Effect of poly-L-arginine in inhibiting scrapie prion protein of cultured cells

Abstract

Biological effect of poly-L-arginine (PLR), the linear homopolymer comprised of L-arginine, was investigated to determine the activity of suppressing prions. PLR decreased the level of scrapie prion protein (PrPSc) in cultured cells permanently infected with prions in a concentration dependent manner. The PrPSc inhibition efficacy of PLR was greater than that of another prion suppressant poly-L-lysine (PLK) in a molecular mass-dependent fashion. The effective concentration of PLR to inhibit prions was achieved safely below the cytotoxic concentrations and overall cytotoxicity of PLR was similar to that of PLK. PLR did not alter the cellular prion protein (PrPC) level and was unable to change the states of preformed recombinant PrP aggregates and PrPSc from prion-infected cells. These data eliminate the possibility that the action mechanism of PLR is through removal of PrPC and pre-existing PrPSc. However, PLR formed complexes with plasminogen that stimulates prion propagation via conversion of PrPC to the misfolded isoform, PrPSc. The plasminogen-PLR complex demonstrated the greater positive surface charge values than the similar complex with PLK, raising the possibility that PLR interferes with the role of cofactor for PrPSc generation better than PLK.

Poly-L-histidine inhibits prion propagation in a prion-infected cell line

“…The strong anti-prion activity (IC 50 = 1.8 µg/mL) was observed only in high-molecular-weight poly-L-His, but not in low-molecular-weight poly-L-His or monomeric L-histidine. While poly-L-His is the third poly-(amino acid) that exhibits anti-prion activity, following poly-L-Lys [8][9][10] and poly-L-Arg [11], it represents the most potent inhibitory activity against Fukuoka-1 strain among the three poly-(amino acid)s. Although strain dependence of the anti-prion activity remains to be demonstrated, the mechanism of action (i.e. direct binding to PrP C ) indicate that poly-L-His might inhibit prion propagation in strain-independent manner.…”

“…However, a careful interpretation is necessary, because the extent of target specificity of poly-(amino acid)s remains elusive. In fact, Ryou and colleagues recently proposed that poly-L-Arg and poly-L-Lys bind to plasminogen activator [11], a molecule that might promote the pathogenic conversion of PrP [37]. A further experiment using pull-down assay coupled with mass spectroscopy is required to identify the target molecule of the poly-(amino acid)s and to further understand the anti-prion mechanism.…”

“…These studies led us to hypothesize that poly-(amino acid)s, charged molecules with repeating units, is a potential molecule for inhibiting prion propagation. In fact, several preceding studies have reported anti-prion activity in a positively charged poly-(amino acid)s, such as poly-L-Lys [8][9][10] and poly-L-Arg [11].…”

Lysine‐Derived Carbon Dots for Chiral Inhibition of Prion Peptide Fibril Assembly

“…The prion hypothesis accounts for the spread and pathogenicity of TSE . Specifically, the conversion of the normal cellular form of the prion peptide, PrP C , to the infectious form PrP Sc is theorized to be a causative agent affecting the brains of people and animals suffering from these diseases . This abnormality is manifested as a conformation change of the protein from an α‐helix into a β‐sheet; this transformation has apparent catalytic properties, propagating within the surrounding proteins.…”

“…Varied substances have been tested for their ability to prevent/retard amyloid plaque formation, including small molecules (primarily polyphenols), peptides, polymers, and nanoparticles . In the search for effective inhibitor compounds, a variety of aggregate features have been targeted.…”