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

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

  • ACS Infect Dis. 2024 Oct 11;10(10):3681-3691. doi: 10.1021/acsinfecdis.4c00553.
Theresa Lohr 1,  Carina Herbst 1,  Nicole M Bzdyl 2,  Christopher Jenkins 3,  Nicolas J Scheuplein 1,  Wisely Oki Sugiarto 4,  Jacob J Whittaker 5,  Albert Guskov 5,  Isobel Norville 3,  Ute A Hellmich 6 7 8,  Felix Hausch 4 9,  Mitali Sarkar-Tyson 2,  Christoph Sotriffer 1,  Ulrike Holzgrabe 1
Affiliations

Affiliations

  • 1 Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Würzburg, 97074, Germany.
  • 2 Marshall Centre for Infectious Diseases Research and Training, School of Biomedical Sciences, University of Western Australia, 35 Stirling Highway, Perth 6009, Australia.
  • 3 DSTL, Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, United Kingdom.
  • 4 Department of Chemistry and Biochemistry Clemens-Schöpf-Institute, Technical University Darmstadt, Alarich-Weiss Straße 4, Darmstadt 64287, Germany.
  • 5 Groningen Institute for Biomolecular Sciences and Biotechnology, University of Groningen, Groningen 9747AG, Netherlands.
  • 6 Institute of Organic Chemistry & Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstraße 10, Jena 07743, Germany.
  • 7 Center for Biomolecular Magnetic Resonance, Goethe-University, Frankfurt/Main 60438, Germany.
  • 8 Cluster of Excellence "Balance of the Microverse, Friedrich Schiller University Jena, Jena 07743, Germany.
  • 9 Centre for Synthetic Biology, Technical University Darmstadt, Darmstadt 64287, Germany.
PMID: 39357850 DOI: 10.1021/acsinfecdis.4c00553
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.

Keywords

FKBP, halogen bond; fluorescence polarization assay; macrophage infectivity potentiator protein; quantum mechanical calculations; structure−activity relationship.

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