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Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Pomplun S,Sippel C,Hähle A,Tay D,Shima K,Klages A,Ünal CM,Rieß B,Toh HT,Hansen G,Yoon HS,Bracher A,Preiser P,Rupp J,Steinert M,Hausch F

doi

10.1021/acs.jmedchem.8b00137

subject

Has Abstract

pub_date

2018-04-26 00:00:00

pages

3660-3673

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

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