中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (4): 1009-1014.doi: 10.4103/NRR.NRR-D-24-00181

• 综述:神经损伤修复保护与再生 • 上一篇    下一篇

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  • 出版日期:2025-04-15 发布日期:2024-06-30

Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

Antonio Masone1, *, Chiara Zucchelli2, *, Enrico Caruso3 , Giovanna Musco2 , Roberto Chiesa1   

  1. 1 Laboratory of Prion Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; 2 Biomolecular NMR Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy; 3 Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
  • Online:2025-04-15 Published:2024-06-30
  • Contact: Antonio Masone, PhD, antonio.masone@marionegri.it; Chiara Zucchelli, PhD, zucchelli.chiara@hsr.it.
  • Supported by:
    This study was supported by Telethon Italy award GGP15225 (to RC and GM), Italian Ministry of Health award RF-2016-02362950 (to RC and CZ), the CJD Foundation USA (to RC), and the Associazione Italiana Encefalopatie da Prioni (AIEnP) (to RC).

摘要: https://orcid.org/0000-0001-8357-5931 (Antonio Masone); https://orcid.org/0000-0003-2857-7170 (Chiara Zucchelli)

Abstract: PrPSc, a misfolded, aggregation-prone isoform of the cellular prion protein (PrPC ), is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals. PrPSc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, posing challenges for the development of effective therapies. Since PrPC is the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity, it represents an attractive therapeutic target for prion diseases. In this minireview, we briefly outline the approaches to target PrPC and discuss our recent identification of Zn(II)-BnPyP, a PrPC -targeting porphyrin with an unprecedented bimodal mechanism of action. We argue that in-depth understanding of the molecular mechanism by which Zn(II)-BnPyP targets PrPC may lead toward the development of a new class of dual mechanism anti-prion compounds.

Key words: anti-prion drug, anti-PrPC antibody, antisense oligonucleotide, neurodegeneration, pharmacological chaperone, porphyrin, prion disease, PrPC degrader, PrPC shedding, zinc finger repressor