Structure-based drug design identifies polythiophenes as antiprion compounds

Science Translational Medicine

Volumn 7, Issue 299, 2015, Pages

  Herrmann, Uli S ^a   Schütz, Anne K ^b   Shirani, Hamid ^c   Huang, Danzhi ^d   Saban, Dino ^a,f   Nuvolone, Mario ^a   Li, Bei ^a   Ballmer, Boris ^a   Aslund, Andreas K O ^c,g   Mason, Jeffrey J ^c   Rushing, Elisabeth ^a   Budka, Herbert ^a   Nyström, Sofie ^c   Hammarström, Per ^c   Böckmann, Anja ^e   Caflisch, Amedeo ^d   Meier, Beat H ^b   Nilsson, K Peter R ^c   Hornemann, Simone ^a   Aguzzi, Adriano ^a  

^a UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^b ETH ZURICH   (Switzerland)

^c LINKÖPING UNIVERSITY   (Sweden)

^d UNIVERSITY OF ZURICH   (Switzerland)

^e UNIVERSITÉ LYON 1   (France)

^f UNIVERSITY HOSPITAL ESSEN   (Germany)

^g NORWEGIAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Norway)

Author keywords

[No Author keywords available]

Indexed keywords

LIN 4027; LIN 5029; LIN 5032; LIN 5044; LIN 5045; LIN 7004; LUMINESCENT CONJUGATED POLYTHIOPHENE DERIVATIVE; PLACEBO; PRION PROTEIN; THIOPHENE DERIVATIVE; UNCLASSIFIED DRUG; POLYMER; POLYTHIOPHENE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BINDING KINETICS; COMPUTER SIMULATION; CONTROLLED STUDY; DRUG DESIGN; DRUG EFFICACY; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; FEASIBILITY STUDY; LIFE EXTENSION; MOLECULAR DYNAMICS; MOUSE; MOUSE MODEL; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; PRION DISEASE; PRIORITY JOURNAL; PROCESS OPTIMIZATION; PROTEIN AGGREGATION; RESIDUE ANALYSIS; SOLID STATE; STRUCTURE ACTIVITY RELATION; SURVIVAL RATE; TRANSGENIC MOUSE; ANIMAL; CHEMISTRY; HAMSTER; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PRION DISEASES;

ANIMALS; CRICETINAE; DRUG DESIGN; MAGNETIC RESONANCE SPECTROSCOPY; MICE; MOLECULAR DYNAMICS SIMULATION; POLYMERS; PRION DISEASES; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

EID: 84938703713     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aab1923     Document Type: Article

References (88)

