Validation of Poly(Propylene Imine) Glycodendrimers Towards Their Anti-prion Conversion Efficiency.

Abstract

Prion diseases, such as the sporadic Creutzfeldt-Jakob disease (sCJD), are a class of fatal neurodegenerative disorders. Currently, there is no efficient treatment or therapy available. Hence, the search for molecules that may inhibit the conversion of the cellular prion protein (PrPC) into its pathological counterpart PrPScrapie (PrPSc) is of great urgency. Here, we report the generation- and dose-dependent biological action of dense-shell poly(propylene imine) (PPI) glycodendrimers by using scrapie-infected neuroblastoma (ScN2a) cells and the real-time quaking-induced conversion assay (RT-QuIC) for validation of anti-prion efficiencies. Whereas the 2nd and 3rd generation of PPI glycodendrimers exhibited anti-prion conversion efficiency in ScN2a cells validated by RT-QuIC analysis, we observed that the 4th generation of glycodendrimers had shown no significant effect. Translational RT-QuIC studies conducted with human prions derived from sCJD patients indicated an anti-prion conversion effect (not on PrPRes degradation) of PPI glycodendrimers against human prions with the highest inhibitory activity of the 4th generation of PPI glycodendrimers towards prion aggregation compared to the 2nd and 3rd generation. In conclusion, our study highlights the potential of PPI glycodendrimers as therapeutic compounds due to their anti-conversion activity on human prions in a PrPSc strain depending manner.

• Authors: Matthias Schmitz, Niccolo Candelise, Eirini Kanata, Franc Llorens, Katrin Thüne, Anna Villar-Piqué, Susana Margarida da Silva Correia, Dimitra Dafou, Theodoros Sklaviadis, Dietmar Appelhans, Inga Zerr
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 57 Issue 4 Pg. 1863-1874 (Apr 2020) ISSN: 1559-1182 [Electronic] United States
• PMID: 31848935 (Publication Type: Journal Article)

Chemical References

• Dendrimers
• Polypropylenes
• Prions
• Protein Aggregates
• poly(propyleneimine)
• Fluorescein-5-isothiocyanate

Topics

• Brain (pathology)
• Cell Line, Tumor
• Creutzfeldt-Jakob Syndrome (cerebrospinal fluid)
• Dendrimers (chemistry)
• Fluorescein-5-isothiocyanate (metabolism)
• Glycosylation
• Humans
• Models, Molecular
• Polypropylenes (chemistry)
• Prions (metabolism)
• Protein Aggregates
• Reproducibility of Results