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

Nat Commun. 2021 Aug 3;12(1):4669. doi: 10.1038/s41467-021-24821-2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / metabolism
  • Blood-Brain Barrier / metabolism
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism
  • Cell Survival / drug effects
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism*
  • Glioblastoma / diagnosis
  • Glioblastoma / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / chemistry
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Molecular Chaperones / metabolism*
  • Molecular Probes / chemistry
  • Molecular Probes / pharmacokinetics
  • Molecular Probes / pharmacology
  • Molecular Probes / therapeutic use
  • Positron-Emission Tomography
  • Protein Interaction Mapping / instrumentation*
  • Proteome / metabolism*

Substances

  • Biomarkers, Tumor
  • HSP90 Heat-Shock Proteins
  • Molecular Chaperones
  • Molecular Probes
  • Proteome

Associated data

  • ClinicalTrials.gov/NCT03371420