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*

*Corresponding author voor dit werk

OnderzoeksoutputAcademicpeer review

Samenvatting

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
Originele taal-2English
Pagina's (van-tot)3681–3691
Aantal pagina's11
TijdschriftACS Infectious Diseases
Volume10
Nummer van het tijdschrift10
Vroegere onlinedatum2-okt.-2024
DOI's
StatusPublished - 11-okt.-2024

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