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:

• Prions disease
• transmissible spongiform encephalopathies
• CJD
• anti-prion agents
• mode of action
• therapeutics

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author Contributions

Conceptualization, K.H.S, N.S., and S.S.A.A.; writing—original draft preparation, N.S.; writing—review and editing, K.H.S, N.S. and S.S.A.A.; funding acquisition, S.S.A.A. All authors read and agreed to the final version of the manuscript.

Additional information

Funding

This research was funded by the National Research Foundation of Korea by the Korean Government (2021R1A2C1093218) and the Korean National Institute of Health Research (National Institute of Health, Korea 2022E210100).