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.
Highlights
Diseases are a manifestation of how thousands of proteins interact
Heat shock protein 90 (HSP90) is a key component of epichaperomes and PU-H71 interacts with epichaperomes through insertion into the N-terminal domain pocket of the HSP9013
PU-H71 bound to HSP90α unveils a subpocket in this region, with the 8-aryl moiety of PU-H71 exposing a lipophilic cavity whereby the phenyl ring becomes stacked between Phe[138] and Leu[107] (PDB:2FWZ)[33]
Summary
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. Cellular stressors appear to disturb the dynamic nature of such interactions, and stabilized oligomeric chaperone species, later dubbed as epichaperomes, were reported on Native PAGE in cells exposed to stressors such as heat stress, glucose deprivation, or a toxin such as antimycin A7 Such stable and soluble heterooligomeric chaperome pools, identified in tumors, Parkinson’s disease (PD) neurons, and Alzheimer’s disease (AD) brain tissues, work as scaffolding platforms rather than in folding[7]. Epichaperomes pathologically rewire PPIs in these diverse diseases at the proteome-wide level They cause thousands of proteins to improperly organize inside cells, aberrantly affecting cellular phenotypes[7]. PU-H71 does not permeate the blood–brain barrier (BBB) rendering it of limited use in the study and treatment of diseases of the central nervous system (CNS)
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