Title:New Approaches for the Selection and Evaluation of Anti-Prion Organic Compounds
Volume: 15
Issue: 2
Author(s): Yraima Cordeiro and Natalia C. Ferreira
Affiliation:
Keywords:
Aggregation, in silico methodologies, organic compounds, pharmacokinetics, prion protein, transmissible
spongiform encephalopathy.
Abstract: Transmissible spongiform encephalopathies (TSEs) are infectious neurodegenerative disorders for
which symptomatic, curative, or prophylactic treatments are not available. TSEs arise as a consequence of the
conversion of soluble cellular prion protein (PrPC) into the scrapie isoform (PrPSc), which aggregates and
accumulates in the central nervous system. Proposed drugs against TSEs range from small organic
compounds to antibodies; various therapeutic strategies have been proposed, including blocking the
conversion of PrPC to PrPSc, increasing PrPSc clearance, and/or stabilizing PrPC. While several compounds
have been effective in vitro and in animal models, none have proven effective in clinical studies to date. Such lack of in
vivo efficacy is attributable to high compound toxicity and the lack of permeability of the selected compounds across the
blood–brain barrier. In this review, we discuss recent advances in the screening and evaluation of organic compounds for
anti-prion activity using multiple approaches, including initial screening in prion-infected cell cultures, in silico prediction
of pharmacokinetic and physicochemical properties, ex vivo evaluation of cellular toxicity, and in vitro assays using
purified recombinant prion proteins. The main challenges for effective discrimination of candidate lead compounds as
therapeutic agents for TSEs, and the disadvantages of each screening strategy are discussed. We propose that a
combination of in vitro, ex vivo, and in silico approaches would be useful for the rapid identification of novel anti-prion
drug candidates with suitable pharmacokinetic and pharmacodynamic properties that would support their use as drugs.
