TY - JOUR
T1 - High Affinity Inhibitors of the Macrophage Infectivity Potentiator Protein from Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila
T2 - A Comparison
AU - Lohr, Theresa
AU - Herbst, Carina
AU - Bzdyl, Nicole M.
AU - Jenkins, Christopher
AU - Scheuplein, Nicolas J.
AU - Sugiarto, Wisely Oki
AU - Whittaker, Jacob J.
AU - Guskov, Albert
AU - Norville, Isobel
AU - Hellmich, Ute A.
AU - Hausch, Felix
AU - Sarkar-Tyson, Mitali
AU - Sotriffer, Christoph
AU - Holzgrabe, Ulrike
PY - 2024/10/11
Y1 - 2024/10/11
N2 - 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
AB - 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
U2 - 10.1021/acsinfecdis.4c00553
DO - 10.1021/acsinfecdis.4c00553
M3 - Article
SN - 2373-8227
VL - 10
SP - 3681
EP - 3691
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 10
ER -