title: Structure-based drug design identifies polythiophenes as antiprion compounds.
abstract: Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrP(Sc), a misfolded and aggregated form of the cellular prion protein (PrP(C)). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by >80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Uli S
authors.initials: US
authors.lastname: Herrmann
authors.affiliation: Physical Chemistry, Eidgenössische Technische Hochschule (ETH) Zürich, 8093 Zürich, Switzerland.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Schütz
authors.affiliation: Department of Physics, Chemistry and Biology (IFM), Linköping University, 58183 Linköping, Sweden.
authors.forename: Hamid
authors.initials: H
authors.lastname: Shirani
authors.affiliation: Department of Biochemistry, University of Zürich, 8057 Zürich, Switzerland.
authors.forename: Danzhi
authors.initials: D
authors.lastname: Huang
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Dino
authors.initials: D
authors.lastname: Saban
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Nuvolone
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Boris
authors.initials: B
authors.lastname: Ballmer
authors.affiliation: Department of Physics, Chemistry and Biology (IFM), Linköping University, 58183 Linköping, Sweden.
authors.forename: Andreas K O
authors.initials: AK
authors.lastname: Åslund
authors.affiliation: Department of Physics, Chemistry and Biology (IFM), Linköping University, 58183 Linköping, Sweden.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Mason
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rushing
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
authors.affiliation: Department of Physics, Chemistry and Biology (IFM), Linköping University, 58183 Linköping, Sweden.
authors.forename: Sofie
authors.initials: S
authors.lastname: Nyström
authors.affiliation: Department of Physics, Chemistry and Biology (IFM), Linköping University, 58183 Linköping, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hammarström
authors.affiliation: Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS/Université de Lyon 1, 69367 Lyon, France.
authors.forename: Anja
authors.initials: A
authors.lastname: Böckmann
authors.affiliation: Department of Biochemistry, University of Zürich, 8057 Zürich, Switzerland.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
authors.affiliation: Physical Chemistry, Eidgenössische Technische Hochschule (ETH) Zürich, 8093 Zürich, Switzerland.
authors.forename: Beat H
authors.initials: BH
authors.lastname: Meier
authors.affiliation: Department of Physics, Chemistry and Biology (IFM), Linköping University, 58183 Linköping, Sweden.
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, University of Zürich, 8091 Zürich, Switzerland. adriano.aguzzi@usz.ch simone.hornemann@usz.ch.
authors.forename: Simone
authors.initials: S
authors.lastname: Hornemann
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, University of Zürich, 8091 Zürich, Switzerland. adriano.aguzzi@usz.ch simone.hornemann@usz.ch.
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D006224:Cricetinae; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D056004:Molecular Dynamics Simulation; D011108:Polymers / Q000737:chemistry / Q000627:therapeutic use; D017096:Prion Diseases / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D011108:Polymers; D013876:Thiophenes; C066730:polythiophene