Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system
| Autor: | Mark Dunphy, Brandon S Imber, Sang-gyu Lee, Teja Kalidindi, Justina Almodovar, Eva Burnazi, Bradley J. Beattie, Fumiko Shimizu, Anson Ku, Andreas Rimner, Pallav D. Patel, Adriana D. Corben, Milan Grkovski, Tony Taldone, Pat Zanzonico, Sahil Sharma, Rashad R. Karimov, Viviane Tabar, Anna Rodina, Stephen D. Ginsberg, Liza Shrestha, Danuta Zatorska, Jason S. Lewis, Suhasini Joshi, Weilin Sun, Nagavarakishore Pillarsetty, Palak Panchal, Serge K. Lyashchenko, Chander Singh Digwal, Stefan O. Ochiana, Ananda Rodilla Martin, Gabriela Chiosis, Pengrong Yan, Alexander Bolaender, Hardik J. Patel, Huazhong He, Steve Larson, Shuo Wang, Maulik R. Patel, Hui Tao, Smit K. Shah |
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| Rok vydání: | 2020 |
| Předmět: |
Central Nervous System
Proteome Cell Survival Science Central nervous system General Physics and Astronomy Single group Disease Computational biology Interactome General Biochemistry Genetics and Molecular Biology Article Clinical study Mice MicroDose Protein Interaction Mapping Biomarkers Tumor Medicine Animals Humans In patient HSP90 Heat-Shock Proteins Multidisciplinary Molecular medicine business.industry Extramural Brain Neoplasms General Chemistry medicine.anatomical_structure Blood-Brain Barrier Molecular Probes Positron-Emission Tomography Cancer imaging business Glioblastoma Chemical tools Molecular Chaperones |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-19 (2021) |
| ISSN: | 2041-1723 |
| Popis: | Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer’s disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems. Here, the authors show structural, biochemical, and functional insights into the discovery of epichaperome‐ directed chemical probes for use in central nervous system diseases. Probes emerging from this work have translated to human clinical studies in Alzheimer’s disease and cancer. |
| Databáze: | OpenAIRE |
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