2. Academic Validation
  3. Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance

Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance

  • J Med Chem. 2022 Jul 14;65(13):8998-9010. doi: 10.1021/acs.jmedchem.2c00205.
Arianna Colini Baldeschi 1,  Marco Zattoni 1,  Silvia Vanni 1,  Lea Nikolic 1,  Chiara Ferracin 1,  Giuseppina La Sala 2,  Maria Summa 3,  Rosalia Bertorelli 3,  Sine Mandrup Bertozzi 4,  Gabriele Giachin 5,  Paolo Carloni 6 7 8,  Maria Laura Bolognesi 9,  Marco De Vivo 2,  Giuseppe Legname 1
Affiliations

Affiliations

  • 1 Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Via Bonomea 265, 34136 Trieste, Italy.
  • 2 Molecular Modeling & Drug Discovery Lab, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • 3 Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • 4 Analytical Chemistry Lab, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
  • 5 Department of Chemical Sciences (DiSC), University of Padua, Via F. Marzolo 1, 35131 Padova, Italy.
  • 6 Institute for Advanced Simulations (IAS)-5/Institute for Neuroscience and Medicine (INM)-9, "Computational Medicine", Forschungszentrum Jülich, 52428 Jülich, Germany.
  • 7 Institute for Neuroscience and Medicine (INM)-11, "Molecular Neuroscience and Neuroimaging", Forschungszentrum Jülich, 52428 Jülich, Germany.
  • 8 Department of Physics, RWTH-Aachen University, 52074 Aachen, Germany.
  • 9 Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
PMID: 35771181 DOI: 10.1021/acs.jmedchem.2c00205
Abstract

Prion diseases are a group of neurodegenerative disorders characterized by the accumulation of misfolded prion protein (called PrPSc). Although conversion of the cellular prion protein (PrPC) to PrPSc is still not completely understood, most of the therapies developed until now are based on blocking this process. Here, we propose a new drug strategy aimed at clearing prions without any direct interaction with neither PrPC nor PrPSc. Starting from the recent discovery of SERPINA3/SerpinA3n upregulation during prion diseases, we have identified a small molecule, named compound 5 (ARN1468), inhibiting the function of these serpins and effectively reducing prion load in chronically infected cells. Although the low bioavailability of this compound does not allow in vivo studies in prion-infected mice, our strategy emerges as a novel and effective approach to the treatment of prion disease.

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