Anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches

• Published in: PloS one Vol. 9; no. 1; p. e84531
• Main Authors: Ferreira, Natalia C, Marques, Icaro A, Conceição, Wesley A, Macedo, Bruno, Machado, Clarice S, Mascarello, Alessandra, Chiaradia-Delatorre, Louise Domeneghini, Yunes, Rosendo Augusto, Nunes, Ricardo José, Hughson, Andrew G, Raymond, Lynne D, Pascutti, Pedro G, Caughey, Byron, Cordeiro, Yraima
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.01.2014; Public Library of Science (PLoS)
• Subjects: Accumulation; Agglomeration; Amyloidogenesis; Animals; Aromatic compounds; Biocompatibility; Biology; Blood-brain barrier; Bovine spongiform encephalopathy; Brain; Cell Line; Chemical compounds; Chemistry; Clinical trials; Computer Simulation; Conversion; Cytotoxicity; Dose-Response Relationship, Drug; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; Infectious diseases; Laboratories; Medicine; Models, Molecular; Molecular docking; Mutagenicity; Nervous system diseases; Neuroblastoma; Neuroblastoma cells; Neurodegenerative diseases; Neurological diseases; Peptides; Pharmacology; Physicochemical properties; Prion protein; Prions (Proteins); Prions - chemistry; Prions - drug effects; Protein Conformation; Proteins; Scrapie; Structural models; Therapy; Toxicity; Transmissible spongiform encephalopathy; Brazil; Rio de Janeiro Brazil; Montana; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084531

The prion protein (PrP) is implicated in the Transmissible Spongiform Encephalopathies (TSEs), which comprise a group of fatal neurodegenerative diseases affecting humans and other mammals. Conversion of cellular PrP (PrP(C)) into the scrapie form (PrP(Sc)) is the hallmark of TSEs. Once formed, PrP(Sc) aggregates and catalyzes PrP(C) misfolding into new PrP(Sc) molecules. Although many compounds have been shown to inhibit the conversion process, so far there is no effective therapy for TSEs. Besides, most of the previously evaluated compounds failed in vivo due to poor pharmacokinetic profiles. In this work we propose a combined in vitro/in silico approach to screen for active anti-prion compounds presenting acceptable drugability and pharmacokinetic parameters. A diverse panel of aromatic compounds was screened in neuroblastoma cells persistently infected with PrP(Sc) (ScN2a) for their ability to inhibit PK-resistant PrP (PrP(Res)) accumulation. From ∼200 compounds, 47 were effective in decreasing the accumulation of PrP(Res) in ScN2a cells. Pharmacokinetic and physicochemical properties were predicted in silico, allowing us to obtain estimates of relative blood brain barrier permeation and mutagenicity. MTT reduction assays showed that most of the active compounds were non cytotoxic. Compounds that cleared PrP(Res) from ScN2a cells, were non-toxic in the MTT assay, and presented a good pharmacokinetic profile were investigated for their ability to inhibit aggregation of an amyloidogenic PrP peptide fragment (PrP(109-149)). Molecular docking results provided structural models and binding affinities for the interaction between PrP and the most promising compounds. In summary, using this combined in vitro/in silico approach we have identified new small organic anti-scrapie compounds that decrease the accumulation of PrP(Res) in ScN2a cells, inhibit the aggregation of a PrP peptide, and possess pharmacokinetic characteristics that support their drugability. These compounds are attractive candidates for prion disease therapy.