1. S. B. Prusiner, Novel proteinaceous infectious particles cause scrapie. Science 216, 136-144 (1982).
2. A. Aguzzi, T. O?Connor, Protein aggregation diseases: Pathogenicity and therapeutic perspectives. Nat. Rev. Drug Discov. 9, 237-248 (2010).
3. B. S. Appleby, C. G. Lyketsos, Rapidly progressive dementias and the treatment of human prion diseases. Expert Opin. Pharmacother. 12, 1-12 (2011).
4. C. Weissmann, A. Aguzzi, Approaches to therapy of prion diseases. Annu. Rev. Med. 56, 321-344 (2005).
5. J. A. Moreno, M. Halliday, C. Molloy, H. Radford, N. Verity, J. M. Axten, C. A. Ortori, A. E. Willis, P. M. Fischer, D. A. Barrett, G. R. Mallucci, Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med. 5, 206ra138 (2013).
6. M. Pietri, C. Dakowski, S. Hannaoui, A. Alleaume-Butaux, J. Hernandez-Rapp, A. Ragagnin, S. Mouillet-Richard, S. Haik, Y. Bailly, J. M. Peyrin, J. M. Launay, O. Kellermann, B. Schneider, PDK1 decreases TACE-mediated a-secretase activity and promotes disease progression in prion and Alzheimer?s diseases. Nat. Med. 19, 1124-1131 (2013).
7. F. L. Heppner, C. Musahl, I. Arrighi, M. A. Klein, T. Rülicke, B. Oesch, R. M. Zinkernagel, U. Kalinke, A. Aguzzi, Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294, 178-182 (2001).
8. M. Polymenidou, F. L. Heppner, E. C. Pellicioli, E. Urich, G. Miele, N. Braun, F. Wopfner, H. M. Sch?tzl, B. Becher, A. Aguzzi, Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection. Proc. Natl. Acad. Sci. U.S.A. 101, 14670-14676 (2004).
9. L. Solforosi, J. R. Criado, D. B. McGavern, S. Wirz, M. S?nchez-Alavez, S. Sugama, L. A. DeGiorgio, B. T. Volpe, E. Wiseman, G. Abalos, E. Masliah, D. Gilden, M. B. Oldstone, B. Conti, R. A. Williamson, Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303, 1514-1516 (2004).
10. T. Sonati, R. R. Reimann, J. Falsig, P. K. Baral, T. O?Connor, S. Hornemann, S. Yaganoglu, B. Li, U. S. Herrmann, B. Wieland, M. Swayampakula, M. H. Rahman, D. Das, N. Kav, R. Riek, P. P. Liberski, M. N. James, A. Aguzzi, The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein. Nature 501, 102-106 (2013).
11. S. Supattapone, J. R. Piro, J. R. Rees, Complex polyamines: Unique prion disaggregating compounds. CNS Neurol. Disord. Drug Targets 8, 323-328 (2009).
12. D. B. Berry, D. Lu, M. Geva, J. C. Watts, S. Bhardwaj, A. Oehler, A. R. Renslo, S. J. DeArmond, S. B. Prusiner, K. Giles, Drug resistance confounding prion therapeutics. Proc. Natl. Acad. Sci. U.S.A. 110, E4160-E4169 (2013).
13. Y. Kawasaki, K. Kawagoe, C. J. Chen, K. Teruya, Y. Sakasegawa, K. Doh-ura, Orally administered amyloidophilic compound is effective in prolonging the incubation periods of animals cerebrally infected with prion diseases in a prion strain-dependent manner. J. Virol. 81, 12889-12898 (2007).
14. D. Lu, K. Giles, Z. Li, S. Rao, E. Dolghih, J. R. Gever, M. Geva, M. L. Elepano, A. Oehler, C. Bryant, A. R. Renslo, M. P. Jacobson, S. J. Dearmond, B. M. Silber, S. B. Prusiner, Biaryl amides and hydrazones as therapeutics for prion disease in transgenic mice. J. Pharmacol. Exp. Ther. 347, 325-338 (2013).
15. J. Wagner, S. Ryazanov, A. Leonov, J. Levin, S. Shi, F. Schmidt, C. Prix, F. Pan-Montojo, U. Bertsch, G. Mitteregger-Kretzschmar, M. Geissen, M. Eiden, F. Leidel, T. Hirschberger, A. A. Deeg, J. J. Krauth, W. Zinth, P. Tavan, J. Pilger, M. Zweckstetter, T. Frank, M. B?hr, J. H. Weishaupt, M. Uhr, H. Urlaub, U. Teichmann, M. Samwer, K. Bötzel, M. Groschup, H. Kretzschmar, C. Griesinger, A. Giese, Anle138b: A novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson?s disease. Acta Neuropathol. 125, 795-813 (2013).
