A modular toolkit to inhibit proline-rich motif–mediated protein–protein interactions
R. Opitz, M. Müller, C. Reuter, M. Barone, A. Soicke, Y. Roskec, K. Piotukha, P. Huy, M. Beerbaum, B. Wiesner, M. Beyermann, P.Schmieder, C. Freund, R.Volkmer, H. Oschkinat, H.-G. Schmalz, R. Kühne – 2015
Protein–protein interactions mediated by proline-rich motifs are involved in regulation of many important signaling cascades. Protein domains specialized in recognition of these motifs expose a flat and relatively rigid binding site that preferentially interacts with sequences adopting a left-handed polyproline helix II. Here, we present a toolkit of new chemical entities that enables rational construction of selective small-molecule inhibitors for these protein domains. As proof of principle, we developed a selective, cell-permeable inhibitor of Drosophila enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains of the Ena/VASP protein family. Invasive breast-cancer cells treated with our EVH1 inhibitor showed strongly reduced cell invasion.