Prion therapeutics: Lessons from the past

Abstract

Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP^C) into scrapie isoform (PrP^Sc) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrP^C to PrP^Sc conversion, increasing PrP^Sc removal, and PrP^C stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity in vitro, only a few were effective in vivo and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.

Keywords: CJD; Prions disease; anti-prion agents; mode of action; therapeutics; transmissible spongiform encephalopathies.

Figure 1.

Schematic representation of some anti-prion agents targeting prion proteins. PrP^C, PrP^Sc, and the conversion of PrP^C to PrP^Sc are the main targets of these anti-prion agents. Chaperones directly interact with PrP^C thereby stabilizing it and preventing/reducing its conversion to PrP^Sc. Another set of compounds clears the toxic aggregates by promoting autophagy. Abbreviations: PrP^C: normal prion protein; PrP^Sc: scrapie prion protein; EGCG: Epigallocatechin-3-gallate; AMT: Aminothiazoles; CPZ: Chlorpromazine; DMSO: Dimethylsulfoxide; QC: Quinacrine.(Prepared by Biorender.com).