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Therapeutic strategies for identifying small molecules against prion diseases

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Abstract

Prion diseases are fatal neurodegenerative disorders, for which there are no effective therapeutic and diagnostic agents. The main pathological hallmark has been identified as conformational changes of the cellular isoform prion protein (PrPC) to a misfolded isoform of the prion protein (PrPSc). Targeting PrPC and its conversion to PrPSc is still the central dogma in prion drug discovery, particularly in in silico and in vitro screening endeavors, leading to the identification of many small molecules with therapeutic potential. Nonetheless, multiple pathological targets are critically involved in the intricate pathogenesis of prion diseases. In this context, multi-target-directed ligands (MTDLs) emerge as valuable therapeutic approach for their potential to effectively counteract the complex etiopathogenesis by simultaneously modulating multiple targets. In addition, diagnosis occurs late in the disease process, and consequently a successful therapeutic intervention cannot be provided. In this respect, small molecule theranostics, which combine imaging and therapeutic properties, showed tremendous potential to cure and diagnose in vivo prion diseases. Herein, we review the major advances in prion drug discovery, from anti-prion small molecules identified by means of in silico and in vitro screening approaches to two rational strategies, namely MTDLs and theranostics, that have led to the identification of novel compounds with an expanded anti-prion profile.

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Acknowledgements

We acknowledge SISSA and the University of Bologna for their support.

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This manuscript was supported by intramural SISSA funding to GL.

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  1. Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, Bologna, Italy

    Elisa Uliassi & Maria Laura Bolognesi

  2. Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Trieste, Italy

    Lea Nikolic & Giuseppe Legname

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  1. Elisa Uliassi
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  2. Lea Nikolic
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  3. Maria Laura Bolognesi
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  4. Giuseppe Legname
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Correspondence to Maria Laura Bolognesi or Giuseppe Legname.

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Uliassi, E., Nikolic, L., Bolognesi, M.L. et al. Therapeutic strategies for identifying small molecules against prion diseases. Cell Tissue Res 392, 337–347 (2023). https://doi.org/10.1007/s00441-021-03573-x

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