16. K. Doh-ura, K. Ishikawa, I. Murakami-Kubo, K. Sasaki, S. Mohri, R. Race, T. Iwaki, Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models. J. Virol. 78, 4999-5006 (2004).
17. H. Honda, K. Sasaki, H. Minaki, K. Masui, S. O. Suzuki, K. Doh-Ura, T. Iwaki, Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion. Neuropathology 32, 124-132 (2012).
18. K. Doh-Ura, T. Iwaki, B. Caughey, Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J. Virol. 74, 4894-4897 (2000).
19. J. Collinge, M. Gorham, F. Hudson, A. Kennedy, G. Keogh, S. Pal, M. Rossor, P. Rudge, D. Siddique, M. Spyer, D. Thomas, S. Walker, T. Webb, S. Wroe, J. Darbyshire, Safety and efficacy of quinacrine in human prion disease (PRION-1 study): A patient-preference trial. Lancet Neurol. 8, 334-344 (2009).
20. S. Ghaemmaghami, M. Ahn, P. Lessard, K. Giles, G. Legname, S. J. DeArmond, S. B. Prusiner, Continuous quinacrine treatment results in the formation of drug-resistant prions. PLOS Pathog. 5, e1000673 (2009).
21. J. Bian, H. E. Kang, G. C. Telling, Quinacrine promotes replication and conformational mutation of chronic wasting disease prions. Proc. Natl. Acad. Sci. U.S.A. 111, 6028-6033 (2014).
22. S. Ha?k, G. Marcon, A. Mallet, M. Tettamanti, A. Welaratne, G. Giaccone, S. Azimi, V. Pietrini, J. R. Fabreguettes, D. Imperiale, P. Cesaro, C. Buffa, C. Aucan, U. Lucca, L. Peckeu, S. Suardi, C. Tranchant, I. Zerr, C. Houillier, V. Redaelli, H. Vespignani, A. Campanella, F. Sellal, A. Krasnianski, D. Seilhean, U. Heinemann, F. Sedel, M. Canovi, M. Gobbi, G. Di Fede, J. L. Laplanche, M. Pocchiari, M. Salmona, G. Forloni, J. P. Brandel, F. Tagliavini, Doxycycline in Creutzfeldt-Jakob disease: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 13, 150-158 (2014).
23. B. Cox, F. Ness, M. Tuite, Analysis of the generation and segregation of propagons: Entities that propagate the [PSI+] prion in yeast. Genetics 165, 23-33 (2003).
24. T. P. Knowles, C. A. Waudby, G. L. Devlin, S. I. Cohen, A. Aguzzi,M. Vendruscolo, E. M. Terentjev, M. E. Welland, C. M. Dobson, An analytical solution to the kinetics of breakable filament assembly. Science 326, 1533-1537 (2009).
25. A. Herland, K. P. Nilsson, J. D. Olsson, P. Hammarström, P. Konradsson, O. Ingan?s, Synthesis of a regioregular zwitterionic conjugated oligoelectrolyte, usable as an optical probe for detection of amyloid fibril formation at acidic pH. J. Am. Chem. Soc. 127, 2317-2323 (2005).
26. K. P. Nilsson, P. Hammarström, F. Ahlgren, A. Herland, E. A. Schnell, M. Lindgren, G. T.Westermark, O. Ingan?s, Conjugated polyelectrolytes-Conformation-sensitive optical probes for staining and characterization of amyloid deposits. Chembiochem 7, 1096-1104 (2006).
27. K. P. Nilsson, A. Herland, P. Hammarström,O. Ingan?s, Conjugated polyelectrolytes: Conformationsensitive optical probes for detection of amyloid fibril formation. Biochemistry 44, 3718-3724 (2005).
28. K. P. Nilsson, K. Ikenberg, A. Aslund, S. Fransson, P. Konradsson, C. Röcken, H. Moch, A. Aguzzi, Structural typing of systemic amyloidoses by luminescent-conjugated polymer spectroscopy. Am. J. Pathol. 176, 563-574 (2010).
