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  Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins

Pomplun, S., Sippel, C., Haehle, A., Tay, D., Shima, K., Klages, A., et al. (2018). Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins. Journal of Medicinal Chemistry, 61(8), 3660-3673. doi:10.1021/acs.jmedchem.8b00137.

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 Creators:
Pomplun, Sebastian1, Author
Sippel, Claudia1, Author
Haehle, Andreas1, Author
Tay, Donald1, Author
Shima, Kensuke1, Author
Klages, Alina1, Author
Uenal, Can Murat1, Author
Riess, Benedikt1, Author
Toh, Hui Ting1, Author
Hansen, Guido1, Author
Yoon, Ho Sup1, Author
Bracher, Andreas2, Author           
Preiser, Peter1, Author
Rupp, Jan1, Author
Steinert, Michael1, Author
Hausch, Felix1, Author
Affiliations:
1external, ou_persistent22              
2Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Free keywords: LEGIONELLA-PNEUMOPHILA; MIP PROTEINS; LIGANDS; FK506; FKBP51; ISOMERASES; INHIBITORS; TARGETS; EXPLORATION; REGULATORSPharmacology & Pharmacy;
 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]-azabicyclic 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 activityrelationship 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.

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Language(s): eng - English
 Dates: 2018
 Publication Status: Issued
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: Journal of Medicinal Chemistry
Source Genre: Journal
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Publ. Info: Washington DC : ACS Publications
Pages: - Volume / Issue: 61 (8) Sequence Number: - Start / End Page: 3660 - 3673 Identifier: ISSN: 0022-2623
CoNE: https://pure.mpg.de/cone/journals/resource/110992357271168