175721-87-6Relevant articles and documents
Development, synthesis and structure–activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei
Seufert, Florian,Kuhn, Maximilian,Hein, Michael,Weiwad, Matthias,Vivoli, Mirella,Norville, Isobel H.,Sarkar-Tyson, Mitali,Marshall, Laura E.,Schweimer, Kristian,Bruhn, Heike,R?sch, Paul,Harmer, Nicholas J.,Sotriffer, Christoph A.,Holzgrabe, Ulrike
, p. 5134 - 5147 (2016)
The bacteria Burkholderia pseudomallei and Legionella pneumophila cause severe diseases like melioidosis and Legionnaire's disease with high mortality rates despite antibiotic treatment. Due to increasing antibiotic resistances against these and other Gram-negative bacteria, alternative therapeutical strategies are in urgent demand. As a virulence factor, the macrophage infectivity potentiator (Mip) protein constitutes an attractive target. The Mip proteins of B. pseudomallei and L. pneumophila exhibit peptidyl-prolyl cis/trans isomerase (PPIase) activity and belong to the PPIase superfamily. In previous studies, the pipecolic acid moiety proved to be a valuable scaffold for inhibiting this PPIase activity. Thus, a library of pipecolic acid derivatives was established guided by structural information and computational analyses of the binding site and possible binding modes. Stability and toxicity considerations were taken into account in iterative extensions of the library. Synthesis and evaluation of the compounds in PPIase assays resulted in highly active inhibitors. The activities can be interpreted in terms of a common binding mode obtained by docking calculations.
Structure-based design of novel, urea-containing FKBP12 inhibitors
Dragovich, Peter S.,Barker, John E.,French, Judy,Imbacuan, Michael,Kalish, Vincent J.,Kissinger, Charles R.,Knighton, Daniel R.,Lewis, Cristina T.,Moomaw, Ellen W.,Parge, Hans E.,Pelletier, Laura A. K.,Prins, Thomas J.,Showalter, Richard E.,Tatlock, John H.,Tucker, Kathleen D.,Villafranca, J. Ernest
, p. 1872 - 1884 (2007/10/03)
The structure-based design and subsequent chemical synthesis of novel, urea-containing FKBP12 inhibitors are described. These compounds are shown to disrupt the cis-trans peptidylprolyl isomerase activity of FKBP12 with inhibition constants (K(i,app)) approaching 0.10 μM. Analyses of several X- ray crystal structures of FKBP12-urea complexes demonstrate that the urea- containing inhibitors associate with FKBP12 in a manner that is similar to, but significantly different from, that observed for the natural product FK506.
