Synapse - Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system

Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system Journal Article

Authors:	Bolaender, A.; Zatorska, D.; He, H.; Joshi, S.; Sharma, S.; Digwal, C. S.; Patel, H. J.; Sun, W.; Imber, B. S.; Ochiana, S. O.; Patel, M. R.; Shrestha, L.; Shah, S. K.; Wang, S.; Karimov, R.; Tao, H.; Patel, P. D.; Rodilla Martin, A.; Yan, P.; Panchal, P.; Almodovar, J.; Corben, A.; Rimner, A.; Ginsberg, S. D.; Lyashchenko, S.; Burnazi, E.; Ku, A.; Kalidindi, T.; Lee, S. G.; Grkovski, M.; Beattie, B. J.; Zanzonico, P.; Lewis, J. S.; Larson, S.; Rodina, A.; Pillarsetty, N.; Tabar, V.; Dunphy, M. P.; Taldone, T.; Shimizu, F.; Chiosis, G.
Article Title:	Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system
Abstract:	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. © 2021, The Author(s).
Journal Title:	Nature Communications
Volume:	12
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2021-08-03
Start Page:	4669
Language:	English
DOI:	10.1038/s41467-021-24821-2
PROVIDER:	scopus
PMCID:	PMC8333062
PUBMED:	34344873
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85111973808&doi=10.1038%2fs41467-021-24821-2&partnerID=40&md5=db5f5b095f6a3228bf5c0667392af95d
Notes:	Article -- Export Date: 1 September 2021 -- Source: Scopus