Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system
© 2021. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Nature communications - 12(2021), 1 vom: 03. Aug., Seite 4669 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bolaender, Alexander [VerfasserIn] |
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| Links: |
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| Themen: |
Biomarkers, Tumor |
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| Anmerkungen: |
Date Completed 17.08.2021 Date Revised 05.04.2022 published: Electronic ClinicalTrials.gov: NCT03371420 Citation Status MEDLINE |
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| doi: |
10.1038/s41467-021-24821-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Bolaender, Alexander |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system |
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| 500 | |a ClinicalTrials.gov: NCT03371420 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021. The Author(s). | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Joshi, Suhasini |e verfasserin |4 aut | |
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