Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins

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.