Heinrich-Heine-University
Universitätsstraße 1 40225 Düsseldorf Nordrhein-Westfalen
Research Interest
The function of each cell and each organism decisively depends on the dynamic interactions between biological macromolecules and on their correct three-dimensional structure. Faulty interaction and incorrectly folded structures eventually lead to diseases and ageing. Our aim is to understand these interactions and to determine the three-dimensional structure of the protein complexes involved in decisive cellular processes - if possible, in atomic resolution. Beyond that, we develop novel methods for the early diagnosis and treatment of neurodegenerative diseases, with a strong focus on Alzheimer's dementia.
Specific Projects
- Development of a truly disease modifying drug for the treatment of Alzheimer’s disease (AD).
More and more data suggest that the toxic protein assemblies of Aβ and TAU behave prion like. The drug candidate PRI-002 has been developed to directly disassemble and destroy toxic Aβ oligomer prions. The first anti-prionic compound PRI-002 (alias “RD2” in publications) is BBB penetrable and has demonstrated target engagement in vitro and in vivo. Treatments of three different transgenic mouse models in three different laboratories yielded improved cognition and deceleration of neurodegeneration. Oral treatment of old-aged transgenic AD mice with full-blown pathology reversed cognitive and behavioral deficits to levels of healthy wild-type littermates. Oral treatment of cognitively impaired old beagle dogs led to significant improvement of cognition and memory that remained after stop of treatment, which clearly shows a truly disease modifying effect of PRI-002. PRI-002 has demonstrated tolerability and safety in a phase I clinical trial in 63 healthy volunteers. Already a single oral dose yielded PRI-002 plasma levels that were observed in the highest dosed animals of the preclinical PoC studies. Thus, PRI-002 has demonstrated successful PoC in four different animal models in four different laboratories. PoC studies in humans for anti-prionic compounds may be based on shorter treatment durations and do not necessarily have to be life-long. The intellectual property rights have been sold to the spin-off company Priavoid that will take care of the further clinical development.
- Transfer of the unique mode of action (MoA) of PRI-002 to other target proteins and other target indications.
The above described unique MoA of PRI-002, which is the direct destruction of Abeta oligomer prions by disassembly into non-toxic monomer building blocks, is currently transferred to Tau, alpha-synuclein, SOD1, TDP43, poly-Q, IAPP and many more proteins. The aim is to develop further anti-prionic compounds for disease-modifying treatment of further protein-misfolding diseases.
Further information
- Department of Physical Biology HHU Düsseldorf
- Institute of Biological Information Processing Structural Biochemistry (IBI-7) Forschungszentrum Jülich
- Manchot Graduate School "Molecules of Infection"
- IHRS Biophysics and Softmatter
- CLIB-Cluster Industrial Biotechnology
- iGRASPseed Graduate School
- SFB 1208: Identity and Dynamics of Membrane Systems - from Molecules to Cellular Functions
Selected Publications
- Gremer L, Schölzel D, Schenk C, Reinartz E, Labahn J, Ravelli R, Tusche M, Lopez-Iglesias C, Hoyer W, Heise H, Willbold D, Schröder GF. Fibril structure of amyloid-ß(1-42) by cryo-electron microscopy. Science 358, 116-119 (2017). PubMed
- Perov S, Lidor O, Salinas N, Golan N, Tayeb-Fligelman E, Deshmukh M, Willbold D, Landau M. Structural Insights into Curli CsgA Cross-β Fibril Architecture Inspire Repurposing of Anti-amyloid Compounds as Anti-biofilm Agents. PLoS Pathog. 15, e1007978 (2019). PubMed
- Röder C, Vettore N, Mangels LN, Gremer L, Ravelli RBG, Willbold D, Hoyer W, Buell AK, Schröder GF. Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy. Nat Commun. 10, 3754 (2019). PubMed
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Röder C, Kupreichyk T, Gremer L, Schäfer LU, Pothula KR, Ravelli RBG, Willbold D, Hoyer W, Schröder GF. Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils. Nat. Struct. Mol. Biol. 27, 660-667 (2020). PubMed
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Willbold D, Strodel B, Schröder GF, Hoyer W, Heise H. Amyloid-type protein aggregation and prion-like properties of amyloids. Chem. Rev. 121, 8285-8307 (2021). PubMed
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Blömeke L, Pils M, Kraemer-Schulien V, Dybala A, Schaffrath A, Kulawik A, Rehn F, Cousin A, Nischwitz V, Willbold J, Zack R, Tropea TF, Bujnicki T, Tamgüney G, Weintraub D, Irwin D, Grossman M, Wolk DA, Trojanowski JQ, Bannach O, Chen-Plotkin A, Willbold D. Quantitative detection of α-Synuclein and Tau oligomers and other aggregates by digital single particle counting. NPJ Parkinsons Dis. 8, 68 (2022). PubMed
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Kass B, Schemmert S, Zafiu C, Pils M, Bannach O, Kutzsche J, Bujnicki T, Willbold D. Aβ oligomer concentration in mouse and human brain and its drug-induced reduction ex vivo. Cell Rep. Med. 3, 100630 (2022). PubMed
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Zielinski M, Peralta Reyes FS, Gremer L, Schemmert S, Frieg B, Schäfer LU, Willuweit A, Donner L, Elvers M, Nilsson LNG, Syvänen S, Sehlin D, Ingelsson M, Willbold D, Schröder GF. Cryo-EM of Aβ fibrils from mouse models find tg-APPArcSwe fibrils resemble those found in patients with sporadic Alzheimer's disease. Nat Neurosci. 26, 2073-2080 (2023). PubMed
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Kutzsche J, Guzman GA, Willuweit A, Kletke O, Wollert E, Gering I, Jürgens D, Breitkreutz J, Stark H, Beck-Sickinger AG, Klöcker N, Hidalgo P, Willbold D. An orally available N-type calcium channel inhibitor for the treatment of neuropathic pain. Br. J. Pharmacol. 181, 1734–1756 (2024). PubMed
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Blömeke L, Rehn F, Kraemer-Schulien V, Kutzsche J, Pils M, Bujnicki T, Lewczuk P, Kornhuber J, Freiesleben SD, Schneider LS, Preis L, Priller J, Spruth EJ, Altenstein S, Lohse A, Schneider A, Fliessbach K, Wiltfang J, Hansen N, Rostamzadeh A, Düzel E, Glanz W, Incesoy EI, Butryn M, Buerger K, Janowitz D, Ewers M, Perneczky R, Rauchmann BS, Teipel S, Kilimann I, Goerss D, Laske C, Munk MH, Sanzenbacher C, Spottke A, Roy-Kluth N, Heneka MT, Brosseron F, Wagner M, Wolfsgruber S, Kleineidam L, Stark M, Schmid M, Jessen F, Bannach O, Willbold D, Peters O. Aβ oligomers peak in early stages of Alzheimer's disease preceding tau pathology. Alzheimers Dement. 16, e12589 (2024). PubMed