29. C. J. Sigurdson, K. P. Nilsson, S. Hornemann, G. Manco, M. Polymenidou, P. Schwarz, M. Leclerc, P. Hammarström, K. Wüthrich, A. Aguzzi, Prion strain discrimination using luminescent conjugated polymers. Nat. Methods 4, 1023-1030 (2007).
30. A. Aslund, C. J. Sigurdson, T. Klingstedt, S. Grathwohl, T. Bolmont, D. L. Dickstein, E. Glimsdal, S. Prokop, M. Lindgren, P. Konradsson, D. M. Holtzman, P. R. Hof, F. L. Heppner, S. Gandy, M. Jucker, A. Aguzzi, P. Hammarström, K. P. Nilsson, Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses. ACS Chem. Biol. 4, 673-684 (2009).
31. T. Klingstedt, A. Aslund, R. A. Simon, L. B. Johansson, J. J. Mason, S. Nyström, P. Hammarström, K. P. Nilsson, Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates. Org. Biomol. Chem. 9, 8356-8370 (2011).
32. T. Klingstedt, H. Shirani, K. O. ?slund, N. J. Cairns, C. J. Sigurdson, M. Goedert, K. P. Nilsson, The structural basis for optimal performance of oligothiophene-based fluorescent amyloid ligands: Conformational flexibility is essential for spectral assignment of a diversity of protein aggregates. Chemistry 19, 10179-10192 (2013).
33. I. Margalith, C. Suter, B. Ballmer, P. Schwarz, C. Tiberi, T. Sonati, J. Falsig, S. Nyström, P. Hammarström, A. Aslund, K. P. Nilsson, A. Yam, E. Whitters, S. Hornemann, A. Aguzzi, Polythiophenes inhibit prion propagation by stabilizing prion protein (PrP) aggregates. J. Biol. Chem. 287, 18872-18887 (2012).
34. A. Ayrolles-Torro, T. Imberdis, J. Torrent, K. Toupet, I. V. Baskakov, G. Poncet-Montange, C. Gregoire, F. Roquet-Baneres, S. Lehmann, D. Rognan, M. Pugniere, J. M. Verdier, V. Perrier, Oligomeric-induced activity by thienyl pyrimidine compounds traps prion infectivity. J. Neurosci. 31, 14882-14892 (2011).
35. M. Fischer, T. Rülicke, A. Raeber, A. Sailer, M. Moser, B. Oesch, S. Brandner, A. Aguzzi, C. Weissmann, Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J. 15, 1255-1264 (1996).
36. A. L. Lau, A. Y. Yam, M. M. Michelitsch, X. Wang, C. Gao, R. J. Goodson, R. Shimizu, G. Timoteo, J. Hall, A. Medina-Selby, D. Coit, C. McCoin, B. Phelps, P. Wu, C. Hu, D. Chien, D. Peretz, Characterization of prion protein (PrP)-derived peptides that discriminate full-length PrPSc from PrPC. Proc. Natl. Acad. Sci. U.S.A. 104, 11551-11556 (2007).
37. M. Polymenidou, S. Prokop, H. H. Jung, E. Hewer, D. Peretz, R. Moos, M. Tolnay, A. Aguzzi, Atypical prion protein conformation in familial prion disease with PRNP P105T mutation. Brain Pathol. 21, 209-214 (2011).
38. J. Falsig, T. Sonati, U. S. Herrmann, D. Saban, B. Li, K. Arroyo, B. Ballmer, P. Liberski, A. Aguzzi, Prion pathogenesis is faithfully reproduced in cerebellar organotypic slice cultures. PLOS Pathog. 8, e1002985 (2012).
39. A. Y.Yam, X.Wang, C. M. Gao, M. D. Connolly, R. N. Zuckermann, T. Bleu, J. Hall, J. P. Fedynyshyn, S. Allauzen, D. Peretz, C. M. Salisbury, A universal method for detection of amyloidogenic misfolded proteins. Biochemistry 50, 4322-4329 (2011).
40. A. Patra, M. Bendikov, Polyselenophenes. J. Mater. Chem. 20, 422-433 (2010).
41. Y. H. Wijsboom, A. Patra, S. S. Zade, Y. Sheynin, M. Li, L. J. Shimon, M. Bendikov, Controlling rigidity and planarity in conjugated polymers: Poly(3,4-ethylenedithioselenophene). Angew. Chem. Int. Ed. Engl. 48, 5443-5447 (2009).
42. F. Laferri?re, P. Tixador, M.Moudjou, J. Chapuis, P. Sibille, L.Herzog, F. Reine, E. Jaumain,H. Laude, H. Rezaei, V. Béringue,Quaternary structure of pathological prion protein as a determining factor of strain-specific prion replication dynamics. PLOS Pathog. 9, e1003702 (2013).
