biostudies-literatureBamia AFondation pour la Recherche MédicaleSorbonne UniversitéUBODIM MALINFAFM-Téléthon eOPMDInsermInstitut de France – Fondation NRJAFM-TéléthonAssociation Institut de MyologieUniversity of MontpellierCNRSMESRINRAEAssociation Défi Organisation1137-1150https://www.ebi.ac.uk/biostudies/studies/S-EPMC8423950biostudies-literatureUnknown18(2)Prion diseases are caused by the propagation of PrP^Sc, the pathological conformation of the PrP^C prion protein. The molecular mechanisms underlying PrP^Sc propagation are still unsolved and no therapeutic solution is currently available. We thus sought to identify new anti-prion molecules and found that flunarizine inhibited PrP^Sc propagation in cell culture and significantly prolonged survival of prion-infected mice. Using an in silico therapeutic repositioning approach based on similarities with flunarizine chemical structure, we tested azelastine, duloxetine, ebastine, loperamide and metixene and showed that they all have an anti-prion activity. Like flunarizine, these marketed drugs reduced PrP^Sc propagation in cell culture and in mouse cerebellum organotypic slice culture, and inhibited the protein folding activity of the ribosome (PFAR). Strikingly, some of these drugs were also able to alleviate phenotypes due to PABPN1 nuclear aggregation in cell and Drosophila models of oculopharyngeal muscular dystrophy (OPMD). These data emphasize the therapeutic potential of anti-PFAR drugs for neurodegenerative and neuromuscular proteinopathies.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeuticsAnti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation.PMC842395017110DEQ20150331689Sinane MNait-Saidi RBeringue VDhiab JSoubigou FFriocourt GHalliez SVoisset CKeruzore MBlondel MBertho ABamia ATrollet CNguyen PHSimonelig MBihel FfalseAnti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation.Prion diseases are caused by the propagation of PrP^Sc, the pathological conformation of the PrP^C prion protein. The molecular mechanisms underlying PrP^Sc propagation are still unsolved and no therapeutic solution is currently available. We thus sought to identify new anti-prion molecules and found that flunarizine inhibited PrP^Sc propagation in cell culture and significantly prolonged survival of prion-infected mice. Using an in silico therapeutic repositioning approach based on similarities with flunarizine chemical structure, we tested azelastine, duloxetine, ebastine, loperamide and metixene and showed that they all have an anti-prion activity. Like flunarizine, these marketed drugs reduced PrP^Sc propagation in cell culture and in mouse cerebellum organotypic slice culture, and inhibited the protein folding activity of the ribosome (PFAR). Strikingly, some of these drugs were also able to alleviate phenotypes due to PABPN1 nuclear aggregation in cell and Drosophila models of oculopharyngeal muscular dystrophy (OPMD). These data emphasize the therapeutic potential of anti-PFAR drugs for neurodegenerative and neuromuscular proteinopathies.2021-01-01T00:00:00Z2021 Apr2025-04-22T09:15:56.366Z2025-04-05T22:59:38.798ZS-EPMC84239503353301110.1007/s13311-020-00992-6