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Title: Chemogenomic profiling of human and microbial fk506-binding proteins
Authors: Pomplun, Sebastian
Sippel, Claudia
Hähle, Andreas
Tay, Donald
Shima, Kensuke
Klages, Alina
Ünal, Can Murat
Rieß, Benedikt
Toh, Hui Ting
Hansen, Guido
Yoon, Ho Sup
Bracher, Andreas
Preiser, Peter
Rupp, Jan
Steinert, Michael
Hausch, Felix
Keywords: FKBP Inhibitors
DRNTU::Science::Biological sciences
Issue Date: 2018
Source: Pomplun, S., Sippel, C., Hähle, A., Tay, D., Shima, K., Klages, A., . . . Hausch, F. (2018). Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins. Journal of Medicinal Chemistry, 61(8), 3660-3673. doi:10.1021/acs.jmedchem.8b00137
Series/Report no.: Journal of Medicinal Chemistry
Abstract: 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.
ISSN: 0022-2623
DOI: 10.1021/acs.jmedchem.8b00137
Rights: © 2018 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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