43. P. Tixador, L. Herzog, F. Reine, E. Jaumain, J. Chapuis, A. Le Dur, H. Laude, V. Béringue, The physical relationship between infectivity and prion protein aggregates is strain-dependent. PLOS Pathog. 6, e1000859 (2010).
44. N. J. Cobb, F. D. Sönnichsen, H. McHaourab, W. K. Surewicz, Molecular architecture of human prion protein amyloid: A parallel, in-register b-structure. Proc. Natl. Acad. Sci. U.S.A. 104, 18946-18951 (2007).
45. R. Diaz-Espinoza, C. Soto, High-resolution structure of infectious prion protein: The final frontier. Nat. Struct. Mol. Biol. 19, 370-377 (2012).
46. B. R. Groveman, M. A. Dolan, L. M. Taubner, A. Kraus, R. B. Wickner, B. Caughey, Parallel in-register intermolecular b-sheet architectures for prion-seeded prion protein (PrP) amyloids. J. Biol. Chem. 289, 24129-24142 (2014).
47. C. Wasmer, A. Lange, H. Van Melckebeke, A. B. Siemer, R. Riek, B. H. Meier, Amyloid fibrils of the HET-s(218-289) prion form a b solenoid with a triangular hydrophobic core. Science 319, 1523-1526 (2008).
48. A. K. Schütz, A. Soragni, S. Hornemann, A. Aguzzi, M. Ernst, A. Böckmann, B. H. Meier, The amyloid-Congo red interface at atomic resolution. Angew. Chem. Int. Ed. Engl. 50, 5956-5960 (2011).
49. S. J. de Vries, M. van Dijk, A. M. Bonvin, The HADDOCK web server for data-driven biomolecular docking. Nat. Protoc. 5, 883-897 (2010).
50. J. Wigenius, M. R. Andersson, E. K. Esbjörner, F. Westerlund, Interactions between a luminescent conjugated polyelectrolyte and amyloid fibrils investigated with flow linear dichroism spectroscopy. Biochem. Biophys. Res. Commun. 408, 115-119 (2011).
51. W. Humphrey, A. Dalke, K. Schulten, VMD: Visual molecular dynamics. J. Mol. Graph. 14, 27-38 (1996).
52. M. Scott, D. Foster, C. Mirenda, D. Serban, F. Coufal, M. W?lchli, M. Torchia, D. Groth, G. Carlson, S. J. DeArmond, D. Westaway, S. B. Prusiner, Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell 59, 847-857 (1989).
53. R. H. Kimberlin, C. A. Walker, Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J. Gen. Virol. 39, 487-496 (1978).
54. C. Govaerts, H. Wille, S. B. Prusiner, F. E. Cohen, Evidence for assembly of prions with lefthanded b-helices into trimers. Proc. Natl. Acad. Sci. U.S.A. 101, 8342-8347 (2004).
55. M. L. DeMarco, V. Daggett, From conversion to aggregation: Protofibril formation of the prion protein. Proc. Natl. Acad. Sci. U.S.A. 101, 2293-2298 (2004).
56. R. Tycko, R. Savtchenko, V. G. Ostapchenko, N. Makarava, I. V. Baskakov, The a-helical C-terminal domain of full-length recombinant PrP converts to an in-register parallel b-sheet structure in PrP fibrils: Evidence from solid state nuclear magnetic resonance. Biochemistry 49, 9488-9497 (2010).
57. S. A. Priola, B. Caughey, K. Wehrly, B. Chesebro, A 60-kDa prion protein (PrP) with properties of both the normal and scrapie-associated forms of PrP. J. Biol. Chem. 270, 3299-3305 (1995).
58. F. Bard, R. Barbour, C. Cannon, R. Carretto, M. Fox, D. Games, T. Guido, K. Hoenow, K. Hu, K. Johnson-Wood, K. Khan, D. Kholodenko, C. Lee, M. Lee, R. Motter, M. Nguyen, A. Reed, D. Schenk, P. Tang, N. Vasquez, P. Seubert, T. Yednock, Epitope and isotype specificities of antibodies to b-amyloid peptide for protection against Alzheimer?s disease-like neuropathology. Proc. Natl. Acad. Sci. U.S.A. 100, 2023-2028 (2003).
59. F. Bard, C. Cannon, R. Barbour, R. L. Burke, D. Games, H. Grajeda, T. Guido, K. Hu, J. Huang, K. Johnson-Wood, K. Khan, D. Kholodenko, M. Lee, I. Lieberburg, R. Motter, M. Nguyen, F. Soriano, N. Vasquez, K. Weiss, B. Welch, P. Seubert, D. Schenk, T. Yednock, Peripherally administered antibodies against amyloid b-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916-919 (2000).
60. J. O. Rinne, D. J. Brooks, M. N. Rossor, N. C. Fox, R. Bullock, W. E. Klunk, C. A. Mathis, K. Blennow, J. Barakos, A. A. Okello, S. Rodriguez Martinez de Liano, E. Liu, M. Koller, K. M. Gregg, D. Schenk, R. Black, M. Grundman, 11C-PiB PET assessment of change in fibrillar amyloid-b load in patients with Alzheimer?s disease treated with bapineuzumab: A phase 2, double-blind, placebocontrolled, ascending-dose study. Lancet Neurol. 9, 363-372 (2010).
61. K. Blennow, H. Zetterberg, J. O. Rinne, S. Salloway, J. Wei, R. Black, M. Grundman, E. Liu; AAB-001 201/202 Investigators, Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch. Neurol. 69, 1002-1010 (2012).
62. R. S. Doody, R. G. Thomas, M. Farlow, T. Iwatsubo, B. Vellas, S. Joffe, K. Kieburtz, R. Raman, X. Sun, P. S. Aisen, E. Siemers, H. Liu-Seifert, R. Mohs; Alzheimer?s Disease Cooperative Study Steering Committee; Solanezumab Study Group, Phase 3 trials of solanezumab for mild-to-moderate Alzheimer?s disease. N. Engl. J. Med. 370, 311-321 (2014).
63. S. Salloway, R. Sperling, N. C. Fox, K. Blennow, W. Klunk, M. Raskind, M. Sabbagh, L. S. Honig, A. P. Porsteinsson, S. Ferris, M. Reichert, N. Ketter, B. Nejadnik, V. Guenzler, M. Miloslavsky, D. Wang, Y. Lu, J. Lull, I. C. Tudor, E. Liu, M. Grundman, E. Yuen, R. Black, H. R. Brashear; Bapineuzumab 301 and 302 Clinical Trial Investigator, Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer?s disease. N. Engl. J. Med. 370, 322-333 (2014).
64. R. D. Terry, E. Masliah, D. P. Salmon, N. Butters, R. DeTeresa, R. Hill, L. A. Hansen, R. Katzman, Physical basis of cognitive alterations in Alzheimer?s disease: Synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572-580 (1991).
65. G. M. Shankar, S. Li, T. H. Mehta, A. Garcia-Munoz, N. E. Shepardson, I. Smith, F. M. Brett, M. A. Farrell, M. J. Rowan, C. A. Lemere, C. M. Regan, D. M. Walsh, B. L. Sabatini, D. J. Selkoe, Amyloid-b protein dimers isolated directly from Alzheimer?s brains impair synaptic plasticity and memory. Nat. Med. 14, 837-842 (2008).
66. L. Ding, M. Jonforsen, L. S. Roman, M. Andersson, O. Ingan?s, Photovoltaic cells with a conjugated poly electrolyte. Synth. Met. 110, 133-140 (2000).
67. R. A. Simon, H. Shirani, K. O. Aslund, M. B?ck, V. Haroutunian, S. Gandy, K. P. Nilsson, Pentameric thiophene-based ligands that spectrally discriminate amyloid-b and tau aggregates display distinct solvatochromism and viscosity-induced spectral shifts. Chemistry 20, 12537-12543 (2014).
68. T. Ueyama, S. Mochida, T. Fukutani, K. Hirano, T. Satoh, M. Miura, Ruthenium-catalyzed oxidative vinylation of heteroarene carboxylic acids with alkenes via regioselective C-H bond cleavage. Org. Lett. 13, 706-708 (2011).
69. B. Hess, C. Kutzner, D. van der Spoel, E. Lindahl, GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory Comput. 4, 435-447 (2008).
70. A. D. MacKerell, D. Bashford, M. Bellott, R. L. Dunbrack, J. D. Evanseck, M. J. Field, S. Fischer, J. Gao, H. Guo, S. Ha, D. Joseph-McCarthy, L. Kuchnir, K. Kuczera, F. T. K. Lau, C. Mattos, S. Michnick, T. Ngo, D. T. Nguyen, B. Prodhom, W. E. Reiher, B. Roux, M. Schlenkrich, J. C. Smith, R. Stote, J. Straub, M. Watanabe, J. Wi?rkiewicz-Kuczera, D. Yin, M. Karplus, All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586-3616 (1998).
