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

Theresa Lohr, Carina Herbst, Nicole M Bzdyl, Christopher Jenkins, Nicolas J Scheuplein, Wisely Oki Sugiarto, Jacob J Whittaker, Albert Guskov, Isobel Norville, Ute A Hellmich, Felix Hausch, Mitali Sarkar-Tyson, Christoph Sotriffer, Ulrike Holzgrabe

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3681-3691
Number of pages11
JournalACS Infectious Diseases
Volume10
Issue number10
Early online date2 Oct 2024
DOIs
Publication statusPublished - 11 Oct 2024

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