Identification of inhibitors of cholesterol transport proteins through the synthesis of a diverse, sterol-inspired compound collection

Luca Laraia*, Thomas Whitmarsh-Everiss, Asger Hegelund Olsen

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Cholesterol transport proteins regulate a vast array of cellular processes including lipid metabolism, vesicular and nonvesicular trafficking, organelle contact sites, and autophagy. Despite their undoubted importance, the identification of selective modulators of this class of proteins has been challenging due to the structural similarities in the cholesterol-binding site. Herein we report a general strategy for the identification of selective inhibitors of cholesterol transport proteins via the synthesis of a diverse sterol-inspired compound collection. Fusion of a primary sterol fragment to an array of secondary privileged scaffolds led to the identification of potent and selective inhibitors of the cholesterol transport protein Aster-C, which displayed a surprising preference for the unnatural sterol AB-ring stereochemistry, and new inhibitors of Aster-A. We propose that this strategy can, and should be applied to any therapeutically relevant sterol-binding protein.
Original languageEnglish
JournalAngewandte Chemie International Edition
ISSN1433-7851
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • Cholesterol transport proteins
  • Compound library synthesis
  • Inhibitors
  • Medicinal chemistry

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