71. W. L. Jorgensen, J. Chandrasekhar, J. D. Madura, R. W. Impey, M. L. Klein, Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926-935 (1983).
72. K. Vanommeslaeghe, E. Hatcher, C. Acharya, S. Kundu, S. Zhong, J. Shim, E. Darian, O. Guvench, P. Lopes, I. Vorobyov, A. D. MacKerell Jr., CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 31, 671-690 (2010).
73. K. Vanommeslaeghe, A. D. MacKerell Jr., Automation of the CHARMM General Force Field (CGenFF) I: Bond perception and atom typing. J. Chem. Inf. Model. 52, 3144-3154 (2012).
74. T. Darden, D. York, L. Pedersen, Particle mesh Ewald: An Nlog(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089-10092 (1993).
75. G. Bussi, D. Donadio, M. Parrinello, Canonical sampling through velocity rescaling. J. Chem. Phys. 126, 014101 (2007).
76. H. J. C. Berendsen, J. P. M. Postma, W. F. van Gunsteren, A. DiNola, J. R. Haak, Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81, 3684-3690 (1984).
77. B. Hess, H. Bekker, H. J. C. Berendsen, J. G. E. M. Fraaije, LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463-1472 (1997).
78. B. Roux, The calculation of the potential of mean force using computer simulations. Comput. Phys. Commun. 91, 275-282 (1995).
79. S. Kumar, D. Bouzida, R.H. Swendsen, P. A. Kollman, J. M. Rosenberg, Theweighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J. Comput. Chem. 13, 1011-1021 (1992).
80. M. Polymenidou, K. Stoeck, M. Glatzel, M. Vey, A. Bellon, A. Aguzzi, Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease. Lancet Neurol. 4, 805-814 (2005).
81. R. Zahn, C. von Schroetter, K. Wüthrich, Human prion proteins expressed in Escherichia coli and purified by high-affinity column refolding. FEBS Lett. 417, 400-404 (1997).
82. D. A. Lysek, K. Wüthrich, Prion protein interaction with the C-terminal SH3 domain of Grb2 studied using NMR and optical spectroscopy. Biochemistry 43, 10393-10399 (2004).
83. S. Hornemann, B. Christen, C. von Schroetter, D. R. Pérez, K. Wüthrich, Prion protein library of recombinant constructs for structural biology. FEBS J. 276, 2359-2367 (2009).
84. A. C. Apetri, D. L. Vanik, W. K. Surewicz, Polymorphism at residue 129 modulates the conformational conversion of the D178N variant of human prion protein 90-231. Biochemistry 44, 15880-15888 (2005).
85. A. Balguerie, S. Dos Reis, C. Ritter, S. Chaignepain, B. Coulary-Salin, V. Forge, K. Bathany, I. Lascu, J. M. Schmitter, R. Riek, S. J. Saupe, Domain organization and structure-function relationship of the HET?s prion protein of Podospora anserina. EMBO J. 22, 2071-2081 (2003).
86. K. Almstedt, S. Nyström, K. P. Nilsson, P. Hammarström, Amyloid fibrils of human prion protein are spun and woven from morphologically disordered aggregates. Prion 3, 224-235 (2009).
87. H. R. Büeler, M. Fischer, Y. Lang, H. Bluethmann, H. P. Lipp, S. J. DeArmond, S. B. Prusiner, M. Aguet, C. Weissmann, Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577-582 (1992).
88. S. Nyström, R. Mishra, S. Hornemann, A. Aguzzi, K. P. Nilsson, P. Hammarström, Multiple substitutions of methionine 129 in human prion protein reveal its importance in the amyloid fibrillation pathway. J. Biol. Chem. 287, 25975-25984 (2012).