Supplementary Materials

Supplementary Material for:

Structure-based drug design identifies polythiophenes as antiprion compounds

Uli S. Herrmann, Anne K. Schütz, Hamid Shirani, Danzhi Huang, Dino Saban, Mario Nuvolone, Bei Li, Boris Ballmer, Andreas K. O. Åslund, Jeffrey J. Mason, Elisabeth Rushing, Herbert Budka, Sofie Nyström, Per Hammarström, Anja Böckmann, Amedeo Caflisch, Beat H. Meier, K. Peter R. Nilsson, Simone Hornemann,* Adriano Aguzzi*

*Corresponding author. E-mail: adriano.aguzzi{at}usz.ch (A.A.); simone.hornemann{at}usz.ch (S.H.)

Published 5 August 2015, Sci. Transl. Med. 7, 299ra123 (2015)
DOI: 10.1126/scitranslmed.aab1923

This PDF file includes:

  • Fig. S1. Western blot analyses of samples from brain homogenates of RML6-infected tga20 mice treated with the LCP mix or the single compounds.
  • Fig. S2. Histopathological analysis of brain sections from tga20 mice treated with vehicle, LIN5032, LIN5001, or LIN5050.
  • Fig. S3. Western blots of fractions after density gradient ultracentrifugation for two further biological replicates of brain homogenates of non-infected, prion-infected vehicle-, LIN5002-, and LIN5001-treated mice using a 10 to 40% OptiPrep gradient.
  • Fig. S4. Western blots of fractions after density gradient ultracentrifugation of brain homogenates of non-infected, prion-infected vehicle-, LIN5002-, and LIN5001-treated mice using a 5 to 20% OptiPrep gradient.
  • Fig. S5. Aliphatic region of solid-state NMR spectra of HET-s(218–289).
  • Fig. S6. Free energy profiles of binding of newly designed LCPs.
  • Fig. S7. The structural stability of in-register parallel β sheet oligomers consisting of eight copies of the 177–216 segment of the mouse prion protein in the absence and presence of LIN5001.
  • Fig. S8. Structural stability of in-register parallel β sheet oligomers consisting of eight copies of the segment of Aβ10–20 in the absence and presence of LIN7001.
  • Fig. S9. Fluorescence excitation binding curves of different LCPs to recombinant rPrP fibrils as a function of LCP concentration.
  • Fig. S10. Molecular structures of additional LCPs used in the in silico approach, but not for in vivo testing.
  • Fig. S11. Silver-stained SDS-PAGE of HET-s(218–289)E265K incubated with LIN5044 (1 μg/ml).
  • Fig. S12. Brain histology of terminal prion-infected tga20 mice treated with LIN5044, LIN5043, or vehicle compared to non-infected, untreated tga20 mice.
  • Fig. S13. Rotarod and Western blot analysis.
  • Fig. S14. In vitro seeding efficiency for LCP- and vehicle-treated mice studied by the ThT fluorescence fibril conversion assay of rPrP.
  • Fig. S15. Flow chart of the iterative cycle of chemical synthesis, in vivo studies, solid-state NMR, and molecular dynamics simulations for the discovery of antiprion drugs.
  • Fig. S16. Schemes of the synthesis of the different LCPs.
  • Table S1. Results of the in vivo experiments.
  • Table S2. NMR-derived distance restraints for the HADDOCK model of LIN5001 in complex with the E265K point mutant of HET-s(218–289).
  • Table S3. Binding affinities of selected LCPs to rPrP in vitro.
  • Legends for movies S1 to S4

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Other Supplementary Material for this manuscript includes the following:

  • Movie S1 (.mpg format). LIN5001 bound to fibrils consisting of T-A-K.
  • Movie S2 (.mpg format). LIN5001 pulled out of the binding with T-A-K.
  • Movie S3 (.mpg format). Molecular dynamics simulation of the octameric hendecapeptide segment Aβ10–20 in the apo form.
  • Movie S4 (.mpg format). Molecular dynamics simulation of the octameric hendecapeptide segment Aβ10–20 in the presence of LIN7001.