protein structure and assembly call into questions the proposed therapeutic uses of this compound or its analogs as inhibitors of amyloid fibril formation (35,36).…”

Spectroscopic and calorimetric studies of congo red dye-amyloid peptide complexes

“…The ITC data obtained for A and A [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Table 2. Due to the highly hydrophobic nature of A , preparation of a purely aqueous solution was not possible.…”

“…In this regard, Congo Red (CR) has been identified as a key inhibitor which reduce the neurotoxicity of AD by binding to protofibrils [11], and this inhibitory activity of CR and its derivatives have been screened as potential therapeutics against amyloid fibril formation [17][18][19][20]. The apolar moiety of CR is comprised of a biphenyl group at the center of the molecule and is extended by a diazo and two naphthalene groups.…”