High Affinity\nInhibitors of the Macrophage Infectivity\nPotentiator Protein from Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophilaA Comparison

Since Chagas disease, melioidosis, and Legionnaires’\ndisease\nare all potentially life-threatening infections, there is an urgent\nneed for new treatment strategies. All causative agents, Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila, express\na virulence factor, the macrophage infectivity potentiator (MIP) protein,\nemerging as a promising new therapeutic target. Inhibition of MIP\nproteins having a peptidyl-prolyl isomerase activity leads to reduced\nviability, proliferation, and cell invasion. The affinity of a series\nof pipecolic acid-type MIP inhibitors was evaluated against all MIPs\nusing a fluorescence polarization assay. The analysis of structure–activity\nrelationships led to highly active inhibitors of MIPs of all pathogens,\ncharacterized by a one-digit nanomolar affinity for the MIPs and a\nvery effective inhibition of their peptidyl-prolyl isomerase activity.\nDocking studies, molecular dynamics simulations, and quantum mechanical\ncalculations suggest an extended σ-hole of the <i>meta</i>-halogenated phenyl sulfonamide to be responsible for the high affinity.