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Bolognesi M.L.,University of Bologna | Bongarzone S.,Kings College London | Aulic S.,International School for Advanced Studies | Ai Tran H.N.,University of Calgary | And 4 more authors.
Future Medicinal Chemistry | Year: 2015

Background: The main pathogenic event of prion disorders has been identified in the deposition of the disease-associated prion protein (PrPSc), which is accompanied by metal dyshomeostasis. Results: The multitarget-directed ligand 1, designed by combining a heteroaromatic prion recognition motif to an 8-hydroxyquinoline metal chelator, has been developed as a potential antiprion disease-modifying agent. Importantly, 1 was found to effectively clear PrPSc from scrapie-infected cells, and, at the same time, inhibit metal-induced prion aggregation and reactive oxygen species generation. 1 was also characterized in terms of pharmacokinetic properties in a preliminary in vitro investigation. Conclusion: Compound 1 has emerged as a suitable lead candidate against prion diseases and as a good starting point for a further optimization process. © 2015 Future Science Ltd. Source

Cong X.,International School for Advanced Studies | Cong X.,RWTH Aachen | Bongarzone S.,International School for Advanced Studies | Bongarzone S.,Barcelona Institute for Research in Biomedicine | And 9 more authors.
Journal of Biomolecular Structure and Dynamics | Year: 2013

Mutations in the prion protein (PrP) can cause spontaneous prion diseases in humans (Hu) and animals. In transgenic mice, mutations can determine the susceptibility to the infection of different prion strains. Some of these mutations also show a dominant-negative effect, thus halting the replication process by which wild type mouse (Mo) PrP is converted into Mo scrapie. Using all-atom molecular dynamics (MD) simulations, here we studied the structure of HuPrP, MoPrP, 10 Hu/MoPrP chimeras, and 1 Mo/sheepPrP chimera in explicit solvent. Overall, ~2 μs of MD were collected. Our findings suggest that the interactions between α1 helix and N-terminal of α3 helix are critical in prion propagation, whereas the β2-α2 loop conformation plays a role in the dominant-negative effect. © 2012 Taylor & Francis. Source

Cong X.,International School for Advanced Studies | Cong X.,Julich Research Center | Cong X.,Institute of Advanced Simulation IAS | Casiraghi N.,Julich Research Center | And 11 more authors.
Journal of Chemical Theory and Computation | Year: 2013

Prion diseases are fatal neurodegenerative disorders in mammals and other animal species. In humans, about 15% of these maladies are caused by pathogenic mutations (PMs) in the gene encoding for the prion protein (PrPC). Seven PMs are located in the naturally unfolded PrPC N-terminal domain, which constitutes about half of the protein. Intriguingly and in sharp contrast to other PMs clustered in the folded domain, N-terminal PMs barely affect the conversion to the pathogenic (scrapie, or PrPSc) isoform of PrPC. Here, we hypothesize that the neurotoxicity of these PMs arises from changes in structural determinants of the N-terminal domain, affecting the protein binding with its cellular partners and/or the cotranslational translocation during the PrPC biosynthesis. We test this idea by predicting the conformational ensemble of the wild-type (WT) and mutated mouse PrPC N-terminal domain, whose sequence is almost identical to that of the human one and for which the largest number of in vivo data is available. The conformational properties of the WT are consistent with those inferred experimentally. Importantly, the PMs turn out to affect in a subtle manner the intramolecular contacts in the putative N-terminal domain binding sites for Cu2+ ions, sulphated glycosaminoglycans, and other known PrPC cellular partners. The PMs also alter the local structural features of the transmembrane domain and adjacent stop transfer effector, which act together to regulate the protein topology. These results corroborate the hypothesis that N-terminal PMs affect the PrPC binding to functional interactors and/or the translocation. © 2013 American Chemical Society. Source

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