A tetracationic porphyrin with dual anti-prion activity

Masone, Antonio; Zucchelli, Chiara; Caruso, Enrico; Lavigna, Giada; Eraña, Hasier; Giachin, Gabriele; Tapella, Laura; Comerio, Liliana; Restelli, Elena; Raimondi, Ilaria; Elezgarai, Saioa R.; Leo, Federica De; Quilici, Giacomo; Taiarol, Lorenzo; Oldrati, Marvin; Lorenzo, Nuria L.; García-Martínez, Sandra; Cagnotto, Alfredo; Lucchetti, Jacopo; Gobbi, Marco; Vanni, Ilaria; Nonno, Romolo; Bari, Michele Angelo Di; Tully, Mark D.; Cecatiello, Valentina; Ciossani, Giuseppe; Pasqualato, Sebastiano; Anken, Eelco van; Salmona, Mario; Castilla, Joaquín; Requena, Jesús R.; Banfi, Stefano; Musco, Giovanna; Chiesa, Roberto

doi:10.1016/j.isci.2023.107480

Cited by 3 publications

(2 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We determined that none of the six most potent sigma receptor ligands identified here had a significant effect on the total levels or cellular localization of PrP C (Figure 7; Supplementary Figure 1). This observation argues against an inhibitory mechanism dependent on reducing or redistributing the PrP C substrate, as has been proposed for some anti-prion compounds (16,51). Although there were some variations in the potency of the compounds when tested on ScN2a cells infected with the RML and 22L strains, all of them significantly reduced PrP Sc levels in cells infected with either strain, suggesting lack of a strong preference for particular PrP Sc conformations (Figure 8).…”

Section: Discussionmentioning

confidence: 67%

“…Anti-prion compounds have also been shown to have strain-specific efficacy both in vitro and in vivo (11–13), complicating efforts to develop therapeutics. It has been demonstrated that some of these molecules prevent prion propagation through a direct interaction with PrP C ; by stabilizing its structure or by sterically occluding its interactions with PrP Sc which are critical for conversion (14–16). Others are known to inhibit the conversion process by direct interaction with PrP Sc (17,18).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sigma receptor ligands are potent anti-prion compounds that act independently of sigma receptor binding

Mercer,

Le,

Houser

et al. 2023

Preprint

View full text Add to dashboard Cite

Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no treatment options. Previous work from our laboratory identified phenethyl piperidines as novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel anti-prion compounds based on their known ability to bind to the sigma receptors, σ1R and2R, which are currently being tested as therapeutic or diagnostic targets for cancer and neuropsychiatric disorders. Surprisingly, however, knockout of the respective genes encoding σ1R and σ2R (Sigmar1andTmem97), in prion infected N2a cells did not alter the anti-prion activity of these compounds, demonstrating that these receptors are not the direct targets responsible the anti-prion effects of their ligands. Further investigation of the most potent molecules established that they are efficacious against multiple prion strains and protect against downstream prion-mediated synaptotoxicity. While the precise details of the mechanism of action of these molecules remains to be determined, the present work forms the basis for further investigations of these compounds in pre-clinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer’s disease, respectively, this work has immediate implications for the treatment of human prion disease.

show abstract

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Sigma receptor ligands are potent anti-prion compounds that act independently of sigma receptor binding

Mercer,

Le,

Houser

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Creutzfeldt–Jakob disease and other prion diseases

Zerr,

Ladogana,

Mead

et al. 2024

Nat Rev Dis Primers

View full text Add to dashboard Cite

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

Masone,

Zucchelli,

Caruso

et al. 2024

Neural Regeneration Research

View full text Add to dashboard Cite

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.

show abstract

A tetracationic porphyrin with dual anti-prion activity

Cited by 3 publications

References 87 publications

Sigma receptor ligands are potent anti-prion compounds that act independently of sigma receptor binding

Sigma receptor ligands are potent anti-prion compounds that act independently of sigma receptor binding

Creutzfeldt–Jakob disease and other prion diseases

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

Contact Info

Product

Resources

About