Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system
Alexander Bolaender, Danuta Zatorska, Huazhong He, Suhasini Joshi, Sahil Sharma, Chander Singh Digwal, Hardik J. Patel, Weilin Sun, Brandon S. Imber, Stefan O. Ochiana, Maulik R. Patel, Liza Shrestha, Smit K. Shah, Shuo Wang, Rashad R. Karimov, Hui Tao, Pallav D. Patel, Ananda Rodilla Martin, Pengrong Yan, Palak Panchal · Nature Communications · 2021
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.