Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins

Sebastian Pomplun, Claudia Sippel, Andreas Hähle, Donald Tay, Kensuke Shima, Alina Klages, Can Murat Ünal, Benedikt Rieß, Hui Ting Toh, Guido Hansen, Ho Sup Yoon, Andreas Bracher, Peter Preiser, Jan Rupp, Michael Steinert, Felix Hausch*

*Korrespondierende/r Autor/-in für diese Arbeit


FK506-binding proteins (FKBPs) are evolutionarily conserved proteins that display peptidyl-prolyl isomerase activities and act as coreceptors for immunosuppressants. Microbial macrophage-infectivity-potentiator (Mip)-type FKBPs can enhance infectivity. However, developing druglike ligands for FKBPs or Mips has proven difficult, and many FKBPs and Mips still lack biologically useful ligands. To explore the scope and potential of C5-substituted [4.3.1]-aza-bicyclic sulfonamides as a broadly applicable class of FKBP inhibitors, we developed a new synthesis method for the bicyclic core scaffold and used it to prepare an FKBP- and Mip-focused library. This allowed us to perform a systematic structure-activity-relationship analysis across key human FKBPs and microbial Mips, yielding highly improved inhibitors for all the FKBPs studied. A cocrystal structure confirmed the molecular-binding mode of the core structure and explained the affinity gained as a result of the preferred substituents. The best FKBP and Mip ligands showed promising antimalarial, antileginonellal, and antichlamydial properties in cellular models of infectivity, suggesting that substituted [4.3.1]-aza-bicyclic sulfonamides could be a novel class of anti-infectives.

ZeitschriftJournal of Medicinal Chemistry
Seiten (von - bis)3660-3673
PublikationsstatusVeröffentlicht - 26.04.2018

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)


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