Combined morphological and proteome profiling reveals target-independent impairment of cholesterol homeostasis.
Cell Chem Biol
; 28(12): 1780-1794.e5, 2021 12 16.
Article
in En
| MEDLINE
| ID: mdl-34214450
ABSTRACT
Unbiased profiling approaches are powerful tools for small-molecule target or mode-of-action deconvolution as they generate a holistic view of the bioactivity space. This is particularly important for non-protein targets that are difficult to identify with commonly applied target identification methods. Thereby, unbiased profiling can enable identification of novel bioactivity even for annotated compounds. We report the identification of a large bioactivity cluster comprised of numerous well-characterized drugs with different primary targets using a combination of the morphological Cell Painting Assay and proteome profiling. Cluster members alter cholesterol homeostasis and localization due to their physicochemical properties that lead to protonation and accumulation in lysosomes, an increase in lysosomal pH, and a disturbed cholesterol homeostasis. The identified cluster enables identification of modulators of cholesterol homeostasis and links regulation of genes or proteins involved in cholesterol synthesis or trafficking to physicochemical properties rather than to nominal targets.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cholesterol
/
Proteome
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Cell Chem Biol
Year:
2021
Document type:
Article
Affiliation country:
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA