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Publication Abstract from PubMed

FK506-binding proteins (FKBPs) are evolutionary conserved proteins that display peptidyl-prolyl isomerase activity and act as co-receptors for immunosuppressants. Microbial macrophage infectivity potentiator (Mip) type FKBPs can enhance infectivity. However, developing drug-like ligands for FKBPs or Mips has proven difficult and many FKBPs/Mips still lack a biologically useful ligand. 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 for the bicyclic core scaffold and used it to prepare a FKBP/Mip-focused library. This allowed a systematic structure-activity relationship analysis across key human FKBPs and microbial Mips, yielding highly improved inhibitors for all FKBPs studied. A co-crystal structure confirmed the molecular binding mode of the core structure and explained the affinity gain by preferred substitutents. The best FKBP/Mip ligands showed promising anti-malarial, anti-leginonella and anti-clamydial properties in cellular models of infectivity, suggesting substituted-[4.3.1]-aza-bicyclic sulfonamides as a novel class of anti-infectives.

Chemogenomic profiling of human and microbial FK506-binding proteins.,Pomplun S, Sippel C, Hahle A, Tay D, Shima K, Klages A, Unal CM, Riess B, Toh HT, Hansen G, Yoon HS, Bracher A, Preiser PR, Rupp J, Steinert M, Hausch F J Med Chem. 2018 Mar 26. doi: 10.1021/acs.jmedchem.8b00137. PMID:29578710^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.