Anti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation

Abstract

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.

The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response

“…A similar synergistic effect with GADD34 −/+ but more pronounced was observed when ICE was provided at 3 mM ( figure 5 b ). To confirm that the observed synergy depended on a direct link between ICE and GADD34 −/+ mutant, we used another small molecule, metixene that is active in the OPMD Drosophila model but acts by reducing protein aggregation through the PFAR activity of the ribosome, not through the UPR [ 28 ]. As ICE, metixene at 2 mM was not active on Act88F-PABPN1-17alaR/+ flies ( figure 5 a ), whereas it shows positive effect on Act88F-PABPN1-17ala/+ flies [ 28 ].…”

“…To confirm that the observed synergy depended on a direct link between ICE and GADD34 −/+ mutant, we used another small molecule, metixene that is active in the OPMD Drosophila model but acts by reducing protein aggregation through the PFAR activity of the ribosome, not through the UPR [ 28 ]. As ICE, metixene at 2 mM was not active on Act88F-PABPN1-17alaR/+ flies ( figure 5 a ), whereas it shows positive effect on Act88F-PABPN1-17ala/+ flies [ 28 ]. However, in contrast to ICE, it did not act synergistically with GADD34 −/+ as the number of GADD34 −/+ ; Act88F-PABPN1-17alaR/+ flies with abnormal wing posture did not decrease in the presence of metixene ( figure 5 a ).…”

“…Although reduction of muscle defects in OPMD animal models is not systematically associated with reduced PABPN1-17ala aggregation [ 33 ], this is nonetheless often the case. Indeed, treatments with diverse anti-aggregation drugs lead to both improvement of muscle function and reduction of aggregate formation [ 28 , 29 , 31 , 32 , 52 ]. These results have led to the conclusion that either the process of aggregation, or the presence of oligomeric forms of PABPN1-17ala play a key role in OPMD pathogenesis.…”

Chaperonin activity of Plasmodium prefoldin complex is essential to guard proteotoxic stress response and presents a new target for drug discovery

“…Similar to Metixene, Biperiden (IUPAC name: 1-{bicyclo[2.2.1]hept-5-en-2-yl}-1-phenyl-3-(piperidin-1-yl)propan-1-ol) is a member of piperidines, and has a role as an antiparkinson drug and a muscarinic antagonist. In a recent investigation, Biperiden along with 16 other FDA-approved drugs, were identified to harbor anti-prion activity (Bamia et al, 2021). In the study, seven out of the 17 compounds with lower IC 50 values were further examined for their ability to inhibit PFAR.…”

“…In a recent investigation by Aline Bamia et al ., novel small molecules with Prion (PrP Sc ) propagation-inhibitory activities were identified, which interfered with the Protein Folding Activity of the Ribosome (PFAR), and significantly prolonged the survival of prion-infected mice (Bamia et al, 2021). Using an in silico therapeutic repositioning approach, we screened LOPAC ®1280 Library of 1,280 Pharmacologically Active Compounds (Sigma-Aldrich) based on similarities with one of the potent PFAR inhibitors identified in the study, Metixene (https://www.sigmaaldrich.com/IN/en/product/sigma/lo1280).…”