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Structure-based drug design identifies polythiophenes as antiprion compounds
University of Zurich Hospital, Switzerland.
ETH, Switzerland.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
University of Zurich, Switzerland.
Vise andre og tillknytning
2015 (engelsk)Inngår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, nr 299, s. 299ra123-Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrPSc, a misfolded and aggregated form of the cellular prion protein (PrPC). 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 greater than80% 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.

sted, utgiver, år, opplag, sider
AMER ASSOC ADVANCEMENT SCIENCE , 2015. Vol. 7, nr 299, s. 299ra123-
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Identifikatorer
URN: urn:nbn:se:liu:diva-121758DOI: 10.1126/scitranslmed.aab1923ISI: 000360940300004PubMedID: 26246168OAI: oai:DiVA.org:liu-121758DiVA, id: diva2:859368
Merknad

Funding Agencies|European Research Council; European Union; Swiss National Foundation; Novartis Research Foundation; University of Zurich; Center for Clinical Research, University Hospital Zurich; Collegio Ghislieri, Pavia; Foundation for Research at the Medical Faculty of the University of Zurich; Swedish Foundation for Strategic Research; Swiss National Science Foundation [200020_146757, 315230_149897]; European Union Seventh Framework Program [Bio-NMR 261863]; Agence Nationale de la Recherche [ANR-11-BSV-8021-01, ANR-12-BS08-0013-01]; FP-7 EU-Health project LUPAS

Tilgjengelig fra: 2015-10-06 Laget: 2015-10-05 Sist oppdatert: 2019-11-08

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