High Affinity Inhibitors of the Macrophage Infectivity Potentiator Protein from <i>Trypanosoma cruzi</i>, <i>Burkholderia pseudomallei</i>, and <i>Legionella pneumophila</i>─A Comparison
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, <i>Trypanosoma cruzi</i>, <i>Burkholderia pseudomallei</i>, and <i>Legionella pneumophila</i>, 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 <i>meta</i>-halogenated phenyl sulfonamide to be responsible for the high affinity.
Authors
- Mitali Sarkar‐Tyson (ORCID: https://orcid.org/0000-0002-6764-8499)
- Nicolas J. Scheuplein (ORCID: https://orcid.org/0000-0003-3261-7964)
- Jacob J. Whittaker (ORCID: https://orcid.org/0000-0001-8966-111X)
- Theresa Lohr (ORCID: https://orcid.org/0000-0001-6473-0983)
- Wisely Oki Sugiarto
- Ulrike Holzgrabe (ORCID: https://orcid.org/0000-0002-0364-7278)
- Christoph Sotriffer (ORCID: https://orcid.org/0000-0003-4713-4068)
- Ute A. Hellmich (ORCID: https://orcid.org/0000-0001-7162-285X)
- Nicole M. Bzdyl (ORCID: https://orcid.org/0000-0003-2204-1172)
- Felix Hausch (ORCID: https://orcid.org/0000-0002-3710-8838)
- Albert Guskov (ORCID: https://orcid.org/0000-0003-2340-2216)
- Isobel H. Norville (ORCID: https://orcid.org/0000-0003-3506-2466)
- Carina Herbst (ORCID: https://orcid.org/0009-0008-0247-7124)
- Christopher N. H. Jenkins
Institutions
- Goethe University Frankfurt (DE)
- Goethe-Institute United Kingdom (GB)
- Defence Science and Technology Laboratory (GB)
- University of Groningen (NL)
- The University of Western Australia (AU)
- University of Würzburg (DE)
- Technische Universität Darmstadt (DE)
- ARC Centre of Excellence in Synthetic Biology (AU)
- Innovation Cluster (Canada) (CA)
- Friedrich Schiller University Jena (DE)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1021/acsinfecdis.4c00553
- Citations
- 1
- Primary Topic
- Trypanosoma species research and implications
- Type
- article
- Field-Weighted Citation Impact
- 0.39
Funders
- Friedrich-Schiller-Universität Jena
- Rijksuniversiteit Groningen
- Bundesministerium für Bildung und Forschung
- Defence Science and Technology Laboratory
- Defence Science and Technology Group