High Affinity Inhibitors of the Macrophage Infectivity Potentiator Protein from Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila─A Comparison

• DOI: 10.1021/acsinfecdis.4c00553
• Publication Date: 2024-10-02T23:42:01Z
• Authors: Theresa Lohr; Carina Herbst; Nicole M. Bzdyl; Christopher Jenkins; Nicolas J. Scheup...; Wisely Oki Sugiarto; Jacob J. Whittaker; Albert Guskov; Isobel Norville; Ute A. Hellmich; Felix Hausch; Mitali Sarkar-Tyson; Christoph Sotriffer; Ulrike Holzgrabe
• Keywords: Molecular Docking Simulation; Structure-Activity Relationship; Burkholderia pseudomallei; Bacterial Proteins; Trypanosoma cruzi; Protozoan Proteins; Humans; Peptidylprolyl Isomerase; Molecular Dynamics Simulation; Legionella pneumophila

Since Chagas disease, melioidosis, and Legionnaires' disease are all potentially life-threatening infections, there is an urgent need for new treatment strategies. All causative agents, Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila, express a virulence factor, the macrophage infectivity potentiator (MIP) protein, emerging as a promising new therapeutic target. Inhibition of MIP proteins having a peptidyl-prolyl isomerase activity leads to reduced viability, proliferation, and cell invasion. The affinity of a series of pipecolic acid-type MIP inhibitors was evaluated against all MIPs using a fluorescence polarization assay. The analysis of structure-activity relationships led to highly active inhibitors of MIPs of all pathogens, characterized by a one-digit nanomolar affinity for the MIPs and a very effective inhibition of their peptidyl-prolyl isomerase activity. Docking studies, molecular dynamics simulations, and quantum mechanical calculations suggest an extended σ-hole of the meta-halogenated phenyl sulfonamide to be responsible for the high affinity.