Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system
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Published:2021-08-03
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Bolaender Alexander, Zatorska Danuta, He Huazhong, Joshi Suhasini, Sharma Sahil, Digwal Chander S., Patel Hardik J., Sun Weilin, Imber Brandon S.ORCID, Ochiana Stefan O., Patel Maulik R., Shrestha Liza, Shah Smit. K., Wang Shuo, Karimov RashadORCID, Tao Hui, Patel Pallav D., Martin Ananda Rodilla, Yan PengrongORCID, Panchal Palak, Almodovar Justina, Corben Adriana, Rimner AndreasORCID, Ginsberg Stephen D.ORCID, Lyashchenko Serge, Burnazi Eva, Ku Anson, Kalidindi Teja, Lee Sang Gyu, Grkovski MilanORCID, Beattie Bradley J., Zanzonico Pat, Lewis Jason S.ORCID, Larson Steve, Rodina Anna, Pillarsetty NagavarakishoreORCID, Tabar Viviane, Dunphy Mark P.ORCID, Taldone Tony, Shimizu FumikoORCID, Chiosis GabrielaORCID
Abstract
AbstractDiseases 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference70 articles.
1. Sahni, N. et al. Widespread macromolecular interaction perturbations in human genetic disorders. Cell 161, 647–660 (2015). 2. Bojadzic, D. & Buchwald, P. Toward small-molecule inhibition of protein-protein interactions: general aspects and recent progress in targeting costimulatory and coinhibitory (immune checkpoint) interactions. Curr. Top. Med. Chem. 18, 674–699 (2018). 3. Ran, X. & Gestwicki, J. E. Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area. Curr. Opin. Chem. Biol. 44, 75–86 (2018). 4. Paladino, A. et al. Chemical perturbation of oncogenic protein folding: from the prediction of locally unstable structures to the design of disruptors of Hsp90–client interactions. Chem. Eur. J. 26, 9459–9465 (2020). 5. Serapian, S. A. & Colombo, G. Designing molecular spanners to throw in the protein networks. Chem. Eur. J. 26, 4656–4670 (2020).
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