1. High Affinity Inhibitors of the Macrophage Infectivity Potentiator Protein from Trypanosoma cruzi , Burkholderia pseudomallei , and Legionella pneumophila ─A Comparison.
- Author
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Lohr T, Herbst C, Bzdyl NM, Jenkins C, Scheuplein NJ, Sugiarto WO, Whittaker JJ, Guskov A, Norville I, Hellmich UA, Hausch F, Sarkar-Tyson M, Sotriffer C, and Holzgrabe U
- Subjects
- Structure-Activity Relationship, Peptidylprolyl Isomerase antagonists & inhibitors, Peptidylprolyl Isomerase metabolism, Peptidylprolyl Isomerase chemistry, Molecular Dynamics Simulation, Humans, Protozoan Proteins antagonists & inhibitors, Protozoan Proteins metabolism, Protozoan Proteins chemistry, Legionella pneumophila drug effects, Burkholderia pseudomallei drug effects, Bacterial Proteins antagonists & inhibitors, Bacterial Proteins chemistry, Bacterial Proteins metabolism, Trypanosoma cruzi drug effects, Molecular Docking Simulation
- Abstract
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.
- Published
- 2024
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