TY - JOUR
T1 - Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins
AU - Pomplun, Sebastian
AU - Sippel, Claudia
AU - Hähle, Andreas
AU - Tay, Donald
AU - Shima, Kensuke
AU - Klages, Alina
AU - Ünal, Can Murat
AU - Rieß, Benedikt
AU - Toh, Hui Ting
AU - Hansen, Guido
AU - Yoon, Ho Sup
AU - Bracher, Andreas
AU - Preiser, Peter
AU - Rupp, Jan
AU - Steinert, Michael
AU - Hausch, Felix
PY - 2018/4/26
Y1 - 2018/4/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85046000459&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b00137
DO - 10.1021/acs.jmedchem.8b00137
M3 - Journal articles
AN - SCOPUS:85046000459
VL - 61
SP - 3660
EP - 3673
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
IS - 8
ER -