Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system. Academic Article uri icon

Overview

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.

authors

publication date

  • August 3, 2021

Research

keywords

  • Central Nervous System
  • Molecular Chaperones
  • Protein Interaction Mapping
  • Proteome

Identity

PubMed Central ID

  • PMC8333062

Scopus Document Identifier

  • 85111973808

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2006.03.030

PubMed ID

  • 34344873

Additional Document Info

volume

  • 12

issue